Familia y Terapia Familiar

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Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP

Associate Professor of Pharmacy Practice
Jefferson College of Pharmacy
Thomas Jefferson University
Philadelphia, Pennsylvania
with
Jennifer M. Cocohoba, PharmD, MAS, BCPS, AAHIVP
UCSF School of Pharmacy
San Francisco, California
Elizabeth M. Sherman, PharmD, AAHIVP

Nova Southeastern University
Fort Lauderdale, Florida
Alice L. Tseng, PharmD, FCSHP, AAHIVP

University of Toronto
Toronto, Ontario, Canada
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Because of ongoing research and improvements in technology, the information and its
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Acquisitions, Special Publishing: Beth Campbell

Editorial Project Manager: Ruth Bloom
Production Manager: Johnna Hershey
Cover & Page Design: David Wade
Composition: Carol Barrer
Library of Congress Cataloging-in-Publication Data

Names: Schafer, Jason J., editor. | Cocohoba, Jennifer M., editor. | Sherman,
Elizabeth M., editor. | Tseng, Alice L., editor. | American Society of
Health-System Pharmacists, issuing body.
Title: HIV pharmacotherapy : the pharmacist’s role in care and treatment /
[editor] Jason J. Schafer with [section editors] Jennifer M. Cocohoba,
Elizabeth M. Sherman, Alice L. Tseng.
Description: Bethesda, MD : American Society of Health-System Pharmacists,
[2018] | Includes bibliographical references and index.
Identifiers: LCCN 2017018002 | ISBN 9781585285761 (pbk.)
Subjects: | MESH: HIV Infections--drug therapy | HIV
Infections--complications | Antiretroviral Therapy, Highly Active--methods
| Patient Care Team | Pharmacists
Classification: LCC RC606.7 | NLM WC 503.2 | DDC 616.97/92061--dc23 LC record avail-
able at
https://lccn.loc.gov/2017018002
© 2018, American Society of Health-System Pharmacists, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, microfilming, and recording, or by any
information storage and retrieval system, without written permission from the American
Society of Health-System Pharmacists.
ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.; regis-
tered in the U.S. Patent and Trademark Office.
ISBN: 978-1-58528-576-1
10 9 8 7 6 5 4 3 2 1
First printing: November 2017
Dedication
To Cassie, Eamon, and Alida for always reminding me to

go instead where there is no path, and to Debbie and Bob
S. for believing in me.
Jason J. Schafer
Many thanks to my husband Viet Vu and son Khai for

inspiring me to maintain balance, and to Evelyn Rodriguez
for her steadfast encouragement.
Jennifer M. Cocohoba
For Ben and Lily and my early mentor Betty.

Elizabeth M. Sherman
Thanks to my husband Mark Pellar and wonderful daugh-

ters Sophie and Beatrice. You inspire me every day.
Alice L. Tseng
Contents
Foreword.................................................................................................................vii
Alice K. Pau, PharmD, FASHP, FIDSA
Preface......................................................................................................................ix
Acknowledgments..................................................................................................... x
Editors and Contributors.........................................................................................xi
List of Tables and Figures.......................................................................................xvi
SECTION I: The Diagnosis and Pharmacologic Management of HIV-1

Infection
Section Editor: Elizabeth M. Sherman, PharmD, AAHIVP
CHAPTER 1: HIV Infection Overview..........................................................................3

Elizabeth M. Sherman, PharmD, AAHIVP, and Marylee Worley, PharmD, BCPS
CHAPTER 2: HIV Testing and Diagnosis...................................................................17

CHAPTER 3: Antiretroviral Therapy..........................................................................25

P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVP; Kristina E. R.
Connolly, PharmD, BCPS; and Celeste R. Caulder, PharmD
CHAPTER 4: Initiating HIV Treatment and Supporting Adherence.........................69

Agnes Cha, PharmD, AAHIVP, BCACP, and Tiffany E. Bias, PharmD, AAHIVP,
BCPS (AQ-ID)
CHAPTER 5: HIV Treatment Failure and Resistance.................................................85

Janet Grochowski, PharmD, BCPS, AAHIVP, and Parya Saberi, PharmD, MAS,
AAHIVP
CHAPTER 6: Preventing HIV Transmission with Antiretroviral Therapy..............103

Katy L. Garrett, PharmD; Mackenzie L. Cottrell, PharmD, MS, BCPS, AAHIVP; and
Angela DM Kashuba, PharmD, DABCP, FCP
SECTION II: The Pharmacologic Management of HIV Co-infections

Section Editor: Alice L. Tseng, PharmD, FCSHP, AAHIVP
CHAPTER 7: Opportunistic Infections....................................................................127

Christine A. Hughes, BScPharm, PharmD, FCSHP, and Deborah Yoong, BScPharm,
ACPR, PharmD
CHAPTER 8: Viral Hepatitis.....................................................................................163

Denise Kreutzwiser, BScH, BScPharm, ACPR, AAHIVP; Pierre Giguère, BPharm, MSc,
AAHIVP; and Alice L. Tseng, PharmD, FCSHP, AAHIVP
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vi HIV PHARMACOTHERAPY
CHAPTER 9: Sexually Transmitted Infections.........................................................185

Deborah V. Kelly, BScPharm, PharmD, FCSHP, AAHIVP, and
Tony Antoniou, PharmD, PhD, BScPharm
CHAPTER 10: HIV and Tuberculosis........................................................................203

Eric F. Egelund, PharmD, PhD, AAHIVE, and Emily C. Huesgen, PharmD, BCACP,
AAHIVP
SECTION III: Primary Care and Special Populations with HIV

Section Editor: Jennifer M. Cocohoba, PharmD, MAS, BCPS, AAHIVP
CHAPTER 11: HIV Primary Care..............................................................................221

Jennifer M. Cocohoba, PharmD, MAS, BCPS, AAHIVP, and Betty J. Dong, PharmD,
FCCP, FASHP, FAPhA, AAHIVP
CHAPTER 12: Neuropsychiatric Disorders, Mental Health, Pain, and

Substance Use.........................................................................................................243
Jennifer E. Thomas, PharmD, AAHIVP, and Joshua Caballero, PharmD, BCPP, FCCP
CHAPTER 13: Care of the Transgender Patient.......................................................261

Bryan M. Bishop, PharmD, BCPS
CHAPTER 14: Women’s Health...............................................................................271

E. Kelly Hester, PharmD, FCCP, BCPS, AAHIVP
CHAPTER 15: Pediatric HIV Infection.....................................................................285

Kathleen K. Graham, PharmD, and Ana M. Puga, MD
CHAPTER 16: HIV and Cancer................................................................................313

Karim Ibrahim, BPharm, DClinPharm, AACPA, MSHP, and Alison Yi Jin Wong,
BPharm, MSc, AAHIVP
CHAPTER 17: Transplant and HIV..........................................................................329

Melissa Badowski, PharmD, MPH, BCPS, AAHIVP; Sarah E. Pérez, PharmD, BCACP,
AAHIVP; and Elizabeth Hetterman, PharmD, BCPS
CHAPTER 18: Care Transitions for Persons Living with HIV.................................341

Michelle M. Foisy, BScPharm, PharmD, ACPR, FCSHP, AAHIVP
Index..................................................................................................................... 353
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Foreword
During my almost 30 years providing pharmaceutical care for persons with human
immunodeficiency virus (HIV), I have witnessed remarkable advances—from
discovery to rapid diagnosis, prevention, and treatment of opportunistic infec-
tions to the development of safe and effective antiretroviral therapy (ART)—in a
relatively short time period. The results of these advances have saved millions of
lives not only in the United States, but globally, including many low income coun-
tries most affected by HIV. For more persons with HIV to receive the full benefit
of therapy, the effort must begin with early diagnosis, followed by linkage to and
retention in care, receipt of appropriate ART, and continuous adherence to therapy
and care.1 Pharmacists at different practice settings can play critical roles in every
stage of the care continuum.
The results of two large randomized controlled trials—the START and
TEMPRANO studies—solidified the roles and benefits of early ART in reducing
both AIDS-associated and non-AIDS comorbidities.2,3 It is now well accepted that
all persons with a diagnosis of HIV infection should be started on ART regardless
of their CD4+ T-cell count. With effective ART, the life expectancy of most persons
living with HIV can approximate those in persons without HIV.1 With the increase
in longevity resulting from ART, most patients remain free of AIDS-related symp-
toms, but many develop comorbidities traditionally associated with aging such as
cardiovascular disease, neurocognitive impairment, and cancer. The complexity of
treatment of HIV infection, opportunistic infections, and other comorbidities, with
resultant polypharmacy, adverse effects, drug interactions, and adherence issues
has made it essential to include a pharmacist as a member of the multidisciplinary
care team. Until there is a cure for HIV infection, persons with HIV are expected to
continue their ART for life. Lifelong ART poses challenges to all patients, even those
who are adherent to their medications. Pharmacists and other healthcare providers
need to keep partnering with patients through this long journey so that benefits
from the prescribed treatments continue.
Traditionally, pharmacists consult medical textbooks, treatment guidelines,
and other publications for information regarding management of patients with
HIV. No single textbook has provided a focused guidance for pharmacists in HIV
care. It is, thus, timely for the editors to assemble a group of pharmacists with
expertise in HIV care for this new book HIV Pharmacotherapy: The Pharmacist’s
Role in Care and Treatment. In the following pages, they share their expertise and
provide guidance to other pharmacists who are beginning to provide, or are already
providing, pharmaceutical care for persons with HIV. This book offers a compre-
hensive compendium for pharmacists on different and important topics associ-
ated with caring for persons with HIV—from the time of diagnosis to initiation
of ART, management of patients with virologic failure, management of different
co-infections, and provision of care for special patient populations. At the end
of each chapter, the authors identify important roles pharmacists should play in
vii
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viii HIV PHARMACOTHERAPY
the care of these patients, as well as specific resources available to consult. This
textbook will be very useful both in the classroom as well as in the clinical setting.
Despite having more potent, less toxic, and easier to take ART drugs now than
in earlier years, long-term adherence to therapy continues to be a challenge for
some patients. Clinical and basic science research efforts are underway to iden-
tify improved treatment outcome. Some of these efforts include new investiga-
tional antiretroviral drugs and biologics that target drug-resistant HIV; longer-
acting agents (e.g., injectable, implantable depots) that target less frequent dosing
and improve adherence; and therapeutic vaccines and other modalities aimed at
achieving functional cure of HIV with the potential for temporary or permanent
discontinuation of ART. Some of these investigational approaches are in advanced
clinical trials and may soon be available, while others are in earlier stages of inves-
tigation. Additionally, clinical research studies are underway to evaluate pharma-
ceutical approaches to pre-exposure prophylaxis such as microbicides, implants,
vaginal rings, and long-acting injectables.
The management of HIV infection is continuously evolving, with treatment
guidelines updated annually, or more frequently, as a result of new drug approval,
new research findings, or emerging toxicities. This textbook is an excellent guide
for all who provide pharmaceutical care for persons with HIV. However, the field is
constantly changing, so you need to also consult the most up-to-date guidelines or
publications when required. Some of these resources are outlined in the textbook,
and many of them are periodically updated electronically.
The safe and effective use of ART and concomitant medications is key to
treatment success for all persons with HIV. The most critical tool for this success
is to have a good understanding of the principles and pharmacology of ART, to
promptly recognize any potential drug interactions and/or toxicities and to design
strategies to avoid both, and to be aware of unique aspects of care related to special
populations. This book provides pharmacists with these basic tools all in one
source. It will be a valuable reference to help in the management of patients with
HIV in the years ahead.
REFERENCES
1. Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated
HIV-positive individuals in the United States and Canada. PLoS One. 2013;8(12):e81355.
2. INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV
infection. N Engl J Med. 2015; 373(9):795-807.
3. TEMPRANO ANRS Study Group. A trial of early antiretrovirals and isoniazid preventive therapy
in Africa. N Engl J Med. 2015;373(9):808-822.
Alice K. Pau, PharmD, FASHP, FIDSA
Staff Scientist (Clinical)
Clinical Pharmacy Specialist
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Maryland
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Preface
HIV infection remains among the most important infectious diseases worldwide.
Although the epidemic has changed significantly over the years, traditional
obstacles to successful care remain such as prevention, early diagnosis, stigma
and public perception, linkage to care, retention in care, and adherence to
antiretroviral therapy. As patients age with HIV infection, new challenges emerge
increasing the importance to provide comprehensive HIV and primary care as
well as identify and manage comorbid conditions and coinfections—all while
maintaining virologic suppression and meeting the unique needs of key patient
populations.
Pharmacists have long been recognized as essential members of the HIV
healthcare team. Their involvement in managing HIV-infected patients improves
outcomes. To address both the traditional and contemporary challenges of HIV
care, the pharmacist’s role is evolving with a focus on providing comprehensive
care to all patients with HIV infection.
PURPOSE
The goal of this book is to provide pharmacists with a consolidated resource that
will assist them in delivering comprehensive care to patients with HIV infec-
tion. All pharmacists practicing HIV medicine will value this resource as the first
comprehensive and consolidated HIV pharmacotherapy reference that they can
use to facilitate learning as well as decision making in the clinical setting. This
resource will also be valuable to student pharmacists and pharmacy residents
eager to establish their knowledge and understanding of HIV medicine to make
meaningful contributions to patient care.
HOW TO USE THIS BOOK
This book covers both core and advanced concepts of HIV care. Because each
chapter first introduces fundamental disease state concepts before moving on to
more advanced information, new practitioners entering the field of HIV medi-
cine can use this book to build a foundation of HIV knowledge. Because each
chapter also covers advanced aspects of care and provides evidence-based, patient
care recommendations, it can also serve as a resource for pharmacists who
encounter patients with HIV infection as a part of their routine practice. Tables
and figures that consolidate information and provide quick reference to key
concepts can also assist in direct patient care decisions. Links and references to
important pieces of primary literature, key practice guidelines, and online tools
at the end of each chapter provide opportunities for additional learning. Each
chapter also concludes with a discussion of the role of the pharmacist, high-
lighting evidence where available and identifying practice gaps for pharmacists
that require additional study.
ix
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Acknowledgments
Thank you, Jen, Liz, and Alice for your knowledge, expertise, encouragement,
and dedication to this project. Most of all, thank you for your partnership. I am
so very grateful to have had the opportunity to work with each of you and hope
that we have many opportunities to work together again.
This work would not be possible without the considerable efforts and contri-
butions of the chapter authors. Thank you all for helping to develop this important
resource by sharing your knowledge and expertise as well as your passion for the
field of HIV medicine. Your contributions will help educate students and practi-
tioners alike, strengthening their knowledge and improving their skills in caring
for patients with HIV infection.
Lastly, thank you to Beth Campbell, Ruth Bloom, and the ASHP Publishing
staff who guided us in the development of this book. It has been a privilege to have
had the opportunity to work with you and to develop this important resource for
pharmacists.
Jason J. Schafer
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Editors and Contributors
EDITOR
Jefferson College of Pharmacy
Thomas Jefferson University
SECTION EDITORS
Jennifer M. Cocohoba, PharmD, MAS, BCPS, AAHIVP
Professor of Clinical Pharmacy
UCSF School of Pharmacy
Pharmacist, UCSF Women’s HIV Program
Elizabeth M. Sherman, PharmD, AAHIVP

Assistant Professor of Pharmacy Practice
Division of Infectious Disease
Memorial Healthcare System
Alice L. Tseng, PharmD, FCSHP, AAHIVP

HIV Pharmacotherapy Specialist
Toronto General Hospital
Assistant Professor
Leslie Dan Faculty of Pharmacy
CONTRIBUTORS
Tony Antoniou, PharmD, PhD, BScPharm
Associate Professor
Department of Family and Community Medicine
St. Michael’s Hospital
xi
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xii HIV PHARMACOTHERAPY
Melissa Badowski, PharmD, MPH, BCPS, AAHIVP

Clinical Associate Professor, Infectious Diseases/HIV
University of Illinois at Chicago
College of Pharmacy
HIV/IDOC Clinical Pharmacist
Chicago, Illinois
Tiffany Bias, PharmD, AAHIVP, BCPS (AQ-ID)

Clinical Pharmacy Specialist, Infectious Diseases
Hahnemann University Hospital

Assistant Professor
University of Toledo
College of Pharmacy and Pharmaceutical Sciences
Toledo, Ohio
P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVP

Associate Professor
Department of Clinical Pharmacy & Outcomes Sciences
Director of Residency & Fellowship Training
University of South Carolina College of Pharmacy
Infectious Diseases PGY2 & Clinical Fellowship Director
University of South Carolina/Palmetto Health
Columbia, South Carolina
Joshua Caballero, PharmD, BCPP, FCCP

Professor, Chair
Department of Clinical and Administrative Sciences
Larkin University College of Pharmacy
Miami, Florida
Celeste R. Caulder, PharmD

Associate Professor
Department of Clinical Pharmacy and Outcomes Sciences
International Director
University of South Carolina College of Pharmacy
Columbia, South Carolina
Agnes Cha, PharmD, AAHIVP, BCACP

Long Island University College of Pharmacy
Clinical Pharmacy Educator HIV Ambulatory Care
The Brooklyn Hospital Center
Brooklyn, New York
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xiii
Kristina E. R. Connolly, PharmD, BCPS

Clinical Pharmacy Specialist, Infectious Diseases
Maine Medical Center
Portland, Maine
Mackenzie L. Cottrell, PharmD, MS, BCPS, AAHIVP

Research Assistant Professor
Pharmacotherapy and Experimental Therapeutics
Eshelman School of Pharmacy
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Betty J. Dong, PharmD, FCCP, FASHP, FAPhA, AAHIVP

Professor of Clinical Pharmacy
Department of Clinical Pharmacy
University of California San Francisco, School of Pharmacy
Eric F. Egelund, PharmD, PhD, AAHIVE

Clinical Assistant Professor
Pharmacotherapy and Translational Research
Infectious Disease Pharmacokinetics Laboratory
University of Florida
Gainesville, Florida

Clinical Pharmacist
Northern Alberta Program, Royal Alexandra Hospital site
Edmonton, Alberta, Canada
Katy L. Garrett, PharmD

Postdoctoral Research Associate, HIV Pharmacology Fellow
Eshelman School of Pharmacy
Pierre Giguère, BPharm, MSc, AAHIVP

The Ottawa Hospital
Ottawa Hospital Research Institute
Ottawa, Ontario, Canada
Kathleen K. Graham, PharmD

HIV Clinical Research Pharmacist
Children’s Diagnostic & Treatment Center
Clinical Affiliate Associate Professor
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xiv HIV PHARMACOTHERAPY
Janet Grochowski, PharmD, BCPS, AAHIVP

Staff Pharmacist
University of California San Francisco

Associate Clinical Professor
Department of Pharmacy Practice
Auburn University Harrison School of Pharmacy
Auburn, Alabama
Elizabeth Hetterman, PharmD, BCPS

Transplant Clinical Pharmacist
Department of Pharmacy
Loyola University Medical Center
Chicago, Illinois
Emily C. Huesgen, PharmD, BCACP, AAHIVP

HIV/HCV Clinical Pharmacist
Indiana University Health
Indianapolis Indiana
Christine A. Hughes, BScPharm, PharmD, FCSHP

Professor
Faculty of Pharmacy and Pharmaceutical Sciences
University of Alberta
Edmonton, Alberta, Canada
Karim Ibrahim, BPharm, DClinPharm, AACPA, MSHP

Senior Haematology and Bone Marrow Transplant Pharmacist
Pharmacy Department
St. Vincent’s Health Network
Darlinghurst, Australia
Angela DM Kashuba, PharmD, DABCP, FCP

John & Deborah McNeill, Jr. Distinguished Professor and Chair
Division of Pharmacotherapy and Experimental Therapeutics
UNC Eshelman School of Pharmacy
Adjunct Professor, Infectious Diseases
Deborah V. Kelly, BScPharm, PharmD, FCSHP, AAHIVP

Associate Professor
Special Advisor, Practice Innovation
School of Pharmacy
Memorial University of Newfoundland
Clinical Pharmacotherapy Specialist
Provincial HIV Program, Eastern Health
St. John’s, Newfoundland
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xv
Denise Kreutzwiser, BScH, BScPharm, ACPR, AAHIVP

Toronto General Hospital
McGill University Health Centre
Sarah E. Pérez, PharmD, BCACP, AAHIVP

Clinical Pharmacist Specialist, Infectious Diseases
Tufts Medical Center Department of Pharmacy
Boston, Massachusetts
Ana M. Puga, MD
Pediatric Infectious Disease Specialist
Community AIDS Network
Parya Saberi, PharmD, MAS, AAHIVP

Assistant Professor
Center for AIDS Prevention Studies
Department of Medicine
University of California San Francisco
Jennifer E. Thomas, PharmD, AAHIVP

Assistant Professor
Husson University School of Pharmacy
Bangor, Maine
Alison Yi Jin Wong, BPharm, MSc, AAHIVP

Pharmacist at the Chronic Viral Illness Service
McGill University Health Centre
Montreal, Quebec, Canada
Marylee Worley, PharmD, BCPS

Assistant Professor
Davie, Florida
Deborah Yoong, BScPharm, ACPR, PharmD

Clinical Pharmacy Practitioner
St. Michael’s Hospital
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List of Tables and Figures
Chapter 1
• TABLE 1-1. Estimated Per-Act Probability of Acquiring HIV from an
Infected Source, by Exposure Act
• TABLE 1-2. Common Signs, Symptoms, and Laboratory Findings of
Acute HIV Infection
• TABLE 1-3. AIDS-Defining Conditions
• FIGURE 1-1. World map of HIV prevalence in persons ages 15 to 49 years

old.
• FIGURE 1-2. HIV typical disease progression.
• FIGURE 1-3. HIV care continuum among persons with HIV in the
United States in 2011.
Chapter 2
• No tables
• FIGURE 2-1. Pattern of HIV serologies and comparison of generations

1–4 HIV tests in detecting HIV in human serum.
• FIGURE 2-2. HIV 1/2 testing algorithm.
Chapter 3
• TABLE 3-1. Summary of Available Antiretrovirals
• TABLE 3-2. Antiretroviral Adverse Effects
• TABLE 3-3. Interactions Between Antiretrovirals and Acid-Suppressing
Agents
• TABLE 3-4. Antiretroviral Enzyme Effects
• TABLE 3-5. Drug-Food Interactions
• TABLE 3-6. Common Barriers to Antiretroviral Adherence
• TABLE 3-7. Rule of “One-Sixth”
• TABLE 3-8. Completed HIV-1 Vaccine Trials
• FIGURE 3-1. Drug therapy targets in the HIV life cycle.

• FIGURE 3-2. Detailed timeline of landmark discoveries in the history of
HIV treatment.
Chapter 4
• TABLE 4-1. Suggested Topics, Questions, and Respective Laboratory
Results That Should Be Obtained Prior to Initiating ART
xvixvi
ERRNVPHGLFRVRUJ
xvii
• TABLE 4-2. Laboratory Monitoring Before ART and Ongoing Assessment

of ART
• TABLE 4-3. Strategies for Pharmacists to Improve Adherence
• TABLE 4-4. Recommended Initial Treatment Regimens
• TABLE 4-5. Advantages and Disadvantages of Recommended Initial
Treatment Regimen Components with Supporting Literature
• No figures
Chapter 5
• TABLE 5-1. Genetic Barrier to Resistance Adapted from Panel on
Antiretroviral Guidelines for Adults and Adolescents
• TABLE 5-2. Selected Important Information on NRTI Resistance
• TABLE 5-3. Weight Factor of ETR Resistance-Associated Mutations
• TABLE 5-4. Major Pathways of Resistance with RAL
• TABLE 5-5. Major Pathways of Resistance with EVG
• No figures
Chapter 6
• TABLE 6-1. Oral PrEP Clinical Trials Efficacy in Preventing HIV
Acquisition and Medication Adherence
• TABLE 6-2. Indications for PrEP Use Among Three High-Risk Populations
• TABLE 6-3. Estimated Per-Act Risk for Acquiring HIV from an Infected
Source, by Exposure Act
• TABLE 6-4. Preferred and Alternative PEP Regimens
• TABLE 6-5. Preferred and Alternative nPEP Regimens
• FIGURE 6-1. Diagnosis risk by transmission group.

• FIGURE 6-2. PrEP drug development pipeline.
• FIGURE 6-3. Algorithm for evaluation and treatment of possible
non-occupational HIV exposures.
Chapter 7
• TABLE 7-1. Pharmacist’s Assessment to Identify, Prevent, and Resolve
OI-Associated Drug Therapy Problems
• FIGURE 7-1. Relationship between CD4 count and types of pathogens.
Chapter 8
• TABLE 8-1. Interpretation of Hepatitis B Serologic Test Results
• TABLE 8-2. Treatment Regimens for Treatment-Naïve Hepatitis C
Genotype 1 Infection
ERRNVPHGLFRVRUJ
xviii HIV PHARMACOTHERAPY
• TABLE 8-3. Treatment Regimens for Treatment-Naïve Hepatitis C

Genotypes 2 to 6
• TABLE 8-4. Antiretroviral Treatment Options for Patients on Hepatitis C
Treatment
• No figures
Chapter 9
• TABLE 9-1. Treatment for Infections Characterized by Urethritis and
Cervicitis
• TABLE 9-2. Treatment for Infections Characterized by Vaginal Discharge
• TABLE 9-3. Treatment for Genital Herpes
• TABLE 9-4. Treatment for Syphilis
• No figures
Chapter 10
• TABLE 10-1. Differences in TST and IGRA Tests
• TABLE 10-2. First- and Second-Line Medications Used to Treat Active
Tuberculosis
• TABLE 10-3. Selected Drug Interactions Between the Rifamycins and ART
with the Expected Effect on ART Concentrations
• No figures
Chapter 11
• TABLE 11-1. ART-Induced Mean Lipid Changes (mg/dL) from Baseline to
48 Weeks (Selected Studies)
• TABLE 11-2. Antiretrovirals Requiring Dose Adjustment in Renal
Dysfunction
• No figures
Chapter 12
• No tables
• No figures
Chapter 13
• TABLE 13-1. Definitions Related to Gender and Sexuality
• TABLE 13-2. Medications Used in the Treatment of Transgender Patients
• No figures
ERRNVPHGLFRVRUJ
xix
Chapter 14
• TABLE 14-1. Management of Drug Interactions Between Antiretroviral
Therapy and Hormonal Contraceptives
• TABLE 14-2. 2016 Recommended Therapies in Pregnancy for Prevention
of Mother-to-Child Transmission
• FIGURE 14-1. Safe conception considerations for serodiscordant couples.
Chapter 15
• TABLE 15-1. Panel’s Recommendations for Initial Postnatal Management
of the HIV-Exposed Neonate
• TABLE 15-2. Neonatal Dosing for Prevention of Perinatal HIV
Transmission
• TABLE 15-3. Special Considerations in Neonates, Infants, Children, and
Adolescents with HIV Infection
• TABLE 15-4. HIV Infection Stage Based on Age-Specific CD4 Cell Count
or Percentage
• TABLE 15-5. Preferred cART Regimens for Initial Treatment of Neonates,
Infants, Children, and Adolescents
• TABLE 15-6. Dosing Guidelines for Preferred Antiretroviral Agents for
the Treatment of Infants and Children with HIV
• TABLE 15-7. Dosing Guidelines for Preferred Antiretroviral Agents for
the Treatment of Adolescents with HIV
• TABLE 15-8. Antiretroviral Treatment Considerations in Infants,
Children, and Adolescents with HIV
• TABLE 15-9. Strategies to Improve Adherence to Antiretroviral
Medications
• TABLE 15-10. Pediatric Vaccine Preventable Diseases and Primary
Prophylaxis for Pneumocystis Pneumonia, Toxoplasma Encephalitis, and
Mycobacterium avium complex
• FIGURE 15-1A. Estimated number of cases of perinatally acquired AIDS,

by year of diagnosis —United States, 1985–2004.
• FIGURE 15-1B. New HIV infections among children (aged 0–14 years)
with and without the provision of antiretroviral medicines to prevent
mother-to-child transmission, global, 1995–2015.
Chapter 16
• TABLE 16-1. Cumulative Cancer Incidence by 75 Years Old (Data from
2005–2009)
• TABLE 16-2. Rituximab Combined with Chemotherapy for Patients with
HIV-Associated NHL
ERRNVPHGLFRVRUJ
xx HIV PHARMACOTHERAPY
• TABLE 16-3. Examples of Some Potential Antiretroviral Agents and

Chemotherapy Interactions
• TABLE 16-4. Summary of Antiretroviral Therapy Choice During
Chemotherapy
• No figures
Chapter 17
• TABLE 17-1. HOPE Act Donor and Recipient Criteria for HIV-Positive to
HIV-Positive Transplantation
• TABLE 17-2. Characteristics of Adverse Effects with Maintenance
Immunosuppressive Agents
• TABLE 17-3. Drug–Drug Interactions
• No figures
Chapter 18
• TABLE 18-1. Medication Errors in the Hospital Setting
• TABLE 18-2. Solutions to Minimize Medication Errors in the Hospital
Setting
• TABLE 18-3. Solutions to Facilitating Continuity of Care in the
Outpatient Setting
• FIGURE 18-1. Integration of infectious diseases clinic services and

specialty pharmacy services.
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SECTION I: The Diagnosis and
Pharmacologic Management
of HIV-1 Infection
Section Editor: Elizabeth M. Sherman, PharmD,
AAHIVP
Chapter 1: HIV Infection Overview

Elizabeth M. Sherman and Marylee Worley
Chapter 2: HIV Testing and Diagnosis

Jason J. Schafer
Chapter 3: Antiretroviral Therapy

P. Brandon Bookstaver, Kristina E. R. Connolly, and
Celeste R. Caulder
Chapter 4: Initiating HIV Treatment and

Supporting Adherence
Agnes Cha and Tiffany E. Bias
Chapter 5: HIV Treatment Failure and

Resistance
Janet Grochowski and Parya Saberi
Chapter 6: Preventing HIV Transmission

with Antiretroviral Therapy
Katy L. Garrett, Mackenzie L. Cottrell, and Angela
DM Kashuba
ERRNVPHGLFRVRUJ
ERRNVPHGLFRVRUJ
1
HIV Infection Overview
Elizabeth M. Sherman, PharmD, AAHIVP, and
Marylee Worley, PharmD, BCPS
INTRODUCTION
This chapter provides an overview of human immunodeficiency virus (HIV) infec-
tion, including geographical perspectives on the HIV epidemic and epidemiologic
trends; data on HIV transmission and their implications on clinical management;
acute HIV infection and disease progression; and the continuum of HIV care from
diagnosis through virologic suppression.
DISTRIBUTION OF HIV STRAINS AND SUBTYPES

HIV is a virus with high genetic variability due to frequent viral replication and
high mutation rates from recombination with the enzyme reverse transcriptase,
which lacks proofreading mechanisms. Over the course of a typical infection, a
patient may harbor viral sequences that differ by up to 10%.1 HIV can be of two
types, type 1 and type 2, with several lineages existing among these types:
• HIV type 1 (HIV-1) groups M, N, O, and P
• HIV type 2 (HIV-2) groups A through H
HIV-1 (also referenced as HIV) group M is responsible for the majority of the
global pandemic with different subtypes (also known as clades) showing distinc-
tive global distribution patterns. HIV group M subtype C is the most common
globally; however, in North America and western Europe, HIV group M subtype B
is the most common.2,3 HIV-2 is a less common cause of the epidemic and is found
primarily in nations of western Africa.
EPIDEMIOLOGY
According to the Joint United Nations Programme on HIV/acquired immuno-
deficiency syndrome (AIDS), in 2015 there were 2.1 million new HIV infections
worldwide and a total of 36.7 million people living with HIV.4 Figure 1-1 provides
a world map of HIV prevalence in persons ages 15 to 49 years old; the overall
prevalence rate is 0.8%. Globally, nearly 70% of all persons living with HIV reside
in sub-Saharan Africa; it remains the world’s most heavily impacted region.5 The
most common mode of infection worldwide is through heterosexual transmis-
sion. There is also a growing prevalence driven primarily by injection drug use
in eastern Europe and central Asia where new HIV infections increased by 57%
3
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4 HIV PHARMACOTHERAPY
from 2010 to 2015.4 In 2014 alone, 1.2 million people worldwide died from AIDS-
related illnesses.6
In the United States, the Centers for Disease Control and Prevention (CDC)
estimates 933,941 persons were living with diagnosed HIV infection at the end
FIGURE 1-1. World map of HIV prevalence in persons ages 15 to 49 years old.
Data from:
• Joint United Nations Programme on HIV/AIDS (UNAIDS). AIDSInfo HIV prevalence in
adults (15–49) country data. http://aidsinfo.unaids.org/. Accessed August 22, 2016.
• The World Factbook: Country comparison HIV/AIDS adult prevalence rate. https://www.
cia.gov/library/publications/the-world-factbook/rankorder/2155rank.html. Accessed
August 22, 2016.
• Public Health England. HIV in the UK–Situation Report 2015: data to end 2014.
https://www.gov.uk/government/uploads/system/uploads/attachment_data/
file/477702/HIV_in_the_UK_2015_report.pdf. Accessed August 22, 2016.
• Joint United Nations Programme on HIV/AIDS (UNAIDS). National Health and Family
Planning Commission of the People’s Republic of China. 2015 China AIDS Response
Progress Report. http://www.unaids.org/sites/default/files/country/documents/CHN_
narrative_report_2015.pdf. Accessed August 22, 2016.
• National AIDS Control Organization. Directory of HIV Data. http://www.naco.gov.in/
NACO/Quick_Links/Surveillance/. Accessed August 22, 2016.
• Canadian AIDS Treatment Information Exchange. The epidemiology of HIV in Canada.
http://www.catie.ca/en/fact-sheets/epidemiology/epidemiology-hiv-canada. Accessed
August 22, 2016.
ERRNVPHGLFRVRUJ
CHAPTER 1 HIV Infection Overview 5
of 2013.7 However, some groups are more affected than others. Men who have
sex with men (MSM) bear the greatest HIV burden, with 70% of infections in
the United States attributed to male-to-male sexual contact. According to recent
CDC calculations, if current HIV diagnosis rates persist, one in 6 MSM will be
diagnosed with HIV in their lifetime, including one in 2 black MSM, one in 4
Latino MSM, and one in 11 white MSM.8 Among races and ethnicities, African
Americans are disproportionately affected; the overall HIV prevalence rate (43%) is
highest in this group, compared to whites (27%), Hispanics/Latinos (23%), Asians
(2%), persons of multiple races (2%), American Indians/Native Alaskans (1%), and
Native Hawaiians/Pacific Islanders (0.1%).9
A growing number of youth ages 13 to 24, and people age 55 and older, are
living with HIV infection. According to the CDC, in 2014 U.S. youth ages 13 to
24 accounted for an estimated 22% of all new HIV diagnoses.10 Additional infor-
mation on HIV infection in the pediatric population can be found in Chapter 15.
People age 55 and older accounted for more than one-quarter (26%) of persons
living with HIV infection in the United States in 2013.11
In the United States, approximately 1 in 4 people living with HIV are women;
however, black/African American women and Hispanic/Latina women continue
to be disproportionally affected compared to women of other races/ethnicities. At
the end of 2013, 61% of women living with diagnosed HIV were African Amer-
ican, 17% were white, and 17% were Hispanic/Latina.12 There is also a high prev-
alence of HIV infection in transgender women. In 2013, a meta-analysis reported
that the estimated HIV prevalence among transgender women was 22% in five
high-income countries, including the United States.13 Additional information
on transgender health and women’s health can be found in Chapters 13 and 14,
respectively.
AIDS incidence also reveals racial disparities, with higher rates among blacks/
African Americans (42%) than other racial and ethnic groups (by comparison,
rates among whites were 31% and among Hispanics/Latinos were 22%).7 In 2014,
an estimated 44,073 people were diagnosed with HIV infection and 20,896 people
were diagnosed with AIDS in the United States.7 The CDC estimates 12,963 people
with an AIDS diagnosis died in 2013, and 673,538 people in the United States with
an AIDS diagnosis have died overall.7
TRANSMISSION
HIV is transmitted from person to person through exposure to blood, tissue, or
other infectious body fluids (e.g., blood, visibly bloody body fluids, semen, vaginal
secretions). Potentially infectious body fluids include cerebrospinal fluid, synovial
fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid, although
the risk of transmission from these fluids is unknown. Feces, nasal secretions, saliva,
sputum, sweat, tears, urine, and vomitus are not considered infectious unless they
are visibly bloody.14 Healthcare workers including pharmacists must be aware of the
risk of contracting HIV when handling or testing all bodily fluids.
ERRNVPHGLFRVRUJ
Broadly, exposures can be categorized into two types: occupational (i.e., occur-
ring in persons working in healthcare settings) and nonoccupational (i.e., occur-
ring in persons with exposure outside healthcare settings). Occupational expo-
sures may include a percutaneous injury (e.g., needlestick) or contact with mucous
membrane or nonintact skin. For occupational exposures, the risk of HIV trans-
mission varies with the type and severity of exposure, with average risk for HIV
transmission after percutaneous exposure estimated at approximately 0.3% and
after a mucous membrane exposure at approximately 0.09%. Factors that may
increase transmission risk include exposure to a larger quantity of body fluid (e.g.,
visibly bloody device, needle used in vein or artery, deep injury), blood from a
source patient with a terminal illness or with a higher titer of HIV in the blood, or
a larger viral inoculum (e.g., deeper injuries, hollow-bore needles).14
Nonoccupational exposures include sexual exposures, needle sharing during
injection drug use, blood transfusions, and mother-to-child transmission. Table
1-1 lists the estimated per-act transmission risk when exposed to infectious fluid
from a person with HIV infection. Sexual practices with the highest risk of trans-
mission include unprotected receptive anal intercourse and unprotected receptive
vaginal intercourse. Injection drug users’ contaminated needles or other injection
equipment are the main cause of parenteral transmission.15 Perinatal infection, or
vertical transmission, is the most common cause of pediatric HIV infection. The
mode of transmission does not affect the disease’s natural history. For additional
information on preventing HIV transmission with antiretroviral therapy (ART),
including pre- and post-exposure prophylaxis, and preventing mother-to-child
transmission, see Chapters 6 and 14, respectively.
Perinatal transmission of HIV occurs when HIV is passed from an HIV-infected
woman to her baby during pregnancy, labor, delivery, or breastfeeding. For an
HIV-infected woman not taking HIV medications, the risk of passing HIV to her
baby ranges from 14% to 32% during pregnancy, labor, and delivery; with breast-
feeding the risk of transmission increases to 25% to 48%.16 Therefore, it is important
for all pregnant women to remain engaged in healthcare and receive effective ART
during pregnancy. Because ART is recommended for all HIV-infected individuals,
the decision to continue ART postpartum should be made in consultation with
the woman and her HIV provider. Recent randomized controlled trial evidence
suggests safety and clinical benefits of continuing ART postpartum in women who
start treatment during pregnancy.17 Following delivery, mothers are recommended
not to breastfeed if formula feeding is available. For additional information on
preventing mother-to-child HIV transmission with ART, refer to Chapter 14.
ACUTE HIV INFECTION AND DISEASE PROGRESSION

Acute HIV infection occurs 1 to 4 weeks after transmission and is accompanied by
profound viral replication and a significant decline in CD4 cell count (Figure 1-2).
Early symptoms are often mistaken for other viral infections and may resemble
influenza or mononucleosis and last for about a week. Common signs, symptoms,
and laboratory findings of HIV infection are shown in Table 1-2. This early infec-
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TABLE 1-1. Estimated Per-Act Probability of Acquiring HIV from an Infected

Source, by Exposure Acta
Exposure Type Rate for HIV Acquisition per 10,000 Exposures
Parenteral
Blood transfusion 9,250
Needle-sharing during injection drug use 63
Percutaneous (needlestick) 23
Sexual
Receptive anal intercourse 138
Insertive anal intercourse 11
Receptive penile-vaginal intercourse 8
Insertive penile-vaginal intercourse 4
Receptive oral intercourse Low
Insertive oral intercourse Low
Otherb
Biting Negligible
Spitting Negligible
Throwing body fluids (including semen or Negligible

saliva)
Sharing sex toys Negligible

a
Factors that may increase the risk of HIV transmission include sexually transmitted diseases, acute and late-stage HIV
infection, and high viral load. Factors that may decrease the risk include condom use, male circumcision, antiretroviral
treatment, and pre-exposure prophylaxis. None of these factors are accounted for in the estimates presented in the
table.
b
Transmission of HIV through these exposure routes is technically possible but unlikely and not well documented.
(Reprinted from: Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure
prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV–United States, 2016. https://
stacks.cdc.gov/view/cdc/38856. Accessed August 18, 2016.)
tion with HIV may be asymptomatic and, in some cases, patients may present with
atypical clinical manifestations, including gastrointestinal and central nervous
system symptoms.18 Patients in this acute phase of infection will have a high HIV
RNA even though traditional HIV antibody tests may be negative; meanwhile,
HIV RNA or p24 antigen are present. Seroconversion to a positive HIV antibody
usually occurs within 4 weeks of acute infection. The nonspecific and transient
nature of symptoms associated with acute HIV infection provides a major diag-
ERRNVPHGLFRVRUJ
1000 1,000,000
900
Clinical latency 100,000
800 Death
700
Serum HIV RNA (copies/mL)

10,000
CD4 Count (cells/mm3)
600
500 1,000
400 Opportunistic
diseases
Acute HIV 100
300
syndrome
200
10
100
0 1
6 weeks
9 weeks
12 weeks
6 years
2 years
1 year
3 years
3 weeks
5 years
4 years
7 years
8 years
9 years
10 years
11 years
CD4 Count (cells/mm3) Serum HIV RNA (copies/mL)
FIGURE 1-2. HIV typical disease progression.

(Data from: Pantaleo G, Graziosi C, Fauci AS. The immunopathogenesis of human
immunodeficiency virus infection. N Engl J Med. 1993;328(5):327-335 and
Fauci AS, Pantaleo G, Stanley S, et al. Immunopathogenic mechanisms of HIV infection. Ann
Intern Med. 1996;124(7):654-663.)
TABLE 1-2. Common Signs, Symptoms, and Laboratory Findings of Acute

HIV Infection
Signs Symptoms Laboratory Findings
Fever Pharyngitis Leucopenia
Lymphadenopathy Myalgias or arthralgias Thrombocytopenia
Night sweats Headache Transaminase elevation
Skin rash Diarrhea
Weight loss
Oral ulcers
Neurologic syndromes
(aseptic meningitis, peripheral
neuropathy)
(Source/Data from: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0. Accessed August 19, 2016.)
ERRNVPHGLFRVRUJ
nostic challenge and contributes to ongoing virus transmissions.18,19 For additional

information on HIV testing and diagnosis and the initiation of ART during acute
HIV infection, please see Chapters 2 and 4.
Within 6 months, the host immune system mounts a response to control
the infection and HIV RNA declines (Figure 1-2). The viral steady-state reached
is referred to as a viral set point. Even without intervention, patients may remain
asymptomatic for many years with a gradual decline in CD4 cell count and stable
HIV RNA. During this period of clinical latency, the viral population continues to
replicate and the immune system gradually deteriorates. Persistently severe symp-
toms, including opportunistic infections, may not appear for a decade or more, and
infected individuals may carry the virus for years without knowing it. However,
infected persons are capable of transmitting the disease. These long, asymptomatic
periods among HIV-infected people make the pandemic particularly difficult to
control. Those persons with undiagnosed HIV or persons diagnosed with HIV but
not in medical care are likely to be a source of new infections.20
AIDS is defined as a CD4 cell count below 200 cells/mm3, a CD4 cell percentage
of total lymphocytes below 14%, or one of several AIDS-defining illnesses. The
CDC has developed a list of these illnesses, and Table 1-3 displays the 27 AIDS-
defining conditions.
The exact time when infection occurs is often unknown, making it difficult
to glean the average amount of time from HIV infection to the progression of
AIDS. In the absence of treatment, AIDS usually develops 8 to 10 years after initial
HIV infection. Because their immune systems become too weak to effectively fight
infection, HIV-infected individuals eventually present with one or more AIDS-
defining illnesses. For additional information regarding the management of
AIDS-defining illnesses, including opportunistic infections and cancers, please see
Chapters 7 and 16, respectively.
CONTINUUM OF CARE
The HIV continuum of care represents a sequential treatment cascade beginning
with HIV diagnosis and continuing through linkage to care, retention in care,
receipt of ART, and viral suppression.21 Figure 1-3 provides the spectrum of engage-
ment in HIV care in the United States and the proportion of the HIV-infected
population who have a suppressed viral load. A person living with HIV may go
through several stages and may also return to earlier stages of the continuum.
Factors influencing movement through the care continuum include availability of
supportive services, including case management, mental health support, substance
abuse treatment programs, transportation, medication coverage benefits, and
care transitions such as entry into or release from incarceration.22 Examining the
proportion of individuals living with HIV at each step of the continuum can help
to identify gaps in HIV services and subsequently assist in implementing targeted
strategies to promote positive health outcomes.
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TABLE 1-3. AIDS-Defining Conditions

Bacterial infections, multiple or recurrenta Lymphoid interstitial pneumonia or
pulmonary lymphoid hyperplasia complexa,b
Candidiasis of bronchi, trachea, or lungs Lymphoma, Burkitt (or equivalent term)
Candidiasis of esophagusb Lymphoma, immunoblastic (or equivalent

term)
Cervical cancer, invasivec Lymphoma, primary, of brain
Coccidioidomycosis, disseminated or Mycobacterium avium complex or Mycobacterium

extrapulmonary kansasii, disseminated or extrapulmonaryb
Cryptococcosis, extrapulmonary Mycobacterium tuberculosis of any

site, pulmonary,b,c disseminated,b or
extrapulmonaryb
Cryptosporidiosis, chronic intestinal Mycobacterium, other species or unidentified

(>1 month’s duration) species, disseminatedb or extrapulmonaryb
Cytomegalovirus disease (other than liver, Pneumocystis jirovecii pneumoniab

spleen, or nodes), onset at age >1 month
Cytomegalovirus retinitis (with loss of vision)b Pneumonia, recurrentb,c
Encephalopathy, HIV related Progressive multifocal leukoencephalopathy
Herpes simplex: chronic ulcers (>1 month’s Salmonella septicemia, recurrent

duration) or bronchitis, pneumonitis, or
esophagitis (onset at age >1 month)
Histoplasmosis, disseminated or Toxoplasmosis of brain, onset at age >1

extrapulmonary monthb
Isosporiasis, chronic intestinal (>1 month’s Wasting syndrome attributed to HIV

duration)
Kaposi sarcomab
a
Only among children aged <13 years.
b
Condition that might be diagnosed presumptively.
c
Only among adults and adolescents aged >13 years.
(Source: Centers for Disease Control and Prevention. Revised Surveillance Case Definitions for HIV Infection Among
Adults, Adolescents, and Children Aged <18 Months and for HIV Infection and AIDS Among Children Aged 18 Months
to <13 Years—United States, 2008, Appendix A.)
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100
86
90
80
80
70
60
Percentage
50
40 37
40
30
30
20
10
0
HIV Diagnosed Linked to Care* Engaged in Care Prescribed ART Virally
Suppressed
*Linked to care uses denominator of number of patients diagnosed, while all
other measures use the denominator of 1.2 million persons living with HIV.
FIGURE 1-3. HIV care continuum among persons with HIV in the United States in 2011.
(Source: Adapted from Centers for Disease Control and Prevention. Vital Signs: HIV diagnosis,
care, and treatment among persons living with HIV–United States, 2011. MMWR Morb Mortal
Wkly Rep. 2011;63(47):1113-1117.)
Identifying New HIV Cases

The HIV care continuum begins with identifying new HIV cases through HIV
testing and diagnosis. According to the CDC in 2011, 86% of the estimated 1.2
million persons living with HIV in the United States were diagnosed with HIV.23
HIV diagnosis is the entry point of the care continuum. Treatment of HIV infection
can only begin once individuals know they are infected with the virus. Individuals
infected with HIV, but unaware they are infected, can unknowingly transmit the
virus on to others. The CDC recommends routine HIV screening because it iden-
tifies more undiagnosed HIV infections than a risk-based approach.24 For those
persons less likely to attend facility-based HIV testing, community-based HIV
testing is recommended.25 Partners and contacts of individuals newly testing posi-
tive should be notified and offered testing. For more information on HIV testing,
including opportunities for pharmacists, please see Chapter 2.
Linkage to Care
The next step of the continuum is linkage to care. This step represents initi-
ating timely HIV care after diagnosis (i.e., CD4 T-cell count and HIV RNA level
drawn within 3 months of diagnosis). The CDC estimates that 80% of individuals
diagnosed with HIV infection are appropriately linked to care.23 Medical care is
required to access HIV treatment; prompt linkage of those testing positive with
medical care and services may reduce disease progression.
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Engagement in Care
The cascade continues with engagement in care, defined as having attended an HIV
medical care visit during a specified time period (e.g., 4 months). Once they access
care, HIV-infected patients must remain in care indefinitely. Only 40% of HIV-in-
fected individuals are retained in continuous HIV medical care.23 Poor retention
in care for HIV infection has a negative impact on survival.26 Methods to improve
entry into and retention in care have been studied extensively, and evidence-based
recommendations are available to optimize this part of the continuum.27 Strategies
include
• strengths-based case management (i.e., encouraging patients to identify
and use internal strengths and assets to overcome obstacles)
• patient navigation
• outreach services
To prevent immune deterioration, prolong life, and decrease HIV transmission
risk, all persons diagnosed with HIV infection should successfully remain in care
with sustained access to treatment, preventative care, and other medical services.
Receipt of ART
The next step of the HIV care continuum is receipt of ART. The CDC estimates
only 37% of all individuals living with HIV infection (including those with undi-
agnosed infection) are prescribed ART.23 Research has identified four main barriers
to successful ART:
1. delay or failure to initiate therapy
2. lack of persistence with therapy (i.e., uninterrupted receipt of treatment)
3. poor adherence to therapy
4. viral resistance to antiretroviral medications21
Current HIV clinical treatment guidelines recommend that all individuals diag-
nosed with HIV infection receive ART, regardless of CD4 count or viral load.28
Effective drug treatment of HIV not only improves clinical outcomes for the
infected patient but also prevents transmission of HIV infection to others. For
additional information on initiating HIV treatment, including who and when to
treat, baseline laboratory considerations, selecting an initial regimen, and regimen
switching, please see Chapter 4.
Viral Suppression
The final step of the care cascade is viral suppression, an indicator of treatment
success. Viral load suppression not only improves individual health outcomes but
also reduces HIV transmission on a population level.29,30 CDC data reveal merely
30% of patients living with HIV infection achieved viral suppression. The greatest
opportunities for increasing the percentage of persons with a suppressed viral load
are reducing undiagnosed HIV infections and increasing the percentage of persons
living with HIV who are engaged in care.23
ERRNVPHGLFRVRUJ
Methods to improve the cascade of HIV care have been studied extensively, and
evidence-based guidance is available.25 Recent estimates suggest that expanding
linkage to care, achievement of viral suppression, and pre-exposure prophylaxis
use could prevent as many as 185,000 new HIV infections in the United States over
the next 5 years.31 One novel strategy to improve the care cascade employed initi-
ation of ART on the same day as HIV diagnosis, a strategy associated with shorter
duration of time to viral suppression.32 As new strategies emerge to optimize the
care continuum, viral suppression remains the ultimate goal to improve individual
health outcomes and reduce HIV acquisition and transmission, thus conferring
community and public health benefits.
ROLE OF THE PHARMACIST IN THE HIV CONTINUUM OF CARE

Pharmacists play an active role in optimizing the HIV care continuum for persons living
with HIV. Pharmacists performing HIV testing in the community can increase testing
coverage and linkage to care. The success of in-pharmacy HIV testing services has been
documented.33,34
Pharmacists can recommend HIV self-testing and provide counseling to patients
purchasing over-the-counter HIV self-test kits about the proper method for administering
the test and directions on what to do once the results are obtained. Pharmacists recom-
mending antiretroviral regimens to clinicians and discussing these regimens with patients,
addressing issues of drug coverage, and screening for drug interactions can also increase
HIV treatment coverage. Lastly, and perhaps most importantly, pharmacists can serve to
increase retention in care, antiretroviral therapy adherence, and viral suppression by
• supporting patient linkage to care through health associations and support
agencies
• monitoring adherence routinely (e.g., monitoring pharmacy refill data)
• providing side effect counseling and management
• recommending mobile health technology, alarm devices, and/or pillbox orga-
nizers to patients
• providing patient education
• offering support for medication adherence and keeping clinic appointments
KEY RESOURCES
• Centers for Disease Control and Prevention. HIV Surveillance Report. www.cdc.gov/
hiv/library/reports/surveillance/. Accessed August 19, 2016.
o This CDC website hosts annual reports of surveillance data on HIV infection
rates and key quality indicators in the United States and dependent areas.
Supplemental reports are also published annually and provide more detailed
information for specific target patient populations.
• International Advisory Panel on HIV Care Continuum Optimization. IAPAC guide-
lines for optimizing the HIV care continuum for adults and adolescents. J Int Assoc
Provid AIDS Care. 2015;14 Suppl 1:S3-34.
ERRNVPHGLFRVRUJ
o This article is a systematic review of evidence-based methods to optimize the

HIV care continuum for adults and adolescents. Thirty-six recommendations
are provided for interventions to optimize the HIV care environment; increase
HIV testing and linkage to care, treatment coverage, retention in care, and viral
suppression; and monitor the HIV care continuum.
• Joint United Nations Programme on HIV/AIDS (UNAIDS). Global AIDS Update 2016.
http://www.who.int/hiv/pub/arv/global-AIDS-update-2016_en.pdf?ua=1. Accessed
August 18, 2016.
o This document contains worldwide data on HIV epidemiologic trends by region
while reviewing both past accomplishments and future challenges in ending the
AIDS epidemic.
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vance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis. 2011;52(6):793-
800.
22. Cheever LW. Engaging HIV-infected patients in care: Their lives depend on it. Clin Infect Dis.
2007;44(11):1500-1502.
23. Centers for Disease Control and Prevention. Vital Signs: HIV diagnosis, care, and treat-
ment among persons living with HIV–United States, 2011. MMWR Morb Mortal Wkly Rep.
2011;63(47):1113-1117.
24. Branson B, Handsfield H, Lampe M, et al. Revised recommendations for HIV testing of adults,
adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR14):1-
17.
25. International Advisory Panel on HIV Care Continuum Optimization. IAPAC guidelines for opti-
mizing the HIV care continuum for adults and adolescents. J Int Assoc Provid AIDS Care. 2015;
Nov–Dec(14, Suppl 1):S3-34.
26. Giordano TP, Gifford AL, White, Jr. AC, et al. Retention in care: A challenge to survival with HIV
infection. Clin Infect Dis. 2007;44(11):1493-1499.
27. Thompson MA, Mugavero MJ, Amico KR, et al. Guidelines for improving entry into and
retention in care and antiretroviral adherence for persons with HIV: Evidence-based recommen-
dations from an International Association of Physicians in AIDS Care panel. Ann Intern Med.
2012;156(11):817-833, W-284, W-285, W-286, W-287, W-288, W-289, W-290, W-291, W-292,
W-293, W-294.
28. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of anti-
retroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human
Services. Available at https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treat-
ment-guidelines/0. Accessed August 19, 2016.
29. Das M, Chu PL, Santos GM, et al. Decreases in community viral load are accompanied by reduc-
tions in new HIV infections in San Francisco. PLoS One. 2010;5(6):e11068.
30. Montaner JS, Lima VD, Barrios R, et al. Association of highly active antiretroviral therapy
coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: A
population-based study. Lancet. 2010;376(9740):532-539.
31. Yaylali E, Farnham P, Jacobson E, et al. Impact of improving HIV care and treatment and initi-
ating PrEP in the United States, 2015–2020. Paper presented at: Conference on Retroviruses and
Opportunistic Infections (CROI); February 22–25, 2016; Boston, MA. Abstract 1051.
32. Pilcher CD, Ospina-Norvell C, Dasgupta A, et al. The effect of same-day observed initiation
of antiretroviral therapy on HIV viral load and treatment outcomes in a U.S. public hospital
setting. J Acquir Immune Defic Syndr. 2017;74(1):44-51.
33. Weidle PJ, Lecher S, Botts LW, et al. HIV testing in community pharmacies and retail
clinics: A model to expand access to screening for HIV infection. J Am Pharm Assoc. (2003).
2014;54(5):486-492.
34. Fernandez-Balbuena S, Belza MJ, Zulaica D, et al. Widening the access to HIV testing: the contri-
bution of three in-pharmacy testing programmes in Spain. PLoS One. 2015;10(8):e0134631.
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2
HIV Testing and Diagnosis
INTRODUCTION
An estimated 1.2 million people in the United States are living with human immu-
nodeficiency virus (HIV), but 15% are not aware of their infection.1 Evidence
suggests that this population of undiagnosed patients is a significant source of
ongoing transmission, accounting for nearly one-third of new infections.2
Worldwide, considerable efforts to improve the rates of testing and diagnosis
have been implemented. In the United States, the proportion of patients unaware
of their infection has improved in the last several years as a result of the Centers
for Disease Control and Prevention (CDC) changes in HIV screening and testing
guidelines, which were first published in 2006.3,4
WHO SHOULD BE TESTED?

The CDC recommends screening for HIV infection in all persons ages 13 to 64
at a minimum of once in their lifetime.4 The U.S. Preventive Services Task Force
(USPSTF) suggests that screening can begin at age 15 unless an individual is iden-
tified at an earlier age with risk factors for HIV infection.5 Screening after age 65
years is indicated if there is ongoing risk for HIV.
Other individuals who should receive testing include
• all patients actively seeking an HIV test
• all patients with signs or symptoms consistent with HIV infection or
an opportunistic illness characteristic of acquired immunodeficiency
syndrome (AIDS)
• all pregnant women, including those who present in labor who have not
been tested and whose HIV status is unknown6
• all patients attending a sexually transmitted disease (STD) clinic or
seeking treatment for an STD
• all patients initiating treatment for tuberculosis
• healthcare workers following an occupational exposure to HIV
Opt in or Opt out

Historically, healthcare professionals would offer HIV screening based on their
assessment of a patient’s risk for infection. If the patient agreed to be tested, they
17
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would often opt in by completing a consent process separate from their general
consent to receive medical care and other basic diagnostic testing. This approach
to testing was limited because it only targeted high-risk individuals and led to
missed opportunities for diagnosis.
The CDC now recommends that healthcare professionals incorporate HIV
screening into a patient’s general informed consent to receive medical care.4 As a
result, HIV testing should now be offered to all qualified patients unless they opt
out or willingly decline the offer. Unless they decline, testing should occur only
after the patient has been informed orally or in writing that HIV testing will be
performed. This change to opt-out testing has increased the overall rate of HIV
testing and diagnosis.7,8
Who Should Receive Repeat Testing?

Patient populations that are recommended by the CDC and USPSTF to receive
more frequent testing (at least annually) include those who are known to be at
higher risk for HIV infection, those who are actively engaged in risky behaviors,
and those who live in a high-prevalence setting.4,5
High-risk patients include
• injection-drug users and their sex partners
• persons who exchange sex for money or drugs
• sex partners of HIV-infected persons
• men having sex with men (MSM) or heterosexual persons who them-
selves or whose sex partners have had more than one sex partner since
their most recent HIV test.
BASIC PRINCIPLES OF DIAGNOSTIC TESTING

Following exposure to HIV, there is a consistent and emerging pattern of serologies
and laboratory markers that can be used to diagnose HIV infection in patients
(Figure 2-1).
• HIV-1 RNA becomes detectable approximately 10 days after infection
and proceeds to increase to very high levels.
• HIV-1 p24 antigen is expressed within 4 to 10 days after HIV-1 RNA.
• IgM antibodies are expressed 3 to 5 days after the p24 antigen is first
detectable, or 10 to 13 days after the appearance of viral RNA.
• IgG antibodies emerge 2 to 3 weeks after the initial detection of viral
RNA and persist throughout the course of HIV infection.
Historically, testing for HIV has occurred using antibody detection.9 The
earliest tests reliably detected the appearance of antibodies roughly 50 days or
more following HIV exposure. Unfortunately, this led to many false negative test
results early in the course of infection when transmission can occur more readily.10
Over the years, antibody screening tests became more sensitive and detected HIV
ERRNVPHGLFRVRUJ
CHAPTER 2 HIV Testing and Diagnosis 19
HIV RNA
HIV
Infection
HIV Antibody
P24 antigen
Days 0 10 20 30 40 50 60 70
Nucleic P24 Antibody Detection
Acid Antigen
Detection Detection
3rd Generation 2nd Generation 1st Generation

EIA Test EIA Test EIA Test
4th
Generation
Ag/Ab Test Western Blot Test
FIGURE 2-1. Pattern of HIV serologies and comparison of generations 1–4 HIV tests in detecting
HIV in human serum.
(Source: Adapted from Centers for Disease Control and Prevention and Association of
Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated
Recommendations. Available at: http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014.)
antibodies earlier. For example, third-generation immunoassays can detect anti-

bodies as early as 3 weeks following infection. Unfortunately, each positive immu-
noassay test also required confirmation with a Western blot test that could not
reliably detect the appearance of antibodies until 40 to 50 days after infection.
This would often lead to conflicting results between the third-generation immu-
noassay and the Western blot early in the course of HIV infection. Additionally,
patients with early or acute HIV could be in the process of seroconversion and
present with a false negative third-generation test despite infection with HIV. This
period of servoconversion is often called the window period.9
Closing the Window Period

The newest HIV tests and testing algorithms are designed to shorten the window
period and improve the clinician’s ability to diagnose early and acute HIV (Figure
2-2).9,11 Emerging evidence suggests that HIV diagnosis and initiation of anti-
retroviral therapy during early or acute infection may improve long-term patient
outcomes and reduce transmission events.12,13
The CDC Guidelines for HIV Testing recommend performing a two- or three-step
process for HIV screening. The first step is using a fourth-generation HIV test that
can not only detect the presence of HIV-1 and HIV-2 antibodies but also the presence
ERRNVPHGLFRVRUJ
Step 1: HIV Antigen/Antibody Combination Immunoassay (“4th Generation HIV Test”)

• Detects antibodies for HIV-1 and HIV-2 Infection
• Detects p24 HIV antigen
Positive
Step 2: HIV 1 and 2 differentiation immunoassay (i.e. a Multi-spot HIV test)

• Detects antibodies to HIV-1 or 2 and differentiates between the two strains
HIV-1 (+) HIV-1 (-) HIV-1 (+) HIV-1 (-)

HIV-2 (-) HIV-2 (+) HIV-2 (+) HIV-2 (-)
HIV-1 HIV-2 HIV Indeterminate

Diagnosis Diagnosis Diagnosis Result
Step 3: HIV-1 nucleic acid testing (i.e. an HIV-1 viral load)

• A positive test leads to a diagnosis of acute HIV-1 infection
FIGURE 2-2. HIV 1/2 testing algorithm.

(Source: Adapted from Centers for Disease Control and Prevention and Association of
Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated
Recommendations. Available at: http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014.)
of the HIV-1 p24 antigen. The p24 antigen can be detected 3 to 5 days prior to the
appearance of HIV antibodies, thereby increasing the ability to detect HIV infection
sooner than previous antibody-only tests. Current versions of the fourth-generation
test are unable to indicate whether a positive result is due to the presence of the
p24 antigen or the p24 antigen plus the presence of HIV-1 or HIV-2 antibodies. As a
result, step two in the algorithm is to perform an HIV-1/HIV-2 antibody differenti-
ation immunoassay, sometimes referred to as a multispot test. A positive multispot
confirms the presence of HIV-1 and/or HIV-2 infection. A negative multispot test
likely indicates that the fourth-generation test detected only the presence of the p24
antigen and the patient has early or acute HIV. This diagnosis can be confirmed by
a positive HIV-1 nucleic acid test such as a plasma HIV RNA level of viral load.
Rapid Testing
Rapid tests are immunoassays that produce results in 30 minutes or less. Rapid
testing allows patients to receive results in a single visit, which is useful in urgent
medical circumstances. These circumstances include testing a source patient
following an occupational exposure (i.e., needlestick injury) or a woman in labor
who did not receive testing during prenatal care. Rapid testing has also been useful
in settings where patients are unlikely to return for HIV test results (e.g., some STD
ERRNVPHGLFRVRUJ
clinics). A positive rapid test in this setting can lead to an earlier entry into HIV
care. Rapid tests use blood or saliva to detect antibodies and, if performed during
the window period, may produce a false negative result. All rapid immunoassays
that are positive require follow-up testing with traditional algorithms to confirm
the result.
The U.S. Food and Drug Administration (FDA) approved the Uni-Gold™
Recombigen® HIV Test in 2003, which can be performed using plasma or whole
blood samples. The Oraquick Advance Rapid HIV Test was approved in 2004 and
can be performed using plasma and whole blood samples as well as samples from
the oral mucosa. Both tests have received a waiver under the Clinical Laboratory
Improvements Amendments (CLIA) and can therefore be used at the point of care.
At-Home Testing
There are two FDA-approved home HIV tests: the Home Access HIV-1 Test System
and the OraQuick In-Home HIV Test.
The Home Access HIV-1 Test System is a home collection kit, which involves
pricking the finger to collect a blood sample, sending the sample to a licensed labo-
ratory, and then calling in for results. The test is anonymous, and results are avail-
able as early as the next business day. In the event of a positive test, a follow-up
test is performed immediately on the same blood sample, and the results reported
include the follow-up test. The manufacturer provides confidential counseling and
referral to confirmatory testing and follow-up treatment.
The OraQuick In-Home HIV Test provides rapid results in the home. The
testing procedure involves swabbing the mouth for an oral fluid sample and using
a kit to test it. Results are available in 20 minutes. Again, the manufacturer provides
confidential counseling and referral to follow-up testing and treatment. Because
the level of antibody in oral fluid is lower than it is in blood, oral fluid tests find
infection later after exposure than do blood tests. According to the manufacturer,
up to 1 in 12 people may have a false negative result with this test.
ROLE OF THE PHARMACIST IN HIV TESTING AND DIAGNOSIS

HIV testing and early diagnosis can improve entry into care and access to treatment
that prolongs life and prevents transmission to others. Unfortunately, HIV testing is not
always easily accessible for patients with limited access to healthcare.
Pharmacists in community and outpatient settings can
• improve patient access to HIV testing by offering onsite rapid HIV testing and
counseling services
• counsel patients on the products available for at-home testing and diagnosis
because HIV testing is often the first step in linking individuals to HIV care
and prevention
• serve as the initial healthcare contact for patients
ERRNVPHGLFRVRUJ
• help patients navigate the healthcare system, linking them to an HIV provider
whenever possible
Evidence establishing the role of pharmacists in the diagnosis of HIV infection continues
to emerge.14-16 One recent study described the success of pharmacist HIV testing services
within the HIV clinic setting and HIV testing implemented in community pharmacies. In
each instance, a positive impact on access and availability of testing to patients at risk of
HIV was demonstrated. In one study in particular, nearly one-third of participants did not
consistently see a healthcare provider, and among those who did nearly half had not been
tested for HIV.15 Among those who tested positive for HIV in these studies, pharmacists
successfully contributed to linking individuals to an HIV care provider. Taken together,
these data demonstrate how pharmacists can improve access and opportunity for HIV
testing in the community setting and help patients gain entry into HIV care.
KEY RESOURCES
• American Academy of HIV Medicine, Referral Link. http://www.aahivm.org/Referral-
Link/exec/frmAdvSearch.aspx
o This referral link can help pharmacists and patients locate HIV providers and
facilitate linkage to HIV care.
• CDC revised recommendations on routine testing for HIV. http://www.cdc.gov/hiv/
guidelines/testing.html.
o The documents listed on this webpage provide the most updated federal guid-
ance on HIV screening and testing for individuals who offer or conduct HIV
testing.
• CDC National HIV Surveillance System and Medical Monitoring Project, HIV Care
Continuum. https://www.aids.gov/federal-resources/policies/care-continuum/.
o Using the most recent CDC data, this resource shows the proportion of individ-
uals living with HIV who are engaged at each stage of the HIV care continuum—
HIV diagnoses, linkage to care, retention in care, receiving art, and achieving
viral suppression.
• HIV Medicine Association HIV Provider Listing. www.hivma.org.
o Similar to the referral link above, this provider listing can be helpful in locating
local HIV providers and facilitating linkage to care.
• National Clinician’s Consultation Center Compendium of State Laws Regarding HIV
Testing. http://www.ucsf.edu/hivcntr/stateLaws/index.html.
o This resource provides a summary of the legal guidelines for HIV testing in each
state. Although no longer an up-to-date resource, it is unique and remains useful
for understanding HIV testing laws throughout the United States.
• New York State Department of Health HIV Testing Toolkit: Resources to Support
Routine HIV Testing for Adults and Teens. http://www.health.ny.gov/diseases/aids/
providers/testing/docs/testing_toolkit.pdf.
o This toolkit is a comprehensive set of resources for HIV testing as a part of
healthcare for all patients aged 13 to 64. Although the toolkit was specifically
developed to help clinicians meet New York State clinical guidelines and legal
requirements for HIV testing, the resources may be helpful to those practicing in
other locations.
ERRNVPHGLFRVRUJ
REFERENCES
1. Hall HI, An Q, Tang T, et al. Prevalence of diagnosed and undiagnosed HIV infection—United
States, 2008–2012. MMWR Morb Mortal Wkly Rep. 2015;64(24):657-662.
each step of the care continuum in the United States. JAMA Intern Med. 2015;175:588–596.
3. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and
care objectives by using HIV surveillance data—United States and 6 dependent areas, 2012.
Atlanta, GA: US Department of Health and Human Services, CDC; 2014. Available at http://
www.cdc.gov/hiv/pdf/surveillance_report_vol_19_no_3.pdf.
4. Branson BM, Handsfield HH, Lampe MA, et al. Centers for Disease Control and Prevention.
Revised recommendations for HIV testing of adults, adolescents, and pregnant women in
health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17.
5. United States Preventive Services Task Force. Final Recommendation Statement. Human Immu-
nodeficiency Virus (HIV) Infection: Screening, April 2013.
6. Routine Human immunodeficiency virus screening. Committee Opinion No. 596. American
College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123:1137-1139.
7. Glew S, Pollard A, Hughes L, Llewellyn C. Public attitudes towards opt out testing for HIV in
primary care: A qualitative study. Br J Gen Pract. 2014;64(619):e60-66.
8. Woodring JV, Kruszon-Moran D, Oster AM, et al. Did CDC’s revised HIV testing recommenda-
tions make a difference? Evaluation of HIV Testing in the US Household Population, 2003–2010.
J Acquir Immune Defic Syndr. 2014;67(3):331-340.
9. Centers for Disease Control and Prevention and Association of Public Health Laboratories.
Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at:
http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014.
10. Brenner BG, Roger M, Routy JP, et al. High rates of forward transmission events after acute/early
HIV-1 infection. J Infect Dis. 2007;195(7):951-959.
11. Lee K, Park HD, Kang ES. Reduction of HIV seroconversion window period and false positive rate
by using ADVIA Centaur HIV antigen/antibody combo assay. Ann Lab Med. 2013;33(6):420-425.
12. Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptom-
atic HIV infection. N Engl J Med. 2015;373:795-807.
13. Hogan CM, Degruttola V, Sun X, et al. The setpoint study (ACTG A5217): Effect of immediate
versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individ-
uals. J Infect Dis. 2012;205(1):87-96.
14. Sherman EM, Elrod S, Allen D, Eckardt P. Pharmacist testers in multidisciplinary healthcare team
expand HIV point-of-care testing program. J Pharm Pract. 2014;27:578-581.
15. Darin KM, Klepser ME, Klepser DE, et al. Pharmacist-provided rapid HIV testing in two
community pharmacies. J Am Pharm Assoc. 2015;55:81-88.
16. Weidle PJ, Lecher S, Botts LW, et al. HIV testing in community pharmacies and retail clinics: A
model to expand access to screening for HIV infection. J Am Pharm Assoc. 2014;54:486-492.
ERRNVPHGLFRVRUJ
ERRNVPHGLFRVRUJ
3
Antiretroviral Therapy
P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVP;
Kristina E. R. Connolly, PharmD, BCPS;
and Celeste R. Caulder, PharmD
HUMAN IMMUNODEFICIENCY VIRUS PATHOGENESIS

The current strategies used for the treatment of human immunodeficiency virus
(HIV) target various points in the HIV life cycle (Figure 3-1). The outer glycoprotein
(gp160) on the surface of the virus, which is composed of two subunits (gp120 and
gp41), has affinity for CD4 receptors present on the surface of T-helper lympho-
cytes, monocytes, macrophages, dendritic cells, and brain microglia.1 Binding to
the CD4 receptor is facilitated by the gp120 subunit and is followed by additional
binding to chemokine coreceptors. The two major chemokine receptors used by
HIV are chemokine (C–C motif) receptor 5 (CCR5) and chemokine (C-X-C motif)
receptor 4 (CXCR4). HIV isolates may contain a mixture of viruses that target one
of these coreceptors, while some viral strains can use both coreceptors and are
referred to as dual-tropic. The HIV strain that preferentially uses CCR5 (R5 virus)
is macrophage-tropic and typically implicated in most cases of sexually trans-
mitted HIV. Individuals with a common 32-base-pair deletion in the CCR5 gene
are protected from progression of HIV disease, and those who are homozygous for
the 32-base-pair deletion have a degree of resistance to acquisition of HIV-1.2,3 The
HIV strain that targets CXCR4, designated X4 virus, is T-cell–tropic and often is
predominant in the later stage of disease. CD4 and coreceptor attachment of HIV
to the cell promotes membrane fusion, which is mediated by gp41, and internal-
ization of viral genetic material including the enzymes necessary for replication.
After internalization, the viral protein shell surrounding the nucleic acid is
uncoated in preparation for replication.1 The genetic material of HIV is single-
stranded RNA, and the virus must transcribe this RNA into DNA. HIV is equipped
with a unique RNA-dependent DNA polymerase enzyme, reverse transcriptase,
which first synthesizes a complementary strand of DNA using viral RNA as a
template. The RNA portion of this DNA–RNA hybrid is then partially removed by
ribonuclease H, allowing HIV reverse transcriptase to complete the synthesis of
a double-stranded DNA molecule. Many mistakes are made during this process;
errors in the final DNA product contribute to rapid mutation of the virus, enabling
the virus to evade immune response and promote the evolution of drug resis-
tance during partially suppressive therapy. The final double-stranded DNA product
migrates into the nucleus and is integrated into the host cell chromosome by inte-
grase, another enzyme unique to HIV, following reverse transcription.
25
ERRNVPHGLFRVRUJ
FIGURE 3-1. Drug therapy targets in the HIV life cycle.

(Source: Figure courtesy of Savannah Mancuso, South Carolina College of Pharmacy, University
of South Carolina.)
HIV can establish a persistent, latent infection particularly in long-lived cells

of the immune system, such as memory T lymphocytes, following the integration
of HIV into the host chromosome. The virus becomes hidden in these cells, which
greatly inhibits the ability to cure HIV infection. Integration of HIV may cause
cellular abnormalities and induce apoptosis.
HIV preferentially replicates in activated cells following integration. Assembly
of new virion particles occurs in a stepwise manner beginning with the coalescence
of HIV proteins beneath the host cell lipid bilayer. The nucleocapsid subsequently
is formed with viral single-stranded RNA and other components packaged inside.
Once packaged, the virion then buds through the plasma membrane, acquiring
ERRNVPHGLFRVRUJ
CHAPTER 3 Antiretroviral Therapy 27
the characteristics of the host lipid bilayer. After the virus buds, the maturation
process begins. Within the virion, protease, another enzyme unique to HIV, begins
cleaving a large precursor polypeptide into functional proteins that are necessary
to produce a complete virus. Without this enzyme, the virion is immature and
unable to infect other cells.
There are three general phases of viral replication and pathogenesis: acute,
chronic, and terminal.4,5 Initial rounds of HIV replication during acute infection
take place largely in the mucosal CD4+ CCR5+ T-cell pools in the gut, resulting
in massive CD4 T-cell depletion in these tissues.4,5 Cells are destroyed by various
mechanisms, including cell lysis from newly budding virions, cytotoxic T-lympho-
cyte–induced cell killing, and induction of apoptosis. Following this destruction, a
state of heightened immune activation ensues during the chronic infection phase,
which can last for several years. The activated state is characterized by high levels
of activation markers on circulating T cells and proinflammatory cytokines that
enables further HIV replication and ultimately leads to continued depletion of
CD4+ CCR5+ T cells. HIV-1 exhibits a very high turnover rate during this chronic
phase, with an estimated 10 billion new viruses produced each day. The immune
system operates well enough during the chronic phase to prevent overt oppor-
tunistic infections that constitute acquired immunodeficiency syndrome (AIDS).
Eventually, the depletion of CD4 cells and continuous cellular activation leads to a
final collapse of the immune system, or AIDS. HIV may use the CXCR4 coreceptor
during this last phase of infection, and these viruses infect a broader range of CD4
cells, increasing disease progression. It is this destruction of CD4 cells that causes
a profoundly compromised immune system and AIDS.4,5
The median incubation period from initial HIV infection to progression to
AIDS for adults is estimated to be approximately 10 years and is shorter in infants
and older adults (>40 years).6 A smaller subset of patients, termed rapid progres-
sors, may progress to AIDS within 1 year of diagnosis. Rapid progression is asso-
ciated with low CD4+ cell counts (<100/mL) in the first year of diagnosis and a
shorter AIDS-free survival.7 Another rare HIV phenotype is linked to markedly
slower disease progression, termed long-term nonprogressors or elite controllers. These
patients will have sustained high CD4+ cell counts (>500 cells/mL) and low levels
of viremia in the absence of treatment for 10 years or more. In untreated persons
diagnosed with AIDS, the median survival time varies; however, the majority of
patients have an average survival of less than 2 years. Earlier diagnosis, availability
of infectious prophylaxis, and antiretroviral therapy (ART) has altered this time-
line significantly.
There are six classes of antiretroviral (ARV) agents available to treat HIV/AIDS,
all of which have specific targets (Figure 3-1). The nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs) competitively inhibit HIV reverse transcriptase
and ultimately terminate the DNA chain, which interrupts the HIV replication
cycle.8 The non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind the p66
subunit, and this noncompetitive binding induces a conformational change in
the enzyme that alters the active site and limits its activity.9 HIV protease inhib-
ERRNVPHGLFRVRUJ
itors (PIs) function as a competitive inhibitor that directly binds to HIV protease
and prevents subsequent cleavage of polypeptides.10 The integrase strand transfer
inhibitors (INSTIs) bind metallic ions in the active site of the integrase enzyme,
which competitively inhibits the strand transfer reaction.11 Fusion inhibitors were
the first class of antiretroviral medications to target the HIV replication cycle extra-
cellularly. Fusion inhibitors prevent the fusion of HIV to the CD4 or other target
cell.12 Chemokine receptor 5 (CCR5) antagonists selectively and reversibly bind
the CCR5 co-receptor, blocking the V3 loop interaction and inhibiting fusion of
the cellular membranes. CCR5 antagonists have no activity against CXCR4 tropic
or dual/mixed tropic virus.13
HISTORY OF ANTIRETROVIRAL THERAPY
Antiretroviral Drug Discovery

Since the first clinical trial began for zidovudine (AZT) in 1985, there have been
over 25 ARV single agents approved from six distinct classes.14 As of 2016, there
have been 13 fixed-dose combinations (FDCs), including six single-tablet, once-
daily regimens that the U.S. Food and Drug Administration (FDA) approved for the
management of HIV-1 infection14 (Table 3-1).
AZT, a 2’,3’-dideoxynucleoside, was first synthesized in 1964 but failed to show
efficacy as a potential anticancer agent. Twenty years later in 1985, scientists from
Burroughs-Wellcome demonstrated the anti-HIV-1 activity of AZT in vitro. They
hypothesized that protecting uninfected cells by blocking viral infection could
permit immune restoration or prevent further loss of immune function.15 In 1986,
a Phase II randomized, placebo-controlled trial was initiated, and within 7 months
the trial was halted due to significantly higher survival rates in the AZT arm as
compared to placebo (mortality rate of 0.7% [1/145] vs. 13.9% [19/137]).15,16 By
October 1986, AZT was made available for compassionate use through a model of
unlicensed cancer drugs, and 3.5 months after a new drug application was filed,
the FDA granted approval in March of 1987.14,15 Landmark discoveries continued
in 1995 and 1996 with FDA approval of the first PI (saquinavir) and NNRTI (nevi-
rapine). The availability of multiclass agents ushered in the era of highly active
antiretroviral therapy (HAART), the use of three or more active agents from at
least two distinct classes. HAART became the standard of care according to the
1997 International AIDS Society–USA sponsored guidelines.17 The first FDC tablet
containing the NRTIs, zidovudine and lamivudine, was FDA approved and marketed
in 1997.14 The decade to follow witnessed the establishment of ritonavir-boosted
PI therapy, two additional ARV drug classes, the fusion inhibitor (enfuvirtide) and
CCR5-inhibitor (maraviroc), and in 2006, the development of the first once-daily
FDC pill to manage HIV-1, Atripla® (tenofovir/emtricitabine/efavirenz).14,15,18 A full
detailed timeline of landmark discoveries in the history of HIV treatment is shown
in Figure 3-2. In 2007, raltegravir, the first agent in the INSTI class, was approved
for use in treatment-experienced patients with documented resistance. In the most
current guidelines, INSTIs, which are now comprised of three agents and have
ERRNVPHGLFRVRUJ
TABLE 3-1. Summary of Available Antiretrovirals

Generic Name (Abbreviation) Brand Name Manufacturer Approval Date
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abacavir (ABC) Ziagen GlaxoSmithKline 1998
Didanosine (ddI) Videx Bristol Myers Squibb 1991; Videx EC

2000
Emtricitabine (FTC) Emtriva Gilead 2003
Lamivudine (3TC) Epivir GlaxoSmithKline 1995
Stavudine (d4T) Zerit Bristol Myers Squibb 1994
Tenofovir Alafenamide Vemlidy Gilead Combo products

Fumarate (TAF) since 2015
Tenofovir Disoproxil Fumarate Viread Gilead 2001

(TDF)
Zidovudine (AZT, ZDV) Retrovir GlaxoSmithKline 1987
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz (EFV) Sustiva (U.S.); Stocrin Bristol Myers Squibb 1998
(abroad)
Etravirine (ETR) Intelence Tibotec 2008
Nevirapine (NVP) Viramune; Viramune Boehringer Ingelheim 1996; 2011 (XR)

XR
Rilpivirine (RPV) Edurant Tibotec 2011
Protease Inhibitors (PIs)

Atazanavir (ATV) Reyataz Bristol Myers Squibb 2003
Atazanavir/Cobicistat (ATV/c) Evotaz Bristol Myers Squibb 2015
Darunavir (DRV) Prezista Tibotec 2006
Darunavir/Cobicistat (DRV/c) Prezcobix Janssen 2015
Fosamprenavir (FPV) Lexiva (U.S.); Telzir GlaxoSmithKline 2003

(Europe)
Indinavir (IDV) Crixivan Merck 1996
Lopinavir/Ritonavir (LPV/r; or Kaletra Abbott 2000; Meltrex

LPV/RTV) formulation
2005
Nelfinavir (NFV) Viracept Pfizer 1997
(continued)
ERRNVPHGLFRVRUJ
TABLE 3-1. Summary of Available Antiretrovirals (continued)

Saquinavir (SQV) Invirase Roche 1995
Tipranavir (TPV) Aptivus Boehringer Ingelheim 2005
Integrase Strand Transfer Inhibitors (INSTIs)

Dolutegravir (DTG) Tivicay GlaxoSmithKline 2013
Elvitegravir (EVG) Gilead 2012, within a

single tablet
regimen
Raltegravir (RAL) Isentress Merck 2007 twice daily

dose, 2017 HD
tablet
CCR5 Antagonist
Maraviroc (MVC) Selzentry (US); Pfizer 2007
Celsentri
(non-US)
Fusion Inhibitor
Enfuvirtide (ENF, T-20) Fuzeon Roche/ Trimeris 2003
Pharmacokinetic Enhancers (PE)

Cobicistat (COBI) Tybost Gilead 2014
Ritonavir (RTV) Norvir Abbott 1996; Tablet

formulation in
2010
Fixed-Dose Combinations
Combination Products (To be given with other antiretroviral classes)
Abacavir/Lamivudine (NRTI/ Epzicom (U.S.); Kivexa GlaxoSmithKline 2004
NRTI) (Europe)
Abacavir/Lamivudine/ Trizivir GlaxoSmithKline 2000

Zidovudine (NRTI/NRTI/
NRTI)
Lamivudine/Zidovudine (NRTI/ Combivir GlaxoSmithKline 1997

NRTI)
Tenofovir Alafenamide Descovy Gilead 2016

Fumarate/Emtricitabine
(NRTI/NRTI)
(continued)
ERRNVPHGLFRVRUJ
TABLE 3-1. Summary of Available Antiretrovirals (continued)

Tenofovir Disoproxil Fumarate/ Truvada Gilead 2004
Emtricitabine (NRTI/NRTI)
Single-Tablet Regimens (Classes)

Abacavir/Lamivudine/ Triumeq ViiV 2014
Dolutegravir (NRTI/NRTI/
INSTI)
Tenofovir Alafenamide Genvoya Gilead 2015

Fumarate/Emtricitabine/
Elvitegravir/Cobicistat (NRTI/
NRTI/INSTI/PE)
Tenofovir Alafenamide Odefsey Gilead 2016

Fumarate/Emtricitabine/
Rilpivirine (NRTI/NRTI/
NNRTI)
Tenofovir Disoproxil Fumarate/ Atripla Gilead & Bristol Myers 2006

Emtricitabine/Efavirenz Squibb
(NRTI/NRTI/NNRTI)
Tenofovir Disoproxil Fumarate/ Stribild Gilead 2012

Emtricitabine/Elvitegravir/
Cobicistat (NRTI/NRTI/
INSTI/PE)
Tenofovir Disoproxil Fumarate/ Complera Gilead + Tibotec 2011

Emtricitabine/Rilpivirine
(NRTI/NRTI/NNRTI)
several once-daily, single-tablet FDCs available, are among the few guideline-
recommended preferred agents for treatment of naïve patients.19
The establishment of several key research enterprises through coordinated
efforts of federal agencies, the pharmaceutical industry, independent researchers,
providers, patients, and HIV/AIDS advocacy groups have assisted ARV discovery.
One initial step occurred in 1985: the American Foundation for AIDS research
(amfAR) was established as a result of a merger of the New York and Los Angeles
AIDS research foundations (http://www.amfar.org/).20 The organization operates
through public policy to advocate for enhanced funding for HIV/AIDS research
and increased access to care. Perhaps at the centerpiece of coordinated research
efforts for HIV therapeutics, the AIDS Clinical Trials Group (ACTG) was estab-
lished in 1987 to assist the emerging research efforts of the National Institute of
Allergy and Infectious Diseases (NIAID). The mission of the ACTG is to develop
and conduct scientifically rigorous, translational research and clinical trials both
ERRNVPHGLFRVRUJ
December 1994: FDA
Timeline of HIV in the United States approves first oral HIV
August 1990: Ryan White test
1981–1995
Care Act established to
provide federal funding
for community-based
January 1982: First care and treatment
HIV/AIDS clinic
established in
San Francisco October 1990: FDA
approves AZT for August 1994: CDC
pediatric use recommends AZT for
March 1987: FDA prevention of vertical
approves zidovudine transmission
September 1983: (AZT), the first August 1987: FDA

CDC identifies all antiretroviral drug, a sanctions testing of
nucleoside reverse May 1992: FDA approves
major routes of candidate vaccine
HIV transmission transcriptase first rapid test for HIV by
against HIV
inhibitor (NRTI) healthcare professionals
1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995
April 1987: FDA

approves Western January 1990: US Public December 1993: CDC
1985: FDA licenses blot test Health Service includes
revises AIDS definition to
the first ELISA AZT in consideration for
ERRNVPHGLFRVRUJ
antibody test occupational postexposure include CD4 count <200
September 1982:
The term “AIDS” for HIV prophylaxis
first used by the December 1995: FDA
CDC approves saquinavir
October 1991: FDA (SQV), first in a new
approves didanosine (ddI), novel class (protease
May 1987: FDA creates second antiretroviral drug inhibitors, PI) of
new class of drugs – antiretroviral drugs
Treatment Investigational leading to
New Drugs accelerating establishment of
approval highly active
FIGURE 3-2. Detailed timeline of landmark discoveries in the history of HIV treatment.
antiretroviral therapy
(HAART)
1987: First HIV
vaccine clinical trial
opened

Timeline of HIV in the United States

1996–2009
September 1998: FDA
approves efavirenz (EFV)
September 2006: CDC
releases revised HIV
December 1998: FDA
March 1996: FDA testing recommendations
approves abacavir (ABC) March 2003: FDA
approves to include routine
ritonavir (RTV), approves enfuvirtide
(T-20), first in a new screening of ages 13-64
second PI on
market class of
September
FIGURE 3-2. (continued)

antiretrovirals, the
1997: FDA
fusion inhibitors July 2006: FDA approves Atripla®, the
approves
1999-2000: Phase III first fixed dose combination to
May 1996: FDA Combivir®, the
vaccine trials initiated combine 2 different antiretroviral
approves first first 2003: Phase III trial to
in US (1999) and classes; also becomes a single tablet,
HIV home test combination
abroad (2000) evaluate novel HIV once daily therapy.
kit antiretroviral
vaccine strategy
initiated US-Thailand
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
June 1996: FDA September 2000: FDA March 2004: FDA

approves HIV 1997: HAART approves Kaletra® approves first oral January 2008: FDA
viral load test becomes (lopinavir/ritonavir), the approves etravirine, the
sample rapid HIV
standard of care PI combination with RTV
ERRNVPHGLFRVRUJ
diagnostic test first NNRTI to show
June 1996: FDA booster
activity against NNRTI-
approves
nevirapine resistant virus
April 1998: CDC
(NVP), the first issues first HIV
in a new class, treatment October 2001:
non-nucleoside August 2007: FDA approves
guidelines for FDA approves
reverse maraviroc (MVC), first in a new
adults and tenofovir (TDF), December 2004: FDA
transcriptase class of antiretrovirals, the CCR-5
adolescents first nucleotide approves generic
inhibitors receptor antagonists
analogue formulation of ddI, the
(NNRTI) first generic October 2007: FDA approves
antiretroviral approval raltegravir (RAL), first in a new
class of antiretrovirals, the
integrase inhibitors
Timeline of HIV in the United States
2010–Present
August 2014: FDA approves
new once daily FDC,
July 2010: Results of Triumeq® containing
the first pre-exposure abacavir/lamivudine/
prophylaxis study dolutegravir.
(iPrEx) demonstrate
effectiveness of 2012: First OTC HIV
Dec 2015: FDA approves new
FIGURE 3-2. (continued)

2010: Fourth generation HIV tenofovir/ antibody test is
emtricitabine in FDA-approved. tenofovir alafenamide
screening test approved,
prevention among fumarate (TAF) based once
allowing for earlier detection
HIV negative men August 2012: FDA daily FDC, Genvoya®

of HIV infection. who have sex with approves elvitegravir
men and transgender in combination as August 2013: FDA March 2016: Additional FDCs
women. Stribild® - a once approves the once-daily with TAF are FDA approved –
daily FDC. INSTI, dolutegravir.
Odefsey® and Descovy®.
2010 2011 2012 2013 2014 2015 2016
2013: Generic version of
ERRNVPHGLFRVRUJ
February 2010: FDA approves new Atripla® is FDA-approved. January 2015: FDA
2012: FDA
tablet formulation of ritonavir that approves new PI-based
approves combos with cobicistat
does not require refrigeration.
Truvada® for booster.
PrEP 2016: HIV/AIDS
guidelines made
August 2011: FDA approves available as app.
rilpivirine, a second generation 2014-15: FDA updates
NNRTI, and Complera®, once daily blood donor policy for
MSM alleviating
FDC.
previous restrictions.
domestically and abroad. The ACTG represents the largest collective of AIDS inves-
tigators and clinicians and has had a marked impact on ARV therapeutics and
treatment strategies in HIV-infected individuals. The ACTG remains funded by the
Department of Health and Human Services, National Institutes of Health, through
the NIAID (www. actgnetwork.org/about-actg).21
Entering the third decade of HAART, the goals of ART remain virtually
unchanged: achieve viral suppression and boost immune function while maxi-
mizing quality of life and minimizing drug-related toxicity. Current therapy has
accomplished an unprecedented increase in life expectancy, nearing that of a
non-HIV infected patient.22 As of 2015, approximately 15.4 million HIV-infected
persons were managed on ART.23 FDCs allow for ease of administration, and
newer regimens have significantly fewer adverse effects compared to earlier ARTs.
However, the future of HIV-1 drug development will have both challenges and
opportunities, including management of emerging ARV resistance, ARV-related
prevention strategies, novel formulations of ARVs (e.g., long-acting depot injec-
tions), and managing long-term ARV-associated toxicities.24,25
ANTIRETROVIRAL AGENTS
Overview
Due to the complexity of ARVs with their numerous formulations, adverse reac-
tions, drug–drug interactions, and drug–food interactions, the pharmacist remains
critical in the management of HIV infection. This section details important ARV
characteristics and considerations for monitoring therapy. For recommendations
on selecting initial treatment or managing ARV resistance, please refer to Chapter
4, “Initiating HIV Treatment and Supporting Adherence” or Chapter 5, “HIV Treat-
ment Failure and Resistance,” respectively.
Appendix 3-A summarizes available antiretroviral formulations and dosing
recommendations, including renal and hepatic adjustments. All of the NRTIs
require renal adjustments, with the exception of abacavir. This can be problem-
atic because all six single-tablet regimens contain lamivudine or emtricitabine,
which warrant dose adjustments in the setting of renal dysfunction.14 Combina-
tion products should be divided into individual dose-adjusted components upon
initiation of therapy in a patient with chronic renal insufficiency or acute kidney
injury. There are no renal adjustments recommended for any of the NNRTIs, PIs,
or INSTIs. Hepatic adjustments, however, should be evaluated for each antiretro-
viral and are available in Appendix 3-A.
Adverse Effects
Advances in the treatment of HIV have led to the development of newer antiret-
roviral therapies with more favorable side effects compared to older agents. Table
3-2 outlines the most notable adverse effects associated with each antiretroviral.
Antiretroviral-associated adverse effects are frequent reasons documented for
ERRNVPHGLFRVRUJ
nonadherence to therapy and must be considered upon initiating, modifying, or

monitoring ART.26
Chronic use of NRTIs can cause the depletion of mitochondrial DNA, resulting
in mitochondrial toxicity such as lactic acidosis, pancreatitis, myopathy, periph-
eral neuropathy, and hepatic steatosis.27 However, the risk of these adverse effects
is lower with newer NRTIs (tenofovir, abacavir, lamivudine, and emtricitabine)
compared to stavudine, zidovudine, and didanosine. Abacavir can cause a severe,
potentially life-threatening hypersensitivity reaction within the first 6 weeks of
initiation of therapy, affecting 5% to 8% of patients. Symptoms are nonspecific
TABLE 3-2. Antiretroviral Adverse Effects

Class Antiretroviral Notable Adverse Effects
NRTI Abacavir Hypersensitivity reaction, nausea, headache
Didanosine Pancreatitis, peripheral neuropathy, gastrointestinal (nausea,

diarrhea, vomiting), headache, optic neuritis
Emtricitabine Generally well tolerated, skin hyperpigmentation of palms/

soles
Lamivudine Generally well tolerated
Stavudine Fatal lactic acidosis, lipodystrophy, peripheral neuropathy,

pancreatitis, diabetes mellitus, hyperlipidemia, rapid
neuromuscular weakness
Tenofovir Nausea, less renal and bone toxicity than TDF, increases lipids
Alafenamide more than TDF
Fumarate
Tenofovir Disoproxil Nephrotoxicity (Faconi-like syndrome), asthenia,

Fumarate osteomalacia
Zidovudine Macrocytic anemia, neutropenia, nausea, vomiting, asthenia,

myopathy, hyperpigmentation of nail beds/mucosa,
lipodystrophy, lactic acidosis
NNRTI Efavirenz Rash, dizziness, headache, suicidal ideation, insomnia, vivid

dreams, inability to concentrate, hypertriglyceridemia,
teratogenicity
Etravirine Rash, nausea
Nevirapine Rash, hepatotoxicity, elevated transaminases, fever
Rilpivirine Rash, depression, added QTc prolongation

(continued)
ERRNVPHGLFRVRUJ
TABLE 3-2. Antiretroviral Adverse Effects (continued)

Class Antiretroviral Notable Adverse Effects
PI Atazanavir Indirect hyperbilirubinemia, rash, prolonged PR interval,
nephrolithiasis
Darunavir Diarrhea, nausea, vomiting, rash, headache
Fosamprenavir Rash, gastrointestinal, oral paresthesias, dyslipidemia, fat

maldistribution
Indinavir Nephrolithiasis, urolithiasis, asymptomatic

hyperbilirubinemia, musculoskeletal pain, hemolytic
anemia
Lopinavir/Ritonavir Severe nausea/vomiting/diarrhea (higher with QD dosing),

asthenia, hyperlipidemia, elevated transaminases
Nelfinavir Diarrhea, flatulence, nausea, rash, elevated transaminases;

Phenylketonuria – 1 gm powder contains 11.2 mg
phenylalanine
Saquinavir Hepatotoxicity, elevated transaminases, GI intolerance
Tipranavir Rash, elevated transaminases, diarrhea
INSTI Dolutegravir Insomnia
Elvitegravir Diarrhea, nausea
Raltegravir Nausea, headache, increased creatinine kinase, myopathy,

rhabdomyolysis
FI Enfuvirtide Injection site reactions
CRA Maraviroc Hepatotoxicity, upper respiratory infection, dizziness,

musculoskeletal
PK Enhancers Cobicistat Nausea, diarrhea, jaundice, rash (reported when combined

with atazanavir)
Ritonavir Nausea, vomiting, diarrhea, abdominal pain, paresthesia

(including oral), fatigue
CRA: CCR5 receptor antagonist; FI: fusion inhibitor; INSTI: integrase strand transfer inhibitors; NNRTI: nonnucleoside
reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; PI: protease inhibitor;
PK: pharmacokinetic
ERRNVPHGLFRVRUJ
and include fever, rash, gastrointestinal tract symptoms, malaise, and shortness of
breath. Because abacavir hypersensitivity is strongly associated with the presence
of the HLA-B*5701 allele, screening for HLA-B*5701 should be performed prior
to initiating abacavir.19,28 Tenofovir alafenamide fumurate (TAF)-containing prod-
ucts are now available as first-line ART due to improved renal and bone effects
compared to tenofovir disoproxil fumarate (TDF) after 48 weeks of therapy.29
Rash and hepatotoxicity are classwide reactions associated with NNRTIs. Rash
is usually mild and self-limiting with continued therapy. However, if a severe rash
occurs due to any NNRTI, switching to another ARV class is recommended.19 The
incidence of rash is less common with rilpivirine (3% at least Grade 2) than nevi-
rapine (35% any Grade), efavirenz (26% any Grade), and etravirine (10% at least
Grade 2).14 Severe hepatotoxicity has been reported with all NNRTIs, but incidence is
highest with nevirapine.14,19 The risk of nevirapine-induced hepatotoxicity is greater
during the first few months of treatment initiation, greater for women than men,
and greater for women with CD4 counts >250 cells/mm3 or men with CD4 counts
>400 cells/mm3 prior to starting nevirapine.19 Efavirenz may cause neuropsychiatric
side effects including dizziness, suicidal ideation, vivid dreams, and depression.14
The true impact of efavirenz on increased rate of suicidality remains unclear due to
conflicting data.30-32 Consequently, higher treatment discontinuation due to adverse
effects has been noted in patients receiving efavirenz compared to raltegravir-based
therapy.33 Due to the availability of newer ARVs with improved tolerability, efavirenz
is now considered an alternative regimen for ARV-naïve patients.19 Efavirenz-based
regimens should be avoided in patients with a neuropsychiatric history due to the
potential to cause central nervous system (CNS) side effects. In addition, efavirenz
has been associated with a potential fetal safety risk of teratogenicity during the
first trimester.19 There are conflicting data among animal and human models, but
the most recent evidence suggests the risk of neural tube defects is low. However,
due to the teratogenicity potential, efavirenz should be used cautiously in woman
of child-bearing age and avoided during the first 8 weeks of pregnancy.
INSTIs are generally well tolerated with minimal metabolic adverse effects.
Because of improved tolerability compared to other antiretroviral therapy, INSTIs
are considered preferred therapy for initial management of HIV infection.19 Side
effects of this class are usually mild but may include nausea, diarrhea, and insomnia.
Common adverse effects associated with PIs include gastrointestinal intoler-
ances and metabolic complications such as dyslipidemia, lipodystrophy, insulin
resistance, and accelerated cardiovascular disease.19 The available PIs differ in their
ability to cause metabolic disease. However, older protease inhibitors (indinavir,
lopinavir/ritonavir, nelfinavir, saquinavir, tipranavir) have fallen out of favor due
to higher rates of metabolic toxicity and gastrointestinal side effects compared to
newer agents (darunavir, atazanavir). Ritonavir-boosted darunavir is the preferred
PI for treatment-naïve patients with HIV infection due to once-daily dosing and
fewer adverse reactions compared to other PIs. Ritonavir-boosted darunavir is
preferred over ritonavir-boosted atazanavir due to improved tolerability with
darunavir compared to atazanavir.34 Clinicians should use caution when initiating
darunavir, fosamprenavir, or tipranavir in patients with a history of sulfa allergy
ERRNVPHGLFRVRUJ
due to the potential for cross-sensitivity with these agents.14 In patients initiating
darunavir with a history of trimethoprim–sulfamethoxazole allergy, the rate of
darunavir allergy is relatively low at 5.1%.35
Other ARVs with notable adverse effects include enfuvirtide and maraviroc.
Enfuvirtide is a subcutaneous injection available for treatment of HIV and most
commonly causes local injection site reactions in up to 96% of patients.14 In patients
receiving maraviroc, hepatotoxicity has been reported (black box warning), which
requires close monitoring of liver function tests in patients receiving maraviroc.14
Drug–Drug Interactions
Clinically significant pharmacokinetic drug interactions between ART and other
drugs are common and may occur during the oral absorption, metabolism, or
elimination of an antiretroviral. Possible mechanisms of these interactions are
P-glycoprotein (Pgp), shared transport proteins (e.g., organic cation protein 2,
OCT2) or cytochrome (CYP) P450 enzymes.14,36
Acid-Suppressing Therapy Interactions

The administration of concomitant acid-suppressing therapy may affect
oral absorption of several ARVs. Acid suppression significantly decreases
the bioavailability of the following agents: atazanavir, rilpivirine, fosam-
prenavir, tipranavir, and nelfinavir.14 Table 3-3 includes recommendations
for managing the clinically significant interactions between ARVs and acid-
suppressing therapy. Clinically significant decreases in INSTI concentrations
are observed with products containing cation antacids or oral supplements
containing calcium or iron. Refer to Table 3-3 for recommendations on the co-
administration of INSTIs and antacids.
Hepatic Enzyme Effects of Antiretrovirals

ARVs can be substrates, inhibitors, inducers, and mixed inducers/inhibitors on
CYP P450 isoenzymes or uridine diphosphate glucuronosyltransferase (UGT).
Table 3-4 includes drug–drug interactions that may occur through the hepatic
enzyme effects of antiretrovirals.36 Major interactions with NRTIs and enfuvirtide
are uncommon due to minimal hepatic metabolism. However, NNRTIs, PIs, and
maraviroc are substrates, inhibitors, and inducers of various cytochrome P450 and
UGT enzymes, which can result in numerous clinically relevant drug interactions
with drugs that are metabolized through these pathways.
Pharmacokinetic Enhancers
PIs and the INSTI elvitegravir are deliberately boosted with the pharmacokinetic
(PK) enhancers, ritonavir or cobicistat, to increase ARV plasma concentrations,
prolong half-life, and reduce frequency of dosing.14,19,37,38 Increased serum concen-
tration of PIs or elvitegravir is achieved through increased absorption through
inhibition of intestinal CYP3A4 and Pgp, as well as potent inhibition of CYP3A4
in the liver. Subsequently, these PK enhancers may impact the concentrations
ERRNVPHGLFRVRUJ
TABLE 3-3. Interactions Between Antiretrovirals and Acid-Suppressing Agents

Antiretroviral Interacting Agent Effect on Antiretroviral Recommendation
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Rilpivirine (RPV) Antacids ↓ RPV expected when Give RPV ≥4 hours prior or
given at same time 2 hours after antacid
H2 Antagonists ↓ RPV Give RPV ≥4 hours prior or

12 hours after H2 antagonist
Proton Pump RPV AUC ↓ 40%, Contraindicated

Inhibitors Cmin ↓ 33%

Atazanavir Antacids ↓ ATV expected when Give ATV ≥2 hours prior or
(ATV) given at same time 1 hour after antacid
H2 Antagonists ATV, ATV/r or ATV/c: Unboosted ATV: Give ATV

↓ ATV ≥2 hours prior or 10 hours
after H2 antagonista
Boosted ATV: Give ATV/r or
ATV/c simultaneously with
and or ≥10 hours after H2
antagonistb,c
Proton Pump ↓ ATV Unboosted ATV: Not

Inhibitors recommended
Boosted ATV: PPIs not
recommended in
PI-experienced patients;
max daily dose equivalent
to omeprazole 20 mg; give
ATV/r or ATV/c at least
12 hours after PPI
Fosamprenavir Antacids APV AUC ↓ 18%; Give FPV simultaneously with

(FPV) ↔ APV Cmin or ≥2 hours prior or 1 hour
after antacids
H2 Antagonists Unboosted FPV: APV If concomitant use is

AUC ↓ 30% necessary, give FPV ≥2 hours
before H2 antagonist
Proton Pump ↔ APV No dose adjustment necessary

Inhibitors
Nelfinavir Proton Pump NFV Cmin ↓ 39% Avoid PPIs

(NFV) Inhibitors
Tipranavir Antacids TPV AUC ↓ 27% Give TPV ≥2 hours prior or

(TPV) 1 hour after antacid
(continued)
ERRNVPHGLFRVRUJ
TABLE 3-3. Interactions Between Antiretrovirals and Acid-Suppressing Agents

(continued)
Antiretroviral Interacting Agent Effect on Antiretroviral Recommendation
Dolutegravir (DTG) Antacids DTG AUC ↓ 74% (at Give DTG ≥2 hours prior or
same time); DTG 6 hours after antacid
AUC ↓ 26% (given
2 hours before
antacid)
Proton Pump ↔ DTG No dose adjustment necessary

Inhibitors
Elvitegravir (EVG) Antacids EVG AUC ↓ 40-50% Give EVG ≥2 hours prior or
(at same time); 2 hours after antacid
EVG AUC ↓ 15-20%
(given 2 hours before
or after)
Proton Pump EVG + PI/r: ↔ EVG No dose adjustment necessary

Inhibitors EVG/c: ↔ EVG
Raltegravir Antacids Al-Mg Hydroxide Do not co-administer with

(RAL) Antacid: RAL Cmin Al-Mg hydroxide antacids;
↓ 54% to 63% no dosing separation
CaCO3 Antacid: RAL necessary with RAL and
Cmin ↓ 32% CaCO3 antacids
Proton Pump RAL AUC ↑ 37% and No dose adjustment necessary

Inhibitors Cmin ↑ 24%
a
Single dose of H2 antagonist should not exceed a dose equivalent to famotidine 20 mg or totally daily dose
equivalent to famotidine 20 mg twice daily in ART-naïve patients.
b
Single dose of H2 antagonist should not exceed a total daily dose equivalent to famotidine 40 mg twice daily in
ART-naïve patients or totally daily dose equivalent to famotidine 20 mg twice daily in ART-experienced patients.
In ART-experienced patients taking both TDF and H2 receptor antagonist, use ATV 400 mg + COBI 150 mg or RTV 100
c
mg.
Al: aluminum; ART: antiretroviral therapy; ATV/c: atazanavir/cobicistat; ATV/r: atazanavir/ritonavir; APV: amprenavir;
AUC: area under the curve; CaCO3: calcium carbonate; Cmin: minimum plasma concentration; EVG/c: elvitegravir/
cobicistat; PI/r: protease inhibitor/ritonavir
ERRNVPHGLFRVRUJ
TABLE 3-4. Antiretroviral Enzyme Effects

Predicted Enzyme Effect
Class Antiretroviral 3A4 2B6 2C9 2C19 2D6 1A2 UGT
NRTIs Abacavir - - - - - -
Didanosine - - - - - - -
Emtricitabine - - - - - - -
Lamivudine - - - - - - -
Stavudine - - - - - - -
Tenofovir - - - - - - -
Zidovudine - - - - - - -
NNRTIs Efavirenz - -
Etravirine - - - -
Nevirapine - - -
Rilpivirine - - - - - - -
PIs Atazanavir - -a -
Darunavir/r -a
Fosamprenavirc
- - -a - - -
Indinavir - - - -a -
Lopinavir/r -a
Nelfinavirc - -
Saquinavir - -a - - - -
Tipranavir/r
INSTIs Raltegravir - - - - - -
Elvitegravir - - - -
Dolutegravir - - - - -
CRA Maraviroc - - - - - -
(continued)
ERRNVPHGLFRVRUJ
TABLE 3-4. Antiretroviral Enzyme Effects (continued)

Predicted Enzyme Effect
Class Antiretroviral 3A4 2B6 2C9 2C19 2D6 1A2 UGT
FI Enfuvirtide - - - - - - -
PEs Cobicistat - - - - -
Ritonavir b
The predicted metabolic effects of antiretroviral agents on various cytochrome (CYP) P450 isoenzymes and uridine
diphosphate glucuronosyltransferase (UGT) are illustrated according to the following: inhibition, induction,
substrate, [-] no significant effect or not determined. The use of low-dose ritonavir for pharmacokinetic boosting is
denoted by lowercase “/r” following individual antiretrovirals.
a
Enzyme not affected at clinically relevant antiretroviral concentrations.
b
Autoinduction of CYP3A4 by ritonavir is observed during the first 2 weeks of therapy, but CYP3A4 inhibition is most
commonly evident with chronic therapy.
c
Fosamprenavir and nelfinavir exhibit mixed induction/inhibition for 3A4.
CRA: CCR5 receptor antagonist; FI: fusion inhibitor; INSTIs: integrase strand transfer inhibitors; NRTIs: nucleoside
reverse transcriptase inhibitors; NNRTIs: non-nucleoside reverse transcriptase inhibitors; PEs: pharmacokinetic
enhancers; PIs: protease inhibitors
(Modified and updated with permission from Rathbun RC, Liedtke MD. Antiretroviral drug interactions: Overview of
interactions involving new and investigational agents and the role of therapeutic drug monitoring for management.
Pharmaceutics. 2011;3:745-781.)
of other ARVs or medications used for non-HIV disease states, leading to clini-
cally significant drug interactions. Ritonavir and cobicistat can alter the concen-
trations of drugs metabolized through CYP3A4 and CYP2D6, as well as inhibit
the intestinal efflux transporter Pgp.36 However, ritonavir can impact a variety of
other enzymes that cobicistat has no significant effect on, including induction
of CYP2B6, CYP2C9, CYP2C19, CYP1A2, and UGT. Cobicistat also inhibits the
tubular secretion of creatinine primarily through inhibition of the renal cation
transporter, MATE1, without impacting true renal glomerular function.14 Small
increases in serum creatinine (~0.14 mg/dL) have been observed within the first
2 weeks of cobicistat initiation and remain stable at 48 weeks.33,39,40 Changes in
serum creatinine are reversible upon discontinuation of cobicistat.39 This interac-
tion is unique to cobicistat and has not been reported with ritonavir.
Intranasal or Inhaled Corticosteroids and PK Enhancer Interactions

The drug–drug interaction between PK enhancers and intranasal or inhaled corti-
costeroids (ICS) best describes the potency and clinical significance of the boosting
abilities of PK enhancers. The serum concentration of fluticasone is increased
350-fold when administered with ritonavir 100 mg orally twice daily.14 Numerous
cases of adrenal insufficiency, including Cushing syndrome, have been reported due
to this interaction.41 National guidelines recommend against the use of ritonavir
or cobicistat with any of the following inhaled or intranasal corticosteroids: flut-
icasone, budesonide, or mometasone. Inhaled beclomethasone when given with
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boosted darunavir results in inconsequential increases (~2-fold) in beclometha-

sone exposure; therefore, beclomethasone is the preferred inhaled or intranasal
corticosteroids in patients with boosted ART.42 Unfortunately, beclomethasone is
not commercially available in a combination product with a long-acting beta-
agonist (LABA) such as fluticasone (fluticasone/salmeterol, Advair®) or budesonide
(budesonide/formoterol, Symbicort®). Therefore, patients taking a combination
ICS and LABA product for asthma or chronic obstructive pulmonary disease and
requiring replacement with beclomethasone due to PK enhancer drug interaction
would require two separate inhalers (e.g., beclomethasone plus LABA).
Statin and PK Enhancer Interactions

Because of the metabolic complications associated with HIV and ARVs, statin and
PK enhancer interactions are frequently encountered in clinical practice. Simvas-
tatin and lovastatin cause significant increases in statin concentrations when given
with a PK enhancer and are considered contraindicated as a result of the potency
of the interaction (simvastatin area under the curve [AUC] increases 3,059% when
given with ritonavir-boosted saquinavir).14,19 The statins with the least potential for
drug–drug interactions include fluvastatin, pitavastatin, and pravastatin. However,
pravastatin AUC increases 81% following a single dose of pravastatin when co-
administered with darunavir.14 The recommendation is to use the lowest pravastatin
starting dose with careful monitoring. Atorvastatin and rosuvastatin should also be
used cautiously due to increased statin concentrations when co-administered with
PK enhancers. The maximum recommended daily dose of atorvastatin is 20 mg
when given with DRV/r (20 mg of atorvastatin similar to 80 mg with booster).14
Ritonavir-boosted atazanavir increases rosuvastatin AUC three-fold and should not
exceed a rosuvastatin daily dose of 10 mg.14 There are countless interactions occur-
ring with the PK enhancers; therefore, critical evaluation of drug interactions in all
patients receiving regimens containing ritonavir or cobicistat is necessary.
Tenofovir Disoproxil vs Tenofovir Alafenamide

Although tenofovir disoproxil and tenofovir alafenamide are both tenofovir
prodrugs and Pgp substrates, there are notable differences in drug–drug inter-
actions. Drugs that induce Pgp activity, such as rifampin and phenytoin, are
expected to decrease the absorption of TAF, resulting in decreased serum concen-
trations. Consequently, Pgp inducers should not be given concomitantly with
tenofovir alafenamide.14 In contrast, tenofovir disoproxil does not have any signif-
icant interactions reported with Pgp inducers.14 Tenofovir disoproxil and rifampin
co-administration leads to minimal changes in tenofovir serum concentrations
and can be co-administered without dose adjustments for patients who are being
treated concurrently for HIV and tuberculosis.14,19,43
Tenofovir disoproxil is commonly co-administered with ritonavir or cobicistat,
inhibitors of Pgp. Significant increases in tenofovir AUC of 22% with darunavir/
ritonavir [DRV/r] and 37% with atazanavir/ritonavir [ATV/r] have been reported.14
When tenofovir disoproxil and a PK enhancer are given with the additional Pgp
inhibitor, ledipasvir, the additive increase in tenofovir plasma concentrations may
increase tenofovir-related adverse effects. Therefore, concomitant therapy with a PK
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booster, tenofovir disoproxil, and ledipasvir is not recommended because of lack of

safety data regarding the significance of augmented tenofovir disoproxil exposure.19
INSTIs Interactions
Raltegravir and dolutegravir have fewer drug interactions compared to other
ARVs. Raltegravir has no effect on the cytochrome P450 pathway but is elimi-
nated by glucuronidation via UGT1A1 and dose adjustments may be warranted
with drugs that induce this enzyme (e.g., rifampin). Dolutegravir inhibits the
renal OCT2, which decreases urine creatinine elimination and causes a 0.1 to
0.2 mg/dL increase in serum creatinine.14,44 This elevation in serum creatinine is
not thought to impact actual renal glomerular function. In addition, dolutegravir
may increase serum concentrations of drugs eliminated via OCT2. For example,
metformin is a substrate of OCT2 and significant increases in metformin plasma
exposure have been reported with concurrent dolutegravir therapy.45 The total
daily dose of metformin when co-administered with dolutegravir should not
exceed 1,000 mg.14 Dofetilide, another OCT2 substrate, is contraindicated with
dolutegravir due to the potential for life-threatening arrhythmia. Elvitegravir
requires co-administration with cobicistat, a pharmacokinetic enhancer. Because
it is a substrate of CYP3A4 and requires boosting with cobicistat, there is the
potential for many drug interactions, as outlined previously.
Maraviroc Interactions
The CCR5 inhibitor maraviroc is a substrate of CYP3A and Pgp and susceptible to
interactions with inhibitors and inducers of these enzymes.14 Clinicians should be
cautious when assessing the dose of maraviroc because it may need to be adjusted
based on various pharmacokinetic interactions. The dose of maraviroc is 300 mg
twice daily when given without agents that inhibit or induce CYP3A (e.g., NRTIs,
tipranavir/ritonavir, nevirapine). When maraviroc is co-administered with potent
CYP3A inhibitors (e.g., atazanavir, darunavir), the recommended dose of mara-
viroc is reduced to 150 mg twice daily. Conversely, when maraviroc is co-admin-
istered with CYP3A inducers (e.g., efavirenz), the recommended dose of mara-
viroc is increased to 600 mg twice daily. When patients are receiving both CYP3A4
inducers and inhibitors, the net effect is inhibition of CYP3A4 (although reduced
compared to when given with only a CYP3A4 inhibitor), which results in overall
higher maraviroc exposure.46 Maraviroc is not expected to impact the plasma
concentrations of drugs metabolized through the CYP P450 enzymes.
Necessity for Updated Interaction Assessments

As newer therapies continue to emerge for the treatment of HIV, the complexity of
ARV interactions is becoming increasingly common and pharmacists play a crucial
role in the detection and management of these interactions. It is imperative that
medication regimens are assessed routinely, especially upon initiating ART and
with the addition of any new prescription or over-the-counter medication or
supplement. Numerous interactions exist among ARVs and over-the-counter medi-
cations (e.g., omeprazole) and supplements (e.g., multivitamins). Medication lists
ERRNVPHGLFRVRUJ
must be comprehensive and consistently updated to minimize drug interactions

and ensure optimal transition between inpatient and outpatient healthcare settings.
Administration
The administration of ARVs in regard to food is essential for optimizing the effi-
cacy and minimizing adverse reactions of many regimens. Table 3-5 includes the
impact of food on the pharmacokinetics of each antiretroviral.14 Food enhances
the absorption of the NNRTIs etravirine and rilpivirine, the PIs atazanavir and
TABLE 3-5. Drug-Food Interactions

Food Effect on Antiretroviral
Class Antiretroviral Concentration Administration
NRTI Abacavir No significant effect Take with or without food
Didanosine ddI Cmax ↓ 55% Take on empty stomach
Emtricitabine No significant effect Take with or without food
Lamivudine No significant effect Take with or without food
Stavudine No significant effect Take with or without food
Tenofovir High fat meal ↑ TAF Take with or without food

Alafenamide bioavailability
Fumarate
Tenofovir Disoproxil High fat meal ↑ TDF Take with or without food
Fumarate bioavailability
Zidovudine No significant effect Take with or without food
NNRTI Efavirenz EFV AUC ↑ 28% and EFV Take on empty stomach
Cmax ↑ 79% with high fat
meal compared to fasting
Etravirine ETR AUC ↓ 50% when fasting Must take with food
compared to meal
Nevirapine No significant effect Take with or without food
Rilpivirine RPV AUC ↓ 40% when fasting Must take with food
compared to meal
INSTI Dolutegravir ↑ the extent and ↓ the rate of Take with or without food
DTG absorption
Elvitegravir ↑ EVG bioavailability Must take with food
Raltegravir No significant effect Take with or without food

(continued)
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TABLE 3-5. Drug-Food Interactions (continued)

Food Effect on Antiretroviral
Class Antiretroviral Concentration Administration
PI Atazanavir ATV AUC ↑ 70% and ATV Must take with food
Cmax ↑ 50% when taken with
food compared to fasting
Darunavir DRV AUC ↑ 40% with food Must take with food
compared to fasting
Fosamprenavir Tablet: No significant effect Tablets: Take with or
Suspension: High-fat meal without food
↓ Cmax by 46% Suspension: Adults: Take
on empty stomach;
Pediatrics: Take with
food
Indinavir IDV AUC ↓ 77% with meal Take on empty stomach
compared to fasting
Lopinavir/ritonavir Tablet: no significant effect Tablets: Take with or
Solution: LPV AUC ↑ 80% and without food
LPV Cmax ↑ 54% with meal Solution: Must take with
compared to fasting food
Nelfinavir NFV AUC and Cmax 2- to Must take with food
3-fold higher with meal
than compared to fasting
Saquinavir ↑ SQV bioavailability Must take with food
Tipranavir When coadministered with When coadministered
RTV: No significant effect with ritonavir: Take
When coadministered with RTV with or without food
tablets: ↑ TPV bioavailability When coadministered
with ritonavir tablets:
Take with food
FI Enfuvirtide N/A N/A
CCR5 Maraviroc MVC AUC ↓ 33% with a Take with or without food
Antagonist high fat breakfast; No food
restrictions in the studies
that demonstrate efficacy
and safety
ATV: atazanavir; AUC: area under the curve; Cmax: maximum plasma concentration; Cmin: minimum plasma
concentration; CRA: CCR5 receptor antagonist; ddI: didanosine; DRV: darunavir; DTG: dolutegravir; EFV: efavirenz;
ETR: etravirine; EVG: elvitegravir; FI: fusion inhibitor; INSTIs: integrase strand transfer inhibitors; INV: indinavir;
LPV: lopinavir; NFV: nelfinavir; NNRTIs: non-nucleoside reverse transcriptase inhibitors; NRTIs: nucleoside reverse
transcriptase inhibitors; PI: protease inhibitors; PK: pharmacokinetic; RPV: rilpivirine; RTV: ritonavir; SQV: saquinavir;
TAF: tenofovir alfenamide fumarate; TDF: tenofovir disoproxil fumarate; TPV: tipranavir
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darunavir, and the INSTI elvitegravir. These agents should be taken with food
when possible. For example, rilpivirine exposure is reduced by approximately 40%
when taken in the fasted state compared to a normal caloric (533 kcal) or high-fat,
high-caloric meal (928 kcal).14 To maintain ARV efficacy, it is imperative that
rilpivirine is taken with either a low-fat or moderate-fat meal.47 On the contrary,
when efavirenz is co-administered with a high-fat meal compared to the fasted
state, efavirenz AUC and Cmax increase by 28% and 79%, respectively.14 Because an
increase in efavirenz exposure may increase neuropsychiatric side effects, efavirenz
should be taken on an empty stomach, preferably at or before bedtime.
Patients unable to take oral medications due to a medical procedure, swal-
lowing conditions, or gastrointestinal diseases may require administration of
liquid or crushed ARVs. For up-to-date information regarding the crushing of
ARVs, please refer to the guide titled “Oral Antiretroviral Administration: Infor-
mation on Crushing and Liquid Drug Formulations” created by the Immunode-
ficiency Clinic at Toronto General Hospital.48 Unfortunately, there are minimal
data evaluating the stability and bioavailability of crushing ARVs and only a few
have commercially available liquid formulations. Many of the film-coated antiret-
roviral tablets are not sustained release but are water soluble, such as Truvada®
(tenofovir/emtricitabine), darunavir, raltegravir, and dolutegravir. Theoretically,
these agents can be crushed without causing significant impact of the pharma-
cokinetics of the drug. However, it is imperative that the entire tablet be ingested
immediately following crushing. Combination products should be divided into
individual components and the liquid formulations should be used when possible.
For example, Atripla® contains efavirenz, tenofovir, and emtricitabine. This combi-
nation cannot be crushed but could be separated into Truvada® (tenofovir/emtric-
itabine) and efavirenz capsules.48 Truvada® (tenofovir/emtricitabine) tablets can be
crushed and dissolved in water, and efavirenz capsules can be opened and admin-
istered in small amounts of food. Consider consultation with a HIV specialist if an
ARV regimen cannot be given crushed or with available liquid formulations.
Enfuvirtide is the only available subcutaneous injection for the treatment of
HIV, but usage has decreased due to the inconvenient route of administration
and twice daily dosing.49 However, enfuvirtide may be a useful salvage therapy in
patients with multidrug-resistant HIV. In patients starting enfuvirtide, the phar-
macist plays an integral role in educating patients on enfuvirtide preparation
and administration. An enfuvirtide vial contains 108 mg of powder that must be
reconstituted with sterile water for injection.14 The patient should be instructed
that it could take up to 45 minutes for the drug to dissolve, and it is important not
to shake the vial because it will cause the drug to foam and take much longer to
dissolve. Enfuvirtide should be injected twice daily at a 45° angle under the skin
in a different location, with each injection at any of the following sites: abdomen,
upper thighs, or upper arms. The patient can mix both daily doses at the same
time and keep the second vial in the refrigerator (up to 24 hours) until the next
dose is due. For more detailed information on patient counseling, please refer to
the enfuvirtide injection instructions provided by the manufacturer.14
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Adherence
ARV adherence has long been directly linked to positive clinical outcomes
in HIV-infected patients.50 Adherence rates vary significantly in HIV-infected
patients. For example, among those receiving post-exposure prophylaxis, adher-
ence rates are often 40% to 60%, despite the risk of acquisition. Measuring adher-
ence can also prove difficult. Direct methods such as directly observed therapy
(DOT) or measurement of drug exposure through therapeutic drug monitoring
are often not feasible. Indirect methods such as pill counts, prescription refills,
medication monitors, and questionnaires are often relied on in both studies and
clinical inquiries.51 Patterson et al. defined adherence in the era of early-market PIs
as a minimum of 95% to achieve optimal viral suppression and reduce the risk of
hospitalization, opportunistic infections, and death.50
With the advent of more potent regimens, including ritonavir- or cobici-
stat-boosted PIs and INSTIs, there is some debate on the optimal threshold for
defining adherence. Some studies have demonstrated that adherence rates of approx-
imately 70% to 80% in PI-based and INSTI-based regimens result in viral suppres-
sion.52,53 In the Pre-exposure Prophylaxis Initiative (iPrEx) study investigating teno-
fovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis, the
study drug reduced HIV infection rates by 44%. Examining results based on adher-
ence, efficacy among those who reported 90% adherence was 73%, and investigators
suggested that optimal adherence would have resulted in efficacy of approximately
92%.54 Although there is no conclusive definition of optimal adherence rates, the
risk of virologic failure from drug resistance secondary to nonadherence leads
most providers to set the threshold for adherence at 95% or greater.
Many barriers have been consistently identified that impact adherence in
HIV-infected patients (Table 3-6). Unfortunately, clinicians are not adept at iden-
tifying or predicting nonadherence.51,52,55 Urquhart and colleagues have suggested
TABLE 3-6. Common Barriers to Antiretroviral Adherence

• Age (younger [<25], older [>65])
• Time since initiation of therapy
• Non-white population
• Underlying psychiatric illness
• IVDU/illicit drug use
• Smoking
• Pill burden
• Frequency of administration
• Increased drug-associated adverse events
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the “1/6th rule” for adherence among patients (Table 3-7).55 Given this model of
thinking, identifying adherence is essential in HIV-infected patients using markers
for nonadherence, such as missed appointments, lack of ARV response (e.g., viral
suppression), and missed refills. Additionally, assessing barriers with a predefined
tool may be of value upon entry into treatment, knowing that many risk factors
are dynamic and should prompt clinicians to continuously re-evaluate. Modifiable
risk factors such as concurrent smoking, complicated regimens, intravenous drug
use, and others should be addressed consistently; however, failure to alter one of
these risk factors should not prevent initiation of ART. Improving adherence can
be grouped into four general categories: (1) patient education; (2) improved dosing
schedules; (3) increased access to healthcare providers; and (4) improved provider–
patient communication.51 Each of these interventions has shown varied success in
the HIV-infected population. The advent of once-daily FDCs has greatly improved
adherence compared to higher pill burdens and multiday administration. It is
unclear, however, if once-daily ARV regimens given as a single tablet versus multi-
tablets results in improved adherence.53,56 Another important aspect of adherence is
the avoidance of iatrogenic nonadherence, which may occur through medication
errors in the healthcare system or unidentified drug–drug interactions.57
Typically, a multifactorial, interdisciplinary approach is required. Pharma-
cists with a practice expertise or training in HIV have been shown to improve
ARV adherence that translates into clinical and laboratory outcomes, including
reduced hospitalization and improved viral suppression.52,58,59 Engaging commu-
nity pharmacists to assist in improving ARV adherence is essential but is currently
underutilized.60 The advent of novel dosing strategies, including long-acting
parenteral agents under investigation, may provide additional avenues to combat
nonadherence.
TABLE 3-7. Rule of “One-Sixth”

• One-sixth of patients approach perfect adherence
• One-sixth take nearly all doses, but with timing irregularity
• One-sixth miss an occasional single day’s dose and have some timing inconsistency
• One-sixth take drug holidays three to four times a year
• One-sixth have a drug holiday monthly or more often
• One-sixth take few or no doses while giving the impression of good adherence
(Source: Reprinted with permission of Urquhart J. The odds of the three nons when an aptly prescribed medicine isn’t
working: Non-compliance, non-absorption, non-response. British Journal of Clinical Pharmacology. 2002;54(2):212-
220. ©2002, John Wiley & Sons.)
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FUTURE OF DRUG DEVELOPMENT AND HIV THERAPEUTICS

Novel Strategies of ARVs
The ARV drug pipeline continues to progress with new targets and innovative
delivery mechanisms. In an HIV pipeline report in 2015, 16 compounds were in
human trials, primarily Phase II or III.61 Since that publication, TAF, the teno-
fovir prodrug, was approved in 2015 as a component in several FDCs (Table 3-1).14
Novel ARV targets under investigation include an attachment inhibitor acting
on gp120, a CCR5 and CCR2 inhibitor, a maturation inhibitor, and monoclonal
antibodies targeting CCR5-receptors and CD4 cells, respectively. The investigation
of a maturation inhibitor currently in a Phase II/III study provides for the first
time an avenue of ARV targets on the viral assembly and budding process.61 One
novel strategy is the paradigm shift in drug delivery to long-acting injections to
improve quality of life and enhance sustained adherence. Both the investigative
agent cabotegravir (an INSTI) and the NNRTI rilpivirine are currently under eval-
uation in combination and individually in Phase III trials as intramuscular injec-
tions given every 4 to 8 weeks.62
Monoclonal antibodies (MAbs) are an emerging area in research on infectious
diseases and HIV. As of this publication, palivizumab for respiratory syncytial virus
and bezlotoxumab for Clostridium difficile infection are the only FDA-approved
MAbs for infectious diseases.14 MAbs in HIV target one of three areas: viral antigens
(e.g., gp120); host antigens (e.g., CCR5 receptor), or immunomodulatory T-cells.63 The
use of MAbs in HIV therapy may provide an alternative to traditional ART or serve as
a transition in patients who are virally suppressed on cART. Several compounds as of
this writing are currently in a Phase I or II study on prevention of or therapy for HIV.
Vaccines
Vaccine development for HIV-1 remains a significant challenge given the diversity of
HIV-1 infection globally and the establishment of a viral reservoir early in the acute
phase of the infection.64-66 In general, the current immune targets for vaccine devel-
opment can be classified into four key proposed strategies: (1) generating an anti-
body response specific to the V2 region of the HIV-1 env protein; (2) generating a
polyfunctional env-specific antibody response; (3) generating a broadly neutralizing
antibody (bNAb) response through local delivery; or (4) generating or enhancing
effector memory T-cell responses. Upon discovery of HIV as the causative virus in
AIDS, many researchers began early work on a vaccine. In 1987, the first studies of
early HIV vaccine candidates began in animal models; however, as of 2016, only
six candidate vaccines have made it to clinical efficacy trials in humans (Table 3-8).
The initial VAX004 and VAX003 trials used the env subunit protein gp120
to induce an antibody response.67-69 These studies were conducted in a popula-
tion of men having sex with men (MSM) and high-risk women in the United
States and Europe with an estimated HIV incidence of 2.6% per 100 person-years
(VAX004) and injection drug users in Thailand with an HIV incidence of 3.4% per
100 person-years (VAX003). Neither study resulted in reduction in HIV-1 infection
ERRNVPHGLFRVRUJ
TABLE 3-8. Completed HIV-1 Vaccine Trials

Study (Phase) Vaccine Used Study Population Location Results
Vax004 (III) AIDSVAX B/B®
MSM and high-risk United States and Not effective
gp120 in alum women Europe
Vax003 (III) AIDSVAX® B/B Injection drug Thailand Not effective

gp120 in alum users
HVTN 502, Step MRKAd5 HIV-1 MSM and United States Not effective;
Trial (IIb) gag/pol/nef B heterosexual study stopped
men and prematurely;
women transient
increased HIV
infection rate
in vaccinees,
specifically MSM
HVTN 503, MRKAd5 HIV-1 Heterosexual men South Africa Not effective;
Phambili trial gag/pol/nef B and women study stopped
(IIb) prematurely;
increased HIV
infection rate in
vaccinees
HVTN 505 (IIb) DNA and rAd5 MSM United States Not effective;
(A,B, and C) study stopped
prematurely
RV144 (III) ALVAC-HIV Standard risk Thailand 60% effective at 12

(vCP1521) and population in months; 31%
AIDSVAX B/E the community effective at 42
rgp120 in alum months; no
effect on HIV
RNA or CD4
count
MSM: men having sex with men
rates compared to placebo. HVTN 502 (Step) conducted in the United States and
HVTN 503 (Phambili) conducted in South Africa were the first trials to use cell-
mediated immunity with an adenovirus (serotype 5) vector to express HIV-1 gag,
pol, and nef proteins.70-72 Neither the Step nor Phambili studies demonstrated a
reduction in HIV-1 infection rates and consequently showed increased infection
risk.70-72 This increased risk of infection is not completely understood. The HVTN
505 study conducted in the MSM population in the United States failed to demon-
strate vaccine effectiveness using a multiclade DNA primary with a recombinant
adenovirus designed to stimulate both humoral and cellular responses.73 The lone
vaccine trial to date to demonstrate efficacy is the RV144 trial using a canarypox
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vector and env subunit protein gp120. The Thailand-based study demonstrated a
60% efficacy at 12 months and 31% efficacy at 42 months.74
The promising results of the RV144 study have stimulated a number of new
pursuits: changing the RV144 vaccine schedule, transferring or adapting the RV144
regimen to a new geographic region, and using different adjuvants to the RV144
regimen.75 Development of an HIV-1 vaccine continues to simultaneously be a
daunting research and development challenge and a global, public health priority
given the nearly 40 million HIV-infected individuals and the over 20 million not
currently receiving therapy.23
ROLE OF THE PHARMACIST

Pharmacists caring for HIV/AIDS patients regardless of the setting have a fundamental
role in patient care that can significantly impact patient outcomes. Pharmacists need
to be knowledgeable about the pharmacology and patient care related to treatment of
HIV; infectious, noninfectious, lifestyle, and/or ageing-related comorbidities; and other
conditions given the expanding scope of HIV disease management. Pharmacists have a
role in preventing the development of drug resistance by aiding in the selection of potent
ARV regimens; monitoring and emphasizing the need for strict adherence; screening for
and managing drug–drug interactions; managing adverse effects, as a means to increase
adherence; providing appropriate education about the relationship between nonadherence
and development of resistance; and aggressively managing treatment failure by switching
therapies to prevent further accumulation of resistance mutations.76
The use of complementary alternative medicine is popular in the HIV patient popula-
tion. Pharmacists can also play a crucial role by providing reliable information related to
complementary and alternative medicine (CAM) to help patients understand the potential
risks, benefits, and uncertainties regarding specific CAM products. Potential pharmacist
interventions include offering therapeutic alternatives, evaluating the risk of drug interac-
tions, recommending therapeutic drug monitoring, and ensuring optimal adherence with
combination ART.77
With the development of various ART classes, HIV infection has become a more chronic,
manageable disease state for patients. HIV care providers may see patients who are stable
on their ART less frequently. Thus, the emphasis has shifted from the HIV specialist to
routine primary care providers, with attention on promotion and maintenance of health.78
Pharmacists, especially those practicing in ambulatory or community settings, can play a
significant role in this aspect of care. Various activities include reaching out to providers
with recommendations to maximize therapy for comorbidities (e.g., hypertension, dyslip-
idemia, diabetes), ensuring patients are up-to-date on routine vaccinations and immu-
nizations, advising on proper diet and nutrition, and providing counseling on personal
health and safety issues.
HIV disease crosses many boundaries related to sex, age, race, culture, socioeconomic
status, language, and lifestyle choice. Pharmacists need to be aware of these social issues
and take into account individual communication style and literacy level when providing
ERRNVPHGLFRVRUJ
counseling. The pharmacist’s ultimate goal is to develop a more personal and trusting
relationship with the patient so that the patient feels comfortable and cared for. This
provides for a more open, candid relationship between the patient and pharmacist in
which any and all issues regarding diseases and treatment can be discussed in a confiden-
tial, nonjudgmental manner.
Medication adherence is a crucial factor affecting the extent and duration of response
to ART. Suboptimal adherence to both HIV therapy and prophylactic regimens against
opportunistic infection may have lasting consequences for the HIV-positive patient,
including increased viral load, development of resistance, reduced efficacy of future
combination therapy, increased risk of hospital admission, increased progression to AIDS,
and decreased survival.79 Pharmacists can support adherence by helping to anticipate and
identify barriers to adherence and strategizing with patients to find solutions that will
work for them.80
Pharmacists should become leaders in the medication reconciliation process. Obtaining
an accurate medication history through reviews of patient-related documents is essential.
Pharmacists use patient interviews and comparison with pharmacy medication profiles
to confirm treatment information. Many studies have shown that more information is
obtained when a pharmacist rather than another healthcare provider collects the medica-
tion history.81 Furthermore, when clinical pharmacists were actively involved in or leading
the medication reconciliation process of hospitalized HIV-positive patients, medication
errors are prevented, further reduced, and/or the duration of uncorrected errors short-
ened.82-84 Pharmacists can provide advice regarding dosage adjustments to address drug
interactions or renal/hepatic insufficiencies, can suggest alternatives if current therapies
or formulations are unsuitable or contraindicated, and can ensure that complete regimens
are prescribed, including concomitant medications—problems that a computerized physi-
cian order-entry system is unlikely to identify or help resolve. Pharmacists should also
be involved in the discharge of hospitalized HIV-positive patients during which process
unintentional medication discrepancies may crop up.85,86
KEY RESOURCES
• Hashimoto C, Tanaka T, Narumi T, et al. The successes and failures of HIV drug
discovery. Expert Opin Drug Discov. 2011;6:1067-1090.
o This expert review summarizes the history of antiretroviral drug development
beginning with nucleoside reverse transcriptase inhibitors through entry and
integrase enzyme inhibitors. Future developments and targets for expanding the
available drug armamentarium are explored. While many of these agents are
subject to development of resistance, adverse events, and other intolerabilities,
drug discovery in this area continues to be a priority looking towards functional
cure of the disease.
• Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to
abacavir. N Engl J Med. 2008;358:568-579.
o Abacavir-hypersensitivity reaction is strongly associated with the presence of the
HLA-B*5701 allele. This double-blind, prospective study randomly assigned HIV
patients who were naïve to abacavir to undergo pharmacogenetic screening. The
prevalence of HLA-B*5701 allele in this study was 5.6%. Screening reduced the
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risk of immunologically confirmed hypersensitivity reaction to abacavir (0% in

screening group vs. 2.7% in control group, P<0.001). The results of this study
demonstrate the utility of the HLA-B*5701 screening tool to prevent abacavir-
hypersensitivity reaction.
• Patterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and
outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21-30.
o Adherence to highly active antiretroviral therapy is essential to ensure appro-
priate long-term management of HIV and to reduce the risk of resistance.
Adverse events, disease stigma, and regimen complexities make this a challenge.
This prospective observational study was conducted in 99 HIV-infected indi-
viduals in the Veterans Affairs medical center and university medical center.
Patients taking protease inhibitor therapy were followed for a median of 6
months. Significantly greater change of virologic suppression and fewer days of
hospitalization were associated with patients with adherence rates >95%. This
publication established the original benchmark for optimal adherence to HAART.
• Stephenson KE, D’Couto HT, Barouch DH. New concepts in HIV-1 vaccine develop-
ment. Curr Opin Immunol. 2016;41:39-46.
o An effective HIV-1 vaccine remains a major public health priority. HIV-1 vaccine
efficacy trials in humans, complemented by active and passive immunization
studies in nonhuman primates, have identified several key vaccine-induced
immunological responses that may correlate with protection against HIV-1
infection. Potential correlates of protection in these studies include V2-specific,
polyfunctional, and broadly neutralizing antibody responses, as well as effector
memory T-cell responses. This review describes how these correlates of protec-
tion are guiding current approaches to HIV-1 vaccine development. More specif-
ically, these approaches include improvements on the ALVAC-HIV/AIDSVAX
B/E vaccine regimen used in the RV144 clinical trial in Thailand, adenovirus
serotype 26 vectors with gp140 boosting, intravenous infusions of bNAbs, and
replicating viral vectors.
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APPENDIX 3-A. ANTIRETROVIRAL DOSING

Generic or
Abbreviation (Brand) Available Formulations Usual Adult Dose Dose Adjustments
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abacavir (Ziagen) Tablet: 300 mg 300 mg Q12H or Renal: None
Oral Solution: 20 mg/ 600 mg Q24H Hepatic: Child-Pugh
mL A – 200 mg twice daily
(use oral solution);
Child-Pugh Class B or
C – Contraindicated
Didanosine EC Capsule: 125, 200, 250, Body Weight ≥60 kg: Renal:
(Videx) or 400 mg 400 mg Q24H Body Weight ≥60 kg:
Body Weight <60 kg: CrCl 30–59 mL/min:
250 mg Q24H 200 mg Q24H
CrCl <29 mL/min, HD:
125 mg Q24H
Body Weight <60 kg:
CrCl 10–59 mL/min:
125 mg Q24H
75 mg Q24Ha
Hepatic: None
Didanosine Oral Oral Powder: 10 mg/ Body Weight ≥60 kg: Body Weight ≥60 kg:
Solution (Videx) mL reconstituted 200 mg Q12H or CrCl 30–59 mL/min:
400 mg Q24H 200 mg Q24H
Body Weight <60 kg: CrCl 10–29 mL/min:
125 mg BID or 150 mg Q24H
250 mg Q24H
100 mg Q24Ha
Body Weight <60 kg:
150 mg Q24H
100 mg Q24H
75 mg Q24Ha
Hepatic: None
(continued)
ERRNVPHGLFRVRUJ
APPENDIX 3-A. ANTIRETROVIRAL DOSING (continued)

Generic or
Emtricitabine Capsule: 200 mg 200 mg Q24H Renal:
(Emtriva) Oral Solution: 10 mg/ 240 mg Q24H CrCl 30–49 mL/min:
mLb 200 mg Q48H
200 mg Q72H
CrCl <15 mL/min or HD:
200 mg Q96Ha
Hepatic: No dosage
recommendation
Lamivudine (Epivir) Tablet: 150 or 300 mg 300 mg Q24H or Renal:

HBV Tablet: 100 mg 150 mg Q12H CrCl 30–49 mL/min:
Oral Solution: 10 mg/ 150 mg Q24H
mL CrCl 15–29 mL/min:
150 mg x 1 dose, then
100 mg Q24H
CrCl 5–14 mL/min:
150 mg x 1 dose, then
50 mg Q24H
<5 or HD: 50 mg x
1 dose, then
25 mg Q24H
Hepatic: None
Stavudine (Zerit) Capsule: 15, 20, 30, or Body Weight ≥60 kg: Renal:
40 mg 40 mg Q12H Body Weight ≥60 kg:
Oral Powder: 1 mg/mL Body Weight <60 kg: CrCl 26–50 mL/min:
when reconstituted 30 mg Q12H 20 mg Q12H
CrCl 10–25 mL/min or
HD: 20 mg Q24H
Body Weight <60 kg:
15 mg Q12H
CrCl 10–25 mL/min or
HD: 15 mg Q24Ha
Hepatic: No dosage
recommendation
(continued)
ERRNVPHGLFRVRUJ

Generic or
Tenofovir Disoproxil Tablet: 150, 200, 250, 300 mg Q24H Renal:
Fumarate (Viread) or 300 mg CrCl 30–49 mL/min:
Oral Powder: 40 mg/ 300 mg Q48H
1 GM CrCl 10–29 mL/min:
300 mg Q72–96H
(twice weekly)
CrCl <10 mL/min,
and not on HD: no
recommendation
On HD: 300 mg every
7 daysa
Hepatic: None
Zidovudine Capsule: 100 mg 300 mg Q12H Renal:

(Retrovir) Tablet: 300 mg CrCl <15 mL/min or HD:
Oral Syrup: 10 mg/mL 100 mg Q8H or
300 mg Q24Ha
IV Solution: 10 mg/mL
Hepatic: No dosage
recommendation
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz (Sustiva) Capsule: 50 or 200 mg 600 mg Q24H at or Renal: None
Tablet: 600 mg before bedtime Hepatic: Mild, use with
caution; Moderate
to severe, not
recommended
Etravirine Tablet: 25, 100, or 200 mg Q12H Renal: None
(Intelence) 200 mg Hepatic: Child-Pugh
Class A or B, none;
Child-Pugh Class C, no
recommendation
Nevirapine Tablet: 200 mg 200 mg Q12H (using IR Renal: Limited data
(Viramune, Immediate Release, formulation) or in HD; No dosage
Viramune XR) 100 mg or 400 mg 400 mg Q24H (using recommendation
Extended Release ER formulation) Hepatic: Child-Pugh
Oral Suspension: Class A or B, none;
50 mg/5 mL Child-Pugh Class C,
contraindicated
(continued)
ERRNVPHGLFRVRUJ

Generic or
Rilpivirine (Edurant) Tablet: 25 mg 25 mg Q24H Renal: None
Hepatic: Child-Pugh
Class A or B, none;
recommendation

Atazanavir (Reyataz) Capsule: 100, 150, 200, 400 mg Q24H or 300 mg Renal: None (not
or 300 mg Q24H (plus RTV recommended in
Oral Powder Packet: 100 mg once daily) ARV-experienced
50 mg patients on HD). For
naïve patients on HD,
must be boosted.
Hepatic: Child-Pugh
Class B, 300 mg
once daily (ritonavir
boosting is not
recommended in
patients with hepatic
impairment)
Child-Pugh Class C, not
recommended
Atazanavir/ Tablet: Atazanavir 1 tablet Q24H Renal: Not

Cobicistat 300 mg/Cobicistat recommended for use
(Evotaz) 150 mg in patients receiving
TDF with a CrCl
<70 mL/min
Hepatic: Not
recommended
Darunavir (Prezista) Tablet: 75, 150, 600, 800 mg once daily (plus Renal: None
or 800 mg RTV 100 mg daily) or Hepatic: Mild to
Oral Suspension: 600 mg twice daily moderate, none;
100 mg/mL (plus RTV 100 mg Severe, not
twice daily)c recommended
Darunavir/ Tablet: Darunavir 1 tablet Q24H Renal: Not

Cobicistat 800 mg/Cobicistat recommended for use
(Prezcobix) 150 mg in patients receiving
TDF with a CrCl
<70 mL/min
Hepatic: Child-Pugh
Class A or B, none;
Child-Pugh Class C,
not recommended
(continued)
ERRNVPHGLFRVRUJ

Generic or
Fosamprenavir Tablet: 700 mg 1400 mg Q12H or Renal: None
(Lexiva) Oral Suspension: 1400 mg Q24H Hepatic: See
50 mg/mL (plus RTV manufacturer labeling
100–200 mg Q24H) for dose adjustments
or 700 mg Q12H (plus
RTV 100 mg Q12H)
Indinavir (Crixivan) Capsule: 200 or 400 mg 800 mg Q8H Renal: None

Hepatic: Mild-Moderate
because of cirrhosis –
600 mg Q8H
Lopinavir/Ritonavir Tablet: LPV 100 mg/RTV LPV/RTV 400/100 mg Renal: None. Avoid
(Kaletra) 25 mg, LPV 200 mg/ Q12H or LPV/RTV once daily dosing in
RTV 50 mg 800/200 mg Q24H patients on HD.
Oral Solution: LPV (Q24H dosing only Hepatic: No dosage
80 mg/RTV 20 mg for PI naïve or PI recommendation; use
per mL experienced patients with caution
with 3 or fewer
mutations; not for
pregnant patients)
Nelfinavir (Viracept) Tablet: 250 or 625 mg 1250 mg Q12H Renal: None

Oral Powder: Hepatic: Mild, none;
50 mg/gm Moderate to severe, do
not use
Saquinavir (Invirase) Tablet: 500 mg 1000 mg Q12H (plus RTV Renal: None
Capsule: 200 mg 100 mg Q12H) Hepatic: Mild to
moderate, use with
caution; Severe,
contraindicated
Tipranavir (Aptivus) Capsule: 250 mg 500 mg Q12H (RTV Renal: None

Oral Solution: 200 mg twice Q12H) Hepatic: Child-Pugh
100 mg/mL Class A, use with
caution; Child-
Pugh Class B or C,
contraindicated
(continued)
ERRNVPHGLFRVRUJ

Generic or
Dolutegravir Tablet: 50 mg 50 mg Q24H or 50 mg Renal: None
(Tivicay) Q12H (Q24H for Hepatic: Child-Pugh
treatment-naïve or Class A or B, none;
treatment-experienced Child-Pugh Class C,
INSTI-naïve; Q12H not recommended
for INSTI-experienced
with INSTI-resistance
substitutions or
clinically suspected
INSTI resistance or
when co-administered
with certain UGT1A or
CYP3A inducers)
Raltegravir Tablet: 400 mg or 400 mg Q12H or Renal: None
(Isentress, 600 mg 1200 mg Q24H Hepatic: Mild
Isentress HD) Chewable Tablet: to moderate,
25 mg or 100 mgd none; Severe, no
Oral Powder for recommendation
Suspension: 100 mg
single-use packetsd
CCR5 Antagonist
Maraviroc Tablet: 150 or 300 mg 300 mg Q12He Renal: CrCl <30 mL/min
(Selzentry) or HD:
Without potent CYP3A
inhibitors or inducers:
300 mg twice daily;
reduce to 150 mg
BID if postural
hypotension occurs
With potent CYP3A
inhibitors or inducers:
Not recommended
Hepatic: No dosage
recommendations, use
with caution
Fusion Inhibitor
Enfuvirtide (Fuzeon) Subcutaneous 90 mg subcutaneous Renal: None
Injection: 90 mg/mL Q12H Hepatic: None
(continued)
ERRNVPHGLFRVRUJ

Generic or
Pharmacokinetic Enhancers
Cobicistat (Tybost) Tablet: 150 mg 150 mg Q24H (must be Renal: None (if
co-administered with administered with TDF
ATV or DRV) and CrCl <70 mL/min,
use not recommended)
Hepatic: Child-Pugh
Class A or B, none;
recommendations
Ritonavir (Norvir) Tablet: 100 mg 100 mg Q24H or Renal: None

Capsule: 100 mgf 100 mg Q12H (must Hepatic: Child Pugh
be co-administered Class A-B, none; Child
Oral Solution:
with PI)g Pugh Class C, not
80 mg/mL
recommended
Fixed-Dose Combinations
Combination Products (NRTI Combination Products)
ABC/3TC (Epzicom) Tablet: Abacavir 1 tablet Q24H Should not be initiated in
600 mg/Lamivudine patients with CrCl
300 mg <50 mL/min
ABC/3TC/AZT Tablet: Abacavir 1 tablet Q12H Should not be initiated in
(Trizivir) 300 mg/Lamivudine patients with CrCl
150 mg/Zidovudine <50 mL/min
300 mg
3TC/AZT (Combivir) Tablet: Lamivudine 1 tablet Q12H Should not be initiated in
150 mg/Zidovudine patients with CrCl
300 mg <50 mL/min
TAF/FTC (Descovy) Tablet: Tenofovir 1 tablet Q24H Should not be initiated in
alafenamide patients with CrCl
25 mg/Emtricitabine <30 mL/min or on HD
200 mg Hepatic: Child Pugh
Class A or B, no
dosage adjustment;
Child Pugh Class
C, no dosage
recommendation
(continued)
ERRNVPHGLFRVRUJ

Generic or
TDF/FTC (Truvada) Tablet: Tenofovir 1 tablet Q24H Should not be initiated in
disoproxil fumarate patients with CrCl
300 mg/Emtricitabine <50 mL/min
200 mg Hepatic: CrCl 30–49
mL/min, Q48H;
CrCl <30, do not
initiate
Single-Tablet Regimens
ABC/3TC/DTG Tablet: Abacavir 600 1 tablet Q24H Should not be initiated in
(Triumeq) mg/Lamivudine patients with CrCl
300 mg/Dolutegravir <50 mL/min
50 mg Hepatic: Mild, none;
Moderate to severe,
contraindicated
TAF/FTC/EVG/COBI Tablet: Tenofovir 1 tablet Q24H Should not be initiated in

(Genvoya) alafenamide 10 mg/ patients with CrCl
Emtricitabine 200 mg/ <30 mL/min
Elvitegravir 150 mg/ Hepatic: Severe, not
Cobicistat 150 mg recommended
TAF/FTC/RPV Tablet: Tenofovir 1 tablet Q24H Should not be initiated in

(Odefsey) alafenamide 25 mg/ patients with CrCl
Emtricitabine 200 mg/ <30 mL/min
Rilpivirine 25 mg Hepatic: Mild, none;
Moderate to severe, no
recommendation
TDF/FTC/EFV Tablet: Tenofovir 1 tablet Q24H Should not be initiated in

(Atripla) disoproxil fumarate patients with CrCl
200 mg/Efavirenz 600 Hepatic: Moderate
mg to severe, not
recommended
TDF/FTC/EVG/COBI Tablet: Tenofovir 1 tablet Q24H Should not be initiated in

(Stribild) disoproxil fumarate patients with CrCl
200 mg/Elvitegravir Hepatic: Mild to
150 mg/Cobicistat 150 moderate, none;
mg/ Severe, not
recommended
(continued)
ERRNVPHGLFRVRUJ

Generic or
TDF/FTC/RPV Tablet: Tenofovir 1 tablet Q24H Should not be initiated in
(Complera) disoproxil fumarate patients with CrCl
200 mg/Rilpivirine Hepatic: Mild
25 mg to moderate,
none; Severe, no
recommendation
a
Take after hemodialysis session on dialysis days.
b
Emtricitabine solution dose differs from the capsule. (A dose of 240-mg oral solution is equal to a dose of 200-mg
oral capsule.)
c
Ritonavir-boosted darunavir 600 mg twice daily is reserved for ARV-experienced patients with at least one darunavir-
associated mutation.
d
Do not substitute raltegravir chewable tablets or oral suspension for the 400-mg film-coated tablets.
e
Dose adjustments needed with concurrent use of CYP3A inducers or inhibitors.
Must be refrigerated.
f
g
Tipranavir should be administered with ritonavir 200 mg Q12H.
3TC: lamivudine; ABC: abacavir; ARV: antiretroviral; ATV: atazanavir; AZT: zidovudine; COBI: cobicistat; CrCl: creatinine
clearance; DRV: darunavir; DTG: dolutegravir; EFV: efavirenz; EVG: elvitegravir; FTC: emtricitabine; H: hour; HD:
hemodialysis; INST: integrase strand transfer inhibitor; IV: intravenous; LPV: lopinavir; Q: every; RPV: rilpivirine; RTV:
ritonavir; TAF: tenofovir alafenamide fumarate; TDF: tenofovir disoproxil fumarate
ERRNVPHGLFRVRUJ
4
Initiating HIV Treatment and
Supporting Adherence
Agnes Cha, PharmD, AAHIVP, BCACP, and
Tiffany E. Bias, PharmD, AAHIVP, BCPS (AQ-ID)
INTRODUCTION
The four goals of antiretroviral treatment are to
1. maximally and durably suppress human immunodeficiency virus (HIV)
viral load
2. restore and preserve immune function
3. decrease morbidity and extend the duration and quality of survival
4. prevent transmission of HIV1
With advances in pharmacologic options, these treatment goals are attainable,
provided patients remain adherent to antiretroviral therapy (ART). With compre-
hension of antiretroviral treatment and adherence strategies, pharmacists are an
essential resource for providing high-quality HIV care.
RECOMMENDATIONS FOR WHEN TO TREAT

Recommendations regarding when to initiate treatment for HIV infection have
evolved over time. Until 2003, treatment was often withheld until CD4 counts fell
below 200 cells/mm3 because of two major concerns. First, most early antiretrovirals
had significant side effects and long-term toxicities. Second, nonadherence due to
large pill burdens was common, resulting in an increased risk of antiretroviral resis-
tance. In recent years, a number of new, well-tolerated antiretroviral medications
with reduced pill burdens have been developed. Also, data have emerged identifying
the benefits of initiating ART earlier in the course of infection, prior to observing
significant CD4 cell declines. As a result, current recommendations are to initiate
antiretroviral treatment for all HIV-infected patients regardless of CD4 cell count.
Two large, randomized controlled trials established that initiating treatment
earlier in the course of infection can decrease the risk of death.2,3 The START (Stra-
tegic Timing of Antiretroviral Treatment) study was a large, multinational, random-
ized controlled trial that demonstrated a reduction in acquired immunodeficiency
syndrome (AIDS)-related and non-AIDS-related serious events among patients
who initiated treatment immediately compared to those who deferred treatment
until their CD4 counts fell below 350 cells/mm3 (hazard ratio [HR] = 0.43; 95%
Confidence Interval [CI]: 0.3–0.62).2 The TEMPRANO study, another randomized,
69
ERRNVPHGLFRVRUJ
controlled trial, also demonstrated that immediate ART resulted in a lower risk of
death or severe HIV-related illness compared to deferred ART (HR = 0.56; 95% CI:
0.41–0.76).3 Evidence from other nonrandomized, observational studies have also
demonstrated a higher risk of AIDS and death with delayed therapy.4,5
Collectively, current evidence supports that starting treatment earlier, even
when CD4 counts are greater than 500 cells/mm3, results in prolonged survival
and reduces disease progression. Additionally, earlier treatment has been shown to
delay, prevent, or reverse non-AIDS-defining complications such as cardiovascular
events, liver disease, HIV-associated nephropathy (HIVAN), neurologic complica-
tions, and malignancies.
Providers may opt to briefly delay ART initiation to resolve issues relating
to untreated major psychiatric disorders, neurocognitive impairment, active
substance abuse, unstable housing, poverty, and other clinical, behavioral, and
social factors. Interventions should be explored to support adherence and rapidly
address these challenges, such as drug abuse treatment programs, behavioral health
specialists, and social workers, for example. ART reduces morbidity and mortality;
therefore, even in patients with relatively poor adherence and drug resistance, ART
should not be withheld for extended periods of time.
BASELINE ASSESSMENT AND CONSIDERATIONS

Obtaining a complete patient history is extremely important to determine status
of disease, comorbidities, and emotional status, and to develop a trusting relation-
ship when establishing care. For treatment-experienced patients, this includes a
thorough ART history including tolerability and drug-resistance test results if avail-
able. Because patients living with HIV often have comorbid conditions, it is neces-
sary to assess other disease states as well during the initial visit. In addition, other
screening tests for sexually transmitted infections (STIs) and tests to rule out oppor-
tunistic infections are recommended in the setting of HIV primary care.6 Table 4-1
provides suggested topics, questions, and laboratory results that should be assessed
during the initial visit with a HIV-infected individual. For additional information
on STIs and primary care assessments, please see Chapters 9 and 11, respectively.
It is important to obtain the patient’s complete history by asking questions
using a nonjudgmental approach, especially when referring to sexual and drug
history. Sexual history should include specific practices and history of STIs, repro-
ductive history, and HIV status of partners if known. Often, the “5 Ps” (Partners,
Practices, Protection, Past history of STI, and Pregnancy) approach allows for
a comprehensive assessment.7 Discussion of this information lends itself to the
opportunity for risk-reduction counseling, which is the cornerstone of prevention.
Pharmacists may also take the opportunity to introduce the importance of safe sex
practices to reduce the risk of transmission, “superinfection,” and other sexually
transmitted infections.
Table 4-2 displays recommendations for laboratory monitoring and specific
tests that should be obtained prior to and during ART.
ERRNVPHGLFRVRUJ
CHAPTER 4 Initiating HIV Treatment and Supporting Adherence 71
TABLE 4-1. Suggested Topics, Questions, and Respective Laboratory Results

That Should Be Obtained Prior to Initiating ART
Topics Examples of Questions Laboratory Tests
HIV testing and • When was your first HIV positive test? • Confirmatory HIV test (at
status of disease • When was your last HIV care visit? initial visit)
• What is your current CD4 (T-cell) count? • Plasma HIV RNA (viral load)
• Do you know your lowest CD4 count? • CD4 count and percentage
• What is your current viral load? • Genotypic resistance testing at
entry into care
ART history • Are you currently taking HIV • Past genotype or phenotypic
medications? resistance test results, if
• Can you describe the medications and available
how you take them? • If viral load is not controlled
• How many doses have you missed in the and >1,000 copies/mL while
past week? Month? on ART, obtain genotype or
phenotype resistance test
• Are you experiencing any side effects?
• CBC, BMP, LFTs, urinalysis
• Do you know what HIV medications you
have taken in the past? • HLA B*5701 testing (if abacavir
naïve and considering use)
• Do you know what your CD4 and viral
load were while taking your medications?
• Do you have any medication allergies?
Other disease states • What other chronic conditions do you • Blood pressure
have? (i.e., hypertension, dyslipidemia, • Fasting lipid panel
COPD, asthma, diabetes mellitius)
• Fasting glucose
• What medications are you taking, if any?
• Past medical records if available
• What herbals or over-the-counter
• Serologies for hepatitis A, B,
medications are you taking, if any?
and C viruses
• Have you ever had hepatitis? What type?
• Screening for other sexually
• Have you ever had sexually transmitted transmitted infections (i.e.,
infections? syphilis, gonorrhea, chlamydia,
• What vaccinations have you received? HPV)
BMP: basic metabolic panel; CBC; complete blood count; COPD: chronic obstructive pulmonary disease; HPV: human
papillomavirus; LFTs: liver function tests
(Source: Adapted with permission from Cha, HIV/AIDS. In J.K. Singleton, ed., Primary Care: An Interprofessional
Perspective, 2nd ed. New York: Springer Publishing Company 565-585; ©2014.)
After all baseline laboratory tests have been obtained, the patient should
return quickly for follow-up to determine the best treatment. Resistance test results
are valuable to help design the ART regimen, even if patients are treatment naïve.
For this reason, the Department of Health and Human Services (DHHS) guidelines
recommend genotypic testing at baseline in all patients prior to ART initiation.
ERRNVPHGLFRVRUJ
TABLE 4-2. Laboratory Monitoring Before ART and Ongoing Assessment of ART
ART Initiation 2-8 Weeks After ART Clinically
Test Entry into Care or Switch Started or Changed Every 3-6 Months Every 6 Months Every 12 Months ART Failure Indicated
Viral load × × × × × × ×
CD4 count × × × × × ×
During first 2 years In stable patients
of ART or if CD4 after 2 years of
<300 or viremia ART consistently
develops while suppressed HIV

on ART RNA. If CD4 >500:
monitoring is
optional
Resistance testing × × × ×
HLA-B*5701 ×
If considering
abacavir
ERRNVPHGLFRVRUJ
Tropism testing × ×
If considering If considering
maraviroc maraviroc
or assessing
for its
failure
Hepatitis B and C × × × ×
serology
(continued)

TABLE 4-2. Laboratory Monitoring Before ART and Ongoing Assessment of ART (continued)
ART Initiation 2-8 Weeks After ART Clinically
Test Entry into Care or Switch Started or Changed Every 3-6 Months Every 6 Months Every 12 Months ART Failure Indicated
Basic chemistry, AST, × × × × ×
ALT, T. bilirubin
ALT, AST, bilirubin × × × × ×
CBC with differential × × × × × ×

If on zidovudine If on zidovudine
Fasting lipid panel × × × × ×

If previous was If previous was
abnormal normal
Fasting glucose or × × × × ×
HbA1c If previous was If previous was
abnormal normal
ERRNVPHGLFRVRUJ
Urinalysis × × × × ×
If on TAF or TDF
ALT: alanine aminotransferase test; AST: aspartate aminotransferase test; CBC: complete blood count; TAF: tenofovir alafenamide fumurate; TDF: tenofovir disoproxil fumarate
(Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human
Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed December 30, 2016.)
In the United States, up to 16% of new infections are due to viruses with trans-
mitted resistance.1 Because the genotype assay is qualitative and more sensitive
for detecting mixed wild-type and resistant virus, it is preferred at baseline over a
phenotype assay. The phenotype assays, which are quantitative, are preferred in
treatment-experienced patients when complex drug resistance mutation patterns
are suspected. For additional information on resistance testing, please see Chapter
5. The HLA-B*5701 test is recommended prior to initiation of abacavir to reduce the
risk of a hypersensitivity reaction characterized as a multiorgan clinical syndrome.
Patients with positive results should have abacavir recorded in the medical record
as a true allergy and should not be prescribed abacavir.
SUPPORTING ADHERENCE
All patients must be willing and able to commit to lifelong therapy and under-
stand the importance of adherence prior to initiating ART. Patients must under-
stand that starting treatment means taking full doses of medications every day,
indefinitely. The provider should initiate treatment only when the patient is ready
to be adherent. In some cases, ART may be deferred for clinical or psychosocial
reasons but should be reconsidered as soon as possible.1 Readiness implies not
only a psychological willingness but also a practical ability to maintain a daily
regimen of potentially several medications. Some patients are eager to start medi-
cations but must wait until their prescription benefits are in place. Other patients
prefer to delay starting medications until they obtain stable housing because they
have no safe place to store medications. Others prefer to discuss the decision with
family members or friends before making the commitment. Pressuring patients to
start treatment before they are ready to take medications they distrust can lead to
poor adherence to the regimen and consequently a poor therapeutic effect.
Medication regimens may be difficult to follow for those with poor health
literacy—the degree to which individuals have the capacity to obtain, process,
and understand information and make appropriate decisions pertaining to their
health.8 Effective strategies to improve patient comprehension include using
plain language, supplementing instructions with pictures, limiting the number
of messages, employing the teach-back method, engaging in cultural competency
training, and utilizing medically trained interpreters.9 A pharmacist can be a valu-
able source of teaching in order for the patient to receive support and encourage-
ment to maintain adherence to the regimen. A multidisciplinary team approach
is recommended to optimize adherence, including pharmacists to provide coun-
seling and education about medications. Table 4-3 provides strategies for phar-
macists to improve adherence to medications and pharmacist-specific examples
of these strategies. Patients must be counseled about the possible failure rates of
ART when doses are missed or not taken as directed. As Dr. C. Everett Koop stated,
“Drugs don’t work in patients who don’t take them.”
Motivational interviewing is a directive patient-centered methodology of facil-
itating behavioral change by collaborating with the patient and engaging their
ERRNVPHGLFRVRUJ
TABLE 4-3. Strategies for Pharmacists to Improve Adherence

Strategies Examples
Implement multidisciplinary Pharmacists working with healthcare providers, nurses, social
team approach workers, dietitians
Identify and address potential Assess for cognitive impairment, psychosocial issues, active
barriers to adherence prior to substance abuse, low health literacy, language barriers, unstable
starting ART housing, skepticism or fear of ART, lack of prescription
medication coverage, history of medication nonadherence
Provide resources for the patient Resources to obtain prescription drug coverage, pillboxes, referrals
for mental health/substance abuse treatment, housing and food
security, transportation
Involve the patient in ARV Assess readiness to start ART, review potential side effects, dosing
regimen selection frequency, pill burden, food requirements, and cost/copayments
for each option
Assess adherence at every clinic Ask open-ended questions, monitor medication effectiveness
visit and tolerability, check pharmacy or insurance fill records, use
positive reinforcement and motivational interviewing
Identify reason for Failure to fill Rx, wrong dose, wrong time, adverse effects,
nonadherence forgetfulness, large pills, pill fatigue, lack understanding of drug
resistance
Improve patient’s knowledge Educate patients on natural history of HIV, treatment goals and
about HIV disease expected outcomes, consequences of nonadherence resulting in
drug resistance and loss of future treatment options
ART: antiretroviral therapy; ARV; antiretroviral; Rx; prescription
(Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in
HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/
contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed December 30, 2016.)
internal motivation as an effective way to optimize adherence. Motivational inter-

viewing has proven to be beneficial, and strategies should be further explored (see
http://www.motivationalinterviewing.org/motivational-interviewing-resources).
By working together with the patient and involving them in the treatment plan,
the patient may feel a sense of ownership with the decision to be adherent. As
the patient determines his or her personal motivations for treatment adherence,
autonomy is established and the patient has the responsibility to comply.
SELECTING REGIMENS FOR TREATMENT-NAÏVE PATIENTS

ART requires a minimum of three active antiretroviral agents from at least two
drug classes. Typically, regimens will consist of two nucleoside reverse transcrip-
tase inhibitors (NRTIs) as the backbone with one of the following: (1) protease
inhibitor (PI) boosted with ritonavir or cobicistat, (2) integrase strand transfer
ERRNVPHGLFRVRUJ
inhibitor (INSTI), or (3) nonnucleoside reverse transcriptase inhibitor (NNRTI).

Other classes and combinations can be employed as optional or salvage therapy.
Table 4-4 lists the current recommended initial treatment regimens.
Evidence from numerous clinical trials have demonstrated the potency,
durable efficacy, minimal toxicity, and ease of use of these antiretroviral combi-
nations.10-18 In the SINGLE trial, dolutegravir was compared to efavirenz in treat-
ment-naïve patients, illustrating a higher rate of virologic suppression primarily
due to the lower rate of discontinuations.16 Furthermore, the FLAMINGO study,
a randomized open-label trial that compared dolutegravir to darunavir, found
similar results even in patients with pretreatment HIV RNA levels >100,00 copies/
mL.18 Elvitegravir had superior efficacy when compared to atazanavir-based regi-
mens in the WAVES trial performed in HIV-infected women.19 Raltegravir, the first
INSTI approved, also demonstrated superiority for the combined virologic efficacy
and tolerability endpoint in the ACTG A5257 trial when evaluated against PI-based
regimens (atazanavir and darunavir)20 and in the STARTMARK study when evalu-
ated against efavirenz-based therapy.8
There is no clinical trial to date evaluating all three currently available INSTIs.
Of note, dolutegravir is noninferior to raltegravir in treatment-naïve patients17
but superior in treatment-experienced patients,21 making it a favorable option in
patients in whom resistance results are not yet available. Similar outcomes were
seen in treatment-experienced patients when elvitegravir was compared to ralte-
gravir.22 Because the virologic efficacy is comparable among the preferred regi-
mens, the pharmacist should consider patient-specific factors and unique charac-
TABLE 4-4. Recommended Initial Treatment Regimens

Preferred Regimens Level of Evidence
INSTI-based dolutegravir/abacavir/lamivudine† (only if HLA-B*5701 negative) AI
dolutegravir + tenofovir disoproxil fumarate/emtricitabine† AI
dolutegravir + tenofovir alafenamide/emtricitabine AII
elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine AI
elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine AI
raltegravir + tenofovir disoproxil fumarate/emtricitabine† AI
raltegravir + tenofovir alafenamide/emtricitabine AII
†
Lamivudine can be substituted for emtricitabine or vice versa; INSTI: integrase strand transfer inhibitor; PI: protease
inhibitor
A: Strong recommendation; B: Moderate recommendation; C: Optional recommendation
I: One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
II: One or more well-designed, non-randomized trials or observational cohort studies with long-term clinical outcomes
III: Expert opinion
(Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in
HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/
contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed November 1, 2017.)
ERRNVPHGLFRVRUJ
teristics of the antiretrovirals when selecting an initial regimen. Table 4-5 describes
the advantages and disadvantages of each recommended initial regimen.
Given the various antiretroviral options, selecting an initial regimen should
be individualized based on
• toxicity
• pill burden
• dosing frequency
• food requirements
• drug interactions
• resistance test results
• comorbid conditions.
Although the guidelines provide preferred treatment regimens for treat-
ment-naïve patients, an alternative regimen may actually be preferred for some
patients depending on the patient-specific factors. The provider must consider
renal function, pregnancy status, psychiatric history, existing comorbid condi-
tions, and drug interactions.
TREATMENT FOR ACUTE HIV INFECTION

Acute HIV infection is defined as the period of HIV disease immediately following
infection characterized by detectable serum HIV RNA or p24 antigen levels in
the absence of HIV-1 antibodies. Recent infection is defined as the period up to
6 months after infection characterized by detectable anti-HIV-1 antibodies. Early
infection represents either acute or recent HIV-1 infection.
Limited clinical trial data exist regarding treatment of acute HIV infection.
Preliminary data suggest that early treatment initiation decreases the severity of
acute disease, lowers the viral set point, reduces the size of the viral reservoir,
delays disease progression, enhances CD4 cell recovery, and preserves mucosal
cell function.1 Current guidelines recommend antiretroviral treatment for all
individuals with HIV infection, including those with early infection. Given the
increased infectiousness of early HIV infection, initiating treatment during the
acute phase has been suggested to reduce the risk of transmission.1 Notably, there
are insufficient data to confirm that treatment during acute infection will result
in long-term clinical benefits. The START and TEMPRANO trials included newly
diagnosed patients, albeit not specifically defined as early infection. The results
demonstrated that immediate treatment results in decreased risk of AIDS-defining
illnesses, or death, thus highlighting that patients should begin ART upon diag-
nosis of infection whenever possible.2,3 Several ongoing studies continue to eval-
uate the outcomes of initiating therapy during early or acute HIV infection.23-27
As with chronic infection, patients with early HIV infection must be willing
to commit to lifelong therapy and understand the importance of adherence prior
to initiating ART. In some cases, ART may be deferred for clinical or psychosocial
reasons but should be reconsidered as soon as possible. Patients should be initiated
on regimens with proven virologic efficacy, high tolerability, low toxicity, and ease
ERRNVPHGLFRVRUJ
TABLE 4-5. Advantages and Disadvantages of Recommended Initial

Treatment Regimen Components with Supporting Literature
Clinical Trials
Advantages Disadvantages Supporting Evidence
Dolutegravir • Highest genetic barrier to • Combination tablet is SINGLE16
resistance among INSTI-class the largest size among SPRING-217
• Virologic response rates are coformulated regimens
FLAMINGO18
superior to efavirenz and • Insomnia and headache
ritonavir-boosted darunavir reported more
• High efficacy in patients with commonly (≥2%) in
baseline HIV RNA >100,000 clinical trials
copies/mL • Decreases tubular
• Superior to raltegravir in excretion of creatinine
treatment-experienced patients leading to increases in
serum creatinine within
• Superior efficacy and tolerability
the first 4 weeks of
to ritonavir-boosted darunavir
therapy but no effect
or efavirenz
on actual glomerular
• Once-daily dosing filtration
• No contraindicated CYP 3A4 • Reduced absorption
interactions with polyvalent cations
• Can be taken without regard to • Lack of long-term safety
meals record
• Coformulated with abacavir/
lamivudine
Elvitegravir • Superior efficacy to • Significant CYP 3A4 Studies 102, 10313,14

ritonavir-boosted atazanavir interactions Studies 104, 11115
in HIV-infected women • Reduced absorption WAVES19
due to fewer treatment with polyvalent cations
discontinuations
• Must be taken with
• Once-daily dosing food
• Coformulated with tenofovoir • Cobicistat inhibits
disoproxil fumarate/ tubular secretion of
emtricitabine/cobicistat creatinine leading to
and tenofovir alafenamide/ increases in creatinine
emtricitabine/cobicistat (limits use in renal
impairment when
coformulated with
tenofovir)
• Mutations confer cross-
resistance to raltegravir
• Lack of long-term safety
record
(continued)
ERRNVPHGLFRVRUJ
TABLE 4-5. Advantages and Disadvantages of Recommended Initial

Treatment Regimen Components with Supporting Literature (continued)
Clinical Trials
Advantages Disadvantages Supporting Evidence
Raltegravir • Superior efficacy to efavirenz • Reduced absorption STARTMRK11
due to fewer discontinuations with polyvalent cations ACTG A525712,20
• Fewer discontinuations • No coformulated single-
compared to ritonavir-boosted pill tablet
atazanavir or darunavir • Creatinine kinase
• No significant CYP 3A4 elevations reported
interactions • Lower genetic barrier to
• Long-term safety profile resistance than PIs and
available dolutegravir
• Can be taken without regard to
meals
INSTI: integrase strand transfer inhibitor; Pgp: P-glycoprotein; PI: protease inhibitor
of administration. Genotypic drug-resistance testing should be performed prior

to initiation; when the results are available, the treatment regimen can be modi-
fied if warranted. While awaiting resistance test results, a regimen of tenofovir/
emtricitabine plus ritonavir-boosted darunavir is recommended given its high
genetic barrier to resistance. Another reasonable option is tenofovir/emtricitabine
plus dolutegravir. Monitoring of HIV RNA levels, CD4 cell counts, and medication
toxicities is imperative and should be assessed accordingly as described in Table
4-2. Therapy should not be discontinued once initiated because data have shown
treatment interruption may lead to increased risk of AIDS and non-AIDS events
and increased markers for inflammation, immune activation, and coagulation.28,29
SWITCHING ANTIRETROVIRAL THERAPY

Since the advent of ART, HIV treatment has become more potent and better toler-
ated. ART switching, or simplification of therapy, is an option for many patients
currently receiving ART. In clinical practice, changing an antiretroviral regimen
to accommodate issues that may affect regimen adherence or to prevent long-
term complications has become commonplace in patients with suppressed viral
replication.
In the setting of viral suppression, clinicians may consider a regimen switch
in an attempt to (1) reduce pill burden and support adherence, (2) decrease
short- and long-term drug toxicities and improve tolerability, (3) avoid food/fluid
requirements, (4) minimize drug interactions, (5) optimize ART during pregnancy,
and 6) reduce costs.1 The benefits of switching ART must be weighed against the
risks of predisposing the patient to new potential toxicities, the emergence of resis-
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tance mutations, and ultimately jeopardizing future options. The cardinal rule
is to maintain viral suppression. Changing an antiretroviral regimen is generally
safe as long as a critical review of the patient’s complete antiretroviral history
and regimen tolerability, viroimmunologic response, and past resistance tests is
performed prior to the change. Switching from a PI-based regimen to one with a
lower barrier of resistance should only be performed if no resistance is suspected
to other components in the regimen. Consultation with an HIV specialist may be
warranted. After a treatment switch, patients should be monitored closely during
the first 3 months after the change to assess for tolerability, adherence, and labo-
ratory abnormalities. Guidelines recommend a telephone call or clinic visit 1 to 2
weeks after the switch to assess for adherence and tolerability and a viral load test 4
to 8 weeks after the switch to assess for rebound viremia.1 If no specific complaints
or laboratory abnormalities are identified, the clinician may resort back to the
regular schedule for clinical and laboratory findings outlined for all HIV patients.
ROLE OF THE PHARMACIST IN TREATMENT AND ADHERENCE

Pharmacists have established a niche in patient care by performing medication adher-
ence counseling and providing patient education.30 As a vital part of the interprofes-
sional model, pharmacists have the opportunity to assess patient adherence and medi-
cation-related problems thoroughly and engage patients in motivational counseling. In
addition, pharmacists can make interventions on selection, initiation, or discontinuation
of antiretrovirals, dosage adjustments for renal impairment, and monitoring for adverse
drug events.31 Evidence of pharmacist interventions on reducing clinically significant
drug–drug interactions and improvement of comorbid outcomes continue to emerge in
the literature.32,33 Reducing drug–drug interactions in both the inpatient and outpatient
settings has been recognized as a significant improvement in patient care that may be
primarily driven by pharmacists. By assessing medication profiles, pharmacists can select
ART regimens that avoid contraindicated drug interactions. Because of their intimate
knowledge of antiretroviral medications, pharmacists have the potential to be a valuable
resource when initiating treatment as well as in improving patient adherence.
KEY RESOURCES
• Centers for Disease Control and Prevention: Materials on Medication Adherence
http://www.cdc.gov/primarycare/materials/medication/.
o This website provides an educational module of how best to support medication
adherence.
• Department of Health and Human Services. AIDS Info Website.
o Official source for HIV/AIDS information from the U.S. Public Health Service
providing U.S. HIV treatment guidelines, clinical trial information, drug and
vaccine overviews, and patient educational materials. www.aidsinfo.nih.gov.
• Department of Health and Human Services. AIDSinfo HIV Drug Database Mobile
Application for iPhone and Android Devices. https://aidsinfo.nih.gov/apps.
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o These free mobile applications provide information on U.S. HIV treatment

guidelines, FDA-approved and investigational HIV/AIDS-related drugs, cell-
phone-assisted medication reminders to support medication adherence, and a
glossary of over 700 terms including images and audio pronunciation.
• INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation
of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;
373(9):795-807.
o This landmark study highlights the importance of initiating ART early to
decrease the risk of death and prevent transmission of HIV.
• http://www.motivationalinterviewing.org/motivational-interviewing-resources.
o This website provides resources, including videos on motivational interviewing.
• Pharmacist’s Letter: Using Motivational Interviewing to Create Change. Volume
2015, Course No. 243, Self-Study Course #150243. http://pharmacistsletter.therapeu-
ticresearch.com/ce/cecourse.aspx?pc=15-243.
o This continuing education course provides a comprehensive review of motiva-
tional interviewing geared toward pharmacists.
• Saberi P, Dong BJ, Johnson MO, et al. The impact of HIV clinical pharmacists on HIV
treatment outcomes: A systematic review. Patient Prefer Adherence. 2012;6:297–322.
o This systematic review provides evidence of the beneficial impact of HIV phar-
macists on HIV treatment outcomes.
• TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, Gabillard D, et al. A trial of
early antiretrovirals and isoniazid preventative therapy in Africa. N Engl J Med. 2015;
373(9):808-822.
o This landmark study highlights the importance of initiating ART early to
decrease the risk of death and prevent transmission of HIV.
REFERENCES
1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiret-
roviral agents in HIV-1-infected adults and adolescents. Department of Health and Human
Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.
pdf. Last accessed May 23, 2016.
2. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral
therapy in early asymptomatic HIV infection. N Engl J Med. 2015; 373(9):795-807. doi:10.1056/
NEJMoa1506816.
3. TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, Gabillard D, et al. A trial of early
antiretrovirals and isoniazid preventative therapy in Africa. N Engl J Med. 2015; 373(9):808-822.
doi:10.1056/NEJMoa1507198.
4. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-
infected adults in Haiti. N Engl J Med. 2010;363(3):257-266. doi:10.1056/NEJMoa0910370.
5. Kitahata MM, Gange SJ, Abraham AG, et al. NA ACCORD Investigators. Effect of early versus
deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815-1826.
doi:10.1056/NEJMoa0807252.
6. Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons
infected with human immunodeficiency virus: 2013 update by the HIV medicine association of
the Infectious Diseases Society of America. Clin Infect Dis. 2014;58(1):1-10. DOI: 10.1093/cid/
cit757.
7. Centers for Disease Control and Prevention. A guide to taking a sexual history. Atlanta, GA: US
Department of Health and Human Services, CDC. Retrieved August 8, 2016 from www.cdc.gov/
std/treatment/SexualHistory.pdf.
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8. U.S. Department of Health and Human Services. Healthy People 2010: Understanding and
Improving Health. 2nd ed. Washington, DC: U.S. Government Printing Office, November 2000.
9. Oates DJ, Paasche-Orlow MK. Health literacy: Communication strategies to improve patient
comprehension of cardiovascular health. Circulation. 2009;119(7):1049-1051.
10. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/
ritonavir compared with lopinavir in HIV-1-infected treatment naïve patients in the ARTEMIS
trial. HIV Med. 2013;14(1):49-59.
11. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus
efavirenz when combined with tenofovir/emtrictabine in treatment naïve HIV-1 infected
patients: Final 5-years results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77-85.
12. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse
transcriptase inhibitor-sparing antiretroviral regimens for treatment-naïve volunteers infected
with HIV-1: A randomized, controlled equivalence trial. Ann Intern Med. 2014;161(7):461-471.
13. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and teno-
fovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1
infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet.
2012;379(9835):2439-2448.
14. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and
tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricit-
abine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: A randomized,
double-blind, phase 3, non-inferiority trial. Lancet. 2012;379(9835):2429-2438.
15. Wohl D, Oka S, Clumeck N, et al. A randomized, double blind comparison of tenofovir
alafenamide (TAF) vs. tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir,
cobicistat and emtricitabine (E/C/F) for initial HIV-1 treatment: Week 96 results. Paper presented
at: 15th European AIDS Conference; October 22, 2015; Barcelona, Spain.
16. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treat-
ment of HIV-1 infection. N Engl J Med. 2013;369:1807-1818.
17. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretro-
viral-naïve adults with HIV-1 infection: 48 week results from the randomized, double-blind,
non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735-743.
18. Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir
for treatment-naïve adults with HIV-1 infection (FLAMINGO): 96 week results from a random-
ized, open-label, phase 3b study. Lancet HIV. 2015;2(4):e127-136.
19. Squires K, Kityo C, Hodder S, et al. Elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/
tenofovir disoproxil fumarate (TDF) is superior to ritonavir (RTV) boosted atazanavir (ATV) plus
FTC/TDF in treatment naive women with HIV-1 infection (WAVES study). Presented at: Eighth
International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; July
18–22, 2015; Vancouver, BC, Canada. Abstract MOLBPE08.
20. Ofotokun I, Na LH, Landovitz RJ, et al; AIDS Clinical Trials Group A5257 Team; AIDS Clinical
Trials Group A5257 Team. Comparison of the metabolic effects of ritonavir-boosted darunavir
or atazanavir vs raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect
Dis. 2015;60(12):1842-1851.
21. Cahn P, Pozniak AL, Mingrone H, et al; Extended SAILING Study Team. Dolutegravir vs ralte-
gravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: Week 48 results
from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700-
708.
22. Elion R, Molina JM, Ramón Arribas López J, et al; Study 145 Team. A randomized phase 3 study
comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects
with HIV-1 infection: 96-week results. J Acquir Immune Defic Syndr. 2013;63(4):494-497.
23. Hoen B, Dumon B, Harzic M, et al. Highly active antiretroviral treatment initiated early in
the course of symptomatic primary HIV-1 infection: Results of the ANRS 053 trial. J Infect Dis.
1999;180(4):1342-1346.
24. Hogan CM, Degruttola V, Sun X, et al. The setpoint study (ACTG A5217): Effect of immediate
versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individ-
uals. J Infect Dis. 2012;205(1):87-96.
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25. Grijsen ML, Steingrover R, Wit FW, et al. No treatment versus 24 or 60 weeks of antiretro-
viral treatment during primary HIV infection: The randomized Primo-SHM trial. PLoS Med.
2012;9(3):e1001196.
26. Strain MC, Little SJ, Daar ES, et al. Effect of treatment, during primary infection, on establish-
ment and clearance of cellular reservoirs of HIV-1. J Infect Dis. 2005;191(9):1410-1418.
27. SPARTAC Trial Investigators, Fidler S, Porter K, et al. Short-course antiretroviral therapy in
primary HIV infection. N Engl J Med. 2013;368(3):207-217.
28. Strategies for Management of Antiretroviral Therapy Study G, El-Sadr WM, Lundgren J, et al.
CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283-
2296.
29. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in
patients with HIV infection. PLoS Med. 2008;5(10):e203.
30. Murphy P, Cocohoba J, Tang A, et al. Impact of HIV specialized pharmacies on adherence and
persistence with antiretroviral therapy. AIDS Patient Care STDs. 2012;26:526–531.
31. Saberi P, Dong B, Johnson M, et al. The impact of HIV clinical pharmacists on HIV treatment
outcomes: A systematic review. Patient Prefer Adherence. 2012;6:297.
32. Cope R, Berkowitz L, Cha A, et al. Evaluating the effects of an interdisciplinary practice
model with pharmacist collaboration on HIV patient co-morbidities. AIDS Patient Care STDs.
2015;29(8):445-453. doi:10.1089/apc.2015.0018.
33. Billedo JA, Berkowitz L, Cha A. Evaluating the impact of a pharmacist-led antiretroviral stew-
ardship program on reducing drug interactions in HIV-infected patients. J Int Assoc Provid AIDS
Care. 2016;15(1):84-88. doi:10.1177/2325957415600700.
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5
HIV Treatment Failure and
Resistance
Janet Grochowski, PharmD, BCPS, AAHIVP, and
Parya Saberi, PharmD, MAS, AAHIVP
INTRODUCTION
Among the goals of antiretroviral therapy (ART) is to achieve maximal and durable
suppression of human immunodeficiency virus (HIV) replication and prevent the
emergence of drug resistance.1 Treatment failure occurs when patients on ART do
not achieve virologic suppression or experience virologic rebound. These patients
are at risk of developing resistance mutations to one or more components of their
regimen. Pharmacists can help patients achieve virologic suppression, identify
patients with treatment failure, assess for the presence of resistance, aid in inter-
preting HIV resistance testing, and assist in selecting new ART regimens in patients
with treatment failure and resistance.
TREATMENT FAILURE TERMS AND DEFINITIONS
Virologic Failure
The Department of Health and Human Services (DHHS) Panel on Antiretroviral
Guidelines for Adults and Adolescents defines virologic failure as HIV RNA level
consistently >200 copies/mL, indicating the inability to attain or sustain suppres-
sion of viral replication.1
Incomplete Virologic Response

Based on the DHHS guidelines, incomplete virologic response is defined as having
two sequential plasma HIV RNA levels ≥200 copies/mL without documented viral
suppression in a person who has been treated with at least 24 weeks of ART.1
Persistent HIV RNA ≥200 copies/mL is associated with accumulation of drug resis-
tance and virologic failure.2
Virologic Blips
The DHHS guidelines define blips as the occurrence of a single detectable HIV RNA
level and subsequent return to levels below the limit of quantification. Blips are
often low levels of virus and are not usually an indication of virologic failure.1
85
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Low-Level Viremia
These are HIV RNA levels that persistently fall between undetectable and <200
copies/mL in individuals on ART. Studies have reported conflicting results as to
whether low-level viremia can result in virologic rebound and evolution of drug
resistance.2-4 One long-term study found a correlation between the risk of viro-
logic failure and an increasing level of viremia, while results from another study
showed that, as a threshold for virologic failure, HIV RNA levels of 200 copies/
mL and <50 copies/mL had the same predictive value for subsequent rebound to
>200 copies/mL.3,4
Suboptimal CD4+ Cell Count Response

ART initiation and viral suppression will result in an increase in CD4+ cell count in
most individuals.1 However, in about 15% to 20% of individuals who start ART at
CD4+ cell counts <200 cells/mm3, CD4+ count recovery may plateau at these low
levels.5,6 Persistently low CD4+ cell counts despite ART use and viral suppression
have been related to an increased risk of morbidity and mortality.7
RESISTANCE
Basic Principles
Transmitted HIV resistance occurs when an individual is infected with a virus that
is already resistant to one or more drugs. The probability that an individual will
acquire a drug-resistant virus can be associated with the prevalence of drug resis-
tance among the population of individuals participating in high-risk behaviors. In
the United States, a study conducted between 2003 and 2008 by the U.S. Center for
AIDS Research showed a prevalence of genotypic resistance to at least one antiret-
roviral (ARV) to be 14.2% (8.3% non-nucleoside reverse transcriptase inhibitor
[NNRTI], 8.2% nucleoside/tide reverse transcriptase inhibitor [NRTI], and 4.2%
protease inhibitor [PI]).8 Importantly, the prevalence of drug resistance reported in
this study varied by geographic region.8
In contrast to transmitted resistance, acquired resistance emerges while a person
is receiving ART and can occur for a variety of reasons, including suboptimal medi-
cation adherence, suboptimal virologic potency of the ART regimen, or interac-
tions that negatively influence ART drug concentrations.9 Innately drug-resistant
viruses that have not been exposed to selective drug pressure are rare.10
Genetic Barriers to Resistance

Genetic barrier to resistance refers to the number of HIV mutations required for the
development of resistance to a specific ARV medication. High barrier to resistance
is considered when a greater number of critical mutations are necessary to render
treatment ineffective. In contrast, ARVs that require fewer mutations before they
are no longer effective are considered to have a lower barrier to resistance.9
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CHAPTER 5 HIV Treatment Failure and Resistance 87
Table 5-1 indicates the relative genetic barrier to resistance varies for some
antiretrovirals. For example, among individuals failing a dolutegravir (DTG)-con-
taining regimen, resistance is uncommon, and transmitted resistance has not yet
been identified. Darunavir/cobicistat (DRV/c), darunavir/ritonavir (DRV/r), and
DTG are considered to have a greater barrier to resistance compared with lopinavir/
ritonavir (LPV/r). DRV/c, DRV/r, and LPV/r have a greater barrier to resistance than
maraviroc (MVC), atazanavir/cobicistat (ATV/c), and atazanavir/ritonavir (ATV/r).
Etravirine (ETR), elvitegravir (EVG), and raltegravir (RAL) have a greater barrier
to resistance than efavirenz (EFV), enfuvirtide (T-20), rilpivirine (RPV), and nevi-
rapine (NVP).1,10
Of the NRTIs, abacavir (ABC), zidovudine (ZDV), stavudine (d4T), didanosine
(ddI), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF) have a
relatively greater barrier to resistance compared with lamivudine (3TC) or emtric-
itabine (FTC). 10
ARV Resistance Mutations

The naming convention of ARV resistance mutations consists of a letter indicating
the amino acid associated with wild-type virus, a number that indicates the muta-
tion’s position in the protein, followed by another letter that indicates the substitu-
tion or substitutions that confer viral resistance. For example, M184V indicates M
= methionine at the 184 position was substituted by V = valine causing resistance
TABLE 5-1. Genetic Barrier to Resistance Adapted from Panel on

Antiretroviral Guidelines for Adults and Adolescents
Genetic Barrier to Resistance Antiretroviral
Higher Integrase strand transfer inhibitors Dolutegravir
Non-nucleoside reverse transcriptase inhibitors Etravirine
Protease inhibitors Darunavir/ritonavir

Darunavir/cobicistat
Lower Fusion inhibitors Enfuvirtide
Integrase strand transfer inhibitors Elvitegravir

Raltegravir
Non-nucleoside reverse transcriptase inhibitors Delavirdine

Efavirenz
Nevirapine
Nucleoside/tide reverse transcriptase inhibitor Emtricitabine

Lamivudine
(Source: Data from references 1 and 10.)
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to some NRTIs. In reference to resistance mutations, amino acid abbreviations are

as follows: alanine (A); cysteine (C); aspartate (D); glutamate (E); phenylalanine
(F); glycine (G); histidine (H); isoleucine (I); lysine (K); leucine (L); methionine
(M); asparagine (N); proline (P); glutamine (Q); arginine (R); serine (S); threonine
(T); valine (V); tryptophan (W); tyrosine (Y).11
In some cases, a viral mixture may be present when there is more than one
amino acid substitution detected at a single position. In this case, the compo-
nents of the mixture are written after the position, often separated by a slash. For
example, K103K/N denotes the sequence has a mixture of the wild-type residue
lysine (K) and the mutant residue asparagine (N) at position 103.
RESISTANCE TESTING
Resistance testing is performed to detect transmitted drug resistance in treat-
ment-naïve patients or acquired resistance in patients experiencing virologic
failure. As a result, testing results can be helpful in determining the most appro-
priate ARV regimen in both treatment-naïve and treatment-experienced patients.
Because 10% to 17% of ART-naïve individuals have drug resistance to at least
one ARV medication, resistance testing is indicated for all individuals living with
HIV who present to care for the first time with either acute or chronic HIV infec-
tion.1 In the rare case when ARV treatment is postponed, repeat resistance testing
should be considered prior to ARV initiation because patients may have had subse-
quent exposure to a drug-resistant virus (i.e., super infection).1
In those who are experiencing virologic failure and/or have HIV RNA levels
>1,000 copies/mL, resistance testing is a necessary aid in choosing active medica-
tions for a new ARV regimen. If HIV RNA is between 500 and 1,000 copies/mL,
resistance testing may be considered although results may be incomplete. This
is because amplification of a small number of HIV copies may render inaccurate
genotypic results.12 Resistance-testing assays are not generally recommended in
individuals when HIV RNA is <500 copies/mL because results are not frequently
successful with such low HIV RNA levels.1
Genotypic Assays
Genotypic assays distinguish drug-resistance mutations in applicable viral genes.
They generally include the sequencing of the reverse transcriptase (RT) and
protease (PR) genes to detect the mutations that convey drug resistance. If inte-
grase resistance strand transfer inhibitor (INSTI) resistance is suspected, it can be
included with the RT and PR assay.
Genotypic assays are generally lower in cost and have a shorter processing
time, and the interpretation of the results is usually less complicated than pheno-
typic assays. The genotypic assay can also identify if a combination of wild-type
and drug-resistant viruses is present. In ARV-naïve individuals, genotypic assays
are generally performed because one test can reveal combinations of RT, PR genes,
ERRNVPHGLFRVRUJ
and, if included, INSTI genes. The gp41 (envelope) genotypic assay, used for
detecting resistance to the fusion inhibitor enfuvirtide, is also available. Results of
genotypic assays usually take 1 to 2 weeks.1
Phenotypic Assays
Phenotypic assays quantify the capability of a virus to replicate in different concen-
trations of ARV drugs. This is accomplished by inserting RT, PR, INSTI, and enve-
lope gene sequences originated from an individual’s plasma HIV RNA into the core
of a laboratory clone of HIV.1 Another method uses generated pseudotyped viruses
that demonstrate the individual-derived HIV genes.11 A reporter gene is used to
monitor reproduction of these viruses at different drug concentrations and is then
compared with reproduction of a reference HIV strain. The drug concentration
that is required to prevent HIV replication by 50% (inhibitory concentration 50,
or IC50) along with how this concentration compares to the concentration of drug
required to inhibit a wild-type HIV clone is reported. The results of phenotypic
assays are reported as fold change above the IC50 of the reference strain.1,13
Phenotypic assays are more costly than genotypic assays, and the results take
approximately 2 to 3 weeks. Clinically significant fold-increase cutoffs are available
for several ARVs, but for a number of ARVs specific fold-increase in IC50 is lacking.
In patients with various drug-resistant mutations, especially to PIs, etravirine, and
some NRTIs such as tenofovir, phenotypic testing in addition to a genotypic assay
can provide additional useful information.1 Phenotypic assays, unlike genotypic
assays, can give the overall cumulative impact of drug resistance for a single ARV.
Phenotypes are recommended to be added to a genotype test in those with known
or suspected complex resistance.
Archived DNA Genotypic Assays

Archived DNA genotypic assays used for suppression management (e.g., Geno-
Sure Archive®) are an option when HIV RNA levels are <500 copies/mL. They test
archived HIV proviral DNA inserted into the host cells during viral replication.
One study examined 48 paired plasma RNA and cell DNA assays where results were
discordant when the archived DNA genotypic assay overlooked mutations seen
in plasma RNA. Four out of 48 tests in PR regions were discordant with historical
RNA and 6 out of 48 for RT regions were discordant. The major false omission rate
(when the archived DNA genotypic assay interprets a resistant variant as wild-
type) ranged from 2% to 4%.14 Due to these discordant results, the clinical useful-
ness of this assay has yet to be determined.1
Virtual Phenotypes
A virtual phenotype is an alternate method for interpreting genotypic drug-
resistance information. The genotypic records of the individual’s HIV RNA are
compared with a sizeable database of paired genotypes and phenotypes from prior
samples. This linkage allows for creation of a “virtual phenotype” by allocating
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estimated fold changes in IC50 using historical data. Virtual phenotypes have not
been shown to better predict clinical response compared to genotypes alone when
choosing next-best regimens and are infrequently used clinically.1
Tropism Assays
A coreceptor tropism assay should be performed if contemplating using a CCR5
coreceptor inhibitor (e.g., maraviroc), and a CCR5 inhibitor should only be used
in those with R5 virus. Phenotypic coreceptor assays are generally used in clinical
practice. If virologic failure occurs while on a CCR5 coreceptor inhibitor, a co-
receptor tropism assay is recommended to test for a shift from a CCR5 to a CXCR4-
using virus. Resistance to CCR5 coreceptor inhibitors is uncommon.1
Drug Resistance by Antiretroviral Class

The HIV virus quickly generates new variants to assist in bypassing the immune
system, thus allowing the virus to foster development of ARV drug resistance. In
the case of an incompletely suppressive regimen or poor adherence, HIV replicates
and the viral mutations that occur are selected by the ARVs that are being used.
These mutations selected by a specific drug may potentiate resistance to that drug
as well as to other drugs in the same therapeutic class.9 Cross-resistance between
ARV therapeutic classes does not occur. This is true even when viruses have high
resistance levels to drugs in one ARV class.10
Resistance Associated with NRTIs

The NRTI class preserves some virologic activity against viruses with NRTI muta-
tions, and this is potentially due to the loss of viral fitness (the ability of the
virus to replicate) with some of the NRTI mutations. The M184V mutation is a
mutation that decreases viral fitness and therefore, when present, may correlate
with decreasing plasma HIV RNA levels by 0.5 log10 copies/mL lower than wild-
type virus.10 The M184V mutation also increases the viral susceptibility (hyper-
sensitivity) to TDF, d4T, and ZDV. Consequently, even in the presence of a M184V
mutation, the use of 3TC or FTC may be continued in salvage regimens because of
their effect on viral fitness, their retention of partial activity, and potential hyper-
sensitivity to other ARVs (e.g., TDF).10
The M184V is commonly the first to appear in a failing regimen that includes
3TC or FTC plus either one of the thymidine analogues, d4T or ZDV. If the failing
regimen is continued, then increasing acquisition of thymidine analogue associ-
ated mutations (TAMs) ensues. TAMs have become less common because thymi-
dine analogue NRTIs are less commonly used and are no longer recommended
among first-line treatment options. Six major TAMs exist: M41L, D67N, K70R,
L210W, T215Y/F, and K219Q/E/N/R—all of which confer different degrees of
cross-resistance with all NRTIs. Cross-resistance increases across the NRTI class as
the number of TAMs increase. There are two different TAM pathways. The M41L,
L210W, and T215Y pathway is associated with greater NRTI cross-resistance,
smaller decreases in resistance when M184V is present (i.e., hypersensitivity), and
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higher ZDV resistance. The second pathway—D67N, K70R, and K219Q—has the
opposite effect: it results in less NRTI cross-resistance, greater decreases in resis-
tance when M184V is present, and lower ZDV resistance.15
When using the current recommended NRTI backbones, ABC + 3TC (or FTC)
or TDF + FTC (or 3TC) or TAF + FTC (or 3TC), without any thymidine analogues,
the common mutations seen upon failure are M184V, K65R, and L74V. K65R is
the main mutation that occurs with TDF failure (although it can occur with ABC);
L74V is the more common mutation that occurs with ABC failure.15 Table 5-2
depicts important NRTI mutations.
Resistance Associated with NNRTIs

K103N is the most common NNRTI mutation, conferring high-level resistance to
the first-generation NNRTIs (DLV, EFV, and NVP) but not to ETR or RPV. It can occur
as the first resistance mutation during virologic failure and can precede the M184V
mutation. The Y181C mutation is selected by NVP and increases the risk of EFV
failure and confers cross-resistance to all NNRTIs. The Y181C mutation has moder-
ate-to-severe impact on ETR and has moderate cross-resistance to RPV. E138K is a
novel mutation associated with RPV failure and leads to cross-resistance to ETR.9
In general, ETR has a higher barrier to resistance compared to the other
NNRTIs. There are 17 mutations that are weighted based on their impact on
response to ETR.16
Viral response to ETR can be predicted by calculating the weighted muta-
tion score (Table 5-3). First, NNRTI mutations present on cumulative genotypes
need to be obtained. Then, the individual weight factors for each mutation are
added to obtain an ETR weighted mutation score. This score is then compared
with the response scale to determine the chance of virologic suppression with
the use of ETR. For example, if the RT mutations include K101P (weight score
2.5) and Y181V (weight score 3), this would result in a total weight score of 5.5,
where response rate would be expected to be only ~38%. This is considered a low
response rate, and ETR would not be recommended in a patient with these RT
mutations.
Resistance Associated with PIs

There are generally two categories of PI mutations:
1. major mutations that cause significant drug resistance and can lead to
some cross-class resistance
2. accessory mutations that can augment drug resistance or viral fitness
when a major mutation is present
A small number of major mutations are specific to a particular PI and do not confer
cross-class resistance; examples include the I50L mutation to ATV and the D30N
mutation to NFV.
Cross-resistance in this class of ARVs is complex due to the large number
of PI resistance mutations and the fact that mutations at the same position can
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TABLE 5-2. Selected Important Information on NRTI Resistance

Note: Current recommended NRTIs are listed in bold-face type.
Important NRTI Mutations
Mutation Selected By Effects
M184V Emtricitabine Loss of susceptibility to emtricitabine &
Lamivudine lamivudine
Decrease in susceptibility to abacavir
Increase susceptibility to tenofovir,
zidovudine, stavudine
K65R Tenofovir Decrease susceptibility to tenofovir,

Abacavir abacavir, didanosine, emtricitabine,
lamivudine
Didanosine
Increase susceptibility to zidovudine
L74V Abacavir Decrease susceptibility to abacavir,

Didanosine didanosine
Increase susceptibility to tenofovir,
zidovudine
TAMs (M41L, D67N, K70R, Zidovudine Decrease susceptibility to all NRTIs based on
L210W, T215Y/F, and Stavudine number of TAMs
K219Q/E/N/R)
Q151M complex Zidovudine/didanosine Q151M complex: resistance to all NRTIs,

Didanosine/stavudine except tenofovir
T69 insertion Zidovudine/didanosine T69 insertion: resistance to all NRTIs

Didanosine/stavudine
E44D, V118I Zidovudine Increase NRTI resistance

Stavudine
NRTIs: nucleotide/side reverse transcriptase inhibitors; TAMs: thymidine analogue associated mutations
(Source: Adapted with permission from Gallant JE. Antiretroviral drug resistance and resistance testing. Top HIV Med.
2005 Dec–2006 Jan;13(5):138-142.)
have different effects on PI susceptibility. Examples of mutations that can have

some cross-class resistance are V32I, M46I/L, G48V/M, I50V, I54V/T/A/L/M, L76V,
V82A/T/F/S, I84V, N88S, and L90M.
Even with the existence of a number of major PI mutations, DRV generally
preserves some susceptibility. Clinical trials demonstrated that it takes the occur-
rence of three or more of the following mutations to weaken the virologic response
to DRV: V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, and L89V.10 Twice-
daily dosing of DRV/r (darunavir 600 mg/ritonavir 100 mg twice daily instead of
darunavir 800 mg/ritonavir 100 mg once daily or darunavir 800 mg/cobicistat 150
mg) is recommended if one or more of these mutations are present.9,17
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TABLE 5-3. Weight Factor of ETR Resistance-Associated Mutations

Resistance-Associated Mutations Weight Score
Y181I/V 3
L100I, K101P, Y181C, M230L 2.5
V106I, V179F, E138A, G190S 1.5
V90I, A98G, K101E/H, V179D/T, G190A 1
Response Rates1 Based on Total Weight Score

0–2 74% Highest response
2.5–3.5 52% Intermediate response
>4 38% Reduced response

(Source: Data from reference 16.)
Resistance Associated with INSTIs

The resistance pattern for RAL involves three independent primary mutations
occurring at early failure time points with nonoverlapping genetic pathways:
N155H, Q148H/R/K, and, less commonly, Y143/R/C/H. There are secondary muta-
tions that appear specifically with each primary mutation.18,19 Table 5-4 depicts the
major resistance pathways of RAL.
RAL selected mutations may have cross-resistance to EVG. Resistance path-
ways 148 and 155 result in EVG resistance; however, mutations at the 143 position
do not influence the susceptibility of EVG, which has additional primary muta-
tions at codon 66 that select for high resistance. E92Q, a RAL secondary mutation,
is a primary resistance mutation for EVG.20 Table 5-5 depicts the major resistance
pathways of EVG.
DTG has a higher barrier to resistance than RAL or EVG. The primary muta-
tions at codons 66, 92, 143, and 155 do not confer DTG resistance; but, if they are
present, the dose of DTG should be increased from 50 mg once daily to 50 mg twice
a day. Mutations at codon 148 result in reduced susceptibility to DTG. The activity
of DTG continues to decline as additional mutations occur.21 The VIKING-3 study
looked at DTG 50 mg twice a day in INSTI-experienced patients. Patients with
N155H, Y143C/H/R, T66A, or E92Q—but no Q148 mutation—achieved a treat-
ment response (HIV RNA <50 copies/mL at week 24 of therapy) of 79%. Patients
with Q148 plus one secondary mutation (either G140A/C/S, E138A/K/T, or L74I)
achieved a lower response rate of 58%. Patients with Q148 and two or more
secondary mutations achieved a response rate of only 24%.22
Resistance Associated with CCR5 Coreceptor Inhibitors

R5-tropic HIV strains predominate in early infection and HIV transmission. Viruses
that remain R5-tropic are susceptible to MVC, the CCR5 coreceptor inhibitor. As
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TABLE 5-4. Major Pathways of Resistance with RAL

Major Pathways of Resistance with Raltegravir
Primary Muations Secondary Mutations
N155H L74M, E92Q, T97A, V151I, G163R
Q148H/K/R L74M, G140A/S, E138K
Y143R/H/C E92Q, T97A

(Source: http://depts.washington.edu/nwaetc/presentations/uploads/71/resistance_to_integrase_strand_transfer_
inhibitors.pdf. Accessed on May 30, 2016.)
TABLE 5-5. Major Pathways of Resistance with EVG

Major Pathways of Resistance with Elvitegravir
Primary Mutations Secondary Mutations
E92Q H51Y, L68V, S153A, E157Q
Q148H/K/R G140C
N155H E157Q
T66A/I ?
(Source: http://depts.washington.edu/nwaetc/presentations/uploads/71/resistance_to_integrase_strand_transfer_
inhibitors.pdf. Accessed on May 30, 2016.)
HIV strains mutate and evolve, some become X4-tropic, rendering them resistant
to MVC, and therefore tropism assays must be performed before starting the drug.23
Two types of mechanisms can result in resistance to MVC. The most common
pattern is when the virus starts to use the CXCR4 coreceptor for cell entry. Rarely,
changes in the V3 loop occur in gp120, and less frequently gp41, and are associ-
ated with resistance to CCR5 coreceptor inhibitors.10
MANAGING A PATIENT WITH ARV TREATMENT FAILURE
Identifying Causes of ARV Failure

Virologic failure can happen for many reasons (suboptimal adherence, patient-
related factors, and regimen-related factors), and the causes need to be identified
with the goal of returning to viral suppression.
Given the need for lifelong medication treatment, suboptimal adherence may
occur; therefore, barriers to ARV adherence need to be corrected while other patient-
and regimen-related issues are addressed. Barriers to adherence include: regimen
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complexity such as high pill burden/dosing frequency, medication adverse effects,

comorbidities (active substance abuse, neurocognitive deficits, psychiatric illness,
etc.), cost of ARVs, interruption in access to medications, and food requirements.
Regimen-related factors resulting in virologic failure include presence of
drug-resistant virus, prior treatment failures, suboptimal pharmacokinetics (e.g.,
malabsorption), drug–drug interactions, and low virologic potency of the ARV
regimen. Patient-related factors that can result in virologic failure include a high
pretreatment HIV RNA level and lower CD4+ nadir.
The pharmacist should assess medication tolerability and ensure proper
absorption of ARVs. This may include determining the patient’s ability to adhere
to food requirements; assessing for presence of side effects such as nausea,
vomiting, and diarrhea; and identifying the presence of concomitant medica-
tions that could negatively influence ARV absorption or metabolism (including
prescription, herbal, or over-the-counter medications) through drug interactions.
Therapeutic drug monitoring may be considered if impaired drug absorption and/
or decreased ARV exposure is thought to be the cause of treatment failure. If resis-
tance is suspected, pharmacists should recommend resistance testing when the
patient is still taking the failing ARV regimen or within 4 weeks of ARV discon-
tinuation. If more than 4 weeks have passed since the suspected failing regimen
was discontinued, the lack of selective drug pressure can cause some mutations
to revert back to wild-type. However, resistance testing should still be performed
because it is possible that mutations may still be present at low levels.
Obtaining Complete ARV Treatment and Resistance-Testing History

To evaluate the extent of drug resistance, the pharmacist should review the
complete past ARV treatment history; all previous resistance test results must
be taken into consideration because drug resistance is cumulative. Records from
previous providers and clinics must be obtained and included in the full history
assessment.
Selecting a New ARV Regimen

Once regimen failure is confirmed, every effort should be made to assess the
factors contributing to suboptimal response to ART. In the case of poor medica-
tion adherence due to high pill burden/frequency, simplification by using fixed-
dose combinations may be an option, or, if possible, switching from a twice-daily
to a once-daily regimen. If side effects are a cause of suboptimal adherence, then
mitigation can include switching one ARV to another in the same class, switching
from one class to another (e.g., boosted PI to INSTI), and symptomatic treatment
(e.g., antidiarrheal or antiemetic medications).
When switching regimens due to virologic failure, the preferred regimen
should contain two, and ideally three, fully active drugs. The switch should be
based on resistance testing; ART history, response, and tolerability; and the mech-
anism of action of drug classes. In the presence of drug resistance, some ARVs,
especially NRTIs, may provide partial activity to a regimen. Other agents such
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as the NNRTIs, RAL, and T-20 are not capable of contributing any activity once
resistance has developed. It should not be assumed that using an ARV to which
a patient has not been exposed will ensure that the ARV will be fully active. This
is due to potential cross-resistance, especially in drugs from the same class. There
is also the potential that archived drug resistance may not be revealed by drug-
resistance testing, particularly if the test was done several months after the drug’s
discontinuation. Consultation with an HIV expert may be required to design a
new antiretroviral regimen for patients with complex drug resistance.1
If an ARV regimen consisting of three fully active drugs (based on resistance
testing and treatment history) is not an option, there are data to support the use
of some boosted PIs plus one other fully active ARV or several partially active ARVs
(i.e., drugs predicted to decrease HIV RNA but not as extensively as if there had
been no underlying resistance) to lower HIV RNA levels in the majority of indi-
viduals.1 Active drugs may be ARVs with unique mechanisms of action or newer
members of existing drug classes that are active against HIV that is resistant to
older drugs in the same class.
Introducing a New Regimen to a Patient

Once it has been decided to change the ARV regimen, the pharmacist should play
an active role in identifying the next-best ARV regimen, counseling the patient
on the new medications, assessing food requirements and drug–drug interactions
(including other prescription and nonprescription medications), and continu-
ously reviewing adherence barriers and troubleshooting ways of overcoming these
barriers. The pharmacist should confirm that the regimen change has been correctly
sent to the dispensing pharmacy, that prior regimens were properly discontinued,
and that there are no insurance problems that would delay providing the new
regimen to the patient.
Providing Close Follow-Up and Monitoring

After it has been established that the patient has received all of the components
of the new regimen and has started taking it, he or she should be evaluated
frequently. A follow-up phone call to the patient or a clinic visit with the phar-
macist in about 1 to 2 weeks after regimen change should be done to monitor
for side effects and adherence. Laboratory testing to assess HIV RNA should
be performed at 4 to 8 weeks following regimen initiation to assess adherence
and potency of the regimen. Preexisting laboratory abnormalities that may be
affected by the new regimen should be evaluated, and other safety laboratory
tests should be conducted on a regular basis and within 3 months of the regimen
switch.1
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MANAGING PATIENTS WHO HAVE FAILED FIRST-LINE ARV

REGIMENS
Managing Low-Level Viremia and Viral Blips

Patients with HIV RNA below the lower limit of quantification with transient
increases in HIV RNA (i.e., blips) do not require a change in treatment.1 However,
there is no consensus on how to manage patients with persistent HIV RNA
levels that are above the lower limit of quantification and below 200 copies/mL
(i.e., low-level viremia). Because the risk of emerging resistance in patients with
persistent low-level viremia is low, it is recommended that these patients maintain
their current regimen and have HIV RNA levels monitored at least every 3 months
to assess the need for ART changes in the future.1
Failing an NNRTI Plus Dual NRTI Regimen

If an individual fails an NNRTI-based regimen, resistance to the NNRTI and
resistance to 3TC and FTC should be suspected (if 3TC or FTC were included in
the failing regimen). The SECOND-LINE,24 HIV STAR Study,25 and the EARNEST
Trial26 investigated the activity of boosted PIs or INSTIs with NRTIs in patients
failing NNRTI-based regimens. Regimens containing a ritonavir-boosted PI (PI/r)
combined with NRTIs were as active as regimens containing the PI/r combined
with RAL in the SECOND-LINE and the EARNEST trials. The HIV STAR and
EARNEST studies demonstrated higher virologic suppression rates with the use of
a PI/r plus NRTIs than with a PI/r alone. Therefore, patients with NNRTI resistance
can often be treated with a boosted PI plus NRTIs or RAL. Even though LPV/r was
used in these studies, most other boosted PIs should perform comparably. The
INSTIs (EVG or DTG) combined with a boosted PI—or ETR with a boosted PI—may
also be potential options in this setting, although more data are needed.1
Failing a Boosted PI Plus Dual NRTI Regimen

Boosted PIs have a high genetic barrier to resistance; therefore, failure in these
cases is often due to nonadherence, food requirements, or drug–drug interac-
tions. In these instances, pharmacists should evaluate and review any barriers to
adherence, such as tolerability, pill burden, and pill size. Ruling out issues with
food requirements and drug–drug interactions is also necessary. Individuals may
present with no, or limited, 3TC and FTC resistance. If tolerability or interactions
are leading to virologic failure, modifying the regimen to a different boosted PI
plus NRTIs or switching to a non-PI-based regimen that contains more than two
fully active agents are options.1
Failing an INSTI Plus Dual NRTI Regimen

Virologic failure with a regimen containing RAL or EVG and 3TC or FTC can often
lead to 3TC or FTC resistance and, in some cases, INSTI resistance. In individ-
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uals failing RAL or EVG, the virus may maintain susceptibility to DTG. If there
is resistance to RAL and EVG or INSTI drug resistance is suspected, DTG 50 mg
twice daily may be an option. However, if the Q148 mutation exists, using DTG
twice daily is less likely to achieve viral suppression. These patients may be treated
with a boosted PI plus NRTIs. If INSTI resistance is not present, another treatment
option may be to combine a boosted PI with DTG.1,22 In clinical trials, a regimen
consisting of DTG plus two NRTIs as first-line treatment has not resulted in devel-
oping resistance to DTG.1
MANAGING PATIENTS WHO HAVE FAILED MULTIPLE ARV

REGIMENS
Depending on treatment history and drug-resistance data, if the virus does not
have documented PI resistance or if the individual has never been treated with a
PI, then the PI class is an important option for patients who have failed multiple
regimens. A boosted PI should then be combined with susceptible NRTIs, INSTIs,
or NNRTIs after considering potential drug–drug interactions between agents.
Ideally, the new regimen will include a minimum of two and preferentially three
fully active agents. CCR5 coreceptor inhibitors can be considered after a tropism
assay has been performed.1
More recently, there are fewer individuals with multiclass ARV resistance due
to the currently available treatment options.27 There is little evidence supporting
the use of NNRTIs, EVG, RAL, or T-20 in a regimen if resistance to these ARVs
has been identified. The persistent use of these drugs, especially the INSTIs in the
presence of virologic failure, may result in the accumulation of more mutations,
limiting future regimen choices.1
In the rare case when maximal virologic suppression cannot be achieved, the
goals of ART will be to preserve immunologic function, avoid disease progression,
and reduce resistance to drug classes that may preclude future treatment options.
Consensus is lacking on the optimal clinical management of these individuals.
Partial virologic suppression of HIV RNA of >0.5 log10 copies/mL from baseline can
be clinically beneficial.1

Pharmacists can play an active role in assisting patients to achieve their treatment goal
of virologic suppression. In the case of virologic failure due to incomplete adherence, phar-
macists can use motivational interviewing skills to assess and manage adherence barriers.
If drug resistance is the suspected cause of virologic failure, pharmacists should recom-
mend resistance testing and review the entire ARV treatment and resistance test history,
working with healthcare providers to help design the next ARV regimen.
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When a new regimen is started, the pharmacist should counsel the patient on the new
medications along with resolving any potential barriers to adherence. The pharmacist
can also confirm that the dispensing pharmacy has received the regimen change and that
insurance will cover the medications.
Lastly, the pharmacist must continue to follow the patient frequently after the change in
regimen. Laboratory testing should assess HIV RNA after 4 to 8 weeks to verify adherence
and potency of the regimen. The pharmacist should order and monitor safety laboratory
tests on a regular basis and within 3 months of the regimen switch.
KEY RESOURCES
• 2017 Update of the Drug Resistance Mutations in HIV.
https://www.iasusa.org/sites/default/files/2017-drug-resistance-mutations-hiv-1-figure.
pdf
o Tool identifies key mutations associated with ARV resistance so users can make
therapeutic decisions.
o Hard-copy pocket cards are available for a nominal fee.
• HIV French Resistance, HIV-1 Drug Resistance Interpretation’s Algorithms.
http://www.hivfrenchresistance.org/2015/Algo2015-hiv1.pdf
o Table of genotype interpretations for RT, PR, Fusion Inhibitor, and INSTI muta-
tions.
• Stanford University HIV Drug Resistance Database.
http://sierra2.stanford.edu/sierra/servlet/JSierra?action=mutationsInput
o Web-based tool allows the user to enter PR, RT, and INSTI mutations from all
resistance tests and receive an output displaying mutation comments, scores,
and predicted antiretroviral resistance.
REFERENCES
Services. Updated July 14, 2016. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultand
adolescentgl.pdf. Accessed August 7, 2016.
2. Aleman S, Söderbärg K, Visco-Comandini U, et al. Drug resistance at low viraemia in HIV-1-
infected patients with antiretroviral combination therapy. AIDS Lond Engl. 2002;16(7):1039-1044.
3. Riabaudo H, Lennox J, Currier J, et al. Virologic failure endpoint definitions in clinical trials:
Is using HIV-1 RNA <200 copies/mL better than <50 copies/mL? An analysis of ACTG studies.
Poster Abstract 580 Presented at: 16th Conference on Retroviruses and Opportunistic Infections;
February 8–11 2009; Montreal, Canada.
4. Laprise C, de Pokomandy A, Baril J-G, et al. Virologic failure following persistent low-level
viremia in a cohort of HIV-positive patients: Results from 12 years of observation. Clin Infect Dis
Off Publ Infect Dis Soc Am. 2013;57(10):1489-1496.
5. Kelley CF, Kitchen CMR, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in
HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis Off Publ Infect
Dis Soc Am. 2009;48(6):787-794.
6. Lok JJ, Bosch RJ, Benson CA, et al. Long-term increase in CD4+ T-cell counts during combina-
tion antiretroviral therapy for HIV-1 infection. AIDS Lond Engl. 2010;24(12):1867-1876.
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7. Engsig FN, Zangerle R, Katsarou O, et al. Long-term mortality in HIV-positive individuals virally
suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis. 2014;58(9):1312-1321.
8. World Health Organization HIV Drug Resistance Report 2012. Geneva, Switzerland. http://apps.
who.int/iris/bitstream/10665/75183/1/9789241503938_eng.pdf. Accessed April 24, 2016.
9. Grant PM, Zolopa AR. HIV-1 Resistance to antiretrovirals. In: AAHIVM Fundamentals of HIV Medi-
cine, 2012 Edition. Washington, DC: American Academy of HIV Medicine; 2012:397-416.
10. Tang MW, Shafer, RW. HIV-1 Antiretroviral resistance scientific principles and clinical applica-
tions. Drugs. 2012;72(9):e1-e25. http://hivdb.stanford.edu/pages/pdf/Tang.AIDSDrugs.2012.pdf.
Accessed May 14, 2016.
11. Wensing, AM, Calvez, V, Gunthard HF, et al. 2015 Update of the drug resistance mutations in
HIV-1. Top Antriviral Med. 2015;23(4):132-141.
12. Gonzalez-Serna A, Min JE, Woods C, et al. Performance of HIV-1 drug resistance testing at
low-level viremia and its ability to predict future virologic outcomes and viral evolution in treat-
ment-naive individuals. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014;58(8):1165-1173.
13. Shafer RW. Assays for antiretroviral resistance. HIV InSite Knowledge Base Chapter. Website:
http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-02-03. June 2002. Accessed May 1,
2016.
14. Toma1 J, Tan Y, Cai1 S, et al. Drug resistance profiles derived from HIV-1 DNA in ARV
suppressed patients correlate with historical resistance profiles obtained from HIV-1 plasma
RNA. In: Trending News in HIV and Associated Co-Morbidities. Interscience Conference on Antimi-
crobial Agents and Chemotherapy; September 17–21, 2015; San Diego, CA.
15. Gallant JE. Antiretroviral drug resistance and resistance testing. Top HIV Med. 2005 Dec–2006
Jan;13(5):138-142. http://www.iasusa.org/sites/default/files/tam/13-5-138.pdf. Accessed May 14,
2016.
16. Vingerhoets J, Tambuyzera L, Azijna H, et al. Resistance profile of etravirine: Combined analysis
of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical
studies. AIDS. 2010;24:503–514.
17. Prezista [package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ 08560; 2006. https://www.
prezista.com/sites/default/files/pdf/us_package_insert.pdf. Accessed October 4, 2016.
18. Fransen S, Gupta S, Danovich R, et al. Loss of raltegravir susceptibility by human immuno-
deficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J Virol.
2009;83(22):11440-11446.
19. Métifiot M, Marchand C, Maddali K, et al. Resistance to integrase inhibitors. Viruses.
2010;2(7):1347-1366.
20. Quashie PK, Mesplède T, Wainberg MA. Evolution of HIV integrase resistance mutations. Curr
Opin Infect Dis. December 2012:1. doi:10.1097/QCO.0b013e32835ba81c.
21. Osterholzer DA, Goldman M. Dolutegravir: A next-generation integrase inhibitor for treat-
ment of HIV Infection. Clin Infect Dis. 2014;59(2):265–271. http://www.natap.org/2014/HIV/
Clin2014--265-71.pdf. Accessed May 30, 2016.
22. Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients with
raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J
Infect Dis. 2014;210(3):354-362.
23. Livingston, S, Young B, Markowitz, M. HIV virology. In: AAHIVM Fundamentals of HIV Medicine,
2012 Edition. Washington, DC: American Academy of HIV Medicine; 2012:329-350.
24. Second-Line Study Group, Boyd MA, Kumarasamy N, et al. Ritonavir-boosted lopinavir plus
nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir
plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard
first-line ART regimen (SECOND-LINE): A randomised, open-label, noninferiority study. Lancet.
2013;381(9883):2091-2099.
25. Bunupuradah T, Chetchotisakd P, Ananworanich J, et al. A randomized comparison of second-
line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in
patients failing NNRTI regimens: The HIV STAR study. Antivir Ther. 2012;17(7):1351-1361.
26. Paton NI, Kityo C, Hoppe A. A pragmatic randomised controlled strategy trial of three second-
line treatment options for use in public health rollout programme settings: The Europe-Africa
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Research Network for Evaluation of Second-line Therapy (EARNEST) Trial. In: Kuala Lumpur,
Malaysia; 2013. http://www.natap.org/2013/IAS/IAS_84.htm. Accessed on January 2, 2017.
27. Paquet AC, Solberg OD, Napolitano LA, et al. A decade of HIV-1 drug resistance in the United
States: Trends and characteristics in a large protease/reverse transcriptase and co-receptor
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6
Preventing HIV Transmission with
Antiretroviral Therapy
Katy L. Garrett, PharmD; Mackenzie L. Cottrell, PharmD, MS,
BCPS, AAHIVP; and Angela DM Kashuba, PharmD, DABCP, FCP
INTRODUCTION
There are approximately 50,000 new diagnoses of human immunodeficiency
virus (HIV) in the United States annually,1 a number that has not seen appre-
ciable decreases despite the use of combination antiretroviral therapy (cART) in
those living with HIV. Additionally, the Centers for Disease Control and Preven-
tion (CDC) estimates up to 1 in 8 HIV-infected individuals does not know his
or her status.1 This can, in turn, lead to high rates of transmission, primarily
through sexual contact and/or injection drug use (IDU). A study published in 2015
found the overwhelming majority (91.5%) of new infections were attributed to
two groups: individuals unaware they were HIV positive and individuals with a
known diagnosis yet not in care.2 The incidence is particularly high among young,
nonwhite men who have sex with men (MSM). The lifetime risk of HIV infection is
1 in 6 within the MSM population and 1 in 2 in the African American MSM popu-
lation (Figure 6-1).3 In an era of imperfect safe sex practices and needle sharing, it
is imperative individuals at high risk of HIV infection are properly empowered to
protect themselves. There are four prevention categories of which the pharmacist
should be knowledgeable:
1. treatment as prevention (TasP)
2. preventing mother-to-child transmission (PMTCT)
3. pre-exposure prophylaxis (PrEP)
4. post-exposure prophylaxis (PEP)
HIV TREATMENT AS PREVENTION

Since HIV was first identified as causing the acquired immunodeficiency syndrome
(AIDS) epidemic, a significant amount of research has focused on how to treat
infected individuals. Previous treatment guidelines placed less emphasis on starting
cART early in infection for various reasons (including significant side effects and
fear of developing drug resistance), so many individuals delayed treatment and
had high amounts of circulating virus in their blood. Until recently, observational
studies had only inferred the link between plasma viral load and degree of infec-
tiousness. To address this, a large, randomized controlled trial, HIV Prevention
103
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FIGURE 6-1. Diagnosis risk by transmission group.

MSM: men who have sex with men
(Source: Centers for Disease Control and Prevention.)
(Source: Hess K, Hu X, Lansky A, et al. Estimating the Lifetime Risk of a Diagnosis of HIV Infection
in the United States. Abstract 52. Conference on Retroviruses and Opportunistic Infections;
February 22–25, 2016; Boston, MA.)
Trials Network (HPTN) study 052, sought to determine if patients on cART were
less likely to transmit HIV to an uninfected partner. The study enrolled 1,763 sero-
discordant couples (one partner is HIV-infected and the other is HIV-noninfected)
and found a 93% reduction in transmission rate when the HIV-infected partner
was on cART and the concentration of viral RNA in their blood was <400 copies/
mL.4 There were eight transmissions linked to a partner who was taking cART;
however, all of these transmissions occurred when the individual had detectable
plasma HIV RNA because they were not yet suppressed with cART or they were
failing therapy due to nonadherence or drug resistance. To date, there have been
no reports of linked transmission by anyone with a suppressed viral load. This
established, effectively, the treatment as prevention (TasP) protocol recommended
by the U.S. Department of Health and Human Services (DHSS) and the World
Health Organization (WHO). Both DHHS and WHO guidelines now recommend
all HIV-infected persons be on cART to prevent HIV transmission.5,6 The cART
regimen is chosen to best address the individual patient’s needs and is selected
based on adverse effects, drug interactions, and HIV resistance, among others.
More information on cART selection can be found in Chapter 4.
The results from HPTN 052 revolutionized the way HIV is treated: from a
purely individual standpoint to one that also incorporates prevention and global
public health. One such impact is the United Nations Programme on HIV/AIDS
(UNAIDS) 90-90-90 campaign.7 The goals sets by 90-90-90 are to have 90% of
HIV-infected individuals diagnosed, 90% of those taking cART, and 90% of those
virally suppressed by 2020. If this is accomplished, effectively, 73% of the HIV
population will have undetectable viral loads and the AIDS epidemic is predicted
to end by 2030. Results from HPTN 052 combined with data from the START
trial,8 which clearly demonstrated patient benefit from early HIV treatment, have
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CHAPTER 6 Preventing HIV Transmission with Antiretroviral Therapy 105
led to innovative practices to identify and treat patients immediately after diag-
nosis. Furthermore, a strategy to improve initiation of cART and subsequent viral
suppression was studied clinically in the RapIT trial. In this study, the investigators
found a 36% increase in cART usage and a 26% increase in viral suppression when
patients were started on cART the same day as diagnosis.9
PREVENTING MOTHER-TO-CHILD TRANSMISSION

An estimated 8,500 HIV-infected women give birth annually.10 Without any inter-
vention, they have a 15% to 45% chance of transmitting HIV to their children
during pregnancy, delivery, or breastfeeding.11 This risk drops to ~1% if anti-
retroviral medicines are given both to mothers during pregnancy and to their chil-
dren after delivery. Therefore, U.S. guidelines recommend universal HIV testing
during pregnancy using an opt-out strategy (HIV testing being a routine part of
care unless a woman declines).12 Because there is a risk of acquiring HIV infec-
tion during pregnancy, guidelines recommend retesting in the third trimester,
and preferably before 36 weeks gestation, for women at high risk for infection
and for those living in certain jurisdictions with elevated rates of HIV infection
among pregnant women. Women at high risk include those using illicit drugs,
having sexually transmitted infections (STIs) during pregnancy, having multiple
sex partners during pregnancy, living in areas with high HIV prevalence, having
HIV-infected partners, and having signs or symptoms consistent with acute HIV
infection. For women in active labor whose HIV status is undocumented, rapid
screening should be performed.
If a pregnant woman is diagnosed with HIV infection, regardless of viral load
and CD4 count, she should receive cART according to current guidelines for preg-
nant women and prevention of perinatal transmission.12 This is because reducing
a pregnant woman’s plasma HIV RNA to undetectable levels before delivery lowers
the risk of mother-to-child transmission to 0% to 2% in developed countries.13
The specific regimen is selected based on the woman’s comorbidities, concomitant
drug interaction potential, and resistance testing results. There is some sugges-
tion in the literature that drug dosing needs to be increased with the progression
of pregnancy due to decreases in total drug concentrations in plasma.14 Because
drug binding proteins (albumin and α1 acid glycoprotein) also decrease during
pregnancy,15 other studies have found that protein-unbound (active) drug concen-
trations do not change and no dosing increase is necessary.16 There have been no
documented HIV infections in babies born to mothers who did not alter their
dosing during pregnancy; however, it is important to review the latest pharmaco-
kinetic literature on antiretroviral drugs in pregnancy before determining dosage
adjustments. Please see Appendix B, Table 7, in the perinatal guidelines for the
most up-to-date dosing recommendations.12
More detailed information on drug therapy during pregnancy and breast-
feeding and infant antiretroviral prophylaxis after delivery can be found in
Chapter 10.
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PRE-EXPOSURE PROPHYLAXIS
Given the success rates of TasP and PMTCT, the incidence of HIV should be
decreasing, especially in resource-rich areas of the world where ART is accessible,
such as the United States. Although a number of public health initiatives, such
as needle exchange programs, have led to dramatic decreases in HIV infections
among certain vulnerable populations,17 they are not enough as evidenced by the
2014 HIV outbreak in Scott County, Indiana. In fact, the estimated incidence of
HIV in the United States has only minimally declined in the past decade. This is
in part because the number of new infections among the MSM population has
increased, especially and disproportionately among the Latino and black MSM
populations.18 Because we have yet to reach the 90-90-90 benchmark, there is
still a need for universal HIV prevention strategies that the uninfected individual,
regardless of his or her at-risk group, can control. One such method of empow-
ering an individual to protect against HIV is through the use of oral pre-exposure
prophylaxis (PrEP).
The Evidence for PrEP

Several Phase III trials have evaluated the efficacy of tenofovir disoproxil fumarate
(TDF), the oral prodrug of tenofovir (TFV), with or without emtricitabine (FTC), to
prevent the transmission of HIV in at-risk individuals. Study populations included
varied demographics to understand the role of PrEP in preventing HIV through
sexual or intravenous contact. Key points from a selection of these pivotal studies
are highlighted here, as is additional primary evidence (Table 6-1).
iPrEx enrolled 2,499 MSM and transgender women (TGW) across six countries
into a randomized trial comparing the use of daily emtricitabine/tenofovir diso-
proxil fumarate (FTC/TDF) to placebo.19 There were a total of 100 new infections
in the study, 36 occurring in those randomized to take FTC/TDF. This equated
to a 44% reduction in HIV incidence. Although a 44% reduction is a substantial
improvement toward HIV prevention, this number was far below ideal standards.
It was discovered, through plasma TFV detection, that a large percentage of the
study population was not perfectly adherent to the study medication. In the 33
individuals assigned to the FTC/TDF arm who acquired HIV during the study and
had plasma samples available, only two had detectable concentrations of either
FTC or TFV. When the study authors adjusted for adherence, FTC/TDF provided
a mathematically derived 92% relative risk reduction in HIV incidence compared
to placebo.
Partners PrEP enrolled 4,578 couples (~60% of seronegative partners were
male) in a randomized study to receive TDF, FTC/TDF, or placebo with HIV sero-
conversion as the primary outcome. There were 82 total seroconversions, 17 in
the TDF arm and 13 in the FTC/TDF arm, during the original study, equating to a
75% risk reduction in the FTC/TDF study arm. When adjusted for adherence rates,
the risk reduction increased to a mathematically derived 90%.20 Upon discontin-
uing the placebo participants and rerandomizing them to either FTC/TDF or TDF,
ERRNVPHGLFRVRUJ
TABLE 6-1. Oral PrEP Clinical Trials Efficacy in Preventing HIV Acquisition
and Medication Adherence
Seroconverters
PrEP Efficacy, % with detectable
Clinical Trial Study Population Study Arm (95% CI) TDF, %
iPrEx19 MSM, TGW FTC/TDF 44 (15 – 63) 6
Partners PrEP20 Heterosexual, FTC/TDF 75 (55 – 8 7) 31

serodiscordant
couples TDF 67 (44 – 81)
VOICE24 Heterosexual women FTC/TDF −4 (−49 – 27) 29
TDF −49 (−129 – 3) 30
FEM-PrEP25 Heterosexual women FTC/TDF 6 (−52 – 41) 24
Bangkok Tenofovir Study23 PWID TDF 49 (10 – 72) 66

FTC: emtricitabine; MSM: men who have sex with men; PrEP: pre-exposure prophylaxis; PWID: people who inject
drugs; TDF: tenofovir disoproxil fumarate; TGW: transgender women
there were a total of 52 seroconversions in participants receiving PrEP—31 in those

receiving TDF and 21 receiving FTC/TDF. When efficacy was adjusted for plasma
TFV detection, FTC/TDF demonstrated a mathematically derived 93% protective
effect.21 Most recently, The Partner’s Demonstration Project combined the use of
PrEP and TasP, finding a 94% reduction in HIV transmission.22
The Bangkok Tenofovir Study enrolled 2,413 people from 17 treatment centers
in Bangkok, Thailand, who injected drugs.23 The participants were randomly
assigned to either placebo or TDF. In this study, a large dropout rate (~30%) was
observed. Nonetheless, there were 50 emergent HIV infections during the study
with an overall 48.9% incidence reduction in the TDF arm compared to placebo.
As in other studies, plasma samples were tested for TFV. Among the seroconverters,
39% had detectable plasma TFV compared to 67% of the nonseroconverters. This
amounted to a mathematically derived 70% risk reduction among those with
detectable plasma TFV.
Two large-scale studies evaluating TDF and FTC/TDF among African women
did not demonstrate efficacy. VOICE enrolled approximately 1,000 young women
(aged 18–40) to receive TDF and another 1,000 to receive FTC/TDF compared to
placebo (this study also evaluated TFV vaginal gel but will not be discussed here).24
There was an overall effectiveness of –4% for FTC/TDF preventing HIV infection.
FEM-PrEP enrolled a similar population as VOICE, randomly assigning the 2,120
participants to either FTC/TDF or placebo.25 Thirty-three infections occurred in
the FTC/TDF arm and 35 in the placebo arm, culminating in a nonstatistically
significant risk reduction of 4%. Adherence in these studies was low, with ≤35%
of samples having detectable plasma TFV concentrations in both the infected and
uninfected participants.
ERRNVPHGLFRVRUJ
The mixed results seen among women are likely the result of multiple etiolo-
gies. First, women enrolled in Partner’s PrEP were in known at-risk relationships,
which contributed to higher adherence. VOICE and FEM-PrEP participants did
not have the same level of risk perception and were less adherent to the study
drug. Additionally, there is evidence the drug concentrations in genital and rectal
tissues differ, contributing to different risk reductions in rectal and vaginal HIV
exposure.26
One study, IPERGAY,27 sought to determine if on-demand dosing of FTC/TDF
in an MSM population (i.e., two doses 2 to 24 hours prior to sexual encounter, one
dose 24 hours after first dose, and one dose 48 hours after first dose for a total of
four tablets) would provide protection with less-than-daily medication adminis-
tration. IPERGAY enrolled 400 men and randomly assigned them to FTC/TDF or
placebo. There were a total of 16 emergent HIV infections, only 2 of which were
among those in the FTC/TDF group. That amounted to an 86% reduction in HIV
incidence. Because the median number of tablets taken per month was 15 (inter-
quartile range 11 to 21), this limits extrapolation of efficacy to those having less
frequent sex. Therefore, this dosing strategy is not currently recommended. More
data are needed to determine if less than daily adherence is sufficient to protect
people from acquiring HIV (Table 6-1).
The Importance of PrEP Adherence

It can be concluded from these Phase III studies that FTC/TDF works to prevent
HIV, but as is the case for other disease states, prevention is heavily dependent
upon medication adherence. The degree of adherence is not fully understood and
may depend upon route of transmission; the women in VOICE and FEM-PrEP
had adherence rates similar to the men and yet transgender women in iPrEx had
drastically different outcomes (no efficacy versus 44% efficacy). At the same time,
women enrolled in Partner’s PrEP had high efficacy, so there is benefit to women.
Regardless, a majority of clinical trials have clearly demonstrated a link between
adherence and efficacy. Unfortunately, the majority of methods used to verify
adherence in these studies involved detection of drug concentrations in plasma.
Because the half-life of TFV in plasma is only ~15 hours, plasma analysis can only
provide a snapshot of adherence and cannot relate TFV concentrations to long-
term exposure.
PrEP Indications/Target Populations

Based on the results of the iPrex19 and Partners PrEP20 trials, in 2012 the U.S. Food
and Drug Administration (FDA) approved the fixed-dose combination tablet
containing 200 mg FTC and 300 mg TDF once daily and used in combination with
safer sex practices (e.g., condom use, decreased number of partners) to reduce the
risk of sexually acquired HIV in high-risk adults. Since this approval, the CDC and
WHO have released clinical practice guidelines for PrEP. Although the CDC guide-
lines recommend offering PrEP to individuals within certain high-risk populations
who are deemed at substantial risk (Table 6-2),28 the WHO guidelines more broadly
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TABLE 6-2. Indications for PrEP Use Among Three High-Risk Populations
1. Men Who Have Sex with Men 2. Heterosexual Men and Women 3. Injection Drug User (IDU)
Who have had sex within the Who have had sex within the Who has recently* injected
past 6 months and are not in past 6 months and are not in drugs not prescribed by a
a monogamous partnership a monogamous partnership clinician
with a recently tested with a recently tested
HIV-negative partner HIV-negative partner
Plus any of the following: Plus any of the following: Plus any of the following:
Recent* condomless anal sex A man who has sex with men Recent* sharing of injection or
(insertive or receptive) and women drug preparation equipment
Recent* STI diagnosis Infrequent condom use with Recent* participation in a
Ongoing sexual relationship a partner of unknown HIV methadone, buprenorphine,
with an HIV-positive partner status who is at substantial or suboxone treatment
risk of HIV (bisexual male or program
IDU) At high risk of sexual acquisition
Ongoing sexual relationship (Box 1 and 2)
with an HIV-positive partner
*Defined as within the past 6 months.
FTC: emtricitabine; LA: long-acting; MVC: maraviroc; PrEP: pre-exposure prophylaxis; STIs: sexually transmitted
infections; TDF: tenofovir disoproxil fumarate
(Source: Adapted from Preexposure Prophylaxis for the Prevention of HIV Infection in the United States—2014. https://
www.cdc.gov/hiv/pdf/prepguidelines2014.pdf.)
recommend offering PrEP to anyone within a population whose HIV incidence is

≥3 per 100 person-years in the absence of PrEP.6 Additionally, PrEP may be consid-
ered to protect the HIV-uninfected partner in serodiscordant relationships during
conception or pregnancy, although safety and efficacy have not been well studied
in this setting.28
PrEP Monitoring
The safety profile of TDF with or without FTC for PrEP has been explored in a
meta-analysis of 10 randomized, placebo-controlled PrEP trials. This analysis found
no difference in the risk of adverse events compared to placebo (pooled risk ratio
[95% CI] = 1.01 [0.99–1.03]).29 The safety profile of FTC/TDF PrEP is quite favorable,
and the most commonly reported side effects in PrEP clinical trials were gastro-
intestinal symptoms (nausea, vomiting, and diarrhea) and fatigue.20,25,30 However,
drug resistance in the event of breakthrough infections is of concern, given that
FTC/TDF is not a fully suppressive HIV treatment regimen. Of eight clinical PrEP
trials reporting HIV genotype, TDF and/or FTC resistance has been observed in 1%
(6/533) of individuals infected post-randomization and 18% (8/44) of individuals
with acute infection at enrollment.29 Thus, establishing the negative HIV status
of any potential PrEP user at the time of PrEP initiation is absolutely essential.
Every PrEP user should have a documented negative HIV test within a week prior
ERRNVPHGLFRVRUJ
to starting PrEP, preferably by an approved fourth-generation HIV antigen/anti-

body laboratory test. For specifics on HIV testing, refer to Chapter 2. Because very
recently infected individuals may not yet test positive for HIV, pharmacists should
before dispensing PrEP for the first time take a thorough patient history to ensure
the potential PrEP user has not experienced clinical signs or symptoms consistent
with acute HIV infection in the last 4 weeks. These include fever, fatigue, myalgia,
skin rash, headache, pharyngitis, cervical adenopathy, arthralgia, night sweats,
and diarrhea.28 Patients who have experienced these symptoms and have engaged
in any recent HIV risk behavior should be referred for further testing to confirm
their HIV status before PrEP is dispensed. Potential confirmatory tests include a
fourth-generation antibody/antigen test and HIV viral load assay or deferring PrEP
for 1 month after initial presentation and testing for HIV antibodies. After starting
PrEP, negative HIV status (via laboratory examination and the absence of signs and
symptoms of acute HIV infection) should be documented every 3 months before
refilling PrEP prescriptions.
Cases of acute renal failure, including Fanconi’s syndrome, have been observed
in HIV-infected patients taking TDF for HIV treatment.28 To date, these more
serious adverse renal events have not been directly linked to PrEP use, although
mild to moderate nonprogressive decline in estimated creatinine clearance (eCrCl)
and tubular proteinuria have been reported in some study populations and are
positively correlated with the level of PrEP adherence.31-33 Therefore, renal function
as measured by eCrCl should be assessed at baseline, 3 months, and then every 6
months after starting PrEP. PrEP should not be used if eCrCl is <60 mL/min.
TDF and FTC are also virologically active against hepatitis B virus (HBV), and
cases of HBV reactivation have been reported among HIV-infected patients and PrEP
users who stop taking these medications.28 Populations at high risk for HIV are also
at increased risk of acquiring HBV, and therefore HBV infection status should be
documented prior to initiating PrEP.28 HBV vaccination should be offered to anyone
who is HBV susceptible. Those with acute or chronic HBV infection should be
referred to a specialist for HBV management, and the decision to initiate FTC/TDF as
concomitant treatment for HBV and PrEP should be made in conjunction with the
specialist. FTC/TDF should only be discontinued in HBV-infected individuals under
the direct supervision of a clinician with experience managing HBV infection.
Finally, as part of routine sexual healthcare, pregnancy should be assessed
every 3 months in women who may become pregnant, and testing for STIs should
be performed every 6 months. The continued need for PrEP should be monitored
on a yearly basis because the practice of high-risk behavior can change signifi-
cantly over time.
A Vision of a Successful PrEP Program

Arguably, the most difficult part of a successful PrEP program is uptake by the
target population. If individuals most at risk of acquiring HIV are not taking
the medicine, the efficacy data are irrelevant. Target populations may not take
PrEP for a number of reasons, including, but not limited to, lack of knowledge,
ERRNVPHGLFRVRUJ
lack of financial resources, and fear of being stigmatized. A major impediment

to accessing PrEP is the cost of Truvada®, which was listed for an average whole-
sale price (AWP) of $1,759.73 for 30 tablets as of July 2016.5 Although the FDA
approved a generic version of Truvada® manufactured by Teva Pharmaceuticals
in June 2017, the release date and planned price point of the generic are still
unknown. Truvada’s manufacturer, Gilead Sciences Inc., does offer a payment assis-
tance program, “The Truvada® for PrEP Medication Assistance Program,” for HIV
uninfected persons who are uninsured.34 Additionally, private insurance providers
and government-based insurance programs (i.e., Medicare/Medicaid and Veteran’s
Affairs) may cover PrEP. Since FTC/TDF was approved for PrEP in 2012, the United
States has seen a substantial increase in the uptake of prescriptions. In 2013, there
were fewer than 4,000 prescriptions for PrEP compared to nearly 31,000 in 2015.35
Almost 88% of these prescriptions were for males. The use of appropriate referrals,
trained medical professionals, and acceptance by the community can lead to a
successful PrEP program, as demonstrated in San Francisco.36
Alternatives to FTC/TDF PrEP in Clinical Development

Incomplete adherence to daily oral FTC/TDF PrEP in some clinical trial popula-
tions may be an indicator that expansion of the HIV prevention toolbox is needed
to satisfy diverse consumer needs and lower the burden of daily dosing. There-
fore, alternatives to oral daily FTC/TDF PrEP are currently being developed. The
most advanced of these next-generation PrEP products are topical formulations in
the form of antiretroviral impregnated gels and rings, both of which have been
explored in Phase III studies. Although a Phase IIb efficacy study of TFV 1% gel
administered before and after sex demonstrated 39% protection overall and up
to 54% among highly adherent study participants (CAPRISA004),37 this pericoital
dosing strategy proved futile in the intention to treat analysis of the Phase III
extension study (FACTS001).38 These disappointing results were largely attributed
to poor adherence with <20% of participants reporting product use for ≥72% of
sex acts.39 TFV 1% gel was also shown to be futile in the Phase III VOICE trial,
also likely due to poor adherence: ~41% of participants randomized to the daily
TFV gel arm did not have pharmacokinetic evidence of recent product use from
samples collected from the female genital tract.24
To further reduce dosing frequency requirements, long-acting products are
being developed. Monthly administration of a vaginal ring impregnated with dapi-
virine, an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI),
demonstrated modest reduction in HIV incidence compared to placebo in the
Phase III trials ASPIRE (27% reduction) and The Ring Study (31% reduction).39,40
Importantly, subgroup analysis from both studies demonstrated higher levels of
protection (37% to 56%) among women >21 years of age. Furthermore, the ring
was associated with 65% protection compared to placebo among women from the
ASPIRE trial who returned vaginal rings with residual dapivirine concentrations
that were indicative of intended use (≤22 mg).41 These increases in protection were
shown to be correlated with better adherence.
ERRNVPHGLFRVRUJ
Long-acting antiretroviral injectables are also being explored as an option

to reduce dosing requirements for PrEP. The most advanced are nanosuspension
formulations of the investigational integrase strand transfer inhibitor (INSTI),
cabotegravir, and the NNRTI, rilpivirine. An 800-mg dose of cabotegravir
administered as two 2-mL intramuscular (IM) injections in the gluteus maximus
every 3 months resulted in plasma drug concentrations below target in a large
proportion of participants (~67%) by the end of the 3-month injection cycle.42
Therefore, a 600-mg cabotegravir injection every 8 weeks is currently being
explored.43 A Phase II PrEP trial to evaluate the safety and efficacy of a 1,200-mg
monthly injection of rilpivirine is ongoing (NCT 02165202).
The compartmental pharmacokinetics and antiviral activity following a single
IM injection of rilpivirine have been evaluated across multiple doses (300, 600,
and 1,200 mg) in healthy volunteers. Drug concentrations were readily detectable
in the plasma and genital tract for 84 days at all doses following a single rilpivirine
injection. Antiviral activity in the female genital tract was greater in the 1,200-mg
(but not 300-mg) dosing group at 28 and 56 days post-injection.37 Notably, one
participant in the 300-mg rilpivirine dosing group became infected with wild-type
virus within 57 days of the injection, which was not identified until day 84, after
she seroconverted.37 When suppressive ART was started on day 115, ongoing viral
replication under the selective pressure of inadequate rilpivirine concentrations
had generated K101E/K mutations that conferred class resistance to NNRTIs. This
isolated case illustrates an important clinical concern regarding the long half-life
of long-acting injectables, namely, how to manage the pharmacokinetic tail in
those who decide to discontinue this type of PrEP. Future studies addressing this
question are needed; and for this reason, removable long-acting formulation prod-
ucts such as implantable devices are also being pursued.44
PrEP Future Studies

Currently, multiple prevention technologies are being evaluated in ongoing Phase
I to Phase III trials supported by two large research networks, the HIV Preven-
tion Trials Network (HPTN) and the Microbicide Trials Network (MTN). Figure
6-2 outlines the clinical development stages of products within the PrEP pipe-
line. The safety and efficacy of VRC01, a broadly neutralizing monoclonal anti-
body, are being evaluated in two Phase IIb studies currently enrolling men and
transgender persons who have sex with men (HPTN085; NCT02716675) and sub-
Saharan African women (HPTN081; NCT02568215). Additionally, cabotegravir
will be the first long-acting injectable to be explored in a Phase II/III PrEP effi-
cacy study controlled against the current standard of care, oral daily FTC/TDF
(HPTN083; NCT02720094). Oral FTC/TDF PrEP will also be explored in expanded
populations in a Phase IIa crossover study to investigate the safety and adher-
ence of the dapivirine containing ring and oral FTC/TDF in adolescent females
(MTN-035; trial not yet registered).
ERRNVPHGLFRVRUJ

HIV PrEP Drug Development Pipeline
neutralizing monoclonal antibody

Product Approved
for Market
Pre-Clinical Phase I Phase II Phase III Phase IV
FIGURE 6-2. PrEP drug development pipeline.

(In vitro and Animal models) (Safety in Healthy Volunteers) (Safety in Target Population) (Efficacy) (Post Marketing)
FT
C/ FT
TD
F for (O C/TD
ERRNVPHGLFRVRUJ
Ado
ral F
Pil
les ls)
ce
nts
FTC: emtricitabine; MCV: maraviroc; TDF: tenofovir disoproxil fumarate; VRC01: a broadly
POST-EXPOSURE PROPHYLAXIS
The CDC maintains guidelines for occupational and nonoccupational post-
exposure prophylaxis against HIV.45,46 Occupational exposure to HIV can occur in
laboratory workers or healthcare workers, so preventing exposures to potentially
infectious blood and body fluids is the most important strategy. This includes
using personal protective equipment and maintaining high safety standards in
the workplace. In general, occupational exposure risks are low. For example, the
risk of HIV infection by a needlestick injury is 23 in 10,000. This risk is modified
by the viral load of the infected individuals and whether or not they are on drug
therapy.47 Biting or spitting carries negligible risk.48 Nonoccupational exposure
to HIV is any exposure occurring outside of the workplace and includes expo-
sure from sexual activity and injection drug use. The risk of acquiring HIV in this
context is higher. For example, the risk in insertive anal intercourse is 11 in 10,000
and in receptive anal intercourse is 138 in 10,000. Risk from receptive or insertive
penile-vaginal intercourse is 4 to 8 in 10,000. This risk is also modified by the
viral load of the infected individual and additional STIs (Table 6-3).47 Behaviors
that avoid HIV exposure in this context are most effective at preventing infection,
including sexual abstinence, consistent and correct condom use, and injection
drug users’ consistent use of sterile equipment. Regardless of type of exposure, if
these measures fail in either occupational or nonoccupational exposure, ART can
be used to prevent HIV infection. This is known as post-exposure prophylaxis
(PEP) for the former and nonoccupational post-exposure prophylaxis (nPEP) for
the latter.
Occupational exposure is considered when there is (1) a percutaneous injury,
such as a needlestick or cut, or contact of mucous membranes or abraded skin, with
(2) potentially infectious blood, tissue, or body fluids. Both criteria must be met
for an exposure to occur. Any visibly bloody body fluids are considered potentially
infectious. Important potentially infectious non-bloody fluids include amniotic
fluid, pericardial or peritoneal fluid, and cerebrospinal fluid. Feces, urine, vomitus,
saliva, sweat, and tears are not considered potentially infectious. In laboratory
workers, any direct contact with concentrated virus is also considered a risk.47,48
Important considerations to initiating PEP include
• determining the HIV status of the exposure-source patient to guide the
need for PEP
• starting PEP medication regimens as soon as possible (preferably within
hours) after exposure and continuing for 4 weeks
If the HIV status of the exposure source is unknown, PEP can be started until the
source is tested and then stopped if found to be negative. PEP regimens should
contain three or more (if HIV drug resistance is suspected) antiretroviral drugs. PEP
patients should have close clinical follow-up, including baseline HIV testing (pref-
erably a rapid combined Ag/Ab, or antibody blood test) and follow-up testing at 6
weeks, 12 weeks, and 6 months after exposure. If a fourth-generation combination
HIV Ag/Ab test is used, HIV follow-up testing could be concluded at 4 months after
ERRNVPHGLFRVRUJ
TABLE 6-3. Estimated Per-Act Risk for Acquiring HIV from an Infected
Source, by Exposure Act
Exposure Type Rate of HIV Acquisition (per 10,000 exposures)
Parenteral
Blood transfusion 9,250
Needle sharing during injection drug use 63
Percutaneous (needlestick) 23
Sexual
Receptive anal intercourse 138
Receptive penile-vaginal intercourse 8
Insertive anal intercourse 11
Insertive penile-vaginal intercourse 4
Receptive oral intercourse Low
Insertive oral intercourse Low
(Source: HIV Risk Behavior Estimate. https://www.cdc.gov/hiv/risk/estimates/riskbehaviors.html.)
exposure. A visit at 72 hours after exposure can provide additional opportunities

for checking adherence and managing any side effects, along with discontinuing
PEP should the source patient be found to be HIV negative.
Although no antiretroviral drugs have an FDA-approved indication for PEP, the
rationale for using ART for PEP is based on the knowledge of the pathogenesis of
HIV infection, studies of efficacy in animal models, and epidemiologic data in HIV-
exposed healthcare workers. There are many antiretroviral combinations available.
However, because side effects are a major reason for not completing the full 4 weeks
of PEP, the regimens selected are heavily influenced by their side effect profile. Other
important considerations include possible drug interactions with current medica-
tions and any drug resistance information available in the source patient.
Occupational exposures to HIV are urgent medical concerns and should be
treated immediately. From animal studies, it appears that PEP is most effective
when started as soon as possible after the exposure (e.g., within hours). In animal
studies, PEP efficacy wanes the longer it is delayed and is ineffective if started after
72 hours. However, the interval after which no benefit is gained from PEP for
humans is undefined. Recommended drug regimens can be found in Table 6-4.
Nonoccupational exposure to HIV comes with varying risks of acquisition
depending on the exposure type (Table 6-3). These risks determine a person’s eligi-
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TABLE 6-4. Preferred and Alternative PEP Regimens

PREFERRED HIV PEP REGIMEN*
Raltegravir (Isentress®; RAL) 400 mg PO Twice Daily
Plus
Truvada™ 1 tablet PO Once Daily
[Tenofovir DF (Viread®; TDF) 300 mg + emtricitabine (Emtriva™; FTC) 200 mg]
ALTERNATIVE REGIMENS
(May combine one drug or drug pair from the left column with 1 pair of nucleoside/
nucleotide reverse transcriptase inhibitors from the right column. Drugs are listed
in order of preference.)
Raltegravir (Isentress®; RAL) Tenofovir DF (Viread®; TDF) + emtricitabine

(Emtriva™; FTC); available as Truvada™
Darunavir (Prezista®; DRV) + ritonavir Tenofovir DF (Viread®; TDF) + lamivudine (Epivir®;
(Norvir®; RTV) 3TC)
Etravirine (Intelence®; ETR) Zidovudine (Retrovir™; ZDV; AZT) + lamivudine
(Epivir®; 3TC); available as Combivir®
Rilpivirine (Edurant™; RPV) Zidovudine (Retrovir®; ZDV; AZT) + emtricitabine
(Emtriva™; FTC)
Atazanavir (Reyataz®; ATV) + ritonavir
(Norvir®; RTV)
Lopinavir/ritonavir (Kaletra®; LPV/RTV)
The following alternative is a fixed-dose combination regimen, and no additional

antiretrovirals are needed:
Stribild™ (elvitegravir, cobicistat, tenofovir DF, emtricitabine)
PEP: post-exposure prophylaxis; PO: by mouth
*See Chapter 3 for ARV dosing strategies, side effects, and monitoring.
(Source: Guideline Summary: Updated U.S. Guidelines for the Management of Occupational Exposures to HIV and
Recommendations for PEP. September 2013. http://www.aidsetc.org, or on AIDSinfo: http://aidsinfo.nih.gov.)
bility for nPEP. Guideline recommendations are based on historic case-control

PEP data, case studies of nPEP efficacy in humans, and expert opinion. There are
many similarities between the PEP and nPEP guidelines, including the selection of
preferred drugs (Table 6-4 and Table 6-5).
An algorithm for non-occupational exposures has been published in the recent
guidelines to help determine a person’s eligibility for therapy (Figure 6-3). Before
starting therapy, routine antibody testing (preferably with a rapid test) should
be performed. Additionally, at baseline, patients should be tested for Hepatitis
B (surface antibody and antigen and core antibody) and C (antibody), syphilis,
gonorrhea, chlamydia, and pregnancy. These tests, with the exception of Hepatitis
B and C, should be repeated after 4 weeks. HIV testing should be repeated again
at 3 and 6 months. If a regimen of tenofovir disoproxil fumerate + emtricitabine
with raltegravir or dolutegravir will be prescribed, then baseline serum creatinine
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TABLE 6-5. Preferred and Alternative nPEP Regimens

Population Preferred Alternative
Adults and adolescents aged ≥13 Truvada™, 1 tab PO once daily Truvada™, 1 tab PO once daily
years, including pregnant [Tenofovir DF (Viread®; TDF) [Tenofovir DF (Viread®; TDF)
women, with normal renal 300 mg + emtricitabine 300 mg + emtricitabine
function (creatinine clearance (Emtriva™; FTC) 200 mg] (Emtriva™; FTC) 200 mg]
≥60 mL/min)
with with
raltegravir 400 mg twice daily darunavir 800 mg once daily
or and
dolutegravir 50 mg once daily ritonavir 100 mg once daily
Adults and adolescents aged ≥13 Zidovudine 300 mg (Retrovir™; Zidovudine 300 mg (Retrovir™;
years with renal dysfunction ZDV; AZT) + lamivudine 150 ZDV; AZT) + lamivudine 150
(creatinine clearance ≤59 mL/ mg (Epivir®; 3TC) twice daily; mg (Epivir®; 3TC) twice daily;
min) available as Combivir ®
available as Combivir®
with with
raltegravir 400 mg twice daily darunavir 800 mg once daily
or and
dolutegravir 50 mg once daily ritonavir 100 mg once daily
Children aged 2–12 years A 3-drug regimen consisting of A 3-drug regimen consisting of
tenofovir DF, emtricitabine, and zidovudine and lamivudine
raltegravir, with
with each drug dosed to age and raltegravir
weight or
lopinavir/ritonavir
with each drug dosed to age and
weight
nPEP: Non-occupational Post-Exposure Prophylaxis; PO: by mouth
(Source: Table 5 from Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug
Use, or Other Nonoccupational Exposure to HIV—United States, 2016. http://www.cdc.gov/hiv/pdf/programresources/
cdc-hiv-npep-guidelines.pdf.)
testing along with aspartate aminotransferase (AST) and alanine aminotransferase

(ALT) should be performed at baseline and after 4 weeks on therapy.
Important differences between the PEP and nPEP guidelines include combining
nPEP with behavioral interventions and counseling to support risk reduction of HIV
acquisition. Adherence to a 4-week regimen is also challenging for this population,
and counseling and follow-up are important factors in success. Adherence is facil-
itated by prescribing medications with fewer side effects, using drugs with fewer
doses per day and fewer pills per dose, educating the patient regarding potential side
effects and providing medications to mitigate these side effects (e.g., antiemetics
for nausea), using medication adherence aids such as pillboxes, helping patients
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Substantial exposure risk Negligible exposure risk
≤ 72 hours since exposure > 72 hours since exposure
Source pt known to be Source pt of unknown

HIV-positive HIV status
nPEP recommended Case-by-case determination nPEP not recommended
Substantial Risk for HIV Acquisition Negligible Risk for HIV Acquisition
Exposure of Exposure of
vagina, rectum, eye, mouth, or other vagina, rectum, eye, mouth, or other
mucous membrane, non-intact skin, or mucous membrane, intact or non-intact
percutaneous contact skin, or percutaneous contact
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With With
blood, semen, vaginal secretions, rectal urine, nasal secretions, saliva, sweat, or
secretions, breastmilk, or any body fluid tears if not visibly contaminated with blood
that is visibly contaminated with blood Regardless
When of the known or suspected HIV status of the
source is known to be HIV-infected source
FIGURE 6-3. Algorithm for evaluation and treatment of possible non-occupational HIV exposures.
identify times in their daily schedules that will fit dose-taking, and providing the
patient with a flexible way of contacting a provider with questions.
Financial assistance is often available for nPEP. Pharmacists can assist patients
with obtaining antiretroviral medications through the pharmaceutical manufac-
turers’ medication assistance programs. People needing nPEP after sexual assault
can be reimbursed for medications and clinical care costs through state crime
victim’s compensation programs funded by the U.S. Department of Justice (see
Key Resources for links to these resources).

As medication therapy experts, pharmacists can play a key role in the prevention of HIV
via TasP, PMTCT, PrEP, and PEP because all four modalities utilize ART. The effec-
tiveness of pharmacists within interdisciplinary care teams has already been demon-
strated in other disease states, such as in lowering patients’ blood pressures, cholesterol,
and smoking rates.49 Additionally, the pharmacist-led management of anticoagulation,
within an HIV clinic, has demonstrated effectiveness with patients having therapeutic
INRs more often than when their anticoagulation was managed by a non-pharmacist
healthcare provider.50
This same approach has been implemented within an HIV clinic in north Alberta to opti-
mize maternal care before, during, and after pregnancy in an effort to prevent MTCTs.
The pharmacist played a crucial role in protocol development as well as in implementa-
tion of services to both the mother and newborn. Since 1999, the clinic has had perinatal
transmission rates of <1%.51 The need for pharmacist expertise in PrEP-focused clinics
has also been identified.52 The need for PrEP monitoring, including possible emergent drug
resistance and safety concerns, is ideally suited to pharmacists’ expertise.
To provide further assistance in the prevention of HIV via PrEP, pharmacists should
• ensure every PrEP user has a documented negative HIV test within a week prior
to starting PrEP and every 3 months while taking PrEP
• take a thorough patient history to check for clinical signs or symptoms consis-
tent with acute HIV infection in the last 4 weeks prior to starting PrEP and
with each refill; a patient history is also essential to avoid drug interactions
• monitor organ function and confirm the vaccination or infection status for HBV
Pharmacists also have a unique opportunity to participate in program and policy devel-
opment, particularly in the area of PEP and nPEP. Because pharmacies are easily acces-
sible, pharmacists have the opportunity for community impact with risk-reduction coun-
seling, ART, and adherence and safety monitoring.53,54 Data have also been published
on a virtual pharmacist–clinician partnership through an electronic interface to assist
with the management of patients prescribed PEP.55 At the institutional level, pharmacists
have a role in partnering with infectious disease and emergency department physicians,
infection control, and employee health to develop and implement policy for nPEP that
will meet Joint Commission and Occupational Safety and Health Administration (OSHA)
standards.
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Because ARVs are used in all four prevention modalities (TasP, PMTCT, PrEP, PEP), phar-
macists can play a key role in ensuring proper use. First, pharmacists should know the
recommended ARV dosages and if/when to adjust them based on patient-specific factors
(i.e., renal or hepatic impairment). Pharmacists should also have expertise in drug metab-
olism and related drug–drug interactions. ARVs notoriously have multiple drug–drug
interactions, and pharmacists should be able to identify any interactions with a patient’s
other medications and/or supplements and recommend appropriate solutions. Arguably,
the most critical aspect of using ARVs to prevent HIV is patient adherence. Pharmacists
are uniquely qualified to optimize medication adherence by patient education about side
effects and management, recommending ARV regimens with dosing consistent with a
patient’s lifestyle (e.g., does the patient do shift-work, have trouble taking medication
consistently every 12 hours, or already consistently take a medication twice daily), moni-
toring refill histories, identifying patient-specific medication reminders, providing pill
boxes, and following up with a phone call. If additional assistance is needed, please refer
to any of the resources below to aid in the best clinical care of patients.
KEY RESOURCES
• AVAC Global Advocacy for HIV Prevention. http://www.avac.org/.
o Myriad of resources and infographics regarding HIV prevention are available.
The user can search by topic, population, geographical area, and many other
routes to identify the most pertinent information. This website is also up-to-date
on drug development and clinical trials.
• CDC HIV Prevention. http://www.cdc.gov/hiv/basics/prevention.html.
o This website provides answers to commonly asked questions regarding HIV
prevention and provides resources to those needing further assistance.
• Clinician Consultation Center at University of California-San Francisco (UCSF).
http://nccc.ucsf.edu/.
o This website and call center provides free consultation with an expert for U.S.
healthcare providers, including pharmacists, managing blood-borne pathogen
exposures, perinatal HIV, and pre-exposure prophylaxis. Healthcare provider
callers can also receive expert consultation on the management of HIV/AIDS and
substance-use management. Various resources are available to assist in patient
care as well as clinical quick guides.
• HIV Prevention Trials Network. https://www.hptn.org/.
o All information regarding the HPTN, specifically all completed and ongoing
studies.
• Microbicide Trials Network. http://www.mtnstopshiv.org/.
o All information regarding the MTN, specifically all completed and ongoing
studies.
• Office for Victims of Crime People and National Association of Crime Victim
Compensation Boards. http://www.ojp.usdoj.gov/ovc/map.html.
http://www.nacvcb.org/index.asp?bid=16.
o Contact information for each state in the event someone is a victim of sexual
assault and in need of nPEP.
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• Partnership for Prescription Assistance. http://www.pparx.org/en/prescription_assis-

tance_programs/list_of_participating_programs.
o Information for specific medications and manufacturers’ assistance programs.
• PrEPWatch. http://www.prepwatch.org/policies-and-programs/local-programs/.
o For patients wanting PrEP and unsure how to get it, this site lists providers and/
or other resources for patients to contact. Information is provided for each state.
• US DHHS HIV/AIDS Medical Practice Guidelines. https://aidsinfo.nih.gov/guidelines.
o The guidelines are available for treatment, PrEP, PEP, and many other realms
applicable to HIV care.
• WHO HIV. http://www.who.int/hiv/en/.
o This link provides access to all the HIV-related data and World Health Organiza-
tion (WHO) publications. Current guidelines for treatment and prevention are
available for access.
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19. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in
men who have sex with men. N Engl J Med. 2010;363(27):2587-2599.
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25. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among
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Expert Opin Drug Metab Toxicol. 2015;11(6):893-905.
27. Molina JM, Capitant C, Spire B, et al. On-demand preexposure prophylaxis in men at high risk
for HIV-1 Infection. N Engl J Med. 2015;373(23):2237-2246.
28. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States—2014. https://
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29. Fonner VA, Dalglish SL, Kennedy CE, et al. Effectiveness and safety of oral HIV preexposure
prophylaxis for all populations. AIDS. 2016;30(12):1973-1983.
30. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for
heterosexual HIV transmission in Botswana. N Engl J Med. 2012; 367(5):423-434.
31. Solomon MM, Lama JR, Glidden DV, et al. Changes in renal function associated with oral
emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS.
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32. Mugwanya K, Baeten JM, Celum CM, et al. Rare Incidence of Proximal Tubular Dysfunction
with Tenofovir-Based Chemoprophylaxis. Abstract 868. Conference on Retroviruses and Oppor-
tunistic Infections; February 22–25, 2016; Boston, MA.
33. Liu AY, Vittinghoff E, Anderson PL, et al. Changes in Renal Function Associated With TDF/FTC
PrEP Use in the US Demo Project. Abstract 867. Conference on Retroviruses and Opportunistic
Infections; February 22–25, 2016; Boston, MA.
34. Truvada® for PrEP Medication Assistance Program. http://www.gilead.com/responsibility/
us-patient-access/truvada%20for%20prep%20medication%20assistance%20program. Accessed
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35. Mera R, McCallister S, Palmer B, et al. Truvada (TVD) for HIV pre-exposure prophylaxis (PrEP)
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Conference; July 18–22, 2016; Durban, South Africa.
36. Volk JE, Marcus JL, Phengrasamy T, et al. No new HIV infections with increasing use of HIV
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37. Krakower DS, Jain S, Mayer KH. Antiretrovirals for primary HIV prevention: The current status
of pre- and post-exposure prophylaxis. Curr HIV/AIDS Rep. 2015;12(1):127-138.
38. Rees H, Delany-Moretlwe S, Lombard C, et al. FACTS 001 Phase III Trial of Pericoital Tenofovir
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39. Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for
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44. Schlesinger E, Johengen D, Luecke E, et al. A tunable, biodegradable, thin-film polymer device as
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SECTION II:
The Pharmacologic
Management of HIV
Co-infections
Section Editor: Alice L. Tseng, PharmD, FCSHP,
AAHIVP
Chapter 7: Opportunistic Infections

Christine A. Hughes and Deborah Yoong
Chapter 8: Viral Hepatitis

Denise Kreutzwiser, Pierre Giguère, and
Alice L. Tseng
Chapter 9: Sexually Transmitted

Infections
Deborah V. Kelly and Tony Antoniou
Chapter 10: Tuberculosis

Eric F. Egelund and Emily C. Huesgen
125
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7
Opportunistic Infections
Christine A. Hughes, BScPharm, PharmD, FCSHP,
and Deborah Yoong, BScPharm, ACPR, PharmD
INTRODUCTION
Human immunodeficiency virus (HIV)-related opportunistic infections (OIs) are defined
as infections that are more frequent or severe as a result of immunosuppression
in persons living with HIV.1 Historically, OIs were a leading cause of hospitaliza-
tions and death of HIV-infected patients.2 Following the widespread availability of
combination antiretroviral therapy (cART) in the mid- to late-1990s, the incidence
of many OIs have markedly decreased.2 Unfortunately, OIs still contribute to signif-
icant morbidity and mortality due to immunodeficiency secondary to medication
nonadherence, drug resistance, or late presentation into care.1
The risk of OIs is related to the extent of immunosuppression (Figure 7-1). cART
is important to initiate and optimize as soon as possible to preserve or reconstitute
the immune system, ultimately reducing risks for other OIs and improving patient
outcomes. This chapter provides a practical overview of common fungal, parasitic,
bacterial, and viral OIs encountered in HIV-infected patients and highlights the
pharmacist’s role in the management of OIs. Special considerations regarding the
optimal timing of antiretroviral therapy (ART) initiation in the setting of acute OIs is
noted due to the potential risk of an inflammatory response caused by the introduc-
tion of HIV therapy known as immune reconstitution inflammatory syndrome (IRIS).3
OROPHARYNGEAL AND ESOPHAGEAL CANDIDIASIS

Oropharyngeal and esophageal candidiasis are frequently encountered in HIV-
infected patients and are suggestive of immune suppression. Vulvovaginal candi-
diasis, on the other hand, commonly occurs in healthy adult women and is not
indicative of HIV infection.1 HIV-infected women with low CD4 counts may
have more severe episodes or more frequent recurrences of vulvovaginal candi-
diasis. Candidiasis is most commonly caused by the yeast-forming fungi C. albi-
cans, although non-albicans Candida species such as C. glabrata and C. krusei have
emerged particularly in patients with refractory mucosal candidiasis and low CD4
Acknowledgments: The authors would like to acknowledge Chen-En Ma for her assistance
in formatting the tables.
127
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Usual pathogens
>500 cells/mm3
Usual pathogens;
200-500 cells/mm3 disease more frequent or severe (e.g., tuberculosis,
oropharyngeal candidiasis)
<200 cells/mm3 Pneumocystis jirovecii, Toxoplasma

gondii, Cryptococcus, Varicella-Zoster*
<50 cells/mm3 Mycobacterium avium

Cytomegalovirus
*Varicella-Zoster reactivation can occur at any CD4 count, but the frequency of herpes zoster is
highest when CD4 <200 cells/mm3.
FIGURE 7-1. Relationship between CD4 count and types of pathogens.1
counts.4 Oropharyngeal and esophageal candidiasis are most commonly seen in

patients with CD4 counts <200 cells/mm3; esophageal candidiasis is an acquired
immunodeficiency syndrome (AIDS)-defining illness and is typically observed
at lower CD4 counts as compared to oropharyngeal infections.1,4 In addition to
immune suppression, other risk factors for oropharyngeal candidiasis include
steroid treatment and antimicrobial therapy.4
The prevalence of oropharyngeal candidiasis as well as the incidence of refrac-
tory disease has substantially decreased with cART.4 In one study, the incidence
rate of esophageal candidiasis as an AIDS-defining illness decreased 58% between
the early (1996–2000) and late (2001–2008) cART eras.2
Clinical Presentation and Diagnosis

Oropharyngeal candidiasis presents as painless, creamy white plaques on the
surface of the tongue and mucous membranes of the mouth that are easily scraped
off with a tongue depressor, a characteristic that helps to differentiate candidiasis
from oral hairy leukoplakia.1 Patients may also experience taste disturbances or
occasionally a burning sensation. Esophageal candidiasis can occur in the pres-
ence or absence of oropharyngeal candidiasis and is characterized by retrosternal
burning or discomfort along with dysphagia.1 Oropharyngeal candidiasis is usually
diagnosed based on the appearance of lesions; esophageal candidiasis is empiri-
cally diagnosed based on symptoms and response to antifungal therapy. Defini-
tive diagnosis of esophageal candidiasis requires endoscopy and histopathologic
confirmation of Candida yeast forms from tissue samples to differentiate from
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CHAPTER 7 Opportunistic Infections 129
other causes of esophagitis in HIV-infected patients such as cytomegalovirus or

herpes simplex virus.1
Treatment
Oral fluconazole is the drug of choice for both oropharyngeal and esophageal
candidiasis (Appendix 7-A).1 Topical therapy may be considered for oropharyngeal
candidiasis and offers advantages of reduced systemic exposure and a lower risk of
drug–drug interactions.1 However, multiple daily dosing for drugs like clotrimazole
and nystatin, as well as unpleasant taste, can lead to poorer tolerability and patient
nonadherence. A newer alternative for oropharyngeal candidiasis (approved in
the United States and Europe) is miconazole mucoadhesive buccal tablets.5 This
therapy is dosed once daily and has similar efficacy to clotrimazole troches, but a
potential disadvantage is higher cost relative to clotrimazole and oral fluconazole.6
Itraconazole oral solution and posaconazole oral suspension are as effective as
fluconazole for oropharyngeal candidiasis and are recommended as alternatives,
especially for patients with fluconazole-refractory disease or for patients who
cannot swallow tablets or tolerate oral fluconazole.1,4 For esophageal candidiasis,
systemic antifungal therapy is always necessary. In patients who cannot tolerate
oral therapy, intravenous (IV) formulations of fluconazole, voriconazole, or an
echinocandin can be used.1,4 For patients with fluconazole-refractory esophageal
candidiasis, evidence supports the use of itraconazole solution, voriconazole,
amphotericin B, or an echinocandin.4 The different characteristics of the drugs,
such as drug interaction potential or toxicities, may guide the choice of therapy
(Appendix 7-B). Of note, treatment of esophageal candidiasis with an echino-
candin has been associated with a higher rate of relapse than seen with fluco-
nazole.1,4 During pregnancy, topical therapy is preferred to treat oropharyngeal
candidiasis and amphotericin B is considered the safest systemic antifungal agent
for treatment of invasive or refractory esophageal candidiasis.1,7
For oropharyngeal candidiasis, 1 to 2 weeks of therapy is recommended; a
longer duration of treatment (2 to 3 weeks) is recommended for esophageal candi-
diasis. Response to treatment for candidiasis is typically rapid, with most patients
experiencing improvement in signs and symptoms of oropharyngeal or esopha-
geal candidiasis within 48 to 72 hours.
Chronic suppressive therapy (secondary prophylaxis) is generally not recom-
mended unless the patient experiences frequent or severe recurrences. If imple-
mented, however, guidelines suggest it is reasonable to discontinue when CD4
count increases above 200 cells/mm3.1
Primary Prevention
Routine primary prophylaxis for oropharyngeal or esophageal candidiasis is
not recommended as the overall risk associated with mucosal disease is low,
and primary prophylaxis can lead to the development of drug-resistant Candida
species.1
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PNEUMOCYSTIS PNEUMONIA
Pneumocystis pneumonia (PCP) is caused by Pneumocystis jirovecii, an organism that
is classified as a fungus and found ubiquitously in the environment.8 Infection
is spread via the airborne route, and the vast majority of cases of PCP occur in
patients with a CD4 count <200 cells/mm3.1,8 CD4 cell percentage <14%, previous
PCP episodes, oral candidiasis, recurrent bacterial pneumonia, unintentional
weight loss, and higher plasma HIV viral load are other factors associated with a
higher risk of PCP.1 In the pre-cART era, PCP was a leading cause of death with a
mortality rate of 20% to 40% in treated patients with advanced immunosuppres-
sion.1 Improved immunity as a result of cART and use of PCP prophylaxis has
resulted in persistent reductions in the incidence of PCP. In a European cohort
study, the incidence of PCP decreased from 4.9 cases per 100 person-years before
March 1995 to 0.3 cases per 100 person-years after March 1998.9 However, PCP is
still among the leading OIs encountered, particularly in patients unaware of their
HIV infection.10

PCP often manifests as a subacute onset of progressive dyspnea, fever, nonpro-
ductive cough, and chest discomfort that worsens over days to weeks.1 Laboratory
findings may include hypoxemia, which can range from mild (PaO2 80–95 mmHg)
to severe (PaO2 <70 mmHg). Elevated lactate dehydrogenase to >500 mg/dL is a
nonspecific finding but commonly seen.1 Chest x-rays, which often reveal bilateral
symmetrical interstitial infiltrates in a butterfly-shaped pattern, can be normal in
patients with early disease.1 Thin-section computer tomography (CT) of the lungs
can be useful as an adjunct to chest x-rays and demonstrates a patchy, ground-glass
appearance. Definitive diagnosis of PCP requires identification of the organism
in specimens from induced sputum or bronchoalveolar lavage fluid using direct
staining techniques.1,8 Polymerase chain reaction (PCR) of respiratory secretions
is an evolving method for detecting PCP; however, specificity is lacking to distin-
guish colonization from disease. Although plasma 1,3ß-D-glucan (a component of
fungal cell walls) measurement has been proposed to aid in the diagnosis of PCP,
sensitivity and specificity are problematic and other fungal infections can cause
elevated measurements.1,11
Treatment
Trimethoprim-sulfamethoxazole (TMP-SMX) for 21 days is the treatment of choice
for PCP (Appendix 7-A).1 Patients with mild-to-moderate disease can be treated
with oral TMP-SMX on an outpatient basis. Alternatives for mild-to-moderate
disease include dapsone plus TMP, primaquine plus clindamycin, and atovaquone
suspension. Dapsone plus TMP is as effective as TMP-SMX and is often used in cases
of mild cutaneous reactions with sulfonamides; however, this treatment involves
more pills. Atovaquone is less effective than TMP-SMX but does not commonly
cause rash, fever, or bone marrow suppression. For moderate-to-severe disease,
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clindamycin plus primaquine or IV pentamidine are recommended as alterna-

tives to TMP-SMX. Due to its toxicity profile, some clinicians may prefer clin-
damycin-primaquine over pentamidine. Patients need to be tested for glucose-6-
phosphate dehydrogenase deficiency prior to use of either dapsone or primaquine.
Clinical data that demonstrated mortality benefit indicated that adjunctive corti-
costeroids should be initiated as soon as possible and within 72 hours of starting
PCP treatment for patients with moderate-to-severe disease (defined as PO2 <70
mmHg on room air or alveolar-arterial O2 gradient ≥35 mmHg).1
Patients should be closely monitored to evaluate treatment response as well as
to identify drug toxicities. Potential side effects of therapies, suggested monitoring
parameters, and other considerations are outlined in Appendix 7-B. Hypersensi-
tivity with TMP-SMX has been associated with greater incidence (up to 60%) in
HIV-infected patients, along with rare and life-threatening reactions.12 TMP-SMX
should be permanently discontinued in severe reactions such as Stevens-Johnson
syndrome or toxic epidermal necrolysis; rechallenge should never be attempted.
In patients with mild-to-moderate reactions (without serious skin eruption or
organ involvement), antihistamines can be used to “treat through” the skin rash.
Gradual reintroduction of TMP-SMX or use of desensitization protocols can also
be successful strategies in enabling the patient to remain on the preferred first-line
therapy.13 Dapsone, a sulfone antimicrobial that does not contain a sulfonamide
moiety, can cause hypersensitivity reactions similar to sulfonamide antibiotics.12
Although the mechanism is unknown, evidence suggests there is a 22% cross-
reactivity rate, and dapsone is generally not recommended in individuals with
previous severe hypersensitivity reaction to sulfonamide antibiotics. The rate of
response to PCP therapy is dependent on numerous factors, including treatment
used, severity of illness, degree of immunodeficiency, and timing of therapy initi-
ation.1 Because pulmonary symptoms may initially worsen with treatment, it is
recommended to wait at least 4 to 8 days before declaring failure of treatment and
switching therapy. For patients not already on ART, it is recommended that ART be
started within 2 weeks of PCP diagnosis if possible. A randomized controlled trial
of 282 patients with OIs other than tuberculosis (~60% had PCP) demonstrated a
significantly lower incidence of AIDS progression or death in patients receiving
early initiation of ART (median 12 days) versus delayed (median 45 days).14 IRIS
has been reported following antiretroviral initiation, and patients usually present
with fever, cough, and shortness of breath—symptoms that are difficult to discern
from PCP treatment failure.3
Secondary prophylaxis for PCP should be started immediately following PCP
treatment and continued until the CD4 count increases above 200 cells/mm3 for
at least 3 months in response to ART. In patients with CD4 counts of 100–200
cells/mm3, if HIV viral load remains below the limits of assay detection for at least
3 to 6 months, data suggests secondary prophylaxis in this setting can be safely
discontinued.1 Secondary prophylaxis should be reintroduced when CD4 count
decreases to <100 cells/mm3, or if the CD4 count is between 100-200 cells/mm3
and HIV viral load is above the limit of assay detection.
ERRNVPHGLFRVRUJ
Primary Prevention
Primary prophylaxis for PCP is recommended in patients with a CD4 count <200 cells/
mm3 or a CD4 percentage <14% (Appendix 7-A).1 Prophylaxis should also be considered
in patients with a CD4 count between 200-250 cells/mm3 when starting ART must be
delayed and close monitoring of CD4 count is not feasible.1 TMP-SMX (double-strength
or single-strength tablet daily) is the preferred agent for prophylaxis and provides cross-
protection against toxoplasmosis and many respiratory bacterial infections. In
patients who are not able to tolerate TMP-SMX, alternatives include dapsone,
aerosolized pentamidine, and atovaquone. Although atovaquone is as effective as
aerosolized pentamidine and dapsone, it is more expensive and should be taken
with a high-fat meal to improve absorption. In patients intolerant of TMP-SMX
requiring both toxoplasmosis and PCP prophylaxis, dapsone plus pyrimethamine
plus leucovorin or atovaquone can be used. Primary prophylaxis is recommended
to be continued until the CD4 count increases above 200 cells/mm3 for at least
3 months in response to ART. Several cohort studies have found a low risk of PCP in
patients with CD4 counts between 100–200 cells/mm3 receiving ART with HIV viral
loads <400 copies/mL.15 Therefore, stopping primary prophylaxis may be considered
in patients with CD4 counts between 100–200 cells/mm3 and HIV viral load below
the limit of assay detection for at least 3 to 6 months.1 Prophylaxis should be rein-
stated if the CD4 falls below 100 cells/mm3, regardless of viral load suppression or if
CD4 is <200 cells/mm3 and HIV viral load is above the limit of detection.1
CRYPTOCOCCAL MENINGITIS
Cryptococcal infections in HIV patients are typically caused by the yeast Crypto-
coccus neoformans.16 This organism can be found in bird droppings and is trans-
mitted via inhalation. Prior to the availability of cART, 5% to 10% of patients with
AIDS developed cryptococcal meningitis.16 However, following the widespread
implementation of cART, the incidence of cryptococcal meningitis has decreased
significantly in developed countries.1,10 Cryptococcal meningitis can still be prob-
lematic in patients who present with advanced HIV infection and is associated
with mortality rates of 10% to 25% even with optimal treatment.16 Current global
estimates for cryptococcal meningitis suggest there are approximately 1 million
cases and over 600,000 deaths each year.17 Patients are at risk of cryptococcal
meningitis when their CD4 count is <100 cells/mm3.16

Cryptococcosis is often disseminated in HIV-infected individuals, and patients may
exhibit skin lesions or pulmonary symptoms.1 Patients typically present with symp-
toms of fever, malaise, and headache.16 Only 25% to 30% of patients will have
classic signs and symptoms of meningitis, such as neck stiffness and photophobia.1
Other patients may experience lethargy and altered mentation due to rises in
intracranial pressure. Investigations for cryptococcal meningitis typically involve
a lumbar puncture. In patients with cryptococcal meningitis, opening pressure in
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the cerebrospinal fluid (CSF) is often elevated (≥25 cm H2O). Analysis of CSF often
demonstrates mildly elevated serum protein, low-to-normal glucose concentra-
tions, and increased white cell count consisting primarily of lymphocytes.1,16 Diag-
nosis of cryptococcal disease can be made through blood cultures, CSF microscopy,
and detection of cryptococcal antigen (CrAg) in the blood and CSF.1
Treatment
Treatment of cryptococcal meningitis involves the phases of induction, consolida-
tion, and maintenance therapy. IV amphotericin B plus oral flucytosine (Appendix
7-A) is the preferred regimen for induction.1 Addition of flucytosine to ampho-
tericin B is associated with faster sterilization of CSF; dose adjustment is required
in patients with renal dysfunction. Liposomal amphotericin B is recommended in
the guidelines over amphotericin B deoxycholate due to similar efficacy but lower
toxicity.1 Amphotericin B deoxycholate can be used in situations where cost is an
issue or the patient has a low risk of renal dysfunction. The induction phase should
continue for at least 2 weeks, and successful response is defined as significant clin-
ical improvement and a negative CSF culture. If CSF culture remains positive at 2
weeks, continuation of amphotericin B plus flucytosine may be considered until
CSF cultures are negative. High-dose (400 mg daily) fluconazole is recommended
for at least 8 weeks as the consolidation phase, followed by dose reduction to 200
mg daily for the chronic maintenance phase. Itraconazole 200 mg daily can be
used as an alternative to fluconazole for chronic maintenance; however, it has infe-
rior efficacy. Data are limited for newer triazoles such as voriconazole or posacon-
azole for primary or maintenance therapy. Chronic maintenance therapy should be
continued for a minimum of 1 year and only discontinued after patients achieve a
CD4 ≥100 cells/mm3 for at least 3 months and virologic suppression on ART.1 Main-
tenance therapy should be restarted if the CD4 count declines to <100 cells/mm3.
The optimal timing of initiation of cART in the setting of cryptococcal menin-
gitis is not clear. A randomized controlled trial that included 35 patients with cryp-
tococcal meningitis suggested that ART could be safely initiated within 2 weeks of
diagnosis;14 however, another study conducted in Africa found poorer outcomes
in patients started on ART within 3 days of diagnosis as compared to delaying ART
for at least 10 weeks.18 Patients in the latter study were treated with fluconazole
alone, as well as older antiretroviral drugs no longer recommended as preferred
initial treatment in the United States and Canada. Another randomized clinical
trial conducted in Africa compared patients started on ART within 1 to 2 weeks
of diagnosis to those who received ART deferred until 5 weeks.19 Patients enrolled
received amphotericin B deoxycholate and fluconazole 800 mg daily for induc-
tion therapy. A significant increase in 6-month mortality was noted in the early
ART group and was most evident during the first 8 to 30 days. Mortality was also
higher in the early ART group if the CSF white cell count was low. It is unclear if
the higher rate of deaths in the early as compared to deferred ART group was due
to cryptococcal meningitis or due to IRIS. Based on these data and expert opinion,
guidelines suggest cART should be started between 2 and 10 weeks after starting
ERRNVPHGLFRVRUJ
cryptococcal treatment.1 In patients with increased intracranial pressure or low

CSF white cell counts (<5 cells/µL), delaying ART may be especially important.
IRIS occurs in approximately 20% to 25% of HIV-infected patients with cryp-
tococcal meningitis who initiate cART.3 Differentiating IRIS from treatment failure
can be challenging, but treatment failure usually involves worsening symptoms
as well as persistent positive cultures.1,16 If IRIS does occur, management includes
continuation of both ART and antifungal therapy, reducing elevated intracranial
pressure if present, and possibly considering a short course of glucocorticoids.1
Primary Prevention
Primary prophylaxis for cryptococcal infection in the absence of a positive serum
CrAg test is not recommended due to the relative low frequency of cryptococcal
disease, lack of survival benefit with prophylaxis, cost, risk of drug–drug interac-
tions, and possibility of developing antifungal resistance.1
CEREBRAL TOXOPLASMOSIS
Cerebral toxoplasmosis is usually caused by reactivation of Toxoplasma gondii, an
intracellular parasite typically acquired from ingestion of undercooked meat that
contains tissue cysts or as a result of ingesting infective oocysts shed in cat feces.
The seroprevalence of anti-Toxoplasma immunoglobulin G (IgG) antibody varies
based on geography, ranging from about 11% in the United States to 50% to 80%
in some European and African countries.20 Individuals infected with HIV should
be tested for IgG antibody following their HIV diagnosis to determine the need for
prophylaxis and assist in diagnosing active disease.1 Cerebral toxoplasmosis most
commonly occurs in anti-toxoplasma IgG-positive patients with a CD4 count <200
cells/mm3, although patients with a CD4 count <50 cells/mm3 are at greatest risk.1

Patients with T. gondii infection often present with focal encephalitis and symp-
toms of headache, confusion, fever, or motor weakness. Disease progression can
result in seizures, stupor, and coma.1 Contrast-enhancing lesions in the grey matter
of the cortex or basal ganglia are typically found on CT or magnetic resonance
(MR) imaging of the brain. HIV-infected patients with cerebral toxoplasmosis are
almost always anti-toxoplasma IgG positive. Definitive diagnosis requires iden-
tification of one or more ring-enhancing lesions on imaging and detection of
T. gondii from a sample of brain tissue or CSF.1 However, most clinicians depend on
an empiric diagnosis based on exclusion of likely alternative diagnoses and clinical
and radiographic improvement as a result of anti-toxoplasma treatment.
Treatment
The treatment options for cerebral toxoplasmosis are listed in Appendix 7-A.
Sulfadiazine plus pyrimethamine plus leucovorin is recommended as the preferred
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regimen; leucovorin is used to reduce the risk of hematologic toxicities due to

pyrimethamine.1 For patients who cannot tolerate sulfadiazine or do not respond
to the preferred regimen, pyrimethamine plus clindamycin plus leucovorin is
the preferred alternative. However, it is important to note that this regimen does
not provide protection against PCP, so additional therapy for PCP prophylaxis
must be used. Although TMP-SMX can also be used as an alternative, provides
PCP coverage, and may be better tolerated, there is less experience with TMP-SMX
for treating toxoplasmosis in developed countries. Therefore, it is recommended
that TMP-SMX be considered if pyrimethamine–sulfadiazine or pyrimethamine–
clindamycin cannot be used.1 Of note, a systematic review found no superior
regimen between pyrimethamine plus sulfadiazine, pyrimethamine plus clinda-
mycin, or TMP-SMX.21 Most patients with cerebral toxoplasmosis respond to acute
therapy within 2 weeks. Acute treatment should be continued for at least 6 weeks;
longer courses of treatment may be needed in patients with inadequate clinical
or radiologic response. Following acute treatment, patients should be maintained
on chronic maintenance therapy (secondary prophylaxis); sulfadiazine plus pyri-
methamine plus leucovorin is the preferred regimen (Appendix 7-A).1
Although data are not available to guide when cART should be initiated in a
patient with cerebral toxoplasmosis, guidelines suggest within 2 to 3 weeks after
diagnosis of toxoplasmosis is reasonable.1 IRIS associated with cerebral toxoplas-
mosis, although rare, has been reported. Because some patients with cerebral toxo-
plasmosis require anticonvulsant therapy, it is important to assess patients for
drug–drug interactions with ART.
Chronic maintenance therapy (secondary prophylaxis) is recommended until
the CD4 count increases to >200 cells/mm3 in response to ART for more than
6 months. Secondary prophylaxis should be restarted if CD4 decreases to
<200 cells/mm3.1
Primary Prevention
Primary prophylaxis should be initiated in patients who are anti-toxoplasma IgG
positive with a CD4 count <100 cells/mm3; the preferred regimen, oral TMP-SMX,
is the same as that used for PCP (Appendix 7-A). Primary prophylaxis should be
continued until patients achieve a CD4 count >200 cells/mm3 in response to
ART for at least 3 months or until CD4 count is between 100–200 cells/mm3 and
HIV viral load is below the limit of assay detection for at least 3 to 6 months.
If, however, the viral load is above the level of detection and the CD4 count is
100–200 cells/mm3, PCP prophylaxis needs to be restarted, which also provides
coverage for toxoplasmosis. Primary prophylaxis should be restarted if the CD4
count decreases to <100–200 cells/mm3.
MYCOBACTERIUM AVIUM COMPLEX DISEASE

Mycobacterium avium complex (MAC) organisms are found ubiquitously in the
environment, and transmission occurs due to inhalation or ingestion.22 The most
ERRNVPHGLFRVRUJ
common organism associated with MAC disease is M. avium.1 With the availability
of cART, the incidence of MAC disease has decreased more than 10-fold.1,22 Patients
with CD4 counts <50 cells/mm3 are at greatest risk; other factors associated with
higher risk of MAC disease include HIV viral load >100,000 copies/mL, previous
OIs, and previous colonization of MAC in the respiratory or gastrointestinal tract.1

Patients with MAC disease and not receiving cART usually exhibit disseminated,
multi-organ infection. Signs and symptoms may include fever, night sweats, weight
loss, fatigue, diarrhea, abdominal pain, anemia, and elevated alkaline phosphatase.1
Signs on physical examination or imaging studies may consist of hepatomegaly,
splenomegaly, or lymphadenopathy. Localized presentation of MAC disease such
as cervical or mesenteric lymphadenitis, pneumonitis, osteomyelitis, or skin or
soft tissue abscesses may occur in patients receiving and responding to ART as a
manifestation of IRIS.1 Signs and symptoms of IRIS can be difficult to distinguish
from active MAC infection. IRIS has been reported in patients with subclinical or
established MAC disease and low CD4 counts who have a rapid rise in CD4 count
(≥100 cells/mm3) following initiation of cART.1 MAC is diagnosed based on signs
and symptoms and the presence of organisms from blood cultures or samples from
the lymph node, bone marrow, or other body fluids that are normally sterile.1
Species identification is important to distinguish from Mycobacterium tuberculosis.
Treatment
Treatment of MAC disease consists of at least two anti-mycobacterial agents to
reduce the development of resistance. The preferred regimen is clarithromycin
and ethambutol; however, azithromycin can be used in place of clarithromycin
in patients who have intolerance or to avoid drug–drug interactions.1 It is recom-
mended that MAC isolates be tested for susceptibility to macrolides due to
increasing macrolide resistance.23 In some cases, rifabutin may be added as a third
drug.22 Guidelines recommend addition of a third or fourth drug in the following
situations: CD4 <50 cells/mm3, high mycobacterial loads (>2 log10 colony-forming
units/mL of blood), absence of effective ART, and settings where mortality is
increased and emergence of drug resistance most likely.1
In patients not yet receiving antiretrovirals, it is recommended that cART be
started as soon as possible following the first 2 weeks of MAC treatment.1 Guide-
lines suggest that initiating MAC treatment first may reduce the risk of IRIS as well
as the initial pill burden. Consideration must be given to the risk of drug–drug
interactions between antiretrovirals and MAC treatment (especially rifabutin).
Treatment for MAC should be continued until patients have completed at least 12
months of MAC therapy, remain asymptomatic, and have a CD4 cell count that
has increased to ≥100 cells/mm3 for at least 6 months after starting ART.1
Clinical response to MAC treatment is expected within 2 to 4 weeks, including
improvement in fever and a decrease in mycobacterial load in blood or tissue.
Blood cultures should be repeated at 4 to 8 weeks after starting MAC treatment
ERRNVPHGLFRVRUJ
in those patients who do not have a clinical response.1 Repeat susceptibility

testing of MAC isolates to macrolides is recommended in patients who experi-
ence disease relapse after initial response. Results of susceptibility testing should
be used to select a new regimen and should include at least two new drugs not
previously used.1 Drugs that may be considered in the setting of macrolide-
resistant MAC are ethambutol, rifabutin, amikacin, or a fluoroquinolone (cipro-
floxacin, levofloxacin, moxifloxacin).
Primary Prevention
Historically, prophylaxis for MAC in patients without previous infection has been
recommended for CD4 counts <50 cells/mm3.1 However, based on observational
data, experts from the 2016 International Antiviral Society–U.S. Panel no longer
recommend primary prophylaxis for MAC provided effective ART is started imme-
diately and the patient achieves virologic suppression.24,25
If prophylaxis is initiated, preferred agents include azithromycin or clarithro-
mycin, which should be continued until the CD4 count increases to >100 cells/
mm3 for at least 3 months and restarted if CD4 decreases again to <50 cells/mm3.
Rifabutin may be used as an alternative in patients who are unable to tolerate
macrolides, but potential for drug interactions with antiretrovirals must be care-
fully reviewed. Prior to starting primary prophylaxis, MAC disease should be ruled
out through clinical assessment (which may include a MAC blood culture) to
avoid the use of monotherapy in active disease.1
CYTOMEGALOVIRUS DISEASE
Cytomegalovirus (CMV) establishes latency after primary infection and can cause
disseminated or end-organ disease through reactivation in HIV-infected individ-
uals with advanced immunodeficiency. Prior to cART, up to a third of patients
diagnosed with AIDS experienced CMV retinitis and had a median survival of 8 to
12 months.1 Cohorts have shown dramatic declines (50% to 95%) in the incidence
of new CMV infection and CMV retinitis cases since the introduction or early use
of cART,2,10 and the 5-year survival probability in a U.S. cohort diagnosed with
CMV disease other than retinitis improved from approximately 1% in the pre-ART
era to near 60% in the cART era.26 In addition to a low CD4 cell count (<50 cells/
mm3), a high HIV viral load, a high CMV viral load, and increasing age are also
associated with a higher incidence of CMV disease.1

Presentation of CMV disease correlates with the site of infection, with CMV reti-
nitis being the most common clinical manifestation in HIV-infected patients
followed by colitis, esophagitis, pneumonitis, and neurological disease.1 In the
case of CMV retinitis, patients may be asymptomatic or present with floaters,
flashing lights, decreased visual acuity, or peripheral or central visual field defects.
Without treatment, disease progression occurs rapidly, usually within 10 to 21
ERRNVPHGLFRVRUJ
days after presentation. Complete visual loss may occur. Although retinitis usually
presents unilaterally, disease can occur in the contralateral eye within 6 months,
especially in the absence of systemic treatment for CMV.1
An experienced ophthalmologist typically makes the diagnosis of CMV reti-
nitis based on characteristic retinal changes seen on fundoscopy. In fulminant
retinitis, fluffy, yellow-white retinal lesions with areas of hemorrhage can be found
on ophthalmologic evaluation.1 CMV viremia will often be detectable in clinical
disease, but it can also be present in the absence of disease. Thus, guidelines do
not recommend screening of serum, stool, or bronchoalveolar lavage for CMV
antigenemia or quantitative PCR to guide diagnosis, monitoring, or treatment of
end-organ disease. The absence of CMV IgG antibodies implies no previous expo-
sure and suggests that CMV disease is unlikely.1
Treatment
Treatment of CMV end-organ disease involves the use of oral valganciclovir, IV
ganciclovir, foscarnet, or cidofovir, which all hinder CMV replication by inhib-
iting viral DNA polymerase.1 The bioavailability of the prodrug valganciclovir
(60%) has enabled the oral formulation to be a viable systemic option, rendering
IV ganciclovir to be used when absorption may be impaired or suboptimal (e.g.,
gastrointestinal disease, nonadherence). Any systemic option is recommended,
although valganciclovir is preferred, in conjunction with intravitreal injection of
ganciclovir, foscarnet, or cidofovir, particularly in patients with any sight-threat-
ening lesion (Appendix 7-A). Due to their potential for toxicity, IV foscarnet or
cidofovir should be reserved for cases of ganciclovir resistance. The systemic expo-
sure facilitates protection to the contralateral eye, guards against extraocular infec-
tion, and improves survival, while the local injection ensures immediate high drug
concentration at the site of the infection. For small peripheral lesions, guidelines
recommend systemic induction and maintenance with anti-CMV therapy to mini-
mize retinal progression and ocular complication while awaiting immune recovery
with cART.1 Management of CMV esophagitis or colitis usually requires only a
short course of anti-CMV therapy, although the optimal duration of treatment
for confirmed CMV pneumonitis and neurologic disease is not well established.1
In all manifestations of CMV disease, including CMV retinitis where an ocular
form of IRIS immune reconstitution uveitis (IRU) may occur,1,27 cART initiation is
recommended within 2 weeks. Intraocular inflammation associated with IRU can
occur months to years after CMV treatment has been completed when immune
recovery occurs; therefore, an experienced ophthalmologist should routinely
monitor patients diagnosed with CMV retinitis to distinguish an immunologic
reaction to CMV or treatment failure and relapse.
Maintenance treatment with systemic anti-CMV therapy should be continued
in patients with CMV retinitis until immune reconstitution occurs (sustained
CD4 >100 cells/mm3 on ART for 3 to 6 months). As relapses have been reported
with CD4 counts greater than 1,000 cells/mm3, some experts recommend regular
ophthalmologic monitoring every 3 months and periodically thereafter regardless
of immune recovery.1
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Primary Prevention
Initiation of cART and maintaining CD4 count >100 cells/mm3 is the best way to
prevent CMV end-organ disease. There is no CMV vaccine, and the use of chronic
oral ganciclovir or valganciclovir as primary prophylaxis was not found to be
cost-effective.28,29
HERPES ZOSTER
After primary infection, the varicella-zoster virus (VZV) establishes lifelong latency
in the sensory ganglion neurons controlled by T-cell immunity.30 Herpes zoster
(HZ) results from reactivation of the dormant VZV. The lifetime risk for HZ is 15%
to 20%, with the elderly and immunocompromised individuals at greatest risk.1
Before the introduction of cART, the incidence of HZ in HIV-infected patients was
estimated to be 10 to 30 times higher than their age-matched controls.1,31 Various
surveillance studies in the cART era, however, have shown a significant decline in
the incidence of HZ, although the risk in HIV-infected individuals still remains
2- to 3-fold higher than in the general population.31,32 The primary risk factor for
HZ is immunodeficiency, which is greatest when CD4 <200 cells/mm3, but it may
occur at any CD4 count. Other risk factors include low CD4 cell nadir, detectable
plasma viral load, and a previous zoster episode.1

HZ often presents as a cutaneous eruption with a dermatomal distribution that
does not cross the midline, most commonly in the thoracic dermatome (40% to
50% of cases), followed by cranial nerve (20% to 25%), cervical (15% to 20%),
lumbar (15%), or sacral dermatomes (5%).1 The initial erythematous maculopap-
ular rash is often preceded by prodromal tingling, itching, or pain, with lesions
emerging and evolving into clear vesicles and pustules for the next 3 to 5 days,
followed by crusting and scabbing for 2 to 3 weeks. During this period, accompa-
nying symptoms may include pruritus, paresthesias, hyper- or dysesthesia, head-
ache, and malaise.1
Immunocompromised patients are vulnerable to more severe, disseminated,
and complicated HZ disease as well as the painful and potentially debilitating
sequelae, postherpetic neuralgia. The rash may be multidermatomal, and the
appearance of new lesions can occur for up to 2 weeks.30 HIV-infected patients
are at greatest risk for dissemination to the central nervous system. In addition,
visual loss may result from acute or progressive outer retinal necrosis from VZV;
HIV-infected patients and CD4 <100 cells/mm3 are at highest risk.32
Diagnosis is usually made clinically, but swabs from a fresh lesion or tissue
biopsy can be sent for viral culture, direct immunofluorescence assay for VZV
antigen, or the highly sensitive and specific PCR assay for detecting VZV DNA.1 A
PCR assay of the blood, CSF, or vitreous humor may be supportive in diagnosing
HZ infection that presents without the characteristic rash (zoster sine herpete)
such as pneumonitis, CNS vasculopathy, or retinitis.1
ERRNVPHGLFRVRUJ
Treatment
Treatment for localized dermatomal HZ involves the use of the oral antiviral
agents acyclovir, valacyclovir, or famciclovir for 7 to 10 days (Appendix 7-A).1
Valacyclovir and famciclovir offer more convenient dosing schedules as compared
to acyclovir. Treatment should be initiated as early as possible before full crusting
of the lesions; however, many experts still recommend starting treatment beyond
the 72-hour window from the onset of the rash in cases where new lesions are
still forming or in severe HZ infections with complications. IV acyclovir is recom-
mended for disseminated infection, visceral or CNS involvement, as well as in
conjunction with intravitreal antiviral administration in the management of HZ
ophthalmicus. The aforementioned antivirals are overall well tolerated with rare
reports of neurologic toxicity that can often be minimized with adequate hydra-
tion and appropriate dose adjustments in renal impairment. Acyclovir-resistant
VZV is rare, but if suspected, treatment with IV foscarnet or IV cidofovir is recom-
mended.1
ART is indicated in all HIV-infected patients, and the incident HZ infection is
not a contraindication to initiate or continue HIV treatment.1 Rather, ART should
be reevaluated and optimized in patients with recurrent HZ infections or severe
VZV disease. Of note, the risk of VZV reactivation increases 2- to 4-fold in the
immediate months after initiation of ART as immune reconstitution occurs.31
Clinical presentation in the setting of immune reconstitution is similar, and these
events should be handled in the same way.1
Primary Prevention
Current guidelines do not recommend primary or secondary prophylaxis, although
a recent study found the use of acyclovir 400 mg orally twice daily significantly
reduced the incidence of HZ in HIV-positive patients by 62% (hazard ratio [HR],
0.38; 95% CI, 0.24–0.67; p <0.001).1,33 The protective effect of acyclovir was
observed regardless of age, CD4 count (<350 and ≥350 cells/mm3), or initiation
of ART. The numbers of participants starting ART after enrollment, however, were
small, and the study may have been underpowered to detect a difference.
The live-attenuated HZ vaccine is indicated in immunocompetent adults aged
50 years and older. The Advisory Committee on Immunization Practices has contra-
indicated it in immunocompromised patients with a CD4 ≤200 cells/mm3.34 There
is a notable absent recommendation for HIV-infected individuals with a CD4 >200
cells/mm3, although arguments have been presented for its indication in this at-risk
population.35 Even though no randomized study has evaluated the clinical efficacy
of the live-attenuated HZ vaccine in the HIV-population, two doses of HZ vaccine
administered 6 weeks apart were found to be safe and immunogenic in 295 VZV-
seropositive HIV-infected adults with a CD4 >200 cells/mm3 receiving suppressive
ART.36 The HIV Medicine Association of the Infectious Diseases Society of America
(IDSA) advises clinicians to consider offering the zoster vaccine to at-risk patients
greater than 60 years of age with CD4 ≥200 cells/mm3 as part of the routine vacci-
nation schedule for HIV-infected adults.37 Finally, another means of preventing HZ
ERRNVPHGLFRVRUJ
is preventing the initial infection and establishment of VZV with the administra-
tion of the live attenuated varicella vaccine, an option only available to those HIV-
positive patients sero-negative for VZV with a CD4 >200 cell/mm3.1

Pharmacists are valuable assets in the efforts to achieve optimal health outcomes, partic-
ularly in complex immunocompromised HIV-infected patients who may need OI prophy-
laxis or treatment in addition to cART.38,39 A summary of a pharmacist’s assessment is
provided in Table 7-1.
Specifically in the context of OIs, pharmacists can
• screen for the appropriate initiation or safe discontinuation of primary or
secondary OI prophylaxis, ensuring prevention therapy is not used if treatment
is required and minimizing unnecessary use of antimicrobials in the absence of
risk or clinical disease
• recommend evidence-based, cost-effective OI therapies that accommodate drug
allergies, drug interactions, drug resistance, and patient preferences
• help select multipurpose treatments to prevent polypharmacy and duplication
of therapy (e.g., antifungals such as amphotericin and fluconazole used for
cryptococcal meningitis may also manage esophageal candidiasis, but echino-
candins used for candidiasis have no activity against cryptococcal species)
• monitor and help manage emergent side effects, thus avoiding concomitant use
of drugs with overlapping toxicities and differentiating medication side effects
from symptoms of immune reconstitution or treatment failure
• suggest optimal timing of compatible antiretroviral regimens to restore immune
function
• facilitate medication adherence through patient education and drug access
Medication access has become an increasing challenge in health care, affecting adher-
ence and health outcomes even in developed nations.40-42 Pharmacists are well positioned
to help identify and address issues of drug access. In the case of OI medications that
have a small niche market and may be subject to product discontinuations, shortages,
or significant price increases, pharmacists must be cognizant of product availability and
the various potential avenues to gain access to first-line therapies (e.g., national special
access programs or compounding pharmacies) or recommend alternative formulations to
minimize delays or gaps in treatment. Some drugs have substantial cost considerations,
are not included on provincial or state drug formularies, have strict criteria for use, or
pose significant financial burdens. Other medications may have special administration
requirements (e.g., aerosolized pentamidine, prolonged IV amphotericin infusions) neces-
sitating specialized outpatient services. Pharmacists need to recognize the obstacles, make
recommendations accordingly, and help patients navigate enrollment into any drug assis-
tance program, facilitating access to the most appropriate therapies needed to achieve
positive outcomes.
ERRNVPHGLFRVRUJ
TABLE 7-1. Pharmacist’s Assessment to Identify, Prevent, and Resolve

OI-Associated Drug Therapy Problems
Assessment for INDICATION (e.g., no valid indication or unnecessary drug, requires drug but not receiving)
• Determine if prescribed medication(s) is for primary or secondary prophylaxis or treatment of
active disease
• Review current CD4 counts and medical history to determine if primary or secondary OI
prophylaxis are indicated or if maintenance/preventative therapy can be safely discontinued
• Refer for medical evaluation if patient presents with signs and symptoms suggestive of active
infection and not receiving therapy or only receiving prophylaxis
• Screen patient history and consider eligibility for vaccine-preventable OIs
• Evaluate appropriate duration of treatment for induction, consolidation, or maintenance therapy
and discourage inappropriate continuation of anti-infectives
Assessment for EFFECTIVENESS (wrong drug/product, dose too low, drug–drug or drug–food interaction)
• Verify appropriate dosing of OI-associated medications, particularly agents that require weight-
based dosing
• Recommend drug formulations that achieve adequate/optimal drug concentrations (e.g.,
intravitreal injections, suspension, tablets) and address swallowing difficulties or patient
preferences
• Assess for any drug–drug interactions (e.g., clarithromycin, itraconazole, voriconazole, rifamycins
have high potential for pharmacokinetic drug interactions), including duplication of therapy
• Recognize when symptoms should improve or be resolved to identify potential failures due to
drug resistance
Assessment for SAFETY (dose too high, adverse drug reaction, drug–drug or drug–food interaction)
• Verify appropriate dosing of OI-associated medications, particularly those that require weight-
based dosing or require dosage adjustment in renal dysfunction
• Monitor for short-term and long-term drug side effects (distinguish from signs/symptoms of
immune reconstitution or drug failure)
• Ensure preemptive therapies to minimize toxicities are also prescribed (e.g., pre- and
post-amphotericin hydration, probenecid pre- and post-cidofovir)
• Confirm prescreening tests completed before initiating specific therapies (e.g., G6PD deficiency)
• Assess for any drug–drug interactions (clarithromycin, itraconazole, voriconazole, rifamycins
have high potential for pharmacokinetic drug interactions) and minimize drugs with overlapping
toxicities where possible (e.g., zidovudine and valganciclovir, tenofovir disoproxil fumerate and
nephrotoxic agents)
• Evaluate safety of alternate therapies and potential risk for cross-sensitivities; consider
desensitization
• Screen for symptoms of active infection before initiating preventive therapy to minimize drug
resistance
• Determine optimal timing for initiation of ART in setting of new opportunistic infection
• Assist with medication reconciliation, especially at medical points of transfer (e.g., hospital
admission/discharge) to minimize medication errors
(continued)
ERRNVPHGLFRVRUJ
TABLE 7-1. Pharmacist’s Assessment to Identify, Prevent, and Resolve

OI-Associated Drug Therapy Problems (continued)
ADHERENCE (education, choice, complexity, acquisition, cost)
• Provide medication counseling, including role of OI therapies and expected duration of therapy
• Review therapeutic options and recommend simplified dosing regimens where possible (e.g.,
daily versus BID versus intermittent dosing) or drugs with multiple indications, minimizing
polypharmacy
• Recognize any financial barriers to accessing medications and assist with enrolling into public or
compassionate drug programs
• Keep abreast of product availability and help navigate special access programs to gain access
or consider contacting specialized pharmacies to assist with medication compounding (e.g.,
pyrimethamine capsules, amphotericin suspension)
• Offer tools to assist with medication adherence (e.g., blister-packs, dosettes)
ART: antiretroviral therapy; BID: twice a day; G6PD: glucose-6-phosphate dehydrogenase; OI: opportunisitic infection
KEY RESOURCES
Guidelines for Prevention and Treatment of Opportunistic Infections
• AIDSinfo, U.S. Department of Health and Human Services (DHHS) Guidelines for the
Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and
Adolescents: Recommendations from the Centers for Disease Control and Prevention,
the National Institutes of Health, and the HIV Medicine Association of the Infectious
Diseases Society of America. https://aidsinfo.nih.gov/guidelines/html/4/adult-and-
adolescent-oi-prevention-and-treatment-guidelines/0.
o These guidelines, available also through a smart-phone app and updated as
relevant changes occur, provide reviews on opportunistic pathogens potentially
encountered by HIV-infected patients and make recommendations for their
prevention and treatment. They also address topics such as when to start anti-
retrovirals in the setting of an acute OI, management of IRIS, and various drug
considerations (e.g., preparations, use in pregnancy, renal dysfunction, drug
interaction concerns).
• British HIV Association (BHIVA): Current Guidelines. http://www.bhiva.org/
guidelines.aspx.
o BHIVA is a leading UK organization that publishes many documents on a wide
range of HIV care. In addition to the treatment and management of HIV, they
have developed many guidelines, including the treatment of opportunistic infec-
tion in HIV-seropositive individuals, use of vaccines in HIV-positive adults, and
the management of tuberculosis and HIV co-infection. These guidelines are also
available through a smart-phone app.
• European AIDS Clinical Society (EACS) Guidelines. http://www.eacsociety.org/
guidelines/eacs-guidelines/eacs-guidelines.html.
o The site provides regularly updated guidelines developed by the EACS to promote
excellence in standards of care in HIV infections and related co-infections. Their
most current guidelines, available in five languages and as a smart-phone app,
contain a section dedicated to the management of opportunistic infections in
ERRNVPHGLFRVRUJ
HIV-positive persons, summarizing national guidelines from the UK, United

States, and several European countries in easy-to-use charts.
• Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-
Exposed and HIV-Infected Children: Recommendations from the National Insti-
tutes of Health (NIH), Centers for Disease Control and Prevention (CDC), the HIV
Medicine Association (HIVMA) of the IDSA, the Pediatric Infectious Diseases Society,
and the American Academy of Pediatrics. https://aidsinfo.nih.gov/guidelines/html/5/
pediatric-oi-prevention-and-treatment-guidelines/0/.
o Similar to the guidelines above for HIV-exposed and infected children.
• International Antiviral Society—USA (IAS-USA) Panel Practice Guidelines.
http://www.iasusa.org/guidelines.
o The IAS-USA provides clinical practice guidelines developed by a volunteer panel
of experts in HIV research and patient care. Updated recommendations on the
use of antiretrovirals in HIV-infected adults were released in 2016 and included a
dedicated section reviewing timing and selection of antiretrovirals in the setting
of OIs.
• World Health Organization (WHO) guidelines. http://www.who.int/hiv/pub/arv/
arv-2016/en/.
o The WHO publishes many documents, including a chapter on managing
common co-infections and comorbidities in their consolidated guidelines on
managing HIV infection. The chapter summarizes key recommendations and
provides guidance to other literature on co-infections, such as tuberculosis, cryp-
tococcal infection, hepatitis B and C, and malaria, with a focus on resource and
capacity-limited settings.
Desensitization Protocol
• AIDS Education & Training Center (AETC), National Coordination Resource Center.
https://aidsetc.org/guide/sulfa-desensitization.
o The website provides an oral sulfa desensitization regimen using the suspension
formulation that extends over 13 days, coupled with the education a patient
should receive. The site also provides references to more rapid protocols.
Drug Interactions with OI Drugs
• HIV/HCV Drug Therapy Guide. University Health Network—Toronto General
Hospital. http://app.hivclinic.ca/.
o This website/app provides current data on HIV and hepatitis C drug therapy
with a main focus on drug interactions. The site allows the user to select one
or more anti-HIV or antihepatitis C virus medication along with one or more
other drugs and provides an evidence-based summary of the interaction with
recommendations. Although the program does not conduct interaction checks
between the non-HIV or HCV drug, the program does provide a link to interac-
tion checks with drugs from similar classes.
• University of Liverpool HIV Pharmacology. http://www.hiv-druginteractions.org/.
o This resource provides up-to-date evidence-based information on drug interac-
tions through its “HIV Drug Interaction Checker.” The user can run a specific
query between the antiretroviral drug and the co-medication for detailed infor-
mation about the interaction or search printable charts organized by anti-
retroviral drug class charts for a summary between the HIV medication and
other drugs in other classes (e.g., interactions with protease inhibitors and anti-
bacterials).
ERRNVPHGLFRVRUJ
Patient Education—Drug Information for Medications Used for OIs

• AIDSinfo, U.S. Department of Health and Human Services (DHHS). https://aidsinfo.
nih.gov/drugs.
o This database enables a user to search for FDA and investigational drug informa-
tion related to HIV and opportunistic infections and co-infections for health care
providers and patients. Information can be found by searching by drug name, by
drug class, or by disease. A patient version or the FDA label (or health profes-
sional version for drugs not yet marketed) can be printed, and all information is
also available in Spanish.
• Immunodeficiency Clinic, University Health Network—Toronto General Hospital.
http://hivclinic.ca/patient-information/medication-fact-sheets/.
o This website provides printable patient medication fact sheets for antiretrovirals
and medications used for opportunistic infections or to manage complications.
They were developed by clinical pharmacists and are available in both English
and in French.
Drug Access
• Government of Canada, Drugs - Special Access to Drugs and Health Products.
https://www.canada.ca/en/health-canada/services/drugs-health-products/special-
access/drugs.html
o This Health Canada website provides information on the Special Access
Programme (SAP) and the forms required to request access to nonmarketed drugs
in Canada (e.g., sulfadiazine, flucytosine).
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APPENDIX 7-A. OPPORTUNISTIC INFECTION PROPHYLAXIS AND

TREATMENT
Opportunistic Infection and Treatment Dosing (based on normal renal

function)
Preferred Alternatives
Oropharyngeal candidiasis
Treatment (Duration: 7 to 14 days)
• Fluconazole 100 mg PO daily • Clotrimazole troches 10 mg PO 5 times daily
• Miconazole mucoadhesive buccal 50 mg
tablet—apply to mucosal surface over the
canine fossa once daily
• Itraconazole oral solution 200 mg PO daily
• Posaconazole oral suspension 400 mg PO BID
× 1 day, then 400 mg daily
• Nystatin suspension 500,000 U (or 5 mL) swish
and swallow four times daily
Esophageal candidiasis
Treatment (Duration: 14 to 21 days)
• Fluconazole 100 mg (up to 400 mg) PO/IV • Voriconazole 200 mg PO/IV BID
daily • Caspofungin 50 mg IV daily
• Itraconazole oral solution 200 mg (20 mL) • Micafungin 150 mg IV daily
PO daily
• Anidulafungin 100 mg IV x 1 dose, then 50 mg
IV daily
• Amphotericin B deoxycholate 0.6 mg/kg IV
daily
• Amphotericin B lipid formulation 3–4 mg/kg
IV daily
Pneumocystis pneumonia (PCP)

Primary Prophylaxis Discontinuation:
Indications: • CD4 count ≥200 cells/mm3 for at least
• CD4 count <200 cells/mm 3 3 months in response to ART
• CD4 <14% • Consider if CD4 count 100–200 cells/mm3
and HIV viral load is below the limit of assay
• CD4 count >200 but <250 cells/mm3 if
detection for at least 3–6 months
monitoring CD4 cell count (e.g., every 3
months) is not possible and ART cannot be
initiated Reinitiation:
• CD4 count <100 cells/mm3 regardless of HIV
viral load
• CD4 count 100–200 cells/mm3 and HIV viral
load above limit of assay detection
(continued)
ERRNVPHGLFRVRUJ

function) (continued)
• TMP-SMX 1 double-strength (DS) tablet PO • TMP-SMX 1 DS tablet PO three times weekly
daily • Dapsone 100 mg PO daily or 50 mg PO BID
• Dapsone 50 mg PO daily + (pyrimethamine
• TMP-SMX 1 single-strength (SS) tablet PO daily 50 mg + leucovorin 25 mg) PO weekly
• (Dapsone 200 mg + pyrimethamine 75 mg +
leucovorin 25 mg) PO weekly
• Aerosolized pentamidine 300 mg via Respigard
IITM nebulizer every month
• Atovaquone 1,500 mg (10 mL) PO daily with
food
• (Atovaquone 1,500 mg [10 mL] +
pyrimethamine 25 mg + leucovorin 10 mg) PO
daily with food
Treatment (Duration: 21 days)

Moderate-to-severe PCP:
• TMP-SMX: [TMP 15–20 mg and SMX 75–100 • Pentamidine 4 mg/kg IV daily infused over at
mg]/kg/day IV given in divided doses every least 60 minutes (may reduce to 3 mg/kg IV
6 or 8 hours; may switch to PO after clinical daily because of toxicities)
improvement • Primaquine 30 mg (base) PO daily +
(clindamycin 600 mg IV q6h or 900 mg IV
q8h) or (clindamycin 450 mg PO q6h or
600 mg PO q8h)
Adjunctive corticosteroids (if PaO2 <70 mmHg on
room air or alveolar-arterial O2 gradient
≥35 mmHg):
• Prednisone 40 mg PO BID x 5 days, then
40 mg PO daily × 5 days, then 20 mg PO daily
× 11 days (should be started as soon as possible
and within 72 hours of PCP therapy)
Mild-to-moderate PCP:
• TMP-SMX: [TMP 15–20 mg and SMX • Dapsone 100 mg PO daily + trimethoprim
75–100 mg]/kg/day PO given in 3 divided 15 mg/kg/day PO (given in 3 divided doses)
doses • Primaquine 30 mg (base) PO daily +
• TMP-SMX 2 DS tablet PO TID (clindamycin 450 mg PO q6h or 600 mg PO
q8h)
• Atovaquone 750 mg (5 mL) PO BID with food
(continued)
ERRNVPHGLFRVRUJ

Secondary Prophylaxis
• TMP-SMX: 1 DS tablet PO daily • TMP-SMX: 1 DS tablet PO three times weekly
• TMP-SMX: 1 SS tablet PO daily • Dapsone 100 mg PO daily or 50 mg PO BID
50 mg + leucovorin 25 mg) PO weekly
• (Dapsone 200 mg + pyrimethamine 75 mg +
leucovorin 25 mg) PO weekly
• Aerosolized pentamidine 300 mg monthly via
Respirgard II™ nebulizer
food
daily with food
Indication:
• Prior PCP
Discontinuation:
• CD4 increased to ≥200 cells/mm3 for
>3 months in response to ART
• Consider if CD4 count 100–200 cells/mm3 and
HIV viral load below limit of assay detection
for at least 3–6 months
• If PCP occurred at CD4 count >200 cells/mm3
while on ART, consideration should be made
to continue prophylaxis for life regardless of
CD4 count
Reinitiation:
• CD4 count <100 cells/mm3 regardless of HIV
viral load
• CD4 count 100–200 cells/mm3 and HIV viral
load above limit of assay detection
(continued)
ERRNVPHGLFRVRUJ

Cryptococcal meningitis
Treatment
Induction therapy (duration at least 2 weeks, followed
by consolidation therapy):
• Liposomal amphotericin B 3–4 mg/kg IV daily • Amphotericin B lipid complex 5 mg/kg IV

+ flucytosine 25 mg/kg PO four times daily daily + flucytosine 25 mg/kg PO four times
• Amphotericin B deoxycholate 0.7–1 mg/kg daily
IV daily + flucytosine 25 mg/kg PO four times • Liposomal amphotericin B 3–4 mg/kg IV daily
daily + fluconazole 800 mg PO/IV daily
• Amphotericin B deoxycholate 0.7–1 mg/kg IV
daily + fluconazole 800 mg PO/IV daily
• Liposomal amphotericin B 3–4 mg/kg IV daily
alone
• Amphotericin B deoxycholate 0.7–1 mg/kg IV
daily alone
• Fluconazole 400 or 800 mg PO/IV daily +
flucytosine 25 mg/kg PO four times daily
• Fluconazole 1,200 mg PO/IV daily alone
Consolidation therapy (duration at least 8 weeks,

followed by maintenance therapy):
• Fluconazole 400 mg PO/IV daily • Itraconazole 200 mg PO BID
Maintenance therapy (duration at least 1 year—

see below for discontinuation criteria):
• Fluconazole 200 mg PO daily
Discontinuation:
• Completion of initial (induction and
consolidation) therapy AND
• Received for at least 1 year AND
• Remain asymptomatic of cryptococcal
infection AND
• CD4 count ≥100 cells/ mm3 for ≥3 months and
with suppressed plasma HIV RNA in response
to ART
Reinitiation of maintenance therapy:

• CD4 count <100 cells/mm3
(continued)
ERRNVPHGLFRVRUJ

Toxoplasma gondii encephalitis
Indications: • CD4 >200 cells/mm3 for >3 months in
• Toxoplasma IgG-positive patients with CD4 response to ART
count <100 cells/mm3 • Consider if CD4 count is 100–200 cells/mm3
and HIV viral load remains below the limit of
assay detection for at least 3–6 months
Reinitiation:
• CD4 count <100 cells/mm3, regardless of the
HIV viral load
• TMP-SMX 1 double-strength (DS) tablet PO • CD4 <100 cells/mm3

daily • TMP-SMX 1 DS tablet PO three times weekly
• TMP-SMX 1 SS tablet PO daily
50 mg + leucovorin 25 mg) PO weekly
• (Dapsone 200 mg + pyrimethamine 75 mg
+ leucovorin 25 mg) PO weekly
food
daily with food
Treatment (Duration of 6 weeks followed by
chronic maintenance therapy)
• Sulfadiazine 1,000 mg (if weight ≤60 kg) or • Clindamycin 600 mg IV/PO q6h +
1,500 mg (if weight >60 kg) PO q6h pyrimethamine 200 mg PO x 1, then 50–75 mg
+ pyrimethamine 200 mg PO x 1, then 50 mg PO daily (based on body weight) + leucovorin
(if weight ≤60 kg) or 75 mg (if weight >60 kg) 10–25 mg PO daily
PO daily • TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg)
+ leucovorin 10–25 mg PO daily IV/PO BID
• Atovaquone 1,500 mg (10 mL) PO BID with
food
+ pyrimethamine 200 mg PO x 1, then
50–75 mg PO daily (based on body weight)
+ leucovorin 10–25 mg PO daily
food
food + sulfadiazine 1,000–1,500 mg (based on
body weight) PO q6h
(continued)
ERRNVPHGLFRVRUJ

Chronic Maintenance Therapy
• Sulfadiazine 2,000–4,000 mg PO daily • Clindamycin 600 mg PO q8h
(in 2–4 divided doses) + pyrimethamine 25–50 mg PO daily
+ pyrimethamine 25–50 mg PO daily + leucovorin 10–25 mg PO daily
+ leucovorin 10–25 mg PO daily • TMP-SMX 1 DS tablet PO BID
• TMP-SMX 1 DS tablet PO daily
• Atovaquone 750–1,500 mg (5–10 mL) PO BID
with food
+ pyrimethamine 25 mg PO daily
+ leucovorin 10 mg PO daily
with food
+ sulfadiazine 2,000–4,000 mg PO daily
(in 2–4 divided doses)
with food
Discontinuation:
• Successfully completed acute treatment AND
• Remain free of signs and symptoms of
toxoplasmosis AND
• CD4 count >200 cells/mm3 for >6 months in
response to ART
Reinitiation:
Disseminated mycobacterium avium complex (MAC) disease

Indications: • CD4 >100 cells/mm3 for ≥3 months in
• CD4 count <50 cells/mm (if not starting
3 response to ART
effect ART right away). Need to rule out active
disseminated MAC disease based on clinical Reinitiation:
assessment.
• CD4 counts <50 cells/mm3
• Azithromycin 1,200 mg PO once weekly • Rifabutin 300 mg daily (dose may need to be
• Clarithromycin 500 mg PO BID adjusted based on concomitant ART); rule out
active TB before starting rifabutin
• Azithromycin 600 mg PO twice weekly
(continued)
ERRNVPHGLFRVRUJ

Treatment (Duration at least 12 months—
discontinuation criteria below)
• Clarithromycin 500 mg PO BID + ethambutol • Option for 3rd or 4th drugs if required
15 mg/kg PO daily (e.g., potential macrolide resistance):
• Azithromycin 500–600 mg + ethambutol S Rifabutin 300 mg PO daily
15 mg/kg PO daily if drug interaction S Moxifloxacin 400 mg PO daily or
or intolerances precludes the use of levofloxacin 500 mg PO daily
clarithromycin
S Amikacin 10–15 mg/kg IV daily or
streptomycin 1 g IV/IM daily
Discontinuation:
• Completion of ≥12 months of therapy AND
• No signs and symptoms of MAC disease AND
• Sustained CD4 count of >100 cells/mm3 for
>6 months in response to ART
Reinitiation:
Cytomegalovirus (CMV) disease

CMV retinitis
Treatment For immediate sight-threatening
lesions—initial therapy followed by chronic
maintenance:
• Valganciclovir 900 mg PO BID × 14–21 days, • Intravitreal injections as listed in preferred
then 900 mg once daily column plus one of the following systemic
+ ganciclovir 2 mg intravitreal injection therapies:
or foscarnet 2.4 mg intravitreal injection S Ganciclovir 5 mg/kg IV q12h × 14–21 days,
× 1–4 doses over 7–10 days then 5 mg/kg IV daily
S Ganciclovir 5 mg/kg IV q12h × 14–21 days,
then valganciclovir 900 mg PO daily
S Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV
q12h for 14–21 days, then 90–120 mg/kg
IV q24h
S Cidofovir 5 mg/kg/week IV for 2 weeks then
5 mg/kg every other week with saline
hydration before and after therapy and
probenecid 2 g PO 3 hours before the dose,
followed by 1 g PO 2 hours after the dose, and
1 g PO 8 hours after the dose (total of 4 g)
(continued)
ERRNVPHGLFRVRUJ

Peripheral lesion—initial therapy followed by chronic
maintenance:
• Valganciclovir 900 mg PO BID x 14–21 days, • Alternative systemic therapies same as above
then 900 mg once daily
Maintenance Therapy
Discontinuation:
• CMV treatment for at least 3–6 months AND
• Lesions are inactive AND
• With CD4 >100 cells/mm3 on stable ART for 3
to 6 months
Reinitiation:
CMV esophagitis or colitis

Treatment (Duration 21–42 days or until signs
and symptoms have resolved; maintenance
therapy usually not necessary) • Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV
q12h
• Ganciclovir 5 mg/kg IV q12h, may switch to • Valganciclovir 900 mg PO BID
valganciclovir 900 mg PO q12h once patients
can absorb and tolerate PO therapy
CMV neurological disease

Treatment (Optimal duration of therapy not
known)
• Doses same as for CMV retinitis
• Treatment should be started right away
• Combination of ganciclovir IV plus foscarnet
IV to stabilize disease and maximize response
• Role of oral valganciclovir has not been
established
(continued)
ERRNVPHGLFRVRUJ

Herpes zoster
Pre-exposure Prevention of Varicella
Zoster Virus (VZV) Primary Infection
Indications:
• CD4 count ≥200 cells/mm3 without
documentation of vaccination, or previous
diagnosis or history of varicella or herpes
zoster, laboratory confirmation of disease or
persons who are seronegative for VZV
• Primary varicella vaccination, 2 doses (0.5 mL
sub-Q) administered 3 months apart
Herpes Zoster (Shingles) Treatment

Acute localized dermatomal (duration 7–10 days;
longer if lesions resolving slowly): • Acyclovir 800 mg PO 5 times daily
• Valacyclovir 1,000 mg PO three times daily
× 7–10 days
• Famciclovir 500 mg PO three times daily
× 7–10 days
Extensive cutaneous lesion or visceral involvement:

• Acyclovir 10–15 mg/kg IV q8h until clinical
improvement
• Change to oral therapy (valacyclovir,
famciclovir, acyclovir) to complete 7–14 days
ART: antiretroviral therapy; BID: twice a day; IV: intravenous; PO: by mouth; QID: four times a day;
sub-Q: subcutaneous; TB: tuberculosis; TID: three times a day; TMP-SMX: trimethoprim-sulfamethoxazole
For additional information see: https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-
treatment-guidelines/354/primary-prophylaxis
ERRNVPHGLFRVRUJ
APPENDIX 7-B. COMMON SIDE EFFECTS AND TOXICITIES OF

THERAPIES USED FOR TREATMENT OR PROPHYLAXIS OF SELECT
HIV-ASSOCIATED OIs1
Select Side Effects/Toxicities Other Considerations (e.g., Drug

Antimicrobial (Formulation) (Monitoring Parameters)¥ Interactions, Drug Access)
*acyclovir (IV/PO), • Nausea, vomiting • Bioavailability of acyclovir
*famciclovir (PO), • Crystalluria with high-dose IV from valacyclovir is 50%–60%
*valacyclovir (PO) acyclovir (SCr, urinalysis) (bioavailability of oral acyclovir
is 15%–30%)
• Agitation, confusion, lethargy,
seizures with high-dose IV • Famciclovir and valacyclovir are
acyclovir in renal impairment cross-resistant with acyclovir
• May compete with tenofovir for
tubular secretion increasing the
concentration of either drug
Amphotericin • Nausea, vomiting • Additive toxicity with other

deoxycholate (IV), • Infusion-related side nephrotoxic drugs
amphotericin lipid effects: fever, chills, rigors, • Lipid formulations more
formulations (IV) hypotension, thrombophlebitis expensive
• Electrolyte wasting (K, Mg, Ca)
• Nephrotoxicity reduced with
hydration and salt loading (SCr)
• Normocytic normochromic
anemia (Hgb)
• Risk of nephrotoxicity and
infusion-related side effects
higher with deoxycholate
formulation
atovaquone (PO) • Nausea, vomiting, diarrhea • Absorption increased with

• Rash high-fat meal
• Hepatotoxicity (ALT, AST, • Inhibits glucuronidation of
bilirubin) zidovudine, increasing AUC by
33%
• Atovaquone AUC significantly
decreased with ritonavir and
efavirenz
(continued)
ERRNVPHGLFRVRUJ

azithromycin (PO), • Nausea, vomiting, diarrhea, • Clarithromycin is a CYP3A4
*clarithromycin (PO) abdominal pain substrate and inhibitor
• Hepatotoxicity (ALT, AST, • Use of azithromycin reduces
bilirubin) risk of pharmacokinetic drug
• Metallic taste interactions
• Reversible ototoxicity with
prolonged use (tinnitus,
changes in hearing)
• QTc prolongation1
caspofungin (IV), • Fever, headache, chills • Caspofungin—not an inhibitor

micafungin (IV), • Nausea, vomiting, diarrhea of any P450 enzyme (in vitro)
anidulafungin (IV) and does not induce CYP3A4;
• Histamine-related infusion
however, manufacturer
reactions: rash, pruritus, facial
suggests increasing dose with
swelling, flushing
concomitant strong enzyme
• Hepatotoxicity (ALT, AST, inducers (e.g., phenytoin,
bilirubin) nevirapine, dexamethasone)
• Electrolyte wasting (K) • Micafungin is a substrate
• Thrombophlebitis for and a weak inhibitor of
CYP3A in vitro, although
hydroxylation by CYP3A is not
a major pathway for metabolism
in vivo
• Anidulafungin not a P450
substrate or inducer/inhibitor
in vitro
*cidofovir (IV) • Dose-dependent nephrotoxicity, • Probenecid 2 g PO 3 h

Fanconi’s syndrome reduced pre-cidofovir, and 1 g PO 2 h
with hydration and use of and 8 h post-cidofovir to block
probenecid (SCr, urinalysis) tubular secretion of cidofovir
• Neutropenia (WBC) • Not recommended if creatinine
• Ocular toxicity: hypotony, clearance of <55 mL/min
uveitis (ophthalmological exam) • Available in Canada only
• Probenecid side effects: chills, through the Special Access
fevers, headache, rash, nausea, Program2
vomiting
(continued)
ERRNVPHGLFRVRUJ

clindamycin (IV/PO) • Nausea, vomiting, diarrhea
including Clostridium difficile
colitis
clotrimazole (troche) • Nausea, vomiting, metallic taste • Product not available in Canada
dapsone (PO) • Nausea • Screen for glucose-6-phosphate

• Bone marrow suppression dehydrogenase deficiency prior
(WBC, Hgb, Plts), hemolytic to use
anemia in glucose-6-phosphate
dehydrogenase deficiency (Hgb),
methemoglobinemia (Hgb)
• Rash
• Hepatotoxicity (ALT, AST,
bilirubin)
• Sulfone syndrome: fever,
malaise, lymphadenopathy
*ethambutol (PO) • Nausea, vomiting, abdominal

pain
• Dose-related optic neuritis
(regular ophthalmological exam
for red/green discrimination,
visual acuity)
*fluconazole (IV/PO), • Nausea, vomiting • IV voriconazole not

itraconazole (PO), • Hepatoxicity (ALT, AST, recommended in renal
voriconazole (IV/PO) bilirubin) impairment due to
sulfobutylether-cyclodextrin
• Itraconazole— adrenal
vehicle in IV product
insufficiency, gynecosmastia,
potentially causing renal
peripheral edema, congestive
toxicity
heart failure
• Fluconazole—substrate of
• Voriconazole—visual
CYP3A4; inhibitor of CYP3A4,
disturbance including
2C9, 2C19
blurriness, color changes, optic
neuritis (ophthalmological • Itraconazole—absorption
exam) dependent on gastric acidity
with suspension greater than
capsules; substrate and inhibitor
of CYP3A4
• Voriconazole—substrate of
CYP2C19, 3A4; inhibitor of
CYP3A4, 2C9, 2C19
(continued)
ERRNVPHGLFRVRUJ

*flucytosine (PO) • Nausea, diarrhea, abdominal • Available in Canada only
pain through the Special Access
• Bone marrow suppression Program2
(WBC, Hgb, plts)
• Hepatotoxicity (rare)
*foscarnet (IV) • Nausea, vomiting • Administer via infusion pump

• Paresthesia • Needs to be diluted if
• Electrolyte wasting (K, Mg, Ca, administered via peripheral vein
phosphate) • Requires hydration to reduce
• Nephrotoxicity nephrotoxicity (i.e., 0.5–1 L
normal saline or D5W with
• Hepatitis (rare)
each infusion or 500–700 mL as
prehydration within
2 hours before starting
induction therapy)
• Available in Canada only
through the Special Access
Program2
*ganciclovir (IV), • Nausea, vomiting, diarrhea, • Bioavailability of ganciclovir

*valganciclovir (PO) abdominal pain from valganciclovir is 60%
• Headache, fatigue • Not recommended to be
• Bone marrow suppression: administered if the absolute
(WBC, ANC, Hgb, plts) neutrophil count is <500 cells/µL,
platelet count is <25,000/µL, or if
the hemoglobin is <8 grams/dL
• Additive toxicity to drugs
causing bone marrow
suppression
*levofloxacin (IV/PO), • Nausea, vomiting • Absorption impaired with

moxifloxacin (IV/PO) • Headache, insomnia, dizziness co-administration of di- or
trivalent cations
• Tendonitis and tendon rupture,
especially in elderly
• Hepatotoxicity (WBC, Hgb, plts)
• QTc prologation1
nystatin (PO) • Nausea, vomiting, bitter taste

(continued)
ERRNVPHGLFRVRUJ

*pentamidine (IV/for • Nausea, vomiting, abdominal • Inhaled pentamidine:
inhalation) pain S Administered via Respirguard
• Metabolic disturbance: II nebulizer in a negative flow
hypoglycemia, hyperglycemia isolation room
• Electrolyte wasting (K, Mg, Ca) S Treatment time may vary
• Infusion-related hypotension between 20–45 minutes
• Nephrotoxicity (SCr, urinalysis) S Pretreatment with
a bronchodilator is
• Pancreatitis
recommended
• Bone marrow suppression
• Intravenous pentamidine:
(WBC, Hgb, Plts)
S Administer reconstituted
• QTc prolongation1
and diluted solution via slow
• Aerosolized pentamidine: infusion (at least 60 minutes
bronchospasm, cough, dyspnea and preferably over 2–3
hours)
primaquine (PO) • Nausea, vomiting, abdominal • Screen for glucose-6-phosphate

pain dehydrogenase deficiency prior
• Hemolytic anemia (Hgb), to use
methemoglobinemia (Hgb),
leukopenia (WBC)
pyrimethamine (PO) • Nausea, vomiting, abdominal • Pyrimethamine oral tablets

pain not available in Canada; could
• Headache, dizziness, insomnia obtain from Special Access
Program2
(WBC, Hgb, Plts) • To contain costs (significant
price increase in Jan. 2016): can
be compounded by pharmacies
that obtain pyrimethamine
powder
*rifabutin (PO) • Red-orange discoloration of • Substrate and inducer of

urine and other body fluids CYP3A4 (less than rifampin)
• Nausea, vomiting • More expensive than rifampin
• Dose-related uveitis
• Myalgia, arthralgia
• Hepatotoxicity (AST, ALT,
bilirubin)
• Neutropenia (WBC)
(continued)
ERRNVPHGLFRVRUJ

*sulfadiazine (PO) • Nausea, vomiting • Available in Canada only
• Rash including Steven-Johnson through the Special Access
syndrome, toxic epidermal Program2
necrolysis
• Fever
(WBC, Hgb, Plts)
• Crystalluria with azotemia (SCr)
bilirubin)
*sulfamethoxazole/ • Nausea, vomiting • Rash is often dose-related

trimethoprim (IV/PO) • Rash, Stevens-Johnson • Various desensitization
syndrome, toxic epidermal protocols available
necrolysis
• Fever
(WBC, Hgb, plts)
• Crystalluria with azotemia (SCr)
bilirubin)
• Trimethoprim: hyperkalemia,
increased serum creatinine
through competitive tubular
secretion
*trimethoprim (PO) • Nausea, vomiting

• Dose-related hyperkalemia (K)
• Increases serum creatinine
through competitive tubular
secretion
*Dose adjustment required in renal insufficiency.
¥Toxicities listed are not all-inclusive but selected based on their frequency or clinical significance.
1
Woosley, RL and Romero, KA, QTdrugs List, www.Crediblemeds.org [accessed: June 20, 2016], AZCERT, Inc. 1822
Innovation Park Dr., Oro Valley, AZ 85755.
2
The Special Access Program provides access to drugs not marketed and sold in Canada. An application must be
completed to be assessed by Health Canada, which then, if it approves the request, authorizes the manufacturer to
release and sell the drug product.
ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: aspartate aminotransferase; AUC: area under
curve; Ca: calcium; Hgb: hemoglobin; IM: intramuscular; IV: intravenous; K: potassium; Mg: magnesium; Plts: platelets;
PO: oral; SCr: serum creatinine; WBC: white blood count
ERRNVPHGLFRVRUJ
8
Viral Hepatitis
Denise Kreutzwiser, BScH, BScPharm, ACPR, AAHIVP;
Pierre Giguère, BPharm, MSc, AAHIVP;
and Alice L. Tseng, PharmD, FCSHP, AAHIVP
INTRODUCTION
With the advent of combination antiretroviral therapy (cART), liver disease
secondary to chronic viral hepatitis has emerged as a major cause of morbidity
and mortality in the human immunodeficiency virus (HIV)-infected population.
According to the Data Collection on Adverse Events of Anti-HIV Drugs (DAD)
study, liver disease accounted for 13% of deaths (11% due to chronic viral hepatitis
and 2% due to liver failure) in HIV-infected individuals between 1999 and 2011
and was the third most common underlying cause of death.1 In 2013, viral hepa-
titis surpassed HIV/acquired immunodeficiency syndrome (AIDS) to become the
seventh leading cause of death in the world.2 This finding is of particular impor-
tance because HIV-infected individuals are disproportionately affected by viral
hepatitis, especially hepatitis B and C,3 and have higher rates of hepatitis-related
disease progression and mortality than the non-HIV-infected population. Recently,
remarkable advances in therapy have made it possible for co-infected patients to
be cured of hepatitis C. The staggering impact of liver disease on morbidity and
mortality underscores the need to specifically address viral hepatitis infections in
HIV-infected individuals.
HEPATITIS A INFECTION
Hepatitis A virus (HAV) infection is the most common type of acute viral hepatitis
globally.4 In the United States, the overall incidence rate in 2014 was 0.4 cases per
100,000 population.3 HAV infection is usually self-limited and does not lead to
chronic infection.3
HAV is a single-stranded RNA virus known as a picornavirus.5 Transmission is
via the fecal-oral route.3 HAV has an incubation period of approximately 28 days
(range: 15 to 50 days).3 HAV-infected individuals are most infectious during the first
1 to 2 weeks prior to the onset of symptoms.5 In the United States, most infections
result from direct contact with an infected household member or sexual partner.3
Exposure to fecally contaminated food or water can result in infection.6 Individuals
particularly at risk for HAV include travelers to countries with high or intermediate
endemic levels of HAV infection, injection and non-injection drug users, men who
have sex with men (MSM), and those with hemophilia or occupational exposure.3,6
163
ERRNVPHGLFRVRUJ
Limited data exist regarding HAV/HIV co-infection. Because HAV and HIV are
transmitted via different routes, it has been suggested that HAV infection among
HIV-positive individuals should be comparable to that seen in the general popu-
lation.4 Interestingly, HIV-infected individuals who contract HAV tend to exhibit
a higher HAV RNA level, as well as a longer duration of viremia and fecal HAV
excretion, than is seen in HIV-uninfected populations.4
Serology Interpretation and Diagnosis

HAV infection is a laboratory diagnosis because the clinical presentation is similar
for all types of acute viral hepatitis.3 Acute HAV infection is diagnosed via the pres-
ence of immunoglobulin M (IgM) HAV antibodies (anti-HAV) in serum.3 Gener-
ally, IgM anti-HAV becomes positive 2 weeks prior to symptom onset and remains
positive for about 6 months. Past HAV infection or vaccination and immunity is
indicated by positive IgG anti-HAV with negative IgM anti-HAV.5
Clinical Presentation, Morbidity, Mortality, and Treatment

Clinical presentation of HAV infection varies based on age, with young children
often being asymptomatic while adults are often symptomatic.3,6 Symptoms can
include fever, fatigue, nausea, vomiting, abdominal discomfort/pain, dark urine,
pale stools, and jaundice.3,5 Symptoms usually persist for less than 2 months,
although 15% of individuals may experience prolonged or relapsing symptoms.3,6
The likelihood of severe hepatic and extrahepatic manifestations is greater in older
patients and those with underlying liver disease.5 Fulminant hepatitis is rare (less
than 1%) but has a 45% mortality risk.6 Due to the self-limited nature of HAV
infection, treatment is supportive.5
Prevention
Routine HAV vaccination of HIV-infected individuals in the absence of other risk
factors is not widely recommended.4 HAV vaccination is recommended for HIV-
infected individuals with risk factors for HAV exposure (e.g., MSM, injection/
noninjection drug use, chronic liver disease, receipt of blood clotting factors,
travel to or close contact with someone from an endemic area, occupational expo-
sure).6,7 American guidelines support two doses (one dose each at 0 and 6 to 12
months) of intramuscular HAV vaccine in HIV-infected individuals regardless of
CD4 count. These guidelines encourage checking IgG anti-HAV response 1 month
after vaccine series completion and revaccinating non-responders when the CD4
count is above 200 cells/µL.8 HIV-infected patients generally experience a reduced
rate, degree, and duration of immune responses to HAV vaccination.6 Factors asso-
ciated with HAV vaccine response include CD4 count, HIV viral load, HAV vaccine
schedule, and gender.4 In HIV-infected individuals receiving cART, HAV antibody
seroconversion rates after at least two HAV vaccine doses range from 48.5% to
93.9%.4 Most patients with high CD4 counts exhibit continued HAV vaccination
responses 5 years postvaccination.6 The vaccine is generally well tolerated.4
ERRNVPHGLFRVRUJ
CHAPTER 8 Viral Hepatitis 165
HEPATITIS B INFECTION
Globally, hepatitis B virus (HBV) infection is the most common chronic viral
infection.9 HBV transmission is via infected blood or bodily fluids, with the most
common modes being perinatal or sexual transmission, as well as unsafe injec-
tions, blood transfusions, or dialysis.9 The risk for chronic HBV infection varies
based on age at the time of infection and is greatest in young children.3 Of the
34 million people globally infected with HIV, 5% to 15% are estimated to be
co-infected with chronic HBV,7 primarily due to shared modes of transmission.
Co-infection prevalence rates vary geographically depending on transmission risk
factors, implementation of HBV vaccination programs, and differing rates of HBV
infection endemicity.7
Virology and Replication

HBV is a small, partially double-stranded DNA virus in the Hepadnaviridae family.
During replication, the partially double-stranded DNA is converted to a viral tran-
scription template known as covalently closed circular DNA (cccDNA).9 Persistence
of cccDNA is believed to be the main mechanism behind the difficulty in
achieving HBV clearance during chronic HBV treatment.9,10 The HBV replication
process involves an RNA intermediate and reverse transcription; such features are
generally associated with retroviruses. The HBV reverse transcriptase enzyme lacks
proofreading ability and is therefore error prone, resulting in a high mutation rate
compared to other DNA viruses.9

HBV infection is a laboratory diagnosis. Proper HBV serologic marker interpreta-
tion is needed to differentiate between immunity and infection (Table 8-1) and
to determine if HBV infection is acute or chronic in nature. Serologic markers of
importance are described next.
• Hepatitis B surface antigen (HBsAg) is a protein on the HBV surface
detected in high levels during acute or chronic infection3 and is the hall-
mark of infection.9 HBsAg can be detected an average of 4 weeks (range
1 to 9 weeks) following HBV exposure.3 Presence of HBsAg for up to 6
months indicates acute infection, while persistence beyond 6 months
indicates chronic infection.9
• Hepatitis B core antigen (HBcAg) is a protein made by HBV-infected
liver cells.
• Hepatitis B core antibody (anti-HBc) results when the immune system
recognizes HBcAg and generates a response. Anti-HBc signifies previous
or continuing HBV infection.3
• IgM antibody to hepatitis B core antigen (IgM anti-HBc) appears 1 to 2
weeks after HBsAg but does not persist. IgM anti-HBc positivity indicates
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TABLE 8-1. Interpretation of Hepatitis B Serologic Test Results

Serologic Marker Result Interpretation
HBsAg negative Susceptible
anti-HBc negative
anti-HBs negative
HBsAg negative Immune due to natural infection

anti-HBc positive
anti-HBs positive
HBsAg negative Immune due to hepatitis B vaccination

anti-HBc negative
anti-HBs positive
HBsAg positive Acutely infected

anti-HBc positive
IgM anti-HBc positive
anti-HBs negative
HBsAg positive Chronically infected

anti-HBc positive
IgM anti-HBc negative
anti-HBs negative
HBsAg negative Interpretation unclear; four possibilities:

anti-HBc positive 1. Resolved infection (most common)
anti-HBs negative 2. False positive anti-HBc, thus susceptible
3. “Low-level” chronic infection
4. Resolving acute infection
anti-HBc: total hepatitis B core antibody; anti-HBs: hepatitis B surface antibody; HBsAg: hepatitis B surface antigen;
IgM anti-HBc: IgM antibody to hepatitis B core antigen
(Source: Reprinted from Department of Health and Human Services Centers for Disease Control and Prevention
Division of Viral Hepatitis. Available at https://stacks.cdc.gov/view/cdc/31556. Published: July 11, 2008.)
acute HBV infection.3 IgM anti-HBc positivity can occur in severe exacer-
bations of chronic HBV infection.9
• IgG antibody to hepatitis B core antigen (IgG anti-HBc) also appears 1
to 2 weeks after HBsAg and, unlike IgM anti-HBc, persists during chronic
infection.9
• Hepatitis B surface antibody (anti-HBs) is produced to HBsAg and
represents immunity to HBV infection. It is the only positive serologic
marker in individuals with acquired immunity via HBV vaccination.
Presence of anti-HBs and IgG anti-HBc suggests recovery from previous
HBV infection.9
• Hepatitis B e antigen (HBeAg) detection indicates active replication and
high infectivity.3,10
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• Hepatitis B e antibody (anti-HBe) positivity usually indicates transition

from active HBV infection to inactive carrier status.8
• HBV DNA is a direct measure of HBV replication activity.9
Clinical Presentation, Morbidity, and Mortality

Acute HBV infection is often asymptomatic. If symptomatic, the patient may
present with abdominal pain, nausea, vomiting, fever, arthralgia, and/or jaun-
dice.8 HIV-infected patients have greater rates of chronic HBV infection following
acute HBV infection.10 Individuals with chronic HBV infection tend to be asymp-
tomatic or present with nonspecific symptoms prior to the development of liver
cirrhosis and portal hypertension.8
The risk of developing cirrhosis in untreated individuals with chronic HBV
infection is 8% to 20% over 5 years.10 The risk of HBV-related hepatocellular carci-
noma (HCC) differs based on the presence or absence of concomitant cirrhosis. In
HBV carriers without cirrhosis, the annual risk is 0.02% to 0.3% in Caucasians and
0.4% to 0.6% in Asians, while in individuals with cirrhosis, the annual risk is 2.2%
and 3.7% in Caucasians and Asians, respectively.11 The most important risk deter-
minants for progression to cirrhosis are HBV DNA levels, alanine aminotransferase
levels, and HBeAg status. HBV DNA levels above 2,000 units/mL, HBeAg status,
and cirrhosis are key predictors of HCC risk.10 HIV-positive individuals with
chronic HBV infection progress to cirrhosis, end-stage liver disease, and/or HCC
faster than the mono-HBV infected population7,10 and have higher mortality rates
than individuals with either infection alone.6 The Multicenter AIDS Cohort Study
found HIV/HBV co-infected men were 8 times as likely to die from liver disease
versus those with mono-HIV infection and almost 19 times as likely to die from
liver disease compared to those with mono-HBV infection.12 Chronic HBV co-
infection does not alter HIV disease progression.7
HBV infection accounts for 54% of hepatocellular carcinomas worldwide,
surpassing the 31% of hepatocellular carcinomas globally attributed to hepatitis C
infection. Key differences in the oncogenic pathways exist for hepatitis B and C. In
the setting of HBV infection, contributors to hepatocarcinogenesis are believed to
include chronic inflammation, integration of HBV DNA into the host hepatocyte
DNA, and the expression of viral proteins that transactivate human oncogenes.
In contrast, chronic inflammation is the main mechanism for oncogenesis in the
setting of HCV infection. HBV-related HCC can occur in the absence of cirrhosis;
HCV-related HCC almost always occurs in the setting of cirrhosis.13
To assess liver disease severity and progression in chronically HBV-infected
patients, it is recommended to monitor complete blood count, ALT, aspartate
aminotransferase (AST), albumin, total bilirubin, alkaline phosphatase, and INR
every 6-12 months. In addition, HCC screening via imaging studies is recom-
mended every 6 months for individuals with chronic HBV infection who are at
increased risk of liver disease progression, namely those with cirrhosis, Asian males
above 40 years of age, Asian females above 50 years of age, or males from sub-Sa-
haran Africa aged 20 years and older. More frequent HCC screening in HIV/HBV
co-infected individuals has not been studied and is, therefore, not recommended.8
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Prevention of HBV Infection in HIV-Infected Individuals

All HIV-infected individuals without chronic HBV infection or HBV immunity
should receive HBV vaccination.8 A significantly lower degree and duration
of response to HBV vaccination is observed in HIV-infected adults versus HIV-
negative adults,8 with rates of anti-HBs seroconversion ranging from 7% to 88%
after standard HBV vaccination.6 Poor vaccine response has been associated with
low CD4 counts, HIV viremia, and hepatitis C co-infection.8
Various HBV vaccination schedules have been recommended.6,8 American
guidelines favor three doses at 0, 1, and 6 months of standard intramuscular
HBV vaccine regardless of CD4 count, and checking anti-HBs status 1-2 months
after the vaccine series is completed.8 Individuals with anti-HBs levels below 10
units/mL are considered nonresponders and should receive a second HBV vaccine
series.8 A meta-analysis of 883 HIV-infected HBV vaccine recipients demonstrated
that high-dose HBV vaccination (40 µg) resulted in significantly higher anti-HBs
response rates compared with the standard dose (20 or 10 µg depending on the
vaccine type used) with a pooled odds-ratio of 1.96 (95% CI: 1.47–2.61).14 The
British HIV Association recommends high-dose HBV vaccine administered at 0, 1,
2, and 6 months in HIV-infected individuals6; this is an alternate regimen in the
American guidelines.8 If the patient has a CD4 count below 200 cells/µL and fails
to respond to vaccination, some clinicians may defer revaccination until immune
reconstitution from cART is achieved.8 HBV vaccination is safe and well tolerated
in the HIV-infected population.4
Treatment of HBV Infection in HIV-Infected Patients

Treatment for acute HBV infection is mainly supportive.3 Nucleos(t)ide analogs
(NRTIs) used in the treatment of chronic HBV infection inhibit reverse transcrip-
tion of the pregenomic RNA into HBV DNA.9 These drugs do not cure HBV infec-
tion because they cannot eliminate cccDNA.10 The goal of treatment is to achieve
sustained HBV replication suppression and prevent liver disease progression and
related mortality.8,9 For HBeAg-positive individuals, loss of HBeAg and develop-
ment of anti-HBe are also considered markers of treatment success.8
Antiretroviral treatment is recommended for all HIV-infected individuals,
with an increased urgency for initiation in HIV/HBV co-infected individuals.7 Four
NRTIs—tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF),
lamivudine, and emtricitabine—possess anti-HBV activity.7 HBV monotherapy
with lamivudine or emtricitabine is not advised due to the high risk of resistance,
with up to 90% of HIV/HBV patients developing HBV lamivudine resistance after
4 years.7,8 Tenofovir is active against lamivudine-resistant HBV infection with no
HBV resistance reported.10 Antiretroviral guidelines recommend using TDF with
either emtricitabine or lamivudine or TAF plus emtricitabine as the NRTI back-
bone to provide effective HIV and HBV treatment.7 In situations where TDF or TAF
cannot be used safely, entecavir is the recommended alternative.7,8 Entecavir must
be used in addition to a fully active HIV regimen because entecavir possesses weak
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activity against HIV7,10 and can select for the M184V mutation.7 In HIV/HBV co-
infected patients without lamivudine-resistant HBV infection, it is unclear whether
co-administration of entecavir and lamivudine/emtricitabine provides additional
benefit compared to entecavir alone.7 Entecavir’s HBV drug resistance profile
overlaps with that of lamivudine and emtricitabine, and entecavir resistance can
develop quickly in patients with lamivudine-resistant HBV.7,8 Therefore, a higher
entecavir dose (e.g., 1 mg versus 0.5 mg daily) with HBV DNA monitoring every 3
months is required for individuals with known or suspected lamivudine-resistant
HBV infection.7
Limited data exist on the use of peg-interferon alfa monotherapy in HIV/HBV
co-infection.7 Interferon use is also limited by toxicity, injection administration,
and a 48-week treatment duration. However, interferon is the only option that
does not predispose co-infected individuals to the development of drug resistance
in the absence of cART.8 Research into new agents that can cure HBV infection via
cccDNA elimination is ongoing.10
Most HIV/HBV co-infected patients taking cART should continue HBV
therapy indefinitely.8 Quantitative HBV DNA testing is recommended every 3 to 6
months.7,8 A primary response is achieved if the HBV DNA declines by more than
one log10 at 12 weeks of therapy.8 If HBV DNA is still detectable after 24 weeks
of treatment, assessment for medication adherence and development of drug
resistance is advised. Of note, HBV DNA levels may decline slowly and remain
detectable for years in up to 10% of patients on tenofovir despite adequate adher-
ence.8,15 For patients who are HBeAg positive, HBeAg testing every 6 to 12 months
is recommended.8 All NRTIs require dose adjustment in renal impairment.10 With
TDF use, additional monitoring parameters include serum electrolytes (including
phosphate), urinalysis for proteinuria and glycosuria, urine protein to creatinine
ratio, and urinary phosphate and calculation of fractional phosphate excretion.7
Immune Reconstitution Inflammatory Syndrome

HIV/HBV co-infected individuals may develop HBV-associated liver disease reac-
tivation following cART initiation due to immune reconstitution. A significant
rise in serum aminotransferases with or without acute hepatitis symptoms may
occur and may be worse in more severe liver disease (e.g., cirrhosis). Hepatology
consultation may be needed to differentiate between immune reconstitution
inflammatory syndrome (IRIS), cART-related hepatotoxicity, or other causes of
hepatotoxicity.8
Stopping/Changing cART in HIV/HBV Co-infected Patients

In situations where HIV therapy requires modification due to virologic failure, it
is critical to avoid the inadvertent removal of effective HBV treatment because
serious hepatocellular damage can result secondary to HBV reactivation. A fully
active cART regimen should be selected to treat HIV infection while the antiret-
roviral agents active against HBV (e.g., TDF/TAF and emtricitabine/lamivudine)
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should be continued, regardless of the presence of HIV drug resistance to ensure

HBV suppression is maintained.7
HEPATITIS C
Worldwide, between 130 and 170 million people (2% to 3% of the population) are
chronically infected with hepatitis C virus (HCV). The prevalence of HCV varies
geographically and approaches up to 20% in some countries, such as Egypt. In
the HIV population, the rate of HCV co-infection varies according to geographical
areas and modes of transmission. In endemic areas where HIV is mainly trans-
mitted sexually, such as in Sub-Saharan Africa, the HIV-HCV co-infection rate is
low (up to 3%). In contrast, in the United States and Canada, the overall preva-
lence is around 20% to 25%, mainly driven by the high prevalence of HIV/HCV
co-infection in the injection drug-use population.16
Virology and Replication

HCV is an RNA virus belonging to the Flaviviridae family. It is 50 to 80 nm in
size and replicates in the cytoplasm of the hepatocytes, producing approximately
1 trillion viral copies daily. The replication complex is composed of a series of
nonstructural (NS) proteins: NS3 and NS4A are responsible for translation and
polyprotein processing, while NS5A interacts with several cellular proteins and
may be involved in RNA binding. Inhibition of NS5A is associated with a dramatic
reduction of HCV replication. NS5B polymerase is responsible for RNA synthesis
and is also a prominent target for antivirals.17
Transmission
Hepatitis C is a blood-borne pathogen and is primarily transmitted via percu-
taneous exposure.16 Acquiring infection from contaminated objects is possible
because HCV can remain infectious for up to 6 weeks ex vivo.18 Heterosexual
transmission is extremely low but is markedly higher in same-sex couples, partic-
ularly among persons with HIV. The Centers for Disease Control and Prevention
(CDC) recommends heterosexual and MSM with HCV infection and more than
one sexual partner, especially those with HIV infection, use male latex condoms
to reduce HCV and HIV transmission. Perinatal transmission is uncommon yet is
still observed in endemic countries.19
HCV Genotypes
Genetically, HCV is extensively heterogeneous and is grouped into seven different
genotypes. Each genotype has a roughly 30% diversity in terms of genomic
sequence. Genotype 1 is the most prevalent worldwide, comprising 46% of all
HCV cases (76% of all cases in North America), followed by genotype 3 which
predominates in South Asia. Genotype 4 is concentrated in central sub-Saharan
Africa, North Africa, and the Middle East. Genotypes and subtypes have differing
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susceptibilities to many direct-acting antivirals (DAAs). Genotype can be an

important indicator of clinical outcomes as some genotypes are associated with
a greater risk of steatosis (genotype 3), fibrosis progression, and hepatocellular
carcinoma (genotype 1b).

HCV diagnosis is a two-step process. The first step involves determining the pres-
ence or absence of HCV-specific antibodies. Highly sensitive and specific enzyme
immunoassays (EIAs) can detect HCV antibodies within 3 to 6 weeks postinfection.
A positive antibody test indicates either active acute or chronic HCV infection, a
past infection that has resolved, or a false positive test result. An HCV RNA test
via polymerase chain reaction (PCR) is indicated to identify those with chronic
infection. Repeated testing is generally unnecessary with a negative PCR result
unless there is a high suspicion for recent infection or in patients with ongoing
risk factors.20
Current recommendations are to test individuals born between 1945 and
1965 regardless of risk factors because 75% of all cases are within this age group.
Others can be screened annually or as indicated based on risk factors such as injec-
tion drug use, percutaneous exposure, children born to an HCV-infected mother,
and HIV-infected MSM.8 Screening every 3 to 6 months can be considered for
individuals with higher risk-exposure activity (e.g., sharing injection drug equip-
ment, sexual activity associated with bleeding or tissue trauma, inconsistent use
of barrier protection, or concomitant ulcerative sexually transmitted infections).
Clinical Presentation, Morbidity, and Mortality

Acute HCV infection is often asymptomatic and may be unrecognized. A common
feature of acute HCV is elevation of liver transaminases 10 to 14 weeks after
acquiring infection. Spontaneous clearance will be achieved in 20% to 25% of
infected persons. In HIV-infected persons, spontaneous clearance is reduced 3-fold,
as CD4 cell-mediated response plays an important role in the immune response
against HCV.21
Chronic HCV infection is characterized by elevated hepatic transaminases
and ongoing viral replication. The direct effect of HCV on metabolic pathways and
chronic inflammation mediated through host immune responses promotes liver
fibrogenesis. It is estimated that 10% to 20% of chronically infected patients will
develop liver cirrhosis within 20 to 30 years. Once cirrhosis is present, hepatocel-
lular carcinoma develops at a rate of 5% to 7% every year.22 Alcohol consumption
accelerates liver fibrosis by 2- to 3-fold, and abstention from alcohol is recom-
mended.23 HIV co-infected patients will progress 3 times faster to cirrhosis than
HCV monoinfected, and progression is exacerbated by low CD4 counts.24 Antiret-
roviral treatment reduces the rate of liver fibrosis, but rates continue to exceed that
observed in monoinfection.24 Extrahepatic manifestations of chronic HCV infec-
tion are observed in up to 75% of cases. Cryoglobulinaemia is the most common
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extrahepatic complication and can manifest as joint pain, muscle pain, pruritus,
glomerulonephritis, and vasculitis. Other typical complications include porphyria
cutanea tarda, diabetes, and cardiomyopathy.
HCV infection is associated with significant health and economic burdens.
A recent analysis revealed that total healthcare cost in the United States associ-
ated with HCV was estimated at $6.5 billion, peaking at $9.1 billion by 2024.
Most of these costs were attributed to advanced liver disease.25 Compared to 1990,
deaths and disability-adjusted life-years attributed to HCV disease have more than
doubled in 2013, reaching 700,000 and 18 million, respectively.2
Treatment of Chronic HCV Infection in HIV-Infected Individuals

New therapies for HCV infection are being developed at a remarkable pace,
resulting in rapid changes in available treatment options and strategies. It is now
possible to avoid pegylated-interferon in first-line treatment, and ribavirin use has
also declined significantly. As such, treatment tolerability and acceptance has been
greatly enhanced.
Several oral DAA combinations are available to treat HCV genotype 1; many
also have activity against other genotypes. Standard regimens involve use of two or
three DAAs from different pharmacological classes for an average of 8 to 12 weeks,20
with sustained virologic response (SVR) rates usually exceeding 90% to 95% for
genotypes 1–6. Extended treatment duration of up to 24 weeks may be required in
some situations such as cirrhosis. Courses as short as 6 weeks are being studied. In
general, SVR rates in HIV/HCV co-infection are similar to those with HCV mono-
infection, and HIV should not be an exclusion factor for HCV therapy.20
Many DAA regimens are available in single-tablet regimen formulations, and
there is an increasing trend for manufacturers to develop complete regimens
consisting of their own products. In certain situations, such as the presence of
baseline resistance-associated substitution (RAS) or cirrhosis, weight-based riba-
virin is included or treatment duration is extended.20 Tables 8-2 and 8-3 summa-
rize treatment recommendations for genotypes 1–6.
Ledipasvir/Sofosbuvir
Sofosbuvir is a pan-genotypic NS5B inhibitor with a high genetic barrier to resis-
tance. Sofosbuvir is a nucleotide prodrug and is phosphorylated in the liver to its
active metabolite, GS-461203, which is not detectable in plasma. Sofosbuvir is a
substrate of P-glycoprotein (Pgp) and BCRP and does not impact cytochrome P450,
uridine diphosphate glucuronosyltransferase (UGT), Pgp, or various transporters.
Sofosbuvir is given 400 mg once daily with other antivirals for treatment of HCV
genotypes 1–4.20 Sofosbuvir is also available as a once-daily co-formulated product
with ledipasvir 90 mg, an NS5A inhibitor for the treatment of HCV genotype 1 and
4.20 Ledipasvir solubility is acid-dependent and should be taken separately from
antacids by at least 4 hours. Low-dose H2-receptor antagonists or proton pump
inhibitors may be used, with specific instructions on timing of doses. Ledipasvir
is a substrate of Pgp and a weak inhibitor of Pgp, BCRP, and OATP1B1/3 and may
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TABLE 8-2. Treatment Regimens for Treatment-Naïve Hepatitis C

Genotype 1 Infection20
Genotype 1a Genotype 1b
With Compensated With Compensated
DAA Regimen Without Cirrhosis Cirrhosis Without Cirrhosis Cirrhosis
Recommended
Elbasvir/ 12 weeks* 12 weeks* 12 weeks 12 weeks
grazoprevir
Glecaprevir/ 8 weeks 12 weeks 8 weeks 12 weeks

pibrentasvir
Ledipasvir/ 8ϒ or 12 weeks 12 weeks 8ϒ or 12 weeks 12 weeks

sofosbuvir
Velpatasvir/ 12 weeks 12 weeks 12 weeks 12 weeks

sofosbuvir
Alternative
Daclatasvir plus 12 weeks 12 weeks
sofosbuvir
Elbasvir/ With RBV for 16 With RBV for 16

grazoprevir weeks if NS5A weeks if NS5A
RASs RASs
Paritaprevir/ With RBV for 12 12 weeks 12 weeks

ritonavir, weeks
ombitasvir,
dasabuvir
Simeprevir plus 12 weeks 12 weeks

sofosbuvir
*If no baseline high fold-change NS5A RASs.
ϒ
8 weeks duration of treatment for non-black, HIV-uninfected, with HCV RNA <6 million IU/mL.
RASs: resistance-associated substitutions; RBV: ribavirin
increase concentrations of substrates of these transporters, such as tenofovir, rosu-

vastatin, digoxin, and amiodarone. Sofosbuvir and ledipasvir should not be co-
administered with potent Pgp inducers due to the risk of reduced DAA exposures.20
Velpatasvir/Sofosbuvir
This fixed-dose, once-daily combination tablet of sofosbuvir 400 mg and velpatasvir
100 mg, a potent NS5A inhibitor, was approved in mid-2016 for treatment of HCV
genotypes 1–6 in patients with and without compensated cirrhosis. Velpatasvir
is a substrate of Pgp, BCRP, OATP1B1, OATP1B3, CYP2B6, CYP2C8, and CYP3A4
and inhibits Pgp, BCRP, OATP1B1, OATP1B3, and OATP2B1. Similar to ledipasvir,
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TABLE 8-3. Treatment Regimens for Treatment-Naïve Hepatitis C

Genotypes 2 to 620
Without Cirrhosis With Compensated Cirrhosis
Genotype 2 Glecaprevir/pibrentasvir (8 weeks) Glecaprevir/pibrentasvir
Velpatasvir/sofosbuvir Velpatasvir/sofosbuvir
Daclatasvir/sofosbuvir (Alternative) Daclatasvir/sofosbuvir
(16-24 weeks) (Alternative)
Genotype 3 Glecaprevir/pibrentasvir (8 weeks) Glecaprevir/pibrentasvir

Velpatasvir/sofosbuvir Velpatasvir/sofosbuvir*
Daclatasvir/sofosbuvir (Alternative) Voxilaprevir/velpatasvir/sofosbuvir if
Y93H is present (Alternative)
Daclatasvir/sofosbuvir +/- ribavirin for 24
weeks (Alternative)
Genotype 4 Elbasvir/grazoprevir Elbasvir/grazoprevir

Glecaprevir/pibrentasvir (8 weeks) Glecaprevir/pibrentasvir
Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir
Paritaprevir/ritonavir, ombitasvir, plus Paritaprevir/ritonavir, ombitasvir, plus
ribavirin (Alternative) ribavirin (Alternative)
Genotypes 5 and 6 Glecaprevir/pibrentasvir (8 weeks) Glecaprevir/pibrentasvir

Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir
Note: Treatment durations are 12 weeks unless otherwise noted.
*Include ribavirin if Y93H RAS is present or consider sofosbuvir/velpatasvir/voxilaprevir.
velpatasvir solubility is acid-dependent, and thus interactions with acid-reducing

agents and substrates of Pgp, BCRP, and OATP, including TDF and rosuvastatin,
need to be considered. Co-administration with inducers of Pgp, CYP2B6, CYP2C8,
or CYP3A4, such as efavirenz, is not recommended.20
Voxilaprevir/Velpatasvir/Sofosbuvir
In mid-2017, a fixed-dose combination of sofosbuvir, velpatasvir, and voxila-
previr, an NS3 protease inhibitor, was approved for use in treatment-experienced
patients with genotypes 1 to 6 previously treated with an NS5A inhibitor-
containing regimen as well as genotypes 1a or 3 previously treated with sofos-
buvir without an NS5A-inhibitor. Similar to sofosbuvir and velpatasvir, voxilaprevir
is a substrate of Pgp and BCRP. Voxilaprevir is also a substrate of OATP1B1 and
OATP1B3. In vitro, voxilaprevir also undergoes metabolism via CYP3A4, as well as
CYP1A2 and CYP2C8. Voxilaprevir/velpatasvir/sofosbuvir may be co-administered
with Pgp, BCRP, and CYP inhibitors but should not be given with inducers of Pgp,
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CYP2B6, CYP2C8, or CYP3A4. Voxilaprevir inhibits the drug transporters Pgp,

BCRP, OATP1B1, OATB1B3, and OATP2B1. Co-administration of this triple DAA
combination may increase concentrations of drugs which are substrates of these
transporters. Concomitant use of BCRP substrates is not recommended.27
Elbasvir/Grazoprevir
The combination of the NS5A inhibitor elbasvir 50 mg with the NS3/4A protease
inhibitor grazoprevir 100 mg in a once-daily fixed-dose tablet is indicated for
treatment of HCV genotypes 1 or 4 with or without ribavirin. Elbasvir and grazo-
previr are substrates of CYP3A4, Pgp, and OATP and inhibit intestinal BCRP. This
regimen is contraindicated with strong CYP3A4 inducers, including efavirenz and
OATP1B inhibitors such as rifampin, cyclosporine, and HIV protease inhibitors.20
Glecaprevir/Pibrentasvir
The fixed dose combination of glecaprevir, an NS3/4A protease inhibitor, and
pibrentasvir, an NS5A inhibitor, was approved in mid-2017 for the treatment of
HCV genotypes 1 to 6. This combination given as 3 tablets once daily with food
provides an 8 week, once daily, ribavirin-free treatment option for treatment-naïve
HCV patients without cirrhosis. For patients with compensated cirrhosis, 12 weeks
of treatment is indicated. Glecaprevir/pibrentasvir is also indicated for the treat-
ment of genotype 1 infection in patients previously treated with an NS5A inhibitor
or an NS3/4A protease inhibitor, but not both. High SVR rates have been observed
in patients with compensated cirrhosis, severe chronic kidney disease, and other
difficult-to-treat populations. Glecaprevir and pibrentasvir are substrates of Pgp
and/or BCRP, and glecaprevir is also a substrate of OATP1B1/3. Drugs that inhibit
OATP1B1/3 may increase systemic glecaprevir concentrations without affecting
total liver exposure of glecaprevir. Strong inducers of Pgp/CYP3A4 may significantly
decrease glecaprevir and pibrentasvir concentrations, and concomitant adminis-
tration is not recommended. Glecaprevir and pibrentasvir inhibit Pgp, BCRP, and
OATP1B1/3 and may increase concentrations of drugs which are substrates of these
transporters. Glecaprevir and pibrentasvir weakly inhibit CYP3A, 1A2, and UGT,
and significant interactions are not anticipated with substrates of these enzymes.26
Paritaprevir/Ritonavir, Ombitasvir, and Dasabuvir

This combination includes paritaprevir, an NS3/4A protease inhibitor; ombitasvir, an
NS5A inhibitor; and dasabuvir, an NS5B inhibitor. Due to its short plasma half-life,
paritaprevir is boosted with ritonavir to allow once-daily dosing. Standard dosing
consists of co-formulated paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg
administered as two pills once daily plus dasabuvir 250 mg (1 tablet) twice daily
with food, or 3 tablets of the extended release formulation (200 mg dasabuvir/8.33
mg ombitasvir/50 mg paritaprevir/33.33 mg ritonavir) once daily with a meal. Riba-
virin is co-administered for treatment of genotype 1a but is not needed for geno-
type 1b treatment. Paritaprevir and ombitasvir are substrates of CYP3A4, Pgp, BCRP,
and OATP; dasabuvir is primarily a substrate of CYP2C8. Ritonavir is a substrate of
CYP3A4 and Pgp and a potent inhibitor of CYP3A4, Pgp, BCRP, and OATP trans-
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porters; there is also a net inhibitory effect of this combination on UGT1A1. This
regimen is contraindicated with sensitive CYP3A4 substrates, moderate-strong
CYP3A4 inducers, and potent inhibitors or inducers of CYP2C8. Moderate-potent
CYP3A4 inhibitors should be used with caution. Atazanavir and once-daily darunavir
may be given without additional boosting. Cobicistat or additional ritonavir should
be avoided due to the potential for significant increases in paritaprevir exposures.
HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) should not be used
due to risk of increased toxicity or reduction in DAA exposures. Estrogen-containing
hormonal contraceptives are contraindicated due to potential for ALT increases.20
Daclatasvir and Sofosbuvir

Daclatasvir is an NS5A inhibitor for treatment of HCV genotypes 1, 2, and 3 with
sofosbuvir, with or without ribavirin. Daclatasvir is a substrate of CYP3A4, Pgp,
and OCT and is a weak-moderate inhibitor of Pgp, BCRP, and OATP1B1. The stan-
dard dose of daclatasvir is 60 mg daily, but this may require adjustment depending
on the use of concomitant CYP3A4 inhibitors or inducers, including ritonavir,
cobicistat, and NNRTIs. Daclatasvir is contraindicated with strong CYP3A4 and
Pgp inducers.20
Simeprevir and Sofosbuvir

Simeprevir is an NS3/4A protease inhibitor dosed at 150 mg daily with sofos-
buvir for HCV genotype 1 treatment. The presence of baseline Q80K polymor-
phism (present in approximately 48% of genotype 1a infection) is associated with
reduced efficacy in cirrhotic patients, and this regimen should be avoided in this
population. Simeprevir is a substrate of CYP3A4, Pgp, and OATP1B1, a mild inhib-
itor of intestinal CYP3A4 and an inhibitor of Pgp and OATP1B1. Simeprevir should
not be used with moderate or strong inducers or inhibitors of CYP3A4, including
most HIV-boosted regimens and NNRTIs.20
Factors to Consider When Initiating HCV Treatment

Factors such as HCV genotype, HCV viral load, presence of cirrhosis, and prior
treatment experience need to be taken into account when selecting an effective
DAA regimen of appropriate duration. Other considerations include drug access,
adherence, toxicity, comorbidities, and drug interactions. Pharmacists are encour-
aged to refer to living documents such as the Infectious Diseases Society of America
and the American Association for the Study of Liver Diseases20 guidelines for up-to-
date recommendations.
For treatment-experienced patients, treatment options are based on factors
including HCV genotype, presence or absence of cirrhosis, and type of previous
HCV treatment. In general, prior treatment with pegylated interferon plus riba-
virin does not impact the efficacy of all-oral DAA regimens for genotype 1, and
most of the recommendations in Table 8-2 may be considered. Voxilaprevir/
velpatasvir/sofosbuvir for 12 weeks is indicated for treatment of genotypes 1a or
3 in patients previously treated with sofosbuvir without an NS5A inhibitor.27 In
ERRNVPHGLFRVRUJ
patients with genotypes 1 to 6 previously treated with sofosbuvir plus ribavirin

with or without pegylated interferon, glecaprevir/pibrentasvir may be used with
treatment durations ranging from 8 to 16 weeks depending upon genotype and
whether cirrhosis is present.26
Until recently, options for patients previously treated with an NS3 protease
inhibitor or NS5A inhibitor were relatively limited, and general principles of
treatment included use of a DAA class to which the patient had not previously
been exposed, extension of treatment duration, and/or inclusion of weight-based
ribavirin. With the advent of voxilaprevir/velpatasvir/sofosbuvir and glecaprevir/
pibrentasvir, treatment-experienced patients now have ribavirin-free, fixed-dose
treatment options available. Voxilaprevir/velpatasvir/sofosbuvir may be used for
treatment of genotypes 1 to 6 in patients previously treated with an NS5A inhib-
itor, for a duration of 12 weeks. Glecaprevir/pibrentasvir may be used for 16 weeks
in patients previously treated with an NS5A inhibitor or 12 weeks in patients
previously treated with an NS3/4A protease inhibitor. Unfortunately, neither of
these options are recommended in patients with decompensated liver disease.
In rare instances where multiclass resistance is suspected, using multiple
agents in combination and/or the addition of pegylated-interferon may be consid-
ered. Enrollment in a clinical retreatment trial may be an option.20
Special Populations
DAAs may be used in patients with mild hepatic impairment, but many are contra-
indicated in moderate or severe (Child Pugh B or C) hepatic impairment due to
safety concerns or lack of data. Sofosbuvir plus ledipasvir, velpatasvir, or daclatasvir
with ribavirin for 12 weeks may be used in patients with decompensated cirrhosis
(Child-Pugh B or C); if ribavirin is contraindicated, treatment duration should be
extended to 24 weeks. A similar approach may be used in post-transplant liver
patients who develop recurrent HCV infection in the allograft.20
All DAAs may be used in mild or moderate renal dysfunction without dose
adjustment.26 In patients with severe renal insufficiency (defined as glomerular
filtration rate less than 30 mL/minute) or end-stage renal disease, treatment options
(depending on genotype) include elbasvir/grazoprevir, glecaprevir/pibrentasvir,
paritaprevir/ritonavir-ombitasvir-dasabuvir, or pegylated interferon plus ribavirin.
Ribavirin requires dose adjustment in renal impairment with close monitoring for
safety and tolerability.28
Monitoring and Treatment Outcomes

Cases of HBV reactivation (ranging from mild to occasionally fulminant) during
or after DAA therapy have been reported in HBV/HCV co-infected patients not
already on HBV suppressive therapy. Therefore, prior to starting DAAs, all patients
should be assessed for HBV co-infection with testing for HBsAg, anti-HBs, and
anti-HBc.20 Checking HBV serology is recommended in all HIV-infected individ-
uals7 so these results may already be available for HIV/HCV co-infected patients
starting DAAs. HBV vaccination is recommended for all susceptible individuals,
ERRNVPHGLFRVRUJ
and HBsAg positive patients should have HBV DNA measured. Patients who meet
the treatment criteria for active HBV infection should initiate HBV therapy before
or at the same time as HCV therapy.20 Of note, most HIV/HBV/HCV tri-infected
individuals meet HBV treatment criteria because patients with concurrent HIV and
HBV infections are advised to take two antiviral drugs with dual activities against
HIV and HBV regardless of HBV DNA levels.8 In contrast, HBV/HCV co-infected
patients with low or undetectable HBV DNA levels should undergo regular moni-
toring (i.e., every 4 weeks) for HBV reactivation and start HBV treatment when
their HBV DNA levels meet treatment criteria.20
For all patients starting DAA therapy, HCV viral load is measured 4 weeks after
treatment initiation, at the end of treatment (optional), and 12 weeks after the end
of treatment (SVR). In clinical trials involving recent DAA, virtually all patients
obtained an undetectable viral load after 4 weeks of treatment, while those with
cirrhosis required up to 8 weeks to achieve the same outcome. Given the potency
of currently available DAAs, early treatment discontinuations are no longer
recommended. Patients who achieve SVR frequently experience some regression
of fibrosis/cirrhosis, and have a substantially reduced risk of developing hepato-
cellular carcinoma, liver-related mortality, and overall mortality compared to those
not receiving or failing treatment.29 Liver function test monitoring is required to
rule out DAA toxicity (uncommon but reported with grazoprevir/elbasvir) and to
assist ruling out liver decompensation. Careful consideration should be given to
individuals with cirrhosis, because up to 24% of those experienced serious adverse
events following initiation of DAA therapy.
Management of Drug Interactions

Interactions between antiretrovirals and DAAs may lead to increased drug toxicity
or potential therapeutic failure of HIV and/or HCV therapy. In some co-infected
cohorts, the risk for potential interactions between antiretrovirals and DAAs has
ranged from 54% to 74%.30,31 The unboosted integrase inhibitors raltegravir or
dolutegravir may be used with all DAAs. Rilpivirine may be used with DAAs except
for paritaprevir/ritonavir, ombitasvir, and dasabuvir, although most other HIV
NNRTIs should be avoided due to risk of toxicity and/or reduction of DAA concen-
trations. HIV protease inhibitors should not be given with simeprevir and elbasvir/
grazoprevir due to potential for significant increases in DAA exposures but may
be used with other DAA regimens with dose adjustment. Ledipasvir and velpa-
tasvir significantly increase TDF concentrations; increased monitoring for renal
toxicity is recommended, or TDF may be replaced with an alternate agent such as
abacavir or TAF. Managing interactions between antiretrovirals and DAAs can be
a challenge in treatment-experienced patients with significant antiretroviral resis-
tance and limited HIV treatment options. Unconventional or novel antiretroviral
regimens may need to be considered, and additional or more frequent monitoring
(including therapeutic drug monitoring if available) may be needed. Interactions
between antiretrovirals and DAAs are summarized in Table 8-4.
Management of interactions between DAAs and other drugs is also neces-
sary given high rates of polypharmacy in the co-infected population. Common
ERRNVPHGLFRVRUJ
TABLE 8-4. Antiretroviral Treatment Options for Patients on Hepatitis C

Treatment
DAA PIs NNRTIs INSTIs NRTIs
Daclatasvir/ May use darunavir, May use rilpivirine. May use All NRTIs
sofosbuvir lopinavir. Use Use daclatasvir dolutegravir,
daclatasvir 90 mg with raltegravir.
30 mg with efavirenz. Avoid Use daclatasvir
atazanavir other NNRTIs 30 mg with
elvitegravir
Elbasvir/ Contraindicated May use rilpivirine. May use All NRTIs

grazoprevir Avoid other dolutegravir,
NNRTIs raltegravir.
Avoid
elvitegravir
Glecaprevir/ Atazanavir is May use rilpivirine. May use all INSTIs All NRTIs
pibrentasvir contraindicated; Avoid other
darunavir and NNRTIs
lopinavir not
recommended
Ledipasvir/ May use atazanavir, May use all May use TDF: monitor for
sofosbuvir darunavir, NNRTIs dolutegravir, toxicity. May
lopinavir raltegravir. use other NRTIs
Caution if
elvitegravir is
co-formulated
with TDF
Paritaprevir/ May use atazanavir. All NNRTIs May use All NRTIs
ritonavir, Caution with contraindicated/ dolutegravir,
ombitasvir, darunavir. Avoid not raltegravir.
dasabuvir lopinavir recommended Avoid
elvitegravir
Simeprevir/ Not recommended May use May use All NRTIs

sofosbuvir rilpivirine. Not dolutegravir,
recommended raltegravir.
with other Avoid
NNRTIs elvitegravir
Velpatasvir/ May use atazanavir, May use rilpivirine. May use TDF: monitor for
sofosbuvir darunavir, Avoid efavirenz dolutegravir, toxicity. May
lopinavir raltegravir. use other NRTIs
Caution if
elvitegravir is
co-formulated
with TDF
(continued)
ERRNVPHGLFRVRUJ
TABLE 8-4. Antiretroviral Treatment Options for Patients on Hepatitis C

Treatment (continued)
DAA PIs NNRTIs INSTIs NRTIs

Velpatasvir/ May use darunavir. May use rilpivirine. May use TDF: monitor for
voxilaprevir/ Atazanavir and Avoid efavirenz dolutegravir, toxicity. May
sofosbuvir lopinavir not raltegravir. use other NRTIs
recommended Caution if
elvitegravir is
co-formulated
with TDF
DAA: direct-acting antivirals; INSTI: integrase inhibitor; NNRTI: nonnucleoside reverse transcriptase inhibitor; NRTI:
nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; TDF: tenofovir disoproxil fumarate
(Source: Adapted with permission from www.hivclinic.ca.)
interacting drug classes include gastric-acid modifying agents, statins, antidepres-

sants, opioid analgesics, anticonvulsants, and antibacterials. Interactions between
immunosuppressants and DAAs are an important consideration in post-transplant
liver patients. Therapeutic drug monitoring with dose adjustment of immuno-
suppressants and close monitoring for toxicity is recommended.
Prevention of HCV Infection and Reinfection

A vaccine for hepatitis C primary prevention does not exist. Immune globulin use
after HCV exposure is not effective for postexposure prophylaxis. Patients should be
advised to cover bleeding cuts/sores, and not share items such as toothbrushes and
razors. People who continue to inject drugs should be counseled not to share or reuse
syringes, water, or drug preparation equipment.32 Prior HCV infection and elimina-
tion via either spontaneous clearance or successful treatment does not provide immu-
nity to future reinfection. High HCV reinfection rates have been reported in HIV-
infected MSM and may be associated with high-risk sexual practices and drug
use.33 Among 606 HIV-positive MSM in the European AIDS Treatment Network
consortium who were cured of HCV, 25% were reinfected within 3 years, with 50%
of those reinfected with a different genotype or subtype.34 Patients with HIV and
HCV and those with multiple sexual partners should use barrier methods (e.g.,
condoms) to prevent sexual transmission.

Pharmacists are a critical part of the healthcare team, especially when it comes to the
prevention and treatment of viral hepatitis infection in HIV-infected individuals. Pharma-
cists can advocate for HAV/HBV immunization in susceptible patients. For patients with
HIV/HBV co-infection, pharmacists can aid in the selection of cART that will effectively
treat both HIV and HBV infection and prevent unintentional HBV treatment cessation
ERRNVPHGLFRVRUJ
when HIV therapy changes are made. Pharmacists can play a vital role in optimizing
factors for successful HBV or HCV therapy by managing drug interactions, facilitating
drug access, ensuring appropriate dose modification in organ dysfunction, and supporting
patient adherence. Pharmacists can also educate patients on the importance of risk reduc-
tion and minimizing alcohol use.
Patients should be encouraged to fill all prescriptions at one pharmacy and always
check before starting any new prescription, nonprescription, or herbal product to reduce
the risk of unrecognized interactions. In some cases, therapeutic drug monitoring may
be helpful. Prescription refill reminders, medication dosing schedules, text messaging
reminder programs, and blister packaging may facilitate adherence. Studies in the co-
infected population suggest an average counseling time of 30 minutes per patient starting
DAA treatment as a requirement.31
Steep drug costs can pose a significant barrier to accessing HCV treatment. Public payers
and private insurers may selectively choose one DAA regimen over others based on cost.
Limitations such as lifetime cap or partial reimbursement may also impose excessive
hardship. Manufacturer patient assistance programs can require significant time and
resources, and pharmacists may play a key role in helping patients navigate these systems.
In a cohort of 54 HIV/HCV patients starting HCV treatment, 87% required preauthori-
zation forms (median 2 forms per patient); 30% of applications were initially denied and
required appeal. The median pharmacist time required was 2.13 hours per patient.31
The morbidity and mortality burden linked with viral hepatitis highlights the importance
of viral hepatitis prevention, care, and treatment. Pharmacists are well positioned to play
an instrumental role in caring for HIV-positive patients infected with viral hepatitis.
KEY RESOURCES
Viral Hepatitis Information
• Hepatitis C On-line, University of Washington. www.hepatitisc.uw.edu.
o Includes online course modules, DAA information, clinical calculators, resource
library, and slide decks.
• Viral Hepatitis Information, Centers for Disease Control and Prevention (CDC).
http://www.cdc.gov/hepatitis/index.htm.
o Excellent overview with links to resources/guidelines for healthcare profes-
sionals.
Treatment Guidelines
• British HIV Association Guidelines on the Use of Vaccines in HIV-Positive Adults
2015. www.bhiva.org/vaccination-guidelines.aspx.
o Good review of HAV and HBV infection and vaccination in HIV-infected
patients.
• Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-
Infected Adults and Adolescents, CDC, NIH and the HIV Medicine Association of the
Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguide-
lines/adult_oi.pdf.
o Includes chapters on HBV and HCV infection in HIV-infected patients.
ERRNVPHGLFRVRUJ
• HCV Guidance: Recommendations for testing, managing, and treating hepatitis C.

Infectious Diseases Society of America and the American Association for the Study of
Liver Diseases. www.hcvguidelines.org.
o Evidence-based, expert-developed recommendations for hepatitis C management.
• Recommendations on treatment of hepatitis C 2016, European Association of
the Study of the Liver (EASL). http://www.easl.eu/research/our-contributions/
clinical-practice-guidelines/detail/easl-recommendations-on-treatment-of-hepati-
tis-c-2016.
o Clinical practice guidelines on management of acute and chronic HCV infection.
Drug Information and Interaction Resources
• Toronto General Hospital & The Ottawa Hospital HIV and HCV Drug Therapy Guide.
http://app.hivclinic.ca.
• University of Liverpool Hepatitis Drug Interaction Checker. www.hep-druginterac-
tions.org.
o These websites allow users to check for interactions between DAAs and other
commonly used medications.
REFERENCES
1. Smith CJ, Ryom L, Weber R, et al. Trends in underlying causes of death in people with HIV from
1999 to 2011 (D:A:D): A multicohort collaboration. Lancet. 2014;384:241-248.
2. Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to
2013: Findings from the Global Burden of Disease Study 2013. Lancet. 2016;388(10049);1081-
1088.
3. Centers for Disease Control and Prevention. Viral hepatitis. September 12, 2016. Available from:
http://www.cdc.gov/hepatitis/index.htm. Accessed September 12, 2016.
4. Mena G, Garcia-Basteiro AL, Bayas JM. Hepatitis B and A vaccination in HIV-infected adults: A
review. Hum Vaccin Immunother. 2015;11:2582-2598.
5. Nelson NP, Murphy TV. Infectious diseases related to travel. In: CDC Health Information for
International Travel 2016. Available from: http://wwwnc.cdc.gov/travel/yellowbook/2016/infec-
tious-diseases-related-to-travel/hepatitis-a.
6. Geretti AM, Brook G, Cameron C, et al. British HIV Association Guidelines on the use of
vaccines in HIV-positive adults 2015. HIV Med. 2016;17:s2-s81.
7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human
Services. July 14, 2016. Available from: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdo-
lescentGL.pdf.
August 3, 2017. Available from: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
9. Trepo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384:2053-2063.
10. World Health Organization. Guidelines for the prevention, care and treatment of persons with
chronic hepatitis B infection. Geneva. March 2015. Available from: http://www.who.int/hiv/
pub/hepatitis/hepatitis-b-guidelines/en/.
11. Michielsen P, Ho E. Viral hepatitis B and hepatocellular carcinoma. Acta Gastroenterol Belg.
2011;74:4-8.
12. Thio CL, Seaberg EC, Skolasky R, Jr., et al. HIV-1, hepatitis B virus, and risk of liver-related
mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921-1926.
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13. Sinn DH, Gwak GY, Cho J, et al. Comparison of clinical manifestations and outcomes between
hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma: Analysis of a nation-
wide cohort. PloS One. 2014;9(11):e112-184.
14. Ni JD, Xiong YZ, Wang XJ, et al. Does increased hepatitis B vaccination dose lead to a better
immune response in HIV-infected patients than standard dose vaccination: A meta-analysis? Int
J STD AIDS. 2013;24:117-122.
15. Boyd A, Gozlan J, Maylin S, et al. Persistent viremia in human immunodeficiency virus/hepatitis
B coinfected patients undergoing long-term tenofovir: Virological and clinical implications.
Hepatology. 2014;60:497-507.
16. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007;13:2436-2441.
17. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly
effective therapies. Nat Med. 2013 Jul;19(7):837-849.
18. Paintsil E, Binka M, Patel A, et al. Hepatitis C virus maintains infectivity for weeks after drying
on inanimate surfaces at room temperature: Implications for risks of transmission. J Infect Dis.
2014;209:1205-1211.
19. Muhlberger N, Schwarzer R, Lettmeier B, et al. HCV-related burden of disease in Europe: A
systematic assessment of incidence, prevalence, morbidity, and mortality. BMC Public Health.
2009;9:34.
20. American Association of the Study of Liver Diseases and the Infectious Diseases Society of
America. Recommendations for testing, managing, and treating hepatitis C. September 21,
2017. Available from: http://www.hcvguidelines.org.
21. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infec-
tion: A systematic review of longitudinal studies. J Viral Hepatitis. 2006;13:34-41.
22. Sebastiani G, Gkouvatsos K, Pantopoulos K. Chronic hepatitis C and liver fibrosis. World J
Gastroenterol. 2014;20:11033-11053.
23. Wiley TE, McCarthy M, Breidi L, et al. Impact of alcohol on the histological and clinical progres-
sion of hepatitis C infection. Hepatology. 1998;28:805-809.
24. Wyles DL, Sulkowski MS, Dieterich D. Management of hepatitis C/HIV coinfection in the era of
highly effective hepatitis C virus direct-acting antiviral therapy. Clin Infect Dis. 2016;63(suppl
1):S3-S11.
25. Razavi H, Elkhoury AC, Elbasha E, et al. Chronic hepatitis C virus (HCV) disease burden and
cost in the United States. Hepatology. 2013;57:2164-2170.
26. AbbVie Inc. Mavyret (glecaprevir and pibrentasvir). Prescribing Information. North Chicago, IL:
August 2017.
27. Gilead Sciences, Inc. Vosevi (sofosbuvir, velpatasvir, and voxilaprevir). Prescribing Information.
Foster City, CA: July 2017.
28. Smolders EJ, de Kanter CT, van Hoek B, et al. Pharmacokinetics, efficacy, and safety of hepatitis
C virus drugs in patients with liver and/or renal impairment. Drug Saf. 2016 Jul;39(7):589-611.
29. Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis
C: A systematic review of the clinical, economic and quality of life benefits. BMC Infect Dis.
2015;15:19.
30. Langness JA, Larson B, Bayer J, et al. Readying HIV/HCV coinfected patients for HCV treatment:
Occurrence and management of antiviral interactions [abstract 18]. 16th International Work-
shop on Clinical Pharmacology of HIV & Hepatitis Therapy, May 26–28, 2015, Washington, DC.
31. McLaughlin M, Kalfayan N, Grant J, et al. Pharmacy-based resource requirements to obtain HCV
therapy for HIV/HCV coinfected patients [abstract 1674]. ID Week, October 7–11, 2015, San
Diego, CA.
32. Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted
diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1-137.
33. Hagan H, Jordan AE, Neurer J, et al. Incidence of sexually transmitted hepatitis C virus infection
in HIV-positive men who have sex with men. AIDS. 2015;29:2335-2345.
34. Ingiliz P, Martin TCS, Rodger A, et al. Hepatitis C virus reinfection incidence and outcomes
among HIV-positive MSM in Western Europe [abstract PS006]. The International Liver Congress,
April 13–17, 2016, Barcelona, Spain.
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9
Sexually Transmitted Infections
Deborah V. Kelly, BScPharm, PharmD, FCSHP, AAHIVP,
and Tony Antoniou, PharmD, PhD, BScPharm
INTRODUCTION
Sexually transmitted infections (STIs) occur commonly among patients with
human immunodeficiency virus (HIV) infection. Host and pathogen-specific
factors can increase the risk of transmission of HIV in the presence of another STI,
and vice versa. The management of most STIs is the same whether the patient has
HIV infection or not. However, the clinical presentation may differ in patients
with immune suppression. Education and counseling, routine and systematic
screening, and appropriate treatment of patients and their partners are necessary
for effective management of STIs. This chapter reviews the diagnosis and manage-
ment of common STIs in adults living with HIV infection; for the management of
children and special cases such as pregnancy, the reader is referred to the Centers
for Disease Control and Prevention (CDC) guidelines.1
ROUTINE SCREENING FOR STIs

All patients with HIV infection should be tested for STIs at the initial HIV care
visit. Screening tests for some STIs should be performed at least annually for those
who are sexually active and more frequently when individual risk factors and/or
local epidemiology of certain STIs are suggestive.1 The CDC guidelines recommend
routine testing for syphilis, gonorrhea, and chlamydia infections in all patients,
as well as for trichomonas infections in women, as these are curable infections.1
Hepatitis C infection is not typically considered an STI; however, it may be trans-
mitted sexually particularly among people with HIV infection, and, therefore,
screening is recommended. Recent outbreaks of sexually transmitted hepatitis
C infection have been reported among men who have sex with men (MSM) in
several regions,2 suggesting that MSM should be screened annually regardless of
HIV status.3 Hepatitis C infection is discussed in more detail in Chapter 8.
INFECTIONS CHARACTERIZED BY URETHRITIS AND CERVICITIS

Neisseria gonorrhoeae and Chlamydia trachomatis (serotypes D to K) are the two major
causes of urethritis and cervicitis. Other causes include Mycoplasma genitalium,
Ureaplasma urealyticum, Trichomonas vaginalis, herpes simplex virus, Epstein-Barr
virus, and adenovirus.1,4 N. gonorrhoeae and C. trachomatis frequently coexist in
185
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the same patient, and each has been found to increase the risk of transmission
and acquisition of HIV infection.4 A diagnosis of chlamydia or gonorrhea should
prompt screening for additional STIs, including HIV and syphilis. Both chlamydia
and gonorrhea are reportable communicable diseases, so suspected and confirmed
cases should be reported to local health departments.
Chlamydia
Chlamydia is the most commonly reported infectious disease in the United
States, at a rate of 456.1 cases per 100,000 population in 2014.5 This likely under-
estimates the actual prevalence due to the frequent asymptomatic nature of the
infection, insufficient routine screening, and underreporting.5 Chlamydia infec-
tions commonly occur in MSM, young women (<25 years old), racial minorities,
and incarcerated persons and have a high prevalence and incidence among HIV-
infected individuals.1 Therefore, when HIV diagnosis is made, routine screening
at baseline is indicated, with annual screening thereafter. Individuals engaging in
ongoing high-risk sexual behaviors may require screening more frequently.
At least 18 serovars of C. trachomatis exist. Serovars L1-L3 cause potentially
invasive lymphogranuloma venereum (LGV) infection, while serovars D through
K cause chlamydial infections, characterized by superficial infection of epithelial
cells.6 In addition to genital infections, pharyngeal and rectal infections may occur
following orogenital or receptive anal intercourse, respectively, with an infected
partner. Ocular infections may occur in infants following vaginal birth from infected
mothers and in adults due to autoinoculation. Serious complications may occur in
women following chlamydia infection, including pelvic inflammatory disease (PID),
ectopic pregnancy, and infertility.6 Therefore, annual screening is recommended for
sexually active women less than 25 years of age and older women at increased risk
(e.g., new or multiple sex partners, sex partners with an STI).1
Because asymptomatic infection is so common, routine screening is important
to avoid serious sequelae such as PID or infertility and to prevent transmission.
Men may experience purulent urethral discharge (usually milder than gonorrhea)
and mild dysuria. Women may experience vaginal discharge, abnormal vaginal
bleeding, or dyspareunia. Rectal infection may be associated with pain, discharge,
or bleeding; pharyngeal infection is usually asymptomatic or may cause mild
pharyngitis.6
Diagnosis is made using urine specimens (first-catch urine preferred), urethral
swabs in men (if symptomatic), or endocervical swabs in women.4 Rectal and
pharyngeal specimens should also be tested for both C. trachomatis and N. gonor-
rhoeae as extragenital infections have remained undetected with urethral testing
alone among MSM and women.7,8 Nucleic acid amplification tests (NAATs) are
most sensitive for C. trachomatis testing and are recommended for diagnosis using
urine, urethral, and endocervical swab specimens.6 NAATs are not approved by the
U.S. Food and Drug Administration (FDA) to be used on rectal or oropharyngeal
specimens, although evidence suggests improved sensitivity of NAATs over culture
using both rectal and oropharyngeal swab specimens.9,10
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CHAPTER 9 Sexually Transmitted Infections 187
Treatment should be initiated promptly to avoid complications. There is no

evidence to suggest that response to therapy is different in HIV-infected patients,
so treatment recommendations are the same as for those who do not have HIV
infection (Table 9-1). Confirmed chlamydia infection without a concomitant
diagnosis of gonorrhea can be treated with a single dose of azithromycin or a
week of doxycycline therapy. Cure rates with either regimen are very high (97% to
98%), although a recent meta-analysis suggests doxycycline may be slightly more
effective in treating symptomatic urethritis in men.11 Single-dose therapy may
be preferable if adherence is a concern. Patients should be instructed to abstain
from sexual intercourse for 7 days and until they are symptom-free, regardless of
which treatment regimen they receive. They should also avoid intercourse until
all their sex partners have been treated to avoid reinfection. All sex partners from
the preceding 60 days from onset of symptoms or chlamydia diagnosis should be
evaluated, tested, and treated presumptively. Expedited partner therapy (EPT) is
a strategy whereby the patient delivers medications or a prescription for therapy
to his or her sex partners directly in addition to information about risk of infec-
tion, adverse effects, and importance of adherence to treatment. If EPT is locally
permissible by law, it may be considered if there is concern that partners may
not access evaluation and treatment services personally. EPT has been shown to
reduce rates of persistent and recurrent chlamydia12; however, it is not a routinely
recommended practice for MSM because of the high rate of concurrent infections
(especially HIV), which may go undiagnosed.
TABLE 9-1. Treatment for Infections Characterized by Urethritis and

Cervicitis
Infection Recommended Regimen Alternative Regimen(s)
Chlamydia Azithromycin 1 g PO × 1 dose Erythromycin base 500 mg PO four
OR times daily × 7 days
Doxycycline 100 mg BID × 7 days OR
Erythromycin ethylsuccinate 800 mg
PO four times daily × 7 days
OR
Levofloxacin 500 mg PO daily × 7 days
OR
Ofloxacin 300 mg PO BID × 7 days
Gonorrhea Ceftriaxone 250 mg IM × 1 dose plus Cefixime 400 mg PO × 1 dose plus

(uncomplicated, Azithromycin 1 g PO × 1 dose Azithromycin 1 g PO × 1 dose
cervix, urethra,
rectum, or
Penicillin allergy (and penicillin-
pharynx)
desensitization not possible):
Azithromycin 2 g × 1 dose
BID: twice a day; IM: intramuscular; PO: by mouth
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Patients should be retested for chlamydia 3 months after treatment, whether

or not they believe their sex partners were treated. Treatment failure is unlikely
when patients are adherent to therapy. However, there is a high risk of recurrence
in the months following initial infection due to sex partners not receiving treat-
ment or having intercourse with an infected partner.1
Gonorrhea
Gonorrhea is the second most commonly reported communicable disease in the
United States. The prevalence has been increasing annually since 2009, with a rate
of 110.7 cases per 100,000 population in 2014.13 MSM, especially those ≤19 years
of age, are infected disproportionately more than women and men who have sex
with women. N. gonorrhoeae has a short incubation period,14 which facilitates trans-
mission of infection, sometimes even before the initial infection becomes symp-
tomatic to prompt treatment. Risk factors include inconsistent use of condoms,
history of previous or coexisting STIs, multiple sex partners, exchanging sex for
money or drugs, and use of illicit substances, especially crystal methamphet-
amine.15 Like chlamydia, gonorrhea infections are common among HIV-infected
individuals. Routine screening at baseline entry into HIV care, as well as at least
annual screening, is recommended for those with HIV infection.
Gonorrhea infection produces more symptoms than chlamydia in men; puru-
lent discharge and severe dysuria are common.14 Rectal infection may result in
pruritis, rectal discharge, and pain. Pharyngeal infection may cause mild phar-
yngitis but is often asymptomatic. Women may experience abnormal vaginal
discharge or bleeding, dysuria, or urinary frequency. However, infection in women
is often asymptomatic, leading to a high risk of complications, including PID,
if not diagnosed and treated. Extragenital disease including conjunctivitis and
disseminated gonococcal infection (DGI) may occur. DGI is caused by gonococci
seeding the bloodstream and manifests as tender necrotic skin lesions (dermatitis),
arthritis, endocarditis, or meningitis.14
The approach to diagnosis is similar to that for chlamydia, and samples may
be used to test for both infections. Although the sensitivity of NAAT is superior to
culture for detecting N. gonorrhoeae,16 culture has the advantage of providing valu-
able sensitivity information as this bacteria has the ability to develop resistance to
antimicrobials. Patients with persistent symptoms despite treatment should have
swab specimens from all affected anatomical sites sent for culture and sensitivity.
If DGI is suspected, urogenital and extragenital specimens from all possible sites
of infection (e.g., skin, synovial fluid, blood, central nervous system) should be
collected for NAAT or culture.1
Due to increasing rates of cephalosporin resistance, dual therapy of a cepha-
losporin plus a macrolide is recommended as first-line treatment for gonorrhea,
whether chlamydia infection is present or not.1 The cephalosporin of choice to
treat N. gonorrhoeae currently is ceftriaxone.1 Susceptibility to cefixime appears
to be decreasing based on reports of increasing minimum inhibitory concentra-
tions and clinical treatment failures.1,17 As an alternative regimen, a single dose
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of cefixime may be used if ceftriaxone is not available.1 Some expert working

group guidelines suggest a single dose of 800 mg may be safe and more effective in
treating gonococcal infections14; however, it should be noted that this exceeds the
manufacturer’s recommended maximum dosage.
Fluoroquinolones have not been recommended for the treatment of gono-
coccal infections in the United States since 2007, due to high prevalence of resis-
tance.17 Reduced susceptibility to macrolides is noted to be increasing in the
United States; however, azithromycin is still recommended as adjunct therapy.13
Treatment failure should be considered if symptoms have not resolved within 3
to 5 days of therapy and the patient reports no sexual contact during this time.1
Suspected treatment failures are more likely to be reinfections than true treatment
failures, so retreatment with the original regimen is reasonable.1 However, repeat
culture and sensitivity results should guide selection of retreatment if there is
reason to suspect true treatment failure. Treatment of DGI or gonococcal conjunc-
tivitis should be guided by antimicrobial susceptibility testing in consultation
with an infectious diseases specialist.1
Due to increasing concerns over antimicrobial resistance, a test of cure is
recommended by some guidelines4 at 2 to 4 weeks after treatment. The CDC does
not recommend a test of cure routinely for patients with uncomplicated gono-
coccal urogenital or rectal infection if treated with recommended or alternative
therapy.1 However, the existing consensus is that all patients should be retested at
3 months to assess for reinfection.1,4 Abstaining from sexual intercourse for at least
7 days and until symptom-free and partner assessment and treatment are essen-
tial to prevent reinfection and reduce transmission, as in the case of chlamydia
infection.
INFECTIONS CHARACTERIZED BY VAGINAL OR URETHRAL

DISCHARGE
The most common infections associated with vaginal discharge are trichomoniasis,
bacterial vaginosis (BV), and vulvovaginal candidiasis (VVC). Although VVC is not
transmitted sexually, it may be mistaken for other STIs and should be considered
as part of the differential diagnosis in women presenting with vaginal discharge.
Trichomoniasis
Trichomoniasis is caused by Trichomonas vaginalis, a protozoa that is transmitted
through sexual contact. It is the most common nonviral STI in the United States,
although it may coexist with other infections, especially BV and nongonococcal
urethritis syndromes.1 Trichomoniasis disproportionately affects women more
than men, and women over 40 years of age are more likely to be affected than
younger women.18 Infection may cause minimal symptoms or be asymptomatic;
therefore, if untreated, infections may last for months. T. vaginalis is readily trans-
missible during penile-vaginal sexual encounters so partner treatment is recom-
mended.1 Trichomoniasis is associated with an increased risk of acquisition and
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transmission of HIV infection and is significantly associated with PID in HIV-

infected women.1 If it occurs during pregnancy, trichomoniasis may cause preterm
birth and other complications.18
In women, symptoms may include malodorous, frothy yellowish vaginal
discharge, pruritis, dysuria, and dyspareunia.18 Erythema and inflammation of
the vulva, vagina, and/or cervix (strawberry cervix) are usually present.18 If the
discharge has a fishy odor, it may indicate a concomitant BV infection. Men tend
to be asymptomatic, but mild urethral irritation and discharge may be present.18
Diagnosis based on symptoms alone is unreliable because symptoms are
nonspecific and asymptomatic infection may occur. Wet-mount microscopy is the
most common diagnostic technique used in women. However, the sensitivity of
wet mount is approximately 51% to 65%, and is even lower in men.1 Trichomonas
culture has higher sensitivity, approximately 75% to 96%, and nearly 100% speci-
ficity, so this method was preferred before nucleic acid amplification tests (NAATs)
became available.1 Vaginal secretions are preferred over urine samples for culture
in women, and for men either a urethral swab, urine sediment, or semen sample
may be used.1 NAAT is the preferred diagnostic method when available as it is
highly sensitive and has been shown to detect 3 to 5 times more trichomonas
infections than wet mount.1 Point-of-care tests for T. vaginalis are available that
provide results in under an hour; however, false positive results are more likely
with these tests than with vaginal wet-mount microscopy.18 Pap tests are not diag-
nostic for trichomoniasis even when T. vaginalis is detected, as false positives as
well as false negatives may occur.1
Treatment is indicated for both symptomatic and asymptomatic patients to
reduce signs and symptoms of infection, transmission to partners, and the risk
of PID, HIV viral load in the genital tract, and HIV viral shedding. The oral nitro-
imidazoles, metronidazole and tinidazole, are effective against T. vaginalis.1 The
intravaginal gel is unlikely to reach sufficient systemic levels and is therefore not
recommended for trichomoniasis.1 Twice-daily treatment with metronidazole
for 7 days may be more effective than single-dose therapy in women with HIV
infection.19 However, adherence may be lower with week-long treatment, which
may justify the choice of single-dose therapy for some patients. Alcohol should be
avoided during treatment, for 24 hours after completion of metronidazole, and for
72 hours following tinidazole treatment to avoid a disulfiram-like reaction. The
same caution should be applied when patients are taking ritonavir or lopinavir/
ritonavir liquid, as both products contain alcohol and, therefore, may cause the
same reaction when combined with metronidazole or tinidazole.20,21 Treatment of
sex partners is necessary to avoid reinfection.1
Women should be retested after 3 months of therapy to ensure resolution of
infection.1 Antibiotic resistance is uncommon; the most likely reason for treat-
ment failure is reinfection by untreated sex partners. Retesting of men is not
recommended due to lack of evidence; however, women should be counseled to
abstain from sex until they have completed their course of therapy and are asymp-
tomatic.1 In the case of treatment failures, patients may be retreated with a higher
dose of metronidazole or tinidazole (2 g) for 5 to 7 days.1,18
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Bacterial Vaginosis
BV tends to be a polymicrobial infection caused by replacement of normal vaginal
flora with an overgrowth of anaerobic bacteria, mycoplasma, and Gardnerella vagi-
nalis.22 Although it is unclear whether BV is an STI, sexual risk factors including
having new and multiple sex partners (male or female) increase the risk of devel-
oping BV.23 BV may be more severe or persistent in women who have HIV infec-
tion (especially those with CD4 counts <200 cells/mm3),22 and its presence can
increase the risk of acquisition of other STIs, including gonorrhea, chlamydia,
genital herpes, as well as HIV.1
BV is often asymptomatic but when symptoms are present, it is character-
ized by a fishy-smelling, thin, white or grey vaginal discharge.24 BV is unlikely
to be associated with pruritis or inflammation, unlike trichomoniasis and VCC.24
Symptoms alone are insufficient for diagnosis; a vaginal swab for Gram stain and
pH testing is indicated. Gram stain is considered the gold standard; however, the
presence of three of the following clinical criteria are considered diagnostic for BV
(Amsel criteria):1,22
• homogenous, thin, white discharge coating the vaginal walls
• presence of clue cells on microscopy of a vaginal saline preparation
• pH of vaginal fluid >4.5
• positive whiff test (fishy odor of vaginal discharge with or without the
addition of 10% potassium hydroxide)
Treatment is the same for women with HIV and for those who do not have
HIV infection. Treatment is indicated only for symptomatic infection, except in
pregnancy where it may be advisable to treat asymptomatic women with docu-
mented BV infection if the woman has a history of preterm labor.22 Oral metroni-
dazole or clindamycin are preferred in pregnancy; the use of clindamycin cream
during the second half of pregnancy has been associated with adverse neonatal
outcomes, including low birth weight and infection.22 Probiotic use to restore
normal vaginal flora has not demonstrated improved outcomes and is not recom-
mended as adjunctive therapy for BV.1 As in the case with trichomoniasis treat-
ment, alcohol should be avoided during treatment, for 24 hours after completion
of metronidazole, and for 72 hours following tinidazole treatment to avoid a disul-
firam-like reaction. Douching should be avoided, and women should refrain from
sexual activity or use of condoms during treatment.1 Patients should be counseled
that clindamycin cream may weaken latex condoms and diaphragms for up to 5
days after use. Treatment of sexual partners does not impact the risk of relapse or
recurrence and is therefore not routinely indicated.1 Follow-up is not required if
symptoms resolve; however, women should be advised to return for reassessment
if symptoms recur (Table 9-2).1
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TABLE 9-2. Treatment for Infections Characterized by Vaginal Discharge

Infection Preferred Regimen Alternative Regimen(s)
Trichomoniasis Metronidazole 500 mg PO BID Posttreatment failure regimen:
× 7 days Metronidazole 2 g PO once daily
OR × 5 days
Metronidazole 2 g PO × 1 dose OR
OR Tinidazole 2 g PO once daily
Tinidazole 2 g PO × 1 dose × 5 days
Bacterial vaginosis, Metronidazole 500 mg PO BID Clindamycin 300 mg PO BID

symptomatic × 7 days × 7 days
(asymptomatic infection OR OR
should not be treated
Metronidazole gel 0.75%, one full Clindamycin ovules 100 mg
except in pregnancy)
applicator (5 g) intravaginally, intravaginally once daily at
once daily × 5 days bedtime × 3 days
OR OR
Clindamycin cream 2%, one full Tinidazole 2 g PO once daily
applicator (5 g) intravaginally, × 2 days
once daily at bedtime × 7 days OR
Tinidazole 1 g PO once daily
x 5 days
BID: twice a day; PO: by mouth
INFECTIONS CHARACTERIZED BY GENITAL ULCERS
Genital Herpes
Genital herpes is caused by herpes simplex virus type 1 (HSV-1) and herpes simplex
virus type 2 (HSV-2).1,25 HSV-1 and HSV-2 are common co-infections in people with
HIV, with seroprevalences of 90% to 100% and 52% to 95%, respectively, in several
populations worldwide.26 The majority of genital herpes infections are transmitted
by individuals who are asymptomatic or unaware that they have the infection.1
Infection with herpes simplex virus (HSV) is a lifelong condition character-
ized by periods of latency, symptomatic reactivation, and asymptomatic shedding
that reflect the balance between the virus and host immune responses.27 HSV-
specific cell-mediated immune responses are critical for attenuating and containing
initial infection, reducing viral spread to neuronal cells, maintaining latency,
and controlling reactivation.28 Consequently, immunocompromised patients,
including people with HIV, may be at greater risk for severe and symptomatic HSV
reactivation than immunocompetent individuals.1
HIV and HSV interact with each other in several ways.29 First, HSV-2 infection
increases the efficiency of both acquisition and transmission of HIV-1 by two-
ERRNVPHGLFRVRUJ
to four-fold. This phenomenon is attributable to the local disruption of epithe-

lial genital barriers to HIV, thereby creating a portal of entry for HIV, and to the
enrichment of submucosal layers with HIV target cells. Second, HSV-2 has been
associated with increased plasma and genital HIV-1 levels, presumably because
of target cell recruitment and increased systemic inflammation. However, despite
this increase in plasma viremia, evidence that HSV-2 is associated with HIV disease
progression is lacking. Finally, oral and genital shedding of both HSV-1 and HSV-2
occurs more frequently among persons with HIV relative to HIV-negative individ-
uals, facilitating viral transmission to sexual partners.29
HSV infections can be classified as primary first clinical episodes, nonprimary first
clinical episodes, and recurrent episodes.1,25
Primary infection with HSV is defined as the first clinically evident episode of
disease in an individual with no HSV antibodies.25 Extensive painful vesiculoulcer-
ative genital lesions that are more severe and last longer than those seen in recur-
rent infections characterize clinical manifestations of primary infection.1,27 HSV
cervicitis occurs in 70% to 90% of primary HSV-2 infections and 70% of primary
HSV-1 infections.30 Clinical differentiation from gonococcal or chlamydial cervi-
citis may be difficult, although cervical ulceration suggests HSV.23 Herpes proctitis
can be observed in MSM.30 Systemic symptoms (e.g., fever, myalgia) occur in 58%
to 62% of patients.25 Extragenital complications include aseptic meningitis (16%
to 26%) and lesions at other sites (10% to 28%).25 Primary genital HSV infection
has a protracted course, lasting approximately 2 to 4 weeks, with average times to
resolution of 16.5 days for men and 23 days for women.25
In contrast to primary clinical episodes, nonprimary disease is defined as the
first clinically evident episode in an individual with preexisting HSV antibody.25
Because of preexisting immunity, nonprimary infections are generally less severe
than primary genital herpes and are characterized by fewer lesions and a lower
prevalence of systemic symptoms (16%), aseptic meningitis (1%), and extragenital
lesions (8%).25
Similarly, recurrent disease, which occurs due to reactivation of latent infection,
is milder than primary infection. Recurrent infections are generally less extensive,
complicated by systemic symptoms in only 5% to 12% of cases and resolve within
9 to 10 days.25 Recurrences may be preceded by prodromal symptoms (e.g., local-
ized tingling, irritation) before the appearance of lesions.30
Asymptomatic shedding of HSV-2 is an important mechanism for ongoing
transmission of the virus, occurring in 80% to 90% of seropositive individuals
on approximately 20% of days.28 Studies have found that most HSV transmission
occurs while patients are asymptomatic, even though the risk of transmission is
greater during symptomatic illness.28
Diagnosis is most typically by culture or polymerase chain reaction (PCR).25
Isolation of HSV in cell culture is the preferred test if genital ulcers or other muco-
cutaneous lesions are present. It is sensitive (70% from ulcers, 94% from vesicles)
and allows identification of HSV type.25 PCR is 4 times more sensitive than viral
culture and has been increasingly used instead of culture in some settings. Sero-
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logical testing is available and can be used to establish a diagnosis of primary

infection and determine whether the infection is due to HSV-1 or HSV-2. Primary
infection is confirmed by the absence of HSV antibody in the acute-phase sample
and the presence of antibody in the convalescent sample.25
The nucleoside analogues acyclovir, valacyclovir, and famciclovir, are the
cornerstones of therapy for genital HSV infections (Table 9-3).1,25,27 The drugs are
well tolerated and equally effective in treating primary and recurrent episodes of
disease and reducing the frequency and severity of recurrence; however, famci-
clovir appears somewhat less effective for suppression of viral shedding. In addi-
tion, valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discor-
dant, heterosexual couples in which the source partner has a history of genital
HSV-2 infection. In these cases, suppressive antiviral therapy can be considered as
part of a larger strategy for preventing transmission, which includes condom use
and avoidance of sexual activity during recurrences.1
Treatment should be individualized based on the number of recurrences and
patient preferences. Individuals with infrequent or mild recurrences may elect
patient-initiated episodic treatment as an option.27 Conversely, those with many
recurrences (i.e., at least 6 episodes per year) may opt for suppressive therapy,
which can reduce the frequency of episodes by 70% to 80%.1,27 Antiviral prophy-
laxis with acyclovir is recommended in pregnant women with a history of genital
herpes from 36 weeks’ gestation until delivery to minimize the risk of active
recurrence at the time of delivery and neonatal herpes.25 Resistance to nucleoside
analogues is uncommon but has been observed in the setting of HIV. Intravenous
and topical foscarnet, topical imiquimod, and cidofovir (topical and intravenous)
have been used to treat nucleoside analogue-resistant HSV.1 Because cidofovir and
TABLE 9-3. Treatment for Genital Herpes

Daily Suppressive
Drug First Episode Episodic Therapy Therapy
Acyclovir 400 mg orally three times daily 400 mg orally three 400–800 mg orally
× 7–10 days times daily × 5–10 BID–three times
days daily
Intravenous acyclovir 5 mg/kg
infused over 60 minutes every
8 hours for severe disease,
with switch to oral therapy
when clinical improvement
Famciclovir 250 mg orally three times daily 500 mg orally BID 500 mg orally BID
× 10 days × 5–10 days
Valacyclovir 1,000 mg orally BID × 10 days 1,000 mg orally BID 500 mg orally BID
× 5–10 days
BID: twice a day
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foscarnet are renally eliminated, dosage adjustment is required when these drugs
are administered intravenously to patients with renal failure.
Lymphogranuloma Venereum
Lymphogranuloma venereum (LGV) is caused by the serovars L1, L2, and L3 of
C. trachomatis.31 In contrast to serovars A to K, which cause a range of clinical
syndromes characterized by infection of mucosal surfaces of the cervix, rectum,
urethra, throat, and conjunctiva, the LGV serovars are invasive, preferentially
affecting the lymph tissue.31 LGV is endemic to parts of East and West Africa,
India, South America, Southeast Asia, and the Caribbean, where it is primarily a
disease of heterosexual men and women and manifests in its classic form with
genital ulcers and lymphadenopathy.31,32 In contrast, most cases in Europe and
North America have occurred as outbreaks of disease comprised predominantly of
hemorrhagic proctitis among MSM, often in the context of concurrent HIV infec-
tion and participation in high-risk sexual activities.31-33
The clinical course of LGV can be divided into three stages: a primary stage
affecting the site of inoculation, a secondary stage involving the regional lymph
nodes and possibly the anorectum, and a tertiary stage characterized by a chronic
inflammatory response and tissue destruction.31,33
Primary LGV has an incubation period of 3 to 30 days, following which a
small, painless papule, pustule, or nodule, which may ulcerate, appears at the site
of inoculation. Although lesions can occasionally appear herpetiform, they can be
differentiated from herpes lesions by a lack of associated pain. The lesion usually
heals within 1 week and may not always occur.33
Secondary LGV begins within 2 to 6 weeks of the onset of the primary lesion
and occurs as either inguinal syndrome or anorectal syndrome, depending on the
site of inoculation.33 Inguinal syndrome is characterized by painful inflammation
of the inguinal or femoral lymph nodes, referred to as buboes. Anorectal disease is
more common among heterosexual women and in MSM.31 Among MSM, hemor-
rhagic proctitis is the primary manifestation of secondary LGV infection.31,33
Symptoms include rectal pain, anorectal bleeding, muco- or hemopurulent rectal
discharge, tenesmus, constipation, and other symptoms of lower gastrointes-
tinal disease. Secondary LGV may also be associated with systemic dissemination
disease, resulting in low-grade fever, chills, myalgias, and arthralgias.33
Tertiary LGV is characterized by chronic inflammation, chronic edema, and
sclerosing fibrosis. If left untreated, the ensuing lymphatic obstruction can lead
to elephantiasis of the genitalia in either sex, and rectal involvement can result in
fistulae, strictures, and stenosis of the rectum. In women, a syndrome of widespread
destruction of the external genitalia called esthiomene has been described.31,33
Because the manifestations of LGV overlap with those of other sexually
acquired ulcerative infections, the clinical diagnosis is not straightforward. Further-
more, nonspecific tests (e.g., culture, nucleic acid amplification) for C. trachomatis
may be positive in patients with LGV but will not discriminate between LGV and
non-LGV serovars of the organism. Definitive diagnosis requires serovar-specific
ERRNVPHGLFRVRUJ
testing using DNA sequencing or restriction fragment length polymorphism.32

Specimens that can be used for diagnostic testing include swabs of the primary
lesion and/or other affected areas (e.g., pharynx, rectum), serology, and aspirate of
fluid from buboes. Identification of C. trachomatis in bubo fluid is highly sugges-
tive of LGV, even without serovar-specific testing.32
Empiric antibiotic therapy should be initiated while waiting for the results
of diagnostic tests. Current guidelines recommend doxycycline (100 mg orally
twice a day for 21 days) as the treatment of choice for LGV.32 Erythromycin (500
mg orally 4 times a day for 21 days) can be used as an alternative. Pregnant and
lactating women should be treated with nonestolate preparations of erythromycin.
Sexual partners from the 60 days preceding symptom onset or date of diagnosis in
asymptomatic individuals also require testing and empiric treatment with either
doxycycline (100 mg orally twice a day for 7 days) or a single 1-gram dose of azith-
romycin. A test of cure using routine tests for C. trachomatis should be performed
3 to 4 weeks after the completion of treatment.32
Syphilis
Syphilis is caused by the spirochete Treponema pallidum.1,34 Timely diagnosis and
treatment of syphilis are important for preventing progression to later stages of
the disease, which can include irreversible and life-threatening involvement of the
cardiovascular and central nervous systems.1,34
HIV and T. pallidum co-infection interact with each other biologically in
several ways. Like other STIs, syphilis may amplify the risk of acquiring HIV.35
This can occur due to an overlap in risk behaviors and through syphilis-mediated
genital ulceration and inflammation, which may act as co-factors in acquiring
HIV. The presence of HIV can also alter the natural history of syphilis in several
ways. Specifically, HIV co-infection has been associated with multiple and deeper
chancres. In addition, up to 25% of HIV-infected patients may present with an
overlap of primary and secondary stage features of syphilis.35
The incidence of syphilis in the United States has increased from 2.1 to 6.3
cases per 100,000 population between 2000 and 2014.36 These trends are primarily
attributable to increased cases among MSM, in whom it is estimated that more than
60% of cases occur. Importantly, reported cases of syphilis are characterized by a
high rate of HIV co-infection, particularly among MSM. In 2014, 51.2% of syphilis
cases among MSM were HIV-positive.36 Similar findings have been observed in
Canada, where in addition to MSM, Indigenous populations are disproportion-
ately burdened by syphilis in several regions of the country.34
Syphilis occurs in three stages (primary, secondary, and latent), classified
based on symptoms and time since infection.1,34 Primary, secondary, and early
latent syphilis collectively comprise a diagnosis of early syphilis, implying infec-
tion within the previous year. Primary syphilis is characterized by painless sores
that often go unnoticed. They typically last for 3 to 6 weeks regardless of treat-
ment. Secondary syphilis usually consists of mucous membrane lesions or rash
over various parts of the body, often including the palms and soles of the feet.
ERRNVPHGLFRVRUJ
Other symptoms, including fever, lymphadenopathy, sore throat, patchy hair loss,
muscle aches, and fatigue, may also be present. Symptoms of secondary syphilis
may occur as the primary lesion is healing or several weeks later and will resolve
whether treatment is received or not. Latent syphilis occurs after primary and
secondary syphilis symptoms have resolved and refers to a stage characterized by
reactive serologic findings in the absence of clinical disease. It is defined as either
early (i.e., within 1 year of infection) or late (i.e., ≥1 year after infection). When the
time of infection is unclear, patients with latent syphilis are treated conservatively
as if the infection were present for more than 1 year.34
Although often considered a manifestation of tertiary syphilis, neurosyphilis
can occur at any stage of the disease. Early neurologic manifestations, including
meningitis, stroke, and auditory or ophthalmic abnormalities, are usually present
within the first few months or years of infection.1 Late neurologic manifestations,
including tabes dorsalis and general paresis, occur 10 to 30 years after infection.1
Because HIV may impart an increased risk of neurologic disease in early syphilis,
careful neurologic evaluation of these patients is required.
Serologic tests are the main diagnostic tools for syphilis infection.1,34 There
are currently two algorithms for the serologic diagnosis of syphilis. In the tradi-
tional CDC-recommended algorithm, patients suspected of having the disease are
screened with nontreponemal tests, such as the Venereal Disease Research Labora-
tory (VDRL) and rapid plasma reagin (RPR) tests.1,34 Patients with a positive VDRL
or RPR undergo confirmatory testing with treponemal assays such as the Trepo-
nema pallidum particle agglutination (TP-PA) or fluorescent treponemal antibody
absorbent (FTA-Abs) tests. Some laboratories have adopted an alternative reverse
sequence screening algorithm that begins with treponemal antibody-specific
enzyme and chemiluminescence immunoassays (EIA/CIA), followed by testing
of reactive sera with a nontreponemal test to confirm whether the infection is
active; discordant results are tested with a different treponemal assay (e.g., TP-PA)
to confirm true syphilis infection. If a second treponemal test is positive, persons
with a history of previous treatment will require no further management unless
sexual history suggests reexposure. In these cases, a repeat nontreponemal test in
2 to 4 weeks is recommended to evaluate for early infection. Individuals without
a history of treatment for syphilis and no serologic evidence of recent infection
should be treated for late latent syphilis.36 Nontreponemal test antibody titers are
used to follow treatment response. A 4-fold change in titer (e.g., from 1:16 to 1:4 or
from 1:8 to 1:32) between two test results obtained using the same nontreponemal
test is considered clinically significant.1
Examination of cerebrospinal fluid for evidence of neurosyphilis is currently
recommended for individuals with late latent syphilis (including syphilis of
unknown duration), when neurologic or ocular findings are present or in
suspected treatment failure.35 Treatment failure can be defined clinically by the
persistence, recurrence, or development of clinical findings attributable to syphilis
in the absence of reinfection, or serologically if the serum nontreponemal anti-
body titer does not decrease 4-fold by 6 to 12 months following the treatment of
ERRNVPHGLFRVRUJ
primary and secondary syphilis or 12 to 24 months following the treatment of

latent syphilis.1 Cerebrospinal fluid abnormalities have been associated with high
serum syphilis titers and advanced HIV infection (CD4 count <350 cells/mm3) at
the time of syphilis diagnosis. However, unless neurologic signs and symptoms are
present, a cerebrospinal fluid examination has not been associated with improved
clinical outcomes.29,37
Syphilis treatment varies according to the stage of the disease. A single dose
of intramuscular benzathine benzylpenicillin (2.4 million units) is the recom-
mended treatment for primary, secondary, and early latent syphilis; patients with
late latent syphilis require three weekly doses of this drug.1,34,35 For patients with
confirmed penicillin allergies, oral doxycycline can be considered. However, there
are limited data describing the efficacy of this drug in persons with HIV.35 Patients
with neurosyphilis, syphilitic eye disease, or syphilitic auditory disease require
intravenous penicillin G.1,34,35 Penicillin desensitization should strongly be consid-
ered for patients with neurosyphilis and a history of penicillin allergy.
Antibiotic treatment for syphilis can precipitate an adverse drug reaction
known as the Jarisch-Herxheimer reaction.1 This reaction typically begins within
24 hours of treatment, usually follows the treatment of early syphilis, and mani-
fests with systemic symptoms including fever, rigors, rash, headache, and myal-
gias. The reaction is usually self-limited, resolving within 24 hours, although anti-
pyretics can be used for symptom relief.
In the absence of a test of cure, nontreponemal tests should be monitored at
3, 6, 9, 12, and 24 months after treatment for primary, secondary, and early latent
syphilis and at 6, 12, 18, and 24 months following treatment for late latent and
syphilis of unknown duration.1,34 The objectives of this monitoring are to ensure
that patients are responding to treatment.
To monitor for treatment failure, the criteria include
• persistence, recurrence, or development of new signs and symptoms of
syphilis, particularly in the central nervous system
• sustained increase in the nontreponemal test titer
• failure of nontreponemal test titer to decrease 4-fold by 6 to 12 months
for primary, secondary, and early latent syphilis and by 12 to 24 months
for late latent syphilis or syphilis of unknown duration
In addition to repeating serologic testing, patients with neurosyphilis also
require cerebrospinal fluid examination every 6 months until the findings (i.e.,
white blood cells, protein) have normalized. If cerebrospinal fluid white blood
cells or protein levels are not normal 2 years following treatment, reevaluation and
retreatment for neurosyphilis may be required.1
Partner notification and treatment is an essential component of syphilis
management. Individuals exposed within the 90 days preceding the diagnosis of
primary, secondary, or early latent syphilis should be treated presumptively for
early syphilis, even if serologic tests are negative.1,35 Individuals who were exposed
>90 days preceding the diagnosis of early syphilis in a sex partner should also
be treated presumptively for early syphilis if serologic results are not available or
ERRNVPHGLFRVRUJ
TABLE 9-4. Treatment for Syphilis

Alternative for Penicillin-Allergic
Stage Preferred Treatment Patients
Primary, secondary, early latent Benzathine penicillin G Doxycycline 100 mg orally BID
2.4 million units IM × 14 days
× 1 dose
Ceftriaxone 1 g IV or IM once
daily × 10 days
Late latent, latent of unknown Benzathine penicillin G Consider penicillin

duration, tertiary syphilis not 2.4 million units IM weekly desensitization
involving the central nervous × 3 doses
system
Doxycycline 100 mg orally BID
× 28 days
Ceftriaxone 1 g IV or IM daily
× 10 days
Neurosyphilis, ophthalmic Penicillin G 3–4 million units IV Strongly consider penicillin

syphilis, otologic syphilis every 4 hours (16–24 million desensitization followed by
units per day) × 10–14 days treatment with penicillin
Ceftriaxone 2 g IV or IM daily
× 10–14 days
BID: twice a day; IM: intramuscular; IV: intravenous
follow-up is uncertain.1,35 If serologic tests are negative, no treatment is needed.

Long-term sex partners of persons who have late latent syphilis should be evalu-
ated clinically and serologically for syphilis and treated accordingly (Table 9-4).
ROLE OF THE PHARMACIST IN STI SCREENING AND TREATMENT

Pharmacists are well positioned to be an important resource for the prevention and control
of STIs among people with HIV.
Possible roles include
• counseling regarding the signs, symptoms, and natural history of STIs
• counseling regarding safer sex practices, the proper role of latex condoms, and
their relative effectiveness in the prevention of different STIs
• counseling patients about the role of oral sex in facilitating the transmission of
certain infections (e.g., gonorrhea, syphilis, herpes)
• discussing, identifying, and managing possible reactions to antimicrobials,
including providing support to desensitization regimens for patients with allergies
ERRNVPHGLFRVRUJ
• educating patients about the importance of adherence to antimicrobial therapy

and nonpharmacologic strategies to resolve infections and prevent transmission
• ensuring that patients are aware of the need for follow-up to ensure resolution
of symptoms, receipt of any required follow-up testing, and follow-through
with partner notification
• encouraging patients to have partners referred for testing and treatment as
indicated, and advising about EPT as an option if legally permissible in their
region
• identifying patients who would benefit from daily suppressive therapy for
genital herpes infection
KEY RESOURCES
• CDC guidelines on Sexually Transmitted Diseases Treatment Guidelines, 2015.
http://www.cdc.gov/std/tg2015/default.htm.
o This document provides the latest guidance on the diagnosis and treatment of
STIs and includes sections for the management of special situations, including
children, pregnancy, sexual assault, and HIV infection.
• New York State Department of Health AIDS Institute, HIV Clinical Resource: Manage-
ment of STIs in HIV infected adults. http://www.hivguidelines.org/clinical-guidelines/
adults/management-of-stis-in-hiv-infected-patients/.
o This website provides guidance on the management of STIs in patients with HIV
infection specifically.
REFERENCES
1. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guide-
lines, 2015. Available at: http://www.cdc.gov/std/tg2015/tg-2015-print.pdf. June 5, 2015.
2. Bradshaw D, Matthews G, Danta M. Sexually transmitted hepatitis C infection: The new
epidemic in MSM? Curr Opin Infect Dis. 2013;26:66-72.
3. Richardson D, Fisher M, Sabin C, et al. Sexual transmission of hepatitis in MSM may not be
confined to those with HIV infection. J Infect Dis. 2008;197:1213-1214.
4. New York State Department of Health AIDS Institute. Gonococcal and Chlamydial Infections.
Available at: http://www.hivguidelines.org/clinical-guidelines/adults/management-of-stis-in-hiv-
infected-patients/gonococcal-and-chlamydial-infections/. October 2007.
5. Centers for Disease Control and Prevention. 2014 Sexually Transmitted Diseases Surveillance.
Chlamydia. Available at: http://www.cdc.gov/std/stats14/chlamydia.htm. Accessed June 28,
2016.
6. Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections:
Chlamydial infections. Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/
section-5-2-eng.php. Accessed June 20, 2016.
7. Patton ME, Kidd S, Llata E, et al. Extragenital gonorrhea and chlamydia testing and infection
among men who have sex with men—STD Surveillance Network, United States, 2010–2012. Clin
Infect Dis. 2014;58(11):1564-1570.
8. Trebach JD, Chaulk CP, Page KR, et al. Neisseria gonorrhoeae and Chlamydia trachomatis
among women reporting extragenital exposures. Sex Transm Dis. 2015;42(5):233-239.
9. Schachter J, Moncada J, Liska S, et al. Nucleic acid amplification tests in the diagnosis of chla-
mydial and gonococcal infections of the oropharynx and rectum in men who have sex with
men. Sex Transm Dis. 2008;35:637-642.
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10. Mimiaga MJ, Mayer KH, Reisner SL, et al. Asymptomatic gonorrhoea and chlamydial infections
detected by nucleic acid amplification tests among Boston area men who have sex with men.
Sex Transm Dis. 2008;35:495-498.
11. Kong FYS, Tabrizi SN, Law M, et al. Azithromycin versus doxycycline for the treatment of
genital chlamydia infection: A meta-analysis of randomized controlled Trials. Clin Infect Dis.
2014;59(2):193-205.
12. Golden MR, Whittington WL, Handsfield HH, et al. Effect of expedited treatment of sex partners
on recurrent or persistent gonorrhoea or chlamydial infection. N Engl J Med. 2005;352:676-685.
Gonorrhea. Available at: http://www.cdc.gov/std/stats14/gonorrhea.htm. Accessed June 28,
2016.
Gonococcal infections. Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/
section-5-6-eng.php. Accessed June 18, 2016.
15. Newman LM, Dowell D, Bernstein K, et al. A tale of two gonorrhoea epidemics: Results from the
STD Surveillance Network. Public Health Rep. 2012;127(3):282-292.
16. Papp JR, Schachter J, Gaydos C et al. Recommendations for the laboratory-based detection of
Chlamydia trachomatis and Neisseria gonorrhoeae–2014. MMWR Recomm Rep. 2014;63(No. RR-o2).
17. Centers for Disease Control and Prevention. Update to CDC’s Sexually Transmitted Diseases
Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment
for Gonococcal Infections. Available at: https://www.cdc.gov/mmwr/preview/mmwrhtml/
mm6131a3.htm?s_cid=mm6131a3_w. Accessed June 22, 2016.
18. New York State Department of Health AIDS Institute. Trichomoniasis. Available at: http://www.
hivguidelines.org/clinical-guidelines/adults/management-of-stis-in-hiv-infected-patients/tricho-
moniasis/. August 2012.
19. Kissinger P, Mena L, Levison J, et al. A randomized treatment trial: Single versus 7-day dose of
metronidazole for the treatment of Trichomonas vaginalis among HIV-infected women. J Acquir
Immune Defic Syndr. 2010;55(5):565-571.
20. Norvir [package insert]. AbbVie Corporation, St. Laurent, QC; 2016. http://www.abbvie.ca/
content/dam/abbviecorp/ca/english/docs/NORVIR_PM_EN.pdf. Accessed September 1, 2016.
21. Kaletra [package insert]. AbbVie Corporation, St. Laurent, QC; 2016. http://www.abbvie.ca/
content/dam/abbviecorp/ca/english/docs/KALETRA_PM_EN.pdf. Accessed September 1, 2016.
22 New York State Department of Health AIDS Institute. Bacterial Vaginosis. Available at: http://
www.hivguidelines.org/clinical-guidelines/adults/management-of-stis-in-hiv-infected-patients/
bacterial-vaginosis-bv/. August 2009.
23. Fethers KA, Fairley CK, Hocking JS, et al. Sexual risk factors and bacterial vaginosis: A systematic
review and meta-analysis. CID. 2008;47:1426-1435.
Vaginal discharge (bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis). Available
at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/section-4-8-eng.php. Accessed June 16,
20119.
Genital herpes simplex virus infections. Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/
cgsti-ldcits/section-5-4-eng.php. Accessed June 17, 2016.
26. Tan DH, Kaul R, Walsmley S. Left out but not forgotten: Should closer attention be paid to coin-
fection with herpes simplex virus type 1 and HIV? Can J Infect Dis Med Microbiol. 2009; 20:e1-e7.
27. Groves MJ. Genital herpes: A review. Am Fam Physician. 2016;93:928-934.
28. Hofstetter AM, Rosenthal SL, Stanberry LR. Current thinking on genital herpes. Curr Opin Infect
Dis. 2014;27:75-83.
29. Van de Perre P, Segondy M, Foulonge V, et al. Herpes simplex virus and HIV-1: Deciphering viral
synergy. Lancet Infect Dis. 2008;8:490-497.
30. Corey L, Wald A. Genital herpes. In: Holmes KK, Sparling PF, Stamm WE, et al. Sexually Trans-
mitted Diseases. 4th ed. New York: McGraw Hill Medical; 2008:399-438.
31. Mabey D, Peeling RW. Lymphogranuloma venereum. Sex Transm Infect. 2002;78:90-92.
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32. Public Health Agency of Canada. Canadian guidelines on sexually transmitted diseases:
Lymphogranuloma venereum. Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ld-
cits/section-5-9-eng.php. Accessed June 17, 2016.
33. Ceovic R, Gulin SJ. Lymphogranuloma venereum: Diagnostic and treatment challenges. Infect
Drug Resist. 2015;8:39-47.
34. Public Health Agency of Canada. Canadian guidelines on sexually transmitted diseases: Syphilis.
Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/section. Accessed June 17,
2016.
35. Zetola NM, Klausner JD. Syphilis and HIV infection: An update. Clin Infect Dis. 2007;44:1222-
1228.
Available at: http://www.cdc.gov/std/stats13/syphilis.htm. Accessed June 21, 2016.
Available at https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-preven-
tion-and-treatment-guidelines/330/syphilis. Accessed September 1, 2016.
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10
HIV and Tuberculosis
Eric F. Egelund, PharmD, PhD, AAHIVE,
and Emily C. Huesgen, PharmD, BCACP, AAHIVP
INTRODUCTION
In 2015, the World Health Organization (WHO) announced that tuberculosis (TB),
an infection caused by Mycobacterium tuberculosis (MTb), is now the leading cause
of death worldwide due to an infectious disease, surpassing human immunodefi-
ciency virus (HIV).1 Among HIV-infected patients, TB is the most common opportu-
nistic infection and the most deadly, accounting for one in every three HIV-related
deaths in 2015.
The Centers for Disease Control and Prevention (CDC) guidelines recom-
mend treating TB and HIV concurrently to reduce mortality.2 However, managing
these two disease states simultaneously is challenging due to the possibility of
drug interactions, overlapping toxicities, immune reconstitution inflammatory
syndrome (IRIS), and poor patient adherence to complex drug regimens. Pharma-
cists can play an active role in managing drug interactions, treatment of IRIS, and
finding innovative ways to increase patient adherence.
EPIDEMIOLOGY
Approximately one-third of the world’s population is believed to be infected with
TB. Worldwide, WHO estimated 9.6 million new cases of active TB in 2014.1 Of
those new cases, 12% (1.1 million) were HIV-positive. An estimated 1.5 million
people died from TB in 2014; one-fourth of those were HIV-positive. The vast
majority of TB and HIV/TB cases occur in developing nations. Three-fourths of
cases of new persons co-infected with HIV/TB occurred in Africa, and there were
an estimated 480,000 cases of multidrug-resistant (MDR) TB. The WHO reports
that an estimated 43 million lives have been saved in the last 15 years due to effec-
tive diagnosis and treatment but emphasizes that TB remains a deadly worldwide
problem, especially in HIV patients.
In 2014, 9,421 cases of TB were reported in the United States.3 Foreign-born
persons accounted for 66% of those cases. Approximately 500 people die each year
due to TB. In the United States, 8.6% of HIV-infected patients are co-infected with
TB, the majority of cases also occurring in foreign-born persons. Ninety-one cases
of TB were MDR-TB. Since the early 1990s, an overall decline in TB, MDR-TB, and
patients co-infected with HIV and TB has continued; however, the rate of decline
has slowed in recent years. Additionally, an increase in the number of foreign-born
persons with TB and HIV/TB has increased each year since 1993.
203
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MICROBIOLOGY
MTb is an acid-fast, rod-shaped, obligate aerobe.4 Tissues with high oxygen concen-
trations, such as lung tissue, are ideal environments for the survival of MTb. Espe-
cially in immunocompromised hosts, MTb can spread to other organs. The cell wall
of MTb consists of a thick waxy coating, rich in lipids (primarily mycolic acids) and
peptidoglycan. The thick cell wall prevents destruction from lysosomal enzymes
and facilitates survival within macrophages. The cell wall structure also prevents
the penetration of many antibiotics. The waxy coating resists Gram staining; Ziehl-
Neelsen staining must be used to identify the bacteria. Two media are used to grow
MTb: Middlebrook’s medium, an agar-based medium, and Lowen-Jensen medium, an
egg-based medium. MTb replicates slowly (15 to 20 hours), and inhibitors to fast-
er-growing bacteria must be added to the media to prevent contamination. The
time for visual growth of colonies is 4 to 6 weeks for both media.
TRANSMISSION AND INFECTION CONTROL

MTb is transmitted via droplets that are expelled through the air by coughing
(sneezing, shouting, etc).2 Infection is related to the amount of bacilli within these
droplets. Infection occurs following the inhalation of droplets and their move-
ment through the respiratory tract to the alveoli. In most immunocompetent
individuals, the immune system prevents any further replication of MTb. Despite
the presence of tubercle bacilli in the body, these individuals are asymptomatic
and are not infectious. Immunologic test results, however, will be positive. These
individuals are considered to have latent TB infection (LTBI). Individuals unable
to prevent replication of MTb develop symptoms and can spread the disease to
others. They are said to have active TB.
Transmission of active TB is possible between patients with TB and health-
care workers in the healthcare setting; therefore, control measures should be in
place to mitigate transmission. The CDC recommends that a TB infection control
program consist of a three-tiered hierarchy of control measures: (1) administrative
measures, (2) environmental controls, and (3) the use of protective respiratory
equipment.2 Administrative measures refer to having procedures and personnel in
place to reduce exposure to TB patients. Such measures include not only managing
patients with TB but having a control plan, educating and training healthcare
workers on TB, and assigning persons to be in charge of TB infection control.
Environmental controls refer to the physical containment of the infection source
through the use of proper ventilation and airflow. Finally, the use of protective
respiratory equipment (e.g., masks) should be employed to reduce exposure to
infective droplet nuclei.
DIAGNOSIS OF ACTIVE TB
The classical signs of active TB typically include fatigue, night sweats, loss of appe-
titite, fever, and unexplained weight loss.2 Pulmonary TB is the most common form
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CHAPTER 10 HIV and Tuberculosis 205
of active TB, and symptoms may include a persistent cough (longer than 3 weeks)
with or without hemoptysis. In addition to recognizing symptoms, diagnosing TB
requires a thorough medical history to determine a history of exposure or infection.
The tuberculin skin test (TST), sometimes referred to as the Mantoux skin test or
blood test (interferon gamma release assay, or IGRA), may be performed to confirm
infection. Sputum samples (thick fluid from the lungs) are often collected for diag-
nostic purposes, sent to a laboratory, and examined under a microscope following
Ziehl-Neelsen staining. The presence of acid-fast bacilli from sputum microscopy,
in addition to clinical symptoms and exposure history, generally leads the clinician
to begin empiric treatment for TB disease.2 Of note, smear microscopy has been
shown to have a greater frequency of negative TB results in HIV-infected persons.5,6
Additionally, sputum smear microscopy is only about 50% to 60% sensitive and
can be difficult to procure in patients without a productive cough. A positive MTb
culture from a patient sample is needed for a definitive diagnosis. Culture results
can take up to 6 weeks. Negative cultures also do not necessarily rule out disease;
thus, clinicians must use their professional judgment in pursuing treatment.
Patients co-infected with HIV/TB may have a different clinical presentation
than patients infected solely with TB, which can make diagnosis challenging.7
The level of immunosuppression alters the progression of TB and impacts how the
patient presents clinically. In immunocompetent individuals (~CD4 count >350
cells/mm3), manifestations of TB parallel those observed in HIV-negative individ-
uals, primarily pulmonary TB. Symptoms include productive cough, fever, night
sweats, and weight loss. Radiographic findings often include upper-lobe infiltrates
and cavitation. In HIV-infected patients with low CD4 counts (<200 cells/mm3),
TB symptoms are sometimes referred to as “subclinical.” Cavitation typically is
absent and extrapulmonary sites, such as the lymph nodes and pleura, become
more involved. Lower-lobe infiltrates are more common radiographic presenta-
tions. It should be noted that more than one-fifth of chest radiographs may appear
normal; thus, clinicians must consider TB in a differential if symptoms are present
despite the lack of radiographic evidence.
DIAGNOSTIC TESTING FOR LTBI

As stated, two tests are used for diagnosing latent TB infection (LTBI): TST and
IGRA.8 The principle behind the TST involves injecting 0.1 mL of tuberculin-
purified protein derivative (PPD) into the dermis using the Mantoux technique,
which will produce a T-cell mediated delayed-type hypersensitivity reaction in
persons infected with MTb. An interpretation of the TST result by a trained health-
care worker is done 48 to 72 hours after placement and is based on the measure-
ment of the induration (not erythema) in millimeters. An induration ≥5 mm is
considered a positive result in HIV-infected patients. For accuracy, TST results must
be evaluated within 48 to 72 hours of placement. Patients who do not return to
clinic within the 72-hour window must be rescheduled for another TST placement.
Two IGRAs have been approved by the U.S. Food and Drug Administration
(FDA) for LTBI screening. The IGRA is a blood test that measures an individual’s
ERRNVPHGLFRVRUJ
immune reactivity to MTb by exposing blood samples to TB antigens. Infected

white blood cells will release interferon-gamma when mixed with the anti-
gens, producing a positive result. Both TST and IGRA tests can be used to screen
HIV-infected individuals for LTBI. Patients with positive TST or IGRA results
must be evaluated for active TB infection (screening for symptoms and a chest
radiograph) prior to starting LTBI treatment. Key differences between the two
tests are listed in Table 10-1.8
WHO SHOULD BE SCREENED FOR LTBI?

Treatment of LTBI in HIV-infected individuals significantly reduces the risk of reac-
tivation and progression to active TB infection by 62%.8,9 Baseline screening for
active and latent TB is recommended by the Department of Health and Human
Services (DHHS) for all individuals at the time of HIV diagnosis regardless of their
risk factors for TB exposure.
Additional LTBI testing is recommended for the following:
• Patients with advanced HIV disease (CD4 count <200 cells/mm3) and a
negative TST or IGRA test result should be rescreened for LTBI after initi-
ation of antiretroviral therapy (ART) and a subsequent increase in CD4
count to >200 cells/mm3.
• Annual screening for LTBI is recommended for individuals who are at
high risk for TB exposure (e.g., HIV-infected individuals, injection drug
users, immigrants from TB-endemic regions, close contact with persons
with active TB disease).
LATENT TB TREATMENT
HIV patients with LTBI are at an increased risk of progression to active disease,
with a 10% chance of activation each year LTBI remains untreated.8,9 The preferred
treatment of LTBI is isoniazid 300 mg daily (or 900 mg biweekly) for 9 months due
to its proven efficacy and limited toxicity in comparison to other antimycobacte-
rial agents. Although isoniazid generally is well tolerated, peripheral neuropathy
is a common side effect. To reduce the risk of peripheral neuropathy, isoniazid
should be given with pyridoxine 25 mg daily. Alternatively, a 12-week course of
TABLE 10-1. Differences in TST and IGRA Tests

Diagnostic Tests Specificity Limitations
TST 56%–95% 2 patient visits; cross-reactivity
with BCG vaccine and NTM
IGRAs 92%–97% More expensive

BCG: Bacillus Calmette-Guérin vaccine; IGRAs: interferon gamma release assays; LTBI: latent TB infection; NTM:
nontuberculosis mycobacteria; TST: tuberculin skin test
ERRNVPHGLFRVRUJ
once-weekly isoniazid 900 mg and rifapentine 900 mg may also be used in patients
receiving a raltegravir- or efavirenz-based regimen, although the regimen currently
must be administered via directly observed therapy (DOT), making it a more expen-
sive option. A daily regimen of rifampin or rifabutin for 4 months may also be used
in HIV-infected patients. However, the rifamycins typically are not recommended
due to their enzyme induction potential and subsequent interactions with HIV
medications; thus, isoniazid for 9 months is the preferred treatment.
Additionally, data from two large randomized trials (START and TEMPRANO)
suggest that ART initiation in HIV patients (with or without isoniazid for LTBI
treatment) can prevent active TB.9 The initiation of ART resulted in a decrease
in both HIV-associated illnesses (including TB) as well as a decrease in mortality,
regardless of CD4+ count. Importantly, no increase in adverse drug events was
seen with early initiation of ART.
ACTIVE TB TREATMENT
Ideally, treatment of active TB is for 6 months; however, CDC statistics (2010)
indicate that fewer than 20% of patients completed therapy within the 6-month
time frame (annual TB slide set available at www.cdc.gov). Additionally, treatment
may be extended in certain situations: pulmonary TB with a positive 2-month
sputum culture, or extra-pulmonary TB with bone and joint involvement, or
central nervous system involvement.2 The 2-month intensive phase consists of
isoniazid, rifampin, pyrazinamide, and ethambutol; the 4-month continuation
phase comprises only isoniazid and rifampin. Susceptibility testing is necessary to
determine if the patient is resistant to one or more of the first-line medications.
Unlike with many antibiotics, the length of treatment necessitates the close moni-
toring of adverse drug events (Table 10-2).2 The increased number of medications
may also lead to overlapping toxicity. For instance, hepatotoxicity is a potential
side effect seen with the first-line TB medications of rifampin, isoniazid, and pyra-
zinamide, and each antiretroviral class has members associated with drug-induced
liver toxicity (primarily, nonnucleoside reverse transcriptase inhibitors [NNRTIs]
and protease inhibitors [PIs]). Asymptomatic increases in alanine aminotransferase
(ALT) concentrations are common with TB medications and antiretrovirals (ARVs).
Monitoring should be increased, but treatment should continue unless ALT levels
are ≥5 times the upper limit of normal (ULN) or symptoms occur with ALT levels
≥3 times the ULN. Other overlapping side effects between first-line TB medications
and certain antiretrovirals include rash, gastrointestinal (GI) disturbances, hema-
tological abnormalities, and QT prolongation. When possible, clinicians should
switch ARVs to agent(s) with less risk of overlapping toxicity.
Second-line TB agents have even greater rates of toxicity (e.g., GI intolerance,
neurotoxicity) and are not as effective, necessitating a far longer duration of treat-
ment (years instead of months).2 For MDR-TB treatment, a later-generation fluo-
roquinolone (e.g., levofloxacin) is recommended as a part of treatment. Parenteral
agents such as capreomycin or an aminoglycoside (amikacin, kanamycin, strep-
tomycin) often are included as well. Additional medications may include ethion-
ERRNVPHGLFRVRUJ
TABLE 10-2. First- and Second-Line Medications Used to Treat Active

Tuberculosis1,2,8
Drug Standard Daily Dose Adverse Drug Effects Clinical Pearls
First-Line Medications
Isoniazid 5 mg/kg Hepatotoxicity, peripheral Food can reduce
neuropathy absorption; avoid
alcohol use
Rifampin 10 mg/kg Flu-like syndrome, Food can reduce absorption

hepatotoxicity,
red-orange secretions
Rifabutin 5 mg/kg Arthralgias, red-orange Exhibits concentration-

secretions, related toxicity
thrombocytopenia
uveitis
Rifapentine 10 mg/kg Flu-like syndrome, Food can increase

hepatotoxicity, absorption
red-orange secretions
Pyrazinamide 15–30 mg/kg Arthralgias, GI upset, Often causes increase in

hepatotoxicity uric acid concentrations
Ethambutol 15–25 mg/kg Optic neuritis May be discontinued

once susceptibility to
rifampin and isoniazid
are confirmed
Second-Line Medications
Aminoglycosides 15–20 mg/kg Nephrotoxicity, ototoxicity Warm compress can help
(Amikacin, with injection-site pain
Kanamycin,
Streptomycin) and
Capreomycin
Clofazimine 5 mg/kg Skin discoloration Skin discoloration can

last months after
discontinuing drug
Cycloserine 10–20 mg/kg CNS toxicity Divided dosing can

minimize CNS effects
Ethionamide 15–20 mg/kg GI upset, hypothyroidism Cross-resistance with

isoniazid is possible
Levofloxacin 750–1,000 mg GI upset, QT prolongation, Space administration

tendonitis of antacids and
multivitamins by
4–6 hours
(continued)
ERRNVPHGLFRVRUJ
TABLE 10-2. First- and Second-Line Medications Used to Treat Active

Tuberculosis1,2,8 (continued)
Drug Standard Daily Dose Adverse Drug Effects Clinical Pearls
Linezolid 10 mg/kg GI upset, lactic acidosis, Caution necessary
myelosuppression, with SSRIs and MAO
pancreatitis inhibitors
Moxifloxacin 400 mg GI upset, QT prolongation, Space administration

tendonitis of antacids and
multivitamins by 4–6
hours
Para-aminosalicylic 150 mg/kg GI upset, hypothyroidism, Available as granules,

acid steatorrhea which should not be
chewed; empty granules
can appear in stool
CNS: central nervous system; GI: gastrointestinal; MAO: monamine oxidase; SSRIs: selective serotonin reuptake
inhibitors
amide (or prothionamide), pyrazinamide, cycloserine, para-aminosalicyclic acid,

clofazimine, and linezolid.
DRUG INTERACTIONS
The most difficult aspect in treating TB/HIV is managing drug interactions, espe-
cially between the rifamycins and ARVs.10 The rifamycins are potent inducers of
the CYP enzyme family, in particular the CYP2C and 3A families, which accounts
for the metabolism of more than half of all drugs used clinically.11 The inclusion of
a rifamycin in TB treatment is necessary to reduce the time of treatment, because
treatment failure is higher in regimens lacking a rifamycin.12,13 The induction
potential of the three rifamycins used in treating TB are rifampin > rifapentine
> rifabutin.14 However, recent studies suggest that rifapentine’s potency, when
administered daily, equals or exceeds that of rifampin.15 Rifabutin is, therefore, the
rifamycin most often recommended for HIV/TB patients. Unfortunately, rifabutin
is a CYP3A4 substrate and susceptible to induction (or inhibition) itself. Addition-
ally, rifabutin is significantly more expensive than rifampin and is unavailable in
many resource-poor countries. A full review of drug interactions involving the TB
and HIV medications is beyond the scope of this chapter. Drug interactions most
likely to be seen in clinical practice are highlighted in Table 10-3.
Rifamycins and the Nonnucleoside Reverse Transcriptase Inhibitor

Rifampin (and rifapentine) reduce the area under the curve (AUC) of efavirenz
(a CYP2B6 substrate) by approximately 15% to 22%, although this varies based
on many factors (e.g., viral strain, CYP2B6 polymorphisms).17 The recommended
efavirenz dose of 600 mg daily does not necessarily need to be adjusted, but some
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TABLE 10-3. Selected Drug Interactions Between the Rifamycins and ART with the Expected Effect on ART Concentrations9,10,18-23
HIV Medication Rifampin Recommendation Rifabutin Recommendation Rifapentine (Once Weekly) Recommendation
Integrase Inhibitors
Dolutegravir DLT AUC ↓ 54% DLT 50 mg twice daily DLT AUC ↓ 5% RBN 300 mg daily Unknown Avoid
DLT Cmin↓ 72% DLT Cmin ↓ 30% co-administration
Elvitegravir/ Expected to significantly Avoid co-administration EVG AUC ↓ 21% Avoid Unknown Avoid
cobicistat reduce concentrations EVG Cmin ↓ 67% co-administration co-administration
RBN active metabolite
AUC ↑ 625%
Raltegravir RALT AUC ↓ 40% Avoid co-administration RALT AUC ↑ 19% RBN 300 mg daily RALT Cmin ↓ 12% Standard doses
RALT Cmin↓ 60% if possible. Use RALT Cmin ↓ 20% RALT AUC ↑ 71%
alternative agent (e.g.,
rifabutin)
NNRTIs
Efavirenz EFV AUC ↓ 22% EFV 600 mg once daily* RBN AUC ↓ RBN dose 450 or 600 EFV Cmin ↓ 15% Standard doses
EFV Cmin ↓ 25% mg per day EFV AUC ↓ 14%
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Etravirine Expected to significantly Avoid co-administration ETR Cmin ↓ 35% RBN dose 300 mg Unknown Avoid
reduce concentrations ETR AUC ↓ 37% if not used with co-administration
ritonavir-boosted PI
RBN AUC ↓ 17%
Nevirapine NVP AUC ↓ 20%–58% Avoid if possible, else No change Standard doses Unknown Avoid
200 mg twice daily co-administration
throughout treatment
(continued)

TABLE 10-3. Selected Drug Interactions Between the Rifamycins and ART with the Expected Effect on ART
Concentrations9,10,18-23 (continued)
HIV Medication Rifampin Recommendation Rifabutin Recommendation Rifapentine (Once Weekly) Recommendation
Rilpivirine RPV AUC ↓ 80% Avoid co-administration RPV AUC ↓ 46% Avoid Unknown Avoid
co-administration co-administration
NRTIs
Tenofovir disoproxil No significant change Standard doses None expected Standard doses TDF Cmin ↓ 13% Standard doses
fumarate TDF AUC ↓ 9%
Tenofovir Unknown Avoid co-administration Unknown Avoid Unknown Avoid
alafenamide co-administration co-administration
PIs
Atazanavir/r Significantly reduces AUC Avoid co-administration RBN ↑ significantly RBN 150 mg daily Unknown Avoid
despite ritonavir RBN 300 mg thrice co-administration
weekly
Darunavir/r Significantly reduces AUC Avoid co-administration RBN ↑ significantly RBN 150 mg daily Unknown Avoid
despite ritonavir co-administration
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RBN 300 mg thrice
weekly
Lopinavir/r Significantly reduces AUC Avoid co-administration RBN ↑ significantly RBN 150 mg daily Unknown Avoid
despite ritonavir RBN 300 mg thrice co-administration
weekly
ART: antiretroviral therapy; AUC: area under curve; Cmin: minimum or “trough” concentration; DLT: dolutegravir; ETR: etravirine; EFV: efavirenz; EVG: elvitegravir; NNRTI, nonnucleoside reverse
transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; NVP: nevirapine; PI: protease inhibitor; r: ritonavir; RALT: raltegravir; RBN: rifabutin; RIF: rifampin; RPV: rilpivirine; TDF:
tenofovir disoproxil fumarate
*Some clinicians recommend EFV 800 mg once daily in patients >60 kg.
(Source: Reprinted with permission from Egelund EF, Dupree L, Huesgen E, Peloquin CA. The pharmacological challenges of treating tuberculosis and HIV coinfections Expert Rev Clin Pharmacol.
2017; 10:213-223.)
have recommended increasing the dose to 800 mg daily in patients weighing

more than 60 kg.10 The recommended efavirenz dose of 600 mg daily does not
necessarily need to be adjusted, but some have recommended increasing the dose
to 800 mg daily in patients weighing more than 60 kg. However, recent studies
indicate that in patients co-treated with rifampin and efavirenz, efavirenz concen-
trations were more affected by factors other than weight, such as CYP2B6 geno-
type.19,20 Further, the studies indicate no difference in virological efficacy at 48
weeks between patients receiving efavirenz-based ART versus those co-treated with
efavirenz-based ART and rifampin. Despite these findings, rifampin does lower
efavirenz concentrations, and TDM should be considered when possible.
Rifabutin appears to have little effect on efavirenz concentrations but efavirenz,
a CYP enzyme inducer, decreases rifabutin’s AUC by approximately 37%; thus, it is
recommended to increase the rifabutin dose from the typical 300 mg to 450 mg to
overcome this reduction in drug exposure.17 Rifampin reduces nevirapine concen-
trations between 20% to 55% but may still be used if necessary.10 Rilpivirine and
etravirine, CYP substrates, are not recommended due to the potential reduction
in their concentrations. Nevirapine may be considered as an alternative but may
be less efficacious and possibly more toxic. If one needed to use nevirapine (e.g.,
a patient with a psychiatric disorder, efavirenz unavailability), then the lead-in
nevirapine dosing of 200 mg daily for 2 weeks is not required if the patient has
already been taking rifampin for at least 2 weeks; 400 mg should be used. In sum,
if using an NNRTI with the rifamycins, then efavirenz at standard dosing should
be the drug of choice; however, nevirapine can be considered as an alternative.
Rifamycins and the Nucleoside Reverse Transcriptase Inhibitors

Unlike the NNRTIs, the nucleoside reverse transcriptase inhibitors (NRTIs) are
not expected to have significant drug interactions with the rifamycins.10,12 The
NRTIs are not metabolized through the liver, with the exception of zidovudine,
which undergoes glucuronidation. Of note, tenofovir alafenamide is a substrate
of p-glycoprotein (Pgp), and co-administration with Pgp inducers may reduce
tenofovir alafenamide concentrations; therefore, concomitant administration
with a rifamycin is not recommended at this time.10,12
Rifamycins and the Protease Inhibitors

The most problematic drug interactions occur with the PIs, due to their ability
to inhibit CYP enzymes and create bidirectional interactions with rifabutin.10,12
Rifampin decreases the PIs an average of 75% and should not be used. Rifabutin
affects concentrations to a lesser degree and is the rifamycin of choice if an alter-
nate regimen cannot be used. However, the PIs can greatly increase rifabutin’s
concentrations. Therefore, rifabutin is recommended to be initiated at a 150-mg
dose once daily, or administered 3 times weekly at the standard 300-mg dose.9 It
should be noted that this recommendation differs from the rifabutin monograph,
which recommends a 75% reduction (i.e., 150 mg every other day) with boosted
PIs. However, there are case reports of acquired rifamycin resistance with this
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regimen in HIV/TB patients on boosted PIs. Finally, similar to rifampin, rifapentine

is not recommended with the PIs.9 In sum, in co-infected patients on a PI-based
regimen, rifabutin with an adjusted dose of 150 mg should be used in place of
rifampin. Therapeutic drug monitoring (TDM) of rifabutin is highly encouraged.
Rifamycins and the Integrase Inhibitors

Rifampin decreases raltegravir’s AUC by 40% and its trough by 61%.10,12 When
used concurrently, raltegravir should be dosed at 800 mg twice daily to account
for these reductions in concentrations. Rifabutin and once-weekly rifapentine
may be used with raltegravir with no dosing adjustments required. Dolutegravir
is partially metabolized through CYP3A4, and a reduction in dolutegravir concen-
trations occurs with rifampin and rifabutin.21 Dolutegravir should be administered
twice daily with rifampin without integrase inhibitor-resistant mutations; no dose
adjustment is necessary with rifabutin. Elvitegravir, a CYP3A4 substrate, is not
recommended to be co-administered with any of the rifamycins.22 Significant
reductions in elvitegravir’s trough (67%) were observed with rifabutin dosed at
150 mg.9,23 A subsequent study suggested that administering cobicistat 150 mg
twice daily with elvitegravir 150 mg (i.e., daily Stribild® plus an extra cobicistat
150 mg daily) and rifabutin 150 mg every 2 days could overcome this interaction,
but this approach is not typically feasible since cobicistat, although licensed as a
single agent (Tybost®), is generally not available.
THERAPEUTIC DRUG MONITORING

TDM may be defined as a method of guiding dosing adjustment using repeated
plasma concentrations of a specific drug. The goal of TDM is to achieve a prespec-
ified target concentration range for the purposes of improving clinical efficacy
and/or avoiding drug toxicity. The routine use of ARV TDM in HIV currently is not
recommended in U.S. treatment guidelines. However, in certain clinical situations
TDM should be considered: suspicion of nonadherence, suspected drug malab-
sorption, drug–drug or drug–food interactions, and when changes in physiology
can alter pharmacokinetics (e.g., pregnancy; impaired renal, hepatic, or gastric
function).
TDM can be particularly helpful in certain drug–drug interactions, such as
rifampin with efavirenz-based ART.24 TDM not only can elucidate rifampin’s induc-
tive effects but also low (or high) concentrations due to the interplay of induc-
tion, genotype, bioavailability, etc. TDM also is recommended when rifabutin is
co-administered with PIs (especially those boosted with ritonavir). Although rifab-
utin’s induction potential is approximately 60% less than that of rifampin, rifab-
utin can substantially reduce PI concentrations. Additionally, rifabutin is a CYP3A
substrate. PIs can increase rifabutin and its metabolite’s concentrations, resulting in
an increased risk of side effects, such as arthralgias, cytopenias, and anterior uveitis.
Malabsorption of the first-line TB drugs is not uncommon in certain disease
states, such as HIV. Several studies show a reduction in concentrations, particularly
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rifampin and isoniazid. In co-infected patients slow to respond to TB treatment,

TDM is strongly encouraged to determine malabsorption.25
Based on pharmacokinetic factors, the timing of blood samples differs between
TB medications and antiretrovirals.24 The AUC is the primary pharmacokinetic
parameter associated with efficacy for most TB medications; however, multiple
blood samples are required to calculate AUC, which is not feasible. Instead, a
2-hour blood sample (3 hours for rifabutin) captures the Cmax of the first-line, and
most second-line drugs. A second sample may be drawn at 6 hours (7 hours for
rifabutin) to determine if the patient is experiencing malabsorption or delayed
absorption. For ART, trough concentrations (prior to the next dose) typically
are used. A minimum 8-hour time frame and three blood draws, therefore, are
necessary to evaluate the concentrations of both TB medications and ART. Appro-
priate collection and shipping of samples is critical to successful interpretation of
concentrations. Health care personnel should be properly trained in sample collec-
tion to prevent errors. Additionally, patients, especially in a clinic setting, need to
be informed of the time involved.
INITIATING ART
In HIV-infected patients, the START and TEMPRANO trials demonstrated that
earlier treatment resulted in a reduction of serious acquired immunodeficiency
syndrome (AIDS)-defining illnesses, including TB and death.9 The optimal time
to initiate ART in HIV-infected patients with active TB has been debated for
many years. The CAMELIA, SAPiT, and STRIDE trials all showed a clear benefit to
starting HIV and TB treatment concurrently in patients with CD4 counts below
50 cells/mm3, where a significant reduction in mortality was observed. Based on
these trials, guidelines recommend initiating HIV treatment within 8 weeks of
TB treatment in those with a CD4 count greater than 50 cells/mm3.2,8 HIV/TB
patients with CD4 counts below 50 cells/mm3 should begin ART within 2 weeks
of initiating TB treatment. No trials involving MDR or extensively drug-resistant
TB co-infected patients have been conducted at this time; however, based on
retrospective studies and case series, many experts argue that ART should begin
within 2 to 4 weeks following the start of TB treatment. In all cases, it cannot be
overstated that patients must be properly informed of not only the benefits of
beginning therapy but the risks as well and that the HIV portion of treatment is
a lifelong commitment.
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME

One of the major concerns facing clinicians when initiating therapy is the poten-
tial occurrence of IRIS—the local and systemic inflammatory response—that can
occur following the initiation of ART.8 IRIS presents as either (1) a paradoxical
worsening of infection (e.g., TB) despite adequate treatment, or (2) an unmasking
of a new infection. Symptoms related to TB-associated IRIS can include fevers, a
ERRNVPHGLFRVRUJ
resumption of cough, abscesses, lymphadenopathy, respiratory distress, and sepsis

syndrome. Onset generally occurs within the first 4 to 8 weeks of beginning ART
but may occur at any time. The incidence of TB-associated IRIS ranges from 8 to
>40% in patients beginning ART following TB diagnosis. The wide range is due
to discrepancies between researchers’ definition of IRIS and how closely IRIS was
monitored. IRIS is more common in patients with low CD4+ counts (<50 cells/
mm3), greater severity of TB disease, and in the three trials mentioned previously
(CAMELIA, SAPiT, and STRIDE), when HIV therapy was initiated early, that is, less
than 30 days between the start of TB and HIV treatments. IRIS, thankfully, is rarely
fatal and often self-limiting when identified and properly managed. Both TB and
HIV treatment are continued unless IRIS symptoms are severe. Typically, using
nonsteroidal anti-inflammatory drugs can manage symptoms, or in more severe
cases, corticosteroids to provide pain relief and reduce inflammation.

The role of the pharmacist in treating TB/HIV patients undoubtedly varies among treat-
ment sites. Counseling patients on adverse drug events and monitoring relevant labora-
tory results is a key aspect of the pharmacist’s job. Additionally, the numerous drug inter-
actions may dictate dose adjustments or consideration of alternate regimens. Pharmacists
can aid in determining if TDM should be considered, and, if TDM is undertaken, the
interpretation of drug concentrations and subsequent dose recommendation. Interpreting
the results of susceptibility testing and subsequently tailoring the drug regimen based on
the results are areas in which pharmacists are adept.
The pharmacist is a great resource regarding not only TB or HIV medications but concom-
itant medications for other disease states. Nurses or physicians in the clinic setting may
be well versed in HIV or TB medications but lack knowledge regarding the drug interac-
tions and side effect profile of other classes of drugs, herbal products, inhalers, or over-
the-counter medications.
The high pill burdens taken by co-infected patients are associated with nonadherence.
Pharmacists are well trained to assist patients in identifying barriers to adherence and
simplifying regimens. One extension of adherence is DOT. In the United States, TB medi-
cations are commonly given via DOT, which has been shown to increase adherence and
reduce the incidence of drug resistance. DOT may also be used in other populations at risk
for nonadherence. For example, drug users with HIV have an increased risk of mortality
compared to nondrug users with HIV, primarily due to nonadherence. Methadone clinics
providing ARV DOT are one example of a co-located care center where pharmacists play a
central role due to their medication knowledge. Further, in MDR-TB patients the regimens
become even more complex and can include intramuscular or intravenous medications,
or more frequent dosing, posing a greater risk of nonadherence. Finally, helping patients
with insurance or co-pay assistance is another valuable service pharmacists can provide.
In sum, pharmacists can be vital in managing the combined disease states and provide a
great service to co-infected patients.
ERRNVPHGLFRVRUJ
KEY RESOURCES
• Acosta EP, Gerber JG. Position paper on therapeutic drug monitoring of antiretroviral
agents. AIDS Res Hum Retroviruses. 2002;18:825-834.
o Guide for clinicians in incorporating antiretroviral TDM in patient care.
• Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tubercu-
losis: An update. Drugs. 2014;74:839-854.
o Comprehensive overview of therapeutic drug monitoring in TB patients.
• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department
of Health and Human Services. Available at: https://aidsinfo.nih.gov/contentfiles/
lvguidelines/adultandadolescentgl.pdf.
o Evidence-based guidelines regarding the management of HIV infected persons.
Also, an excellent source for drug-drug interactions.
• Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guide-
lines for the prevention and treatment of opportunistic infections in HIV-infected
adults and adolescents: Recommendations from the Centers for Disease Control and
Prevention, the National Institutes of Health, and the HIV Medicine Association
of the Infectious Diseases Society of America. Available at: http://aidsinfo.nih.gov/
contentfiles/lvguidelines/adult_oi.pdf.
o Comprehensive guidelines on treating any opportunistic infection, including
TB, in HIV-infected patients.
• University of California, San Francisco. HIV InSite. Available at: http://hivinsite.ucsf.
edu/InSite?page=kb-05-01-06#S2X.
o This resource is a very comprehensive database maintained by the HIV experts at
the University of California San Francisco. Very useful for the latest information
on HIV epidemiology, testing, and drug interactions.
• Laboratories That Offer Therapeutic Drug Monitoring Services
o Hospital for Sick Children, Toronto, Canada. http://www.sickkids.ca/paediatri-
clabmedicinems/test-catalogue/therapeutic-drug-monitoring-tdm-listing.html
(for antiretrovirals and certain anti-infectives)
o Infectious Disease Pharmacokinetics Laboratory, University of Florida. http://
idpl.pharmacy.ufl.edu/ (for antimycobacterials, antifungals, antiretrovirals, and
others)
o National Jewish Health, Denver, CO. https://www.nationaljewish.org/for-profes-
sionals/diagnostic-testing/adx/diagnostic-lab-expertise/therapeutic-drug-moni-
toring (for antimycobacterials, antifungals, antiretrovirals, and others)
o Quebec Antiretroviral Therapeutic Drug Monitoring Program, Canada. https://
muhc.ca/quebec_tdm/dashboard (for antiretrovirals)
REFERENCES
1. Global Tuberculosis Report 2015. World Health Organization, 2015.
2. Centers for Disease Control and Prevention. Tuberculosis. Guidelines by Topic. Available at:
http://www.cdc.gov/tb/publications/guidelines/default.htm.
3. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2014.
Atlanta, GA: U.S. Department of Health and Human Services. Available at: https://www.cdc.gov/
tb/statistics/reports/2014/pdfs/tb-surveillance-2014-report.pdf. Accessed August 22, 2016.
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4. Todar K. Todar’s Mycobacterium tuberculosis and tuberculosis. In: Todar K, ed. Online Textbook
of Bacteriolog. Available at: http://textbookofbacteriology.net/tuberculosis.html. Accessed August
21, 2016.
5. Swaminathan S, Padmapriyadarsini C, Narendran G. HIV-associated tuberculosis: Clinical
update. Clin Infect Dis. 2010;50:1377-1386.
6. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: Epidemiology, diagnosis & manage-
ment. Indian J Med Res. 2005;121:550-567.
7. Selwyn PA, Alcabes P, Hartel D, et al. Clinical manifestations and predictors of disease progres-
sion in drug users with human immunodeficiency virus infection. N Engl J Med. 1992; 327:1697-
1703.
Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
Services. Available at http: //www.aidsinfo.nih.gov/ContentFiles/Adul- tandAdolescentGL.pdf.
Accessed June 27, 2016.
10. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis. Centers for Disease
Control. www.cdc.gov/tb/publications/pdf/tbhiv.pdf. Accessed May 27, 2016.
11. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene
expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103-141.
12. Regazzi M, Carvalho AC, Villani P, et al. Treatment optimization in patients co-infected with
HIV and Mycobacterium tuberculosis infections: Focus on drug-drug interactions with rifamy-
cins. Clin Pharmacokinet. 2014;53:489-507.
13. Nunn AJ, Jindani A, Enarson DA. Results at 30 months of a randomised trial of two 8-month
regimens for the treatment of tuberculosis. Int J Tuberc Lung Dis. 2011;15:741-745.
14. Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmaco-
dynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001; 40:327-341.
15. Winter H, Egizi E, Murray S, et al. Evaluation of the pharmacokinetic interaction between
repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult
subjects. Antimicrob Agents Chemother. 2015; 59:1219-1224.
16. Lopez-Cortes LF, Ruiz-Valderas R, Viciana P, et al. Pharmacokinetic interactions between
efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clin Pharmacokinet.
2002;41:681-690.
17. Weiner M, Benator D, Peloquin CA, et al. Evaluation of the drug interaction between rifabutin
and efavirenz in patients with HIV infection and tuberculosis. Clin Infect Dis. 2005; 41:1343-
1349.
18. Farenc C, Doroumian S, Cantalloube C, et al. Rifapentine once-weekly dosing effect on
efavirenz, emtricitabine and tenofovir pharmacokinetics [poster P-H1]. Conference on Retrovi-
ruses and Opportunistic Infections; 2014 March 3–6; Boston, Massachusetts.
19. Habtewold A, Makonnen E, Amogne W, et al. Is there a need to increase the dose of efavirenz
during concomitant rifampicin-based antituberculosis therapy in sub-Saharan Africa? The
HIV-TB pharmagene study. Pharmacogenomics. 2015; 16:1047-1064.
20. Manosuthi W, Kiertiburanakul S, Sungkanuparph S, et al. Efavirenz 600 mg/day versus efavirenz
800 mg/day in HIV-infected patients with tuberculosis receiving rifampicin: 48 weeks results.
AIDS. 2006;20:131-132.
21. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV inte-
grase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: Results
of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013;62:21-27.
22. Ramanathan S, Wang H, Stondell T, et al. Pharmacokinetics and drug interaction profile of cobi-
cistat boosted-EVG with atazanavir, rosuvastatin or rifabutin. 13th International Workshop on
Clinical Pharmacology of HIV Therapy. April 16–18, 2012. Barcelona. Abstract: O_03.
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23. Stribild [package insert]. Foster City, CA: Gilead Sciences, Inc.; August 2012.
24. Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: An
update. Drugs. 2014; 74:839-854.
25. Holland DP, Hamilton CD, Weintrob AC, et al. Therapeutic drug monitoring of antimyco-
bacterial drugs in patients with both tuberculosis and advanced human immunodeficiency virus
infection. Pharmacotherapy. 2009;29:503-510.
ERRNVPHGLFRVRUJ
SECTION III: Primary Care and
Special Populations with HIV
Section Editor: Jennifer M. Cocohoba, PharmD,
MAS, BCPS, AAHIVP
Chapter 11: HIV Primary Care

Jennifer M. Cocohoba and Betty J. Dong
Chapter 12: Neuropsychiatric Disorders,

Mental Health, Pain, and Substance Use
Jennifer E. Thomas and Joshua Caballero
Chapter 13: Care of the Transgender

Patient
Bryan M. Bishop
Chapter 14: Women’s Health

E. Kelly Hester
Chapter 15: Pediatric HIV Infection

Kathleen K. Graham and Ana M. Puga
Chapter 16: HIV and Cancer

Karim Ibrahim and Alison Yi Jin Wong
Chapter 17: Transplant and HIV

Melissa Badowski, Sarah E. Pérez, and Elizabeth
Hetterman
Chapter 18: Care Transitions for

Persons Living with HIV
Michelle M. Foisy
219
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ERRNVPHGLFRVRUJ
11
HIV Primary Care
Jennifer M. Cocohoba, PharmD, MAS, BCPS, AAHIVP,
and Betty J. Dong, PharmD, FCCP, FASHP, FAPhA, AAHIVP
INTRODUCTION
Human immunodeficiency virus (HIV) disease can be controlled with timely
antiretroviral initiation and high adherence to therapy. Because HIV is now
managed as a chronic disease, most clinicians have broadened their care focus
to include management of other chronic comorbid conditions, and some clinics
provide HIV treatment plus primary care services in a medical home model. The
goal of this chapter is to provide the practicing pharmacist with guidance on
selected important primary care topics related to the care of HIV-infected persons.
THE INITIAL PRIMARY CARE VISIT WITH AN HIV+ PATIENT

The HIV Medicine Association and Infectious Diseases Society of America guide-
lines outline important elements of the initial visit.1 It is important to obtain a
complete history on any HIV+ patient entering or transferring care. The pharma-
cist, other clinicians, mental health professionals, and psychosocial support staff
should gather these history elements to ensure coordinated documentation in the
patient’s medical record.
The general medical history should include:
• Past and present medical history including family history of common
chronic conditions such as cardiovascular disease, mental health condi-
tions, or cancer.
• Prior surgical history and major hospitalizations; these may prove
helpful for understanding the course of the disease.
• Mental health history: presence of depression, anxiety, or other psychi-
atric conditions, past and current experience with therapy, case manage-
ment, or other mental health services.
• Social history: prior cities lived in and history of travel (to assess
patient’s risk for regional infections such as coccidioidomycosis and
histoplasmosis); immigration/refugee status (if appropriate); and
history and current use of illicit substances, tobacco, and alcohol. Other
elements such as HIV disclosure status, current housing situation,
insurance, employment, social support, and food insecurity may provide
useful insight into potential antiretroviral adherence barriers.
221
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• Sexual history: gender identity, gender of partners (men, women, both),

number of current partners and number of partners over the last 12
months, sexual practices (vaginal/penile, anal, oral), use of protection,
HIV status or known risk factors of partners, and history of sexually
transmitted diseases.
• A baseline physical examination and review of systems.
Patient’s HIV-specific medical history should include:
• Date and/or year of HIV and/or acquired immunodeficiency syndrome
(AIDS) diagnosis with CD4+ and viral load at diagnosis, if known.
• Lowest CD4+ cell count (nadir).
• Mode of HIV transmission (if known) and risk factors for transmission.
• History of any opportunistic infections and AIDS-defining conditions.
• For those who have been treated with antiretroviral therapy (ART), it is
important to obtain information about the dates of treatment, regi-
mens used, dosages and formulations used, reasons for discontinuation,
adverse effects, and any related resistance tests performed. Copies of all
resistance tests results should be obtained if possible.
Baseline labs should include:
• HIV diagnostic testing (for inclusion in patient’s chart)
• HIV viral load and CD4+ cell count
• Complete blood count with differential
• Comprehensive metabolic panel, including serum creatinine and fasting
blood glucose
• Fasting lipid panel
• Liver function tests
• Viral hepatitis serologies
• Urinalysis with protein
• Sexually transmitted infections screening: syphilis, gonorrhea, and chla-
mydia
• Toxoplasmosis immunoglobulin (IgG)
• Anti-cytomegalovirus (CMV) IgG (may be of limited value in those who
used intravenous [IV] drugs, or in men who have sex with men [MSM] as
these populations are assumed to screen positive)
• Purified protein derivative (PPD) or interferon gamma release assay (e.g.,
Quantiferon-TB® or T-spot), and/or chest x-ray to screen for tuberculosis
• HLA-B*5701 screening for risk of abacavir hypersensitivity (not neces-
sary if the patient is currently on an abacavir-containing regimen and
has had no history of allergic reaction)
• Baseline antiretroviral resistance testing if the patient is not currently on
antiretrovirals or if they are on ART but not virologically suppressed
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CHAPTER 11 HIV Primary Care 223
The initial visit is also an opportunity to address the patient’s communication

preferences:
• preferred name
• language preference
• best contact information (phone and address)
• ability of healthcare providers to leave a message on phone voicemail
• names/contact information for other healthcare providers and specialists
The pharmacist plays an instrumental role in the care of HIV+ patients by
taking a thorough medication history. Information about the patient’s pharmacies
used, prescription drug insurance, allergies and intolerances, current prescription
medications and adherence to those, use of over-the-counter medications, herbal
medications, and dietary supplements should be carefully recorded in the patient’s
record and updated on a regular basis to assess for potential drug–drug interac-
tions. When taking the medication history, pharmacists can encourage patients,
whenever possible, to utilize a single pharmacy for obtaining their medications.
HEALTHCARE MAINTENANCE
Routine Laboratory Tests

For patients not taking ART, CD4+ cell counts should be drawn every 3 to
6 months. For patients on ART, CD4+ cell count and HIV viral load should be
drawn every 3 to 6 months; this interval may be extended for persons stable
on therapy.2 The Department of Health and Human Services (DHHS) guidelines
suggest monitoring every 3 to 6 months until CD4+ reaches 300 cells/mm3;
if CD4+ remains >300 and viral load remains suppressed for at least 2 years on
ART, CD4+ cell count monitoring may be extended to every 12 months. Similarly,
International Antiviral Society (IAS)-USA guidelines suggest monitoring every
3 to 4 months until CD4+ counts reach 350; if above 350 and virally suppressed
for a year, monitoring intervals may be extended to every 6 months.3 Both IAS
and DHHS guidelines concur that if CD4+ counts remain persistently above
500 cells/mm3 and virus is consistently suppressed on ART, CD4+ monitoring
becomes optional. For more resource-limited settings, a study conducted in the
TREATASIA cohort suggests that CD4+ and viral load measurements drawn every
12 months were adequate for clinical management in patients who had a history
of suppressed viral load and CD4+ cell counts >250 cells/mm3.4 In stable patients
established on ART, routine laboratory tests such as comprehensive metabolic panel,
renal function assessment, liver function tests, hemoglobin A1c, fasting glucose,
and lipid panel may be drawn semi-annually to annually or as clinically indicated.
Laboratory tests should be drawn more frequently in patients who recently
started or changed antiretrovirals. Depending on the elements of the ART regimen,
a clinician may wish to assess renal function, liver function, and other potential
markers of toxicity 2 to 4 weeks after initiation of the new regimen. HIV viral load
should be monitored 4 to 8 weeks after starting or changing therapy.
ERRNVPHGLFRVRUJ
Immunizations in HIV Infection

Immunogenicity appears somewhat lower and shorter-lived in HIV-infected persons
compared to the noninfected population.5 In general, HIV-infected persons and
their household contacts should not receive live, attenuated vaccines unless the
benefit outweighs the risk. Because vaccine responses may be suboptimal, espe-
cially if immunocompromised (e.g., CD4 counts ≤200 cells/mm3; CD4 <15%), it
is reasonable to first try to improve immune responsiveness and viral suppression
with ART before starting immunizations. If immunizations are administered during
CD4 decline or before immunologic recovery and postvaccination titers are subop-
timal, then repeat immunizations after immunologic recovery may be warranted.
Standard inactivated vaccinations are recommended and should be kept up-to-
date. These include influenza; pneumococcal 13 valent conjugate vaccine (PCV13)
and polysaccharide vaccine (PPSV23); tetanus and diphtheria (Td) boosters every
10 years; substitute tetanus, diphtheria, and pertussis (Tdap) once; and human
papillomavirus (HPV).6
Vaccination against HPV is recommended for all HIV-infected adolescents
aged 11 or 12 years and up to age 26 if previously unvaccinated:
• Some experts also recommend vaccination in older MSM.
• Three formulations are available to be administered at 0, 1 to 2, and 6
months: the 9 valent, bivalent, and quadrivalent.
• The 9 valent may be preferable because it provides greater HPV coverage
against genital warts although the Advisory Committee on Immuniza-
tion Practices (ACIP) recommends any vaccine in HIV-infected females
and the 9-valent and quadrivalent vaccines in HIV-infected males.
All HIV-infected patients regardless of CD4 counts should receive vaccination
against Streptococcus pneumoniae:
• In general, patients should receive one dose of the PCV13 followed by
the PPSV23 (preferable if CD4 count is >200 cells/mm3) at least 8 weeks
later.
• Revaccination is subsequently performed with PPSV23 at least 5 years
after the initial PPSV23 dose.
• If PPSV23 was given first, administer PCV13 at least 1 year after the
PPSV23. Administer a second dose of PPSV23 at least 8 weeks after
PCV13 and at least 5 years after the first dose of PPSV23.
Certain live vaccines can be safely administered in children and adults without
severe immunosuppression (e.g., CD4 counts <200 cells/mm3 or CD4 percentage
<15%):
• Adults without a history of MMR immunization or evidence of measles,
rubella, or mumps immunity should receive two doses of MMR at least
28 days apart, unless they have severe immunosuppression.
• Two doses of varicella vaccine, administered 3 months apart, is recom-
mended in HIV-infected adults and adolescents with CD4 cell counts
ERRNVPHGLFRVRUJ
≥200 cells/mm3 born after 1979 or who do not show immunity (anti-
varicella IgG antibody levels). Varicella vaccine should be avoided in
those with severe immunosuppression.
• Rotavirus vaccination is not contraindicated, and dosing recommenda-
tions are similar to those for HIV-negative infants.
• Yellow fever vaccine can be administered, if indicated, to HIV-infected
patients with CD4 cell counts ≥200 cells/mm3.
• Live, intranasal influenza vaccines are contraindicated in HIV-
infected patients.
• Zoster is also contraindicated in those with severe immunosuppression
but can be considered in those aged 60 years or older with CD4 counts
>200 cells/mm3.
Immunity against hepatitis B and hepatitis A are also recommended:
• The hepatitis B vaccine series containing 20 mcg antigen (HBsAg) should
be administered at baseline, 1, and 6 months following the first dose to
nonimmune patients.
• Hepatitis B vaccine containing 20 μg HBsAg combined with HepA
vaccine (Twinrix), 3-dose series, can also be used for HIV-infected
patients aged ≥12 years.
• One to 2 months after completing the vaccine series, a postvaccination
anti-HB concentration of >10 mIU/mL ensures immunity.
• Administration of a second HBV series is appropriate if patients do not
respond to an initial vaccine series.
• Some experts recommend double-dose hepatitis vaccinations (40 mcg
antigen) for HIV-positive persons, especially if not responsive to the
initial vaccine series.
• In addition, hepatitis A vaccination is recommended in MSM, injection
drug users, hepatitis B and hepatitis C co-infected persons, or those with
chronic liver disease if not already immune.
HIV infection is a specific indication for meningococcal vaccines (Menactra® or
Menveo®). Meningococcal outbreaks have been reported in New York City, Los
Angeles, and San Francisco especially in MSM or those individuals in close contact,
which includes kissing, sharing water bottles, sharing eating or drinking uten-
sils, sharing cigarettes, or being within a 3-foot distance for 8 hours or more. For
HIV-positive persons:
• Administration of a two-dose meningococcal conjugate vaccine series
of MenACWY: quadrivalent (protects against serogroups A, C, W, and Y)
is recommended with the second dose administered 2 months or more
after the first dose.
• The polysaccharide meningococcal vaccine (MPSV4, Menomune) is
not preferred because it is expected to be suboptimal in HIV-infected
individuals.
• There are currently no ACIP recommendations regarding the use of
Group B vaccine at this time.
ERRNVPHGLFRVRUJ
MANAGEMENT OF COMMON CHRONIC COMORBID

CONDITIONS IN HIV+ PATIENTS
Widespread use of effective ART has resulted in an aging HIV-positive population
that is now facing increases in serious non-AIDS-related events. Various cohort
studies have found increased CD4+ cell counts and rates of viral suppression
associated with a rise in the number of chronic comorbid conditions in patients.
Compared to their age-matched HIV-negative counterparts, significant increases
in respiratory diseases (chronic obstructive pulmonary disease [COPD], asthma,
pneumonias), metabolic syndrome (insulin resistance, dyslipidemia, abdom-
inal obesity), thyroid disturbances, renal impairment, osteopenia/osteoporosis,
neurocognitive impairment, atherosclerosis, and cardiovascular disease have been
observed in patients with HIV.
Hypertension and HIV

The prevalence of hypertension (HTN) in HIV-infected individuals ranges from
4% to 54%.7 Risk factors for HTN are similar to those of HIV-negative persons (e.g.,
older age, male gender, African American race, obesity, history of previous cardio-
vascular [CV] events, chronic kidney disease, positive family history, diabetes,
dyslipidemia). Several cohort studies such as the Data Collection on Adverse Events
of Anti-HIV Drugs (DAD) and Multicenter AIDS Cohort Study (MACS) found
that using ART for more than 2 years increased the risk of systolic and diastolic
blood pressure elevations.8,9 Blood pressure treatment goals are similar to those
for the noninfected population. Antihypertensive agents such as diuretics, angio-
tensin-converting enzyme inhibitors (ACEs)-I, and angiotensin-receptor blockers
(ARBs) may be preferable due to their low interaction potentials with ART. Poten-
tial drug interactions with cobicistat or ritonavir-boosted protease inhibitors and
some nonnucleoside reverse transcriptase inhibitors (NNRTIs) with antihyperten-
sive agents that are CYP450 3A4 or 2D6 substrates (e.g., calcium channel blockers,
beta blockers) should be recognized. No interactions with unboosted integrase
inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) are anticipated.
Cardiovascular Disease and HIV

HIV-infected persons have a greater prevalence of dyslipidemia (70% to 80%),
earlier incidence and progression of coronary heart disease/atherosclerosis, and
a nearly 2-fold increased risk for myocardial infarction (MI) compared with un-
infected persons. The risk of heart failure was 1.8-fold higher in HIV-infected
persons compared to matched HIV-negative persons.10 A meta-analysis of 11 heart
failure studies found a prevalence of 8.3% for systolic dysfunction and 43.4%
for diastolic dysfunction.11 Preexisting cardiovascular disease (CVD) risk factors,
persistent inflammation from low-level viremia, and ART, especially following
prolonged exposure to protease inhibitors (PIs) (e.g., lopinavir/ritonavir),
all contribute to this accelerated and increased risk for CVD in HIV infection.
ERRNVPHGLFRVRUJ
However, the association with abacavir (ABC) remains controversial with several
observational studies finding an increased risk of MI and CV events while others
(e.g., meta-analysis and industry-sponsored) finding no risk.12 A study channeling
bias has been suggested since many ABC users avoid tenofovir disoproxil fumerate
(TDF) due to existing renal dysfunction, which is also a CVD risk factor. Positive
studies found that ABC-induced CVD risks are not immediate but accumulate with
increased duration of use longer than 3 years. Increased vascular inflammation,
endothelial dysfunction, and platelet reactivity have all been implicated as poten-
tial mechanisms because ABC does not cause insulin resistance. In patients with
high CVD risk, tenofovir alafenamide (TAF) can be a viable alternative to ABC and
TDF in those with CrCl greater than 30 mL/min. In those with more severe renal
dysfunction, ABC or no NRTI therapy can be considered.
Increased total cholesterol, low-density lipoprotein (LDL) cholesterol,
high-density lipoprotein (HDL) cholesterol, and triglycerides, are common after
more than a year of ART use (Table 11-1). Negative effects on the lipid profile have
been observed primarily with boosted PIs, efavirenz, cobicistat-boosted elvitegravir,
ABC, and TAF. However, significant improvements in HDL cholesterol are often
reported with efavirenz (17%) and nevirapine (21%). Changing from an efavirenz-
based regimen to newer NNRTIs such as etravirine or rilpivirine is also associated
with improvements in cholesterol and triglyceride values. About 50% of subjects
receiving PIs develop a 20% increase in triglycerides, total cholesterol, and LDL
within 12 weeks after starting therapy. A systematic review of studies showed that
the use of PIs, especially lopinavir/ritonavir, was associated with increased levels
of total cholesterol (36 [75%] of 48 studies), triglycerides (35 [73%] of 48 studies),
and LDL (12 [100%] of 12 studies).13 Ritonavir-boosted atazanavir and darunavir
have similar impact and less potential for lipid abnormalities compared to other
PIs.14 Conversely, TDF but not TAF has been associated with a beneficial effect on
lipids. Switching from an ABC to a TDF-based regimen or switching from a PI to
an ABC-containing regimen is usually associated with an improved lipid profile
(total cholesterol, LDL cholesterol, and triglycerides) and a less atherogenic LDL
profile. The unboosted integrase inhibitors dolutegravir and raltegravir appear to
have neutral effects on the lipid profile.
Prompt correction of lipid abnormalities is mandatory to reduce the poten-
tial consequences of premature coronary heart disease. Two double-blind, place-
bo-controlled trials among HIV-infected persons with LDL cholesterol <130 mg/dL
found significant reductions in inflammation markers and CVD risk using atorvas-
tatin and rosuvastatin. Further data will be forthcoming from REPRIEVE (Random-
ized Trial to Prevent Vascular Events in HIV; http://www.reprievetrial.org/) that
will randomize 6,500 HIV-infected persons to pitavastatin or placebo and followed
for primary cardiac clinical endpoints.
The prevalence of cigarette smoking ranges in studies as high as 40% and is
higher in HIV-positive persons compared to the general population. Smoking is
associated with a two-fold increase in mortality from non-AIDS malignancies (e.g.,
lung cancer) or CVD (MI, strokes) that increases with age and pulmonary disease
ERRNVPHGLFRVRUJ
TABLE 11-1. ART-Induced Mean Lipid Changes (mg/dL) from Baseline to

48 Weeks (Selected Studies)
Total LDL HDL
Cholesterol Cholesterol Cholesterol Triglycerides Comments
Nucleoside Reverse Transcriptase Inhibitors
Tenofovir ↓ 18.4 ↓ 9.5 ↓ 2.97 ↓ 29.8 mg/dL Overall favorable lipid
Disoproxil lowering
Fumarate15
Tenofovir ↑ 30# ↑ 17 ↑ 7## ↑ 19 Comparative study;

Alafenamide/ both combined with
Emtricitabine**16 elvitegravir/cobicistat
Tenofovir
Disoproxil
Fumarate/ ↑ 17# ↑ 11 ↑ 3## ↑8
Emtricitabine **
Abacavir**17 ↑ 34 ↑ 13 ↑9 ↑ 25 Compared with TDF/FTC

+/− EFV or ATV/r
(p ≤0.05)
Nonnucleoside Reverse Transcriptase Inhibitors

Efavirenz18 ↑ 24.1–30.5 ↑ 13.1–17 ↑ 8–10.4 ↑ 12.4–18.6 Dyslipidemia >> other
NNRTI
Rilpivirine19 ↑3 ↓ 0.77 ↑4 ↓ 6.9 Compared to efavirenz

(p <0.05)
Protease Inhibitors: Highest Risk for Dyslipidemia

Ritonavir for ↑ by 10% ↑ by 16% ↓ 5% ↑ by 26%
boosting
Atazanavir/ ↑ 13.1 ↑ 3.7 ↑ 4.6 ↑ 15.9 ATV/r similar to DRV/r

Ritonavir20,21 ↑ ATV/r >ATV/c for TC/TG#
Darunavir/ ↑ 15.3 ↑ 6.1–15.2 ↑ 2.2 ↑ 15.2–33.1 DRV/r similar to ATV/r

Ritonavir22
Lopinavir/ ↑ 29–34 ↑ 15.5 ↑ 3.5–8.8 ↑ 62.6 ↑ TG# >> ATV/r or DRV/r

Ritonavir22
Integrase Inhibitors: Least Negative Lipid Effects

Dolutegravir* ↑ 9.9 ↑ 4.8 ↑ 3.6 ↑ 8.7 TC/HDL −0.1. Neutral
impact
Raltegravir23 ↑9 ↑ 3.3 ↑ 2.7 ↑ 10 Compared with

dolutegravir, similar
(continued)
ERRNVPHGLFRVRUJ
TABLE 11-1. ART-Induced Mean Lipid Changes (mg/dL) from Baseline to

48 Weeks (Selected Studies) (continued)
Total LDL HDL
Cholesterol Cholesterol Cholesterol Triglycerides Comments
Elvitegravir/ ↑ 9.7–14.9 ↑5 ↑ 23 Combined with TDF/FTC
Cobicistat16
**Median values.
#
p <0.05 but NS @48 weeks.
*Pooled data from Spring 1, Spring 2, Single, and Flamingo studies.
ART: antiretroviral therapy; ATV/c: atazanavir/cobicistat; ATV/r: atazanavir/ritonavir; DRV/r: darunavir/ritonavir; EFV:
efavirenz; HDL: high-density lipoprotein; LDL; low-density lipoprotein; NNRTI: nonnucleoside reverse transcriptase
inhibitor; TC: total cholesterol; TDF/FTC: tenofovir disoproxil fumarate/emtricitabine; TG: triglyceride
(pneumonia, COPD) in HIV-infected persons receiving ART. The life expectancy of

smokers was on average 8 years less than that of nonsmokers compared to 3 years
from HIV-related factors.24
In summary, HIV-positive persons are at higher risk of CVD. Responsible causes
are unclear but may include genetics, older age, higher presence of traditional risk
factors, ART-related toxicities, and persistent inflammation (e.g., elevated IL-1β,
IL-6, TNF-α) despite complete virologic suppression and immunologic recovery on
ART.25 Clinicians should consider the following cardioascular health recommen-
dations:
• A baseline and routine risk assessment for major CV risk factors (ciga-
rette smoking, hypertension, HDL cholesterol <40 mg/dL, family history
of premature coronary heart disease, and age >45 years for men and
>55 years for women, insulin resistance/diabetes, obesity) should be
conducted in all HIV-infected persons.
• An estimate of the 10-year risk of heart attacks or death should be
assessed using the atherosclerotic cardiovascular disease risk algorithm
(ASCVD) scoring.26 Neither the ASCVD risk calculator nor the Fram-
ingham risk equation accounts for HIV as a potential risk factor for CVD,
and both of these may be less accurate in predicting CVD events in HIV+
persons. The DAD score may be a more accurate predictor of CVD events
in HIV populations, although this score is not yet widely used in clinical
practice.27
• Fasting lipids should be measured at baseline and then 3 to 6 months
after starting ART or after 1 to 2 months if baseline lipids, especially
triglycerides, are abnormal.
• Patients should be evaluated for concomitant lifestyle factors that
increase inflammation. If appropriate, implement lifestyle interven-
tions, such as smoking cessation (an important role for pharmacists),
ERRNVPHGLFRVRUJ
increasing regular aerobic exercise, weight reduction if obese (defined as

a body mass index [BMI] at or above 30), dietary changes to reduce fats,
normalizing blood sugar, alcohol restriction, and elimination of meth-
amphetamine use.
• Treatment of concomitant viral infections (e.g., hepatitis B virus [HBV],
hepatitis C virus [HCV], herpes) may also reduce inflammation.
• Addition of statins (e.g., rosuvastatin, low-dose atorvastin) may reduce
immune activation and development of aortic plaque.28 Avoid simvas-
tatin and lovastatin due to the risk of serious drug interactions with ART.
The 2014 American College of Cardiology/American Heart Association
guidelines recommend statin therapy for the following groups29:
• People without CVD who are 40 to 75 years old and have a 7.5% or
higher risk of having a heart attack or stroke within 10 years.
• People with a history of a CV event (heart attack, stroke, stable or
unstable angina, peripheral artery disease, transient ischemic attack,
or coronary or other arterial revascularization).
• People 21 and older who have LDL cholesterol levels of 190 mg/dL
or higher.
• People with type-1 or type-2 diabetes who are 40 to 75 years old.
• Omega 3 fatty acids at 3 g given daily to twice daily can reduce
triglycerides by 46%. For triglyceride levels >500 mg/dL, fenofibrate or
gemfibrozil is appropriate.
• For patients with elevated LDL cholesterol >160 mg/dL and triglyceride
<400 mg/dL, dual therapy with fibric acid derivatives and statins is
preferred.
• In the setting of hyperlipidemia, changing ART should be considered,
if feasible. Unboosted integrase inhibitor-based regimens may be more
forgiving of lipid abnormalities and CV risks than PI, NNRTI, or NRTI,
but further confirmation is required.
Thyroid Dysfunction and HIV

Overt thyroid disease has been reported in 1% to 3% of HIV-infected persons
although thyroid laboratory abnormalities may occur in up to 30% to 40%,
especially in those with AIDS, opportunistic infections of the thyroid gland, and
weight loss.30,31 Thyroid abnormalities may include a low serum reverse triodo-
thyronine (T3) levels with normal T3 levels early in disease and isolated low
serum free thyroxine (FT4) levels later. The exact cause of these laboratory abnor-
malities is unclear, but no thyroid treatment is indicated because the thyroid-
stimulating hormone (TSH) level is usually normal and pituitary dysfunction is
unlikely. Although older reports identify stavudine as causing thyroid dysfunc-
tion, it is more likely that immune reconstitution rather than a specific ART is
responsible. Immune reconstitution may be responsible for the 2-fold higher
prevalence of subclinical and clinical hypothyroidism in HIV compared to HIV-
negative persons and also the 4-fold higher prevalence of Graves’ hyperthyroidism
ERRNVPHGLFRVRUJ
(3% in women and 0.2% in men) compared to the HIV-negative population. In one
retrospective UK study, the average time of onset of Graves’ disease was 17 months
(range 8 to 33 months) after starting ART.32 Despite this increased risk, there is
no specific guidance for management of hypothyroidism and hyperthyroidism in
HIV-infected individuals. Clinicians should generally follow the same treatment
guidelines used for HIV-negative persons. Hypothyroidism has been reported with
the co-administration of levothyroxine (T4) and ritonavir, indinavir, or lopinavir/
ritonavir due to increased T4 elimination from induction of T4 glucuronidation.
Close monitoring of thyroid function tests is recommended, and an increase in T4
dose may be warranted. At this time, there are limited data to recommend routine
thyroid screening in HIV infection.
Diabetes and HIV

Estimated diabetes mellitus (DM) prevalence in HIV-infected persons varies from
3% to 14% depending on the biomarker used to define diabetes and the diversity
of the sampled cohort.33 HIV-infected persons who develop diabetes have a further
magnified risk of developing organ complications such as CVD, chronic kidney
disease, and peripheral neuropathy. The predominant factors associated with
development of diabetes in HIV-infected persons are the traditional risk factors
such as race, obesity, genetics, and presence of comorbid conditions such as hepa-
titis C. Postulated HIV-specific risk factors for diabetes are related to the impact of
the virus or the impact of ART on the body. Inflammation caused by circulating
HIV and effects of the virus on the liver can affect glucose processing and insulin
sensitivity. The DAD study found that cumulative exposure to ART increased the
relative risk of developing diabetes to 1.11 per year (95% CI 1.07–1.15, P <0.0001),
after adjustment for confounding factors. The NRTI thymidine analogs stavu-
dine, zidovudine, didanosine, and the PI indinavir were associated with incident
diabetes. For the NRTIs, the postulated mechanism is via mitochondrial toxicity.34
These ART components are essentially no longer used in the United States, and the
DAD diabetes analysis did not include more modern ART; therefore, the magni-
tude of risk that newer drugs pose in raising diabetes is less clear. PIs have been
associated with changes in peripheral insulin sensitivity, inhibition of the GLUT4
glucose transporter, and impaired β-cell function.
The American Association of Clinical Endocrinologists (AACE) and the Amer-
ican Diabetes Association (ADA) guidelines dictate standards of care for all persons
living with diabetes.35,36 There have been no specific studies that compare effi-
cacy of different diabetes treatments in the setting of HIV, and guidelines for the
general population can be applied to the care of HIV-infected persons.
Key considerations for diabetes screening and treatment in HIV-positive
persons are listed here:
• There is no preferred screening tool for diabetes in HIV. Monitoring for
glucose abnormalities is recommended at entry to care using either a
fasting glucose or a hemoglobin A1c (HbA1c). For HbA1c, HIV primary
care guidelines recommend using 5.8% as the threshold value for
ERRNVPHGLFRVRUJ
screening. Both HIV primary care guidelines and the ADA recommend
an A1c goal of <7%, while the AACE guidelines recommend a goal of
<6.5%.
• HIV primary care guidelines suggest screening for diabetes every 6 to 12
months, as opposed to the every 3 years that is recommended for the
general population. The optimal interval for screening for diabetes in
HIV+ patients is not known.
• As with CVD, encourage patients to practice diabetes prevention via
therapeutic lifestyle changes with a healthy diet low in saturated fats,
weight management, and aerobic exercise.
• Consider initiating or switching to non-PI-based regimens in patients
who have a strong family history of diabetes and/or other traditional
risk factors. Long-term use of PIs may precipitate development of insulin
resistance.
• Dolutegravir interacts with metformin, commonly used as a first-line
antidiabetes agent. The clinical significance regarding the increased
metformin levels is not well established. Current recommendations are
to limit total daily metformin doses to less than 1,000 mg. Patients on
dolutegravir who require higher daily doses of metformin should be
assessed for adverse effects, particularly gastrointestinal side effects.
Chronic Kidney Disease in HIV

The estimated prevalence of chronic kidney disease (CKD) in HIV-infected indi-
viduals is 4.7% to 9.7%. The incidence of renal functional decline or develop-
ment of new CKD ranges in reports from 3.9 to 11.2 cases per 1,000 person-years,
although higher rates have been reported when CKD was defined by reduced
glomerular filtration rate (GFR) or proteinuria.37 Diagnostic elements defined by
the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Work
Group (KDIGO) apply in both HIV+ and negative populations.38 The presence of
any abnormalities in urine albumin, sediment, or electrolytes; kidney histology or
structure, or a history of renal transplant; or impaired glomerular function rates
(GFR) <60 mL/min/1.73 m2 for 3 months or longer constitute the presence of CKD.
These criteria are also present in the HIV Medicine Association/Infectious Diseases
Society of America (HIVMA/IDSA) guidelines for management of chronic kidney
disease in HIV.39
Primary types of CKD in HIV+ patients include HIV-associated nephropathy
(HIVAN) and HIV-associated immune complex disease (HIVIC) disease.40 HIVAN
is caused by HIV infection of renal epithelial cells and accounts for the majority
of cases in HIV+ persons. African Americans and those with advanced AIDS are
particularly susceptible; the disease results in a rapid decline in renal function, and
presence of proteinuria and must be diagnosed by biopsy. HIVIC is an alternative
diagnosis in which the relationship with HIV disease is less clear. It affects a more
diverse population, occurs in the setting of higher CD4+ cell counts, and may
have a more indolent appearance as compared to HIVAN. The major distinction
ERRNVPHGLFRVRUJ
between the two is that ART is recommended as primary treatment for HIVAN,
whereas ART has a more variable impact on renal outcomes in HIVIC. Evaluation
of the impact of ART on HIVAN or HIVIC is limited to observational studies and
case series. From these, it appears that when ART is initiated and viral suppres-
sion is achieved, HIVAN may improve, but the course of HIVIC may not change
because suppression depends on the specific form of HIVIC.
Pharmacists evaluating patients for CKD may wish to obtain the following
laboratory tests: serum electrolytes, blood urea nitrogen, creatinine, and a urinal-
ysis to examine protein, albumin, glucose, and acidification. The patient’s diabetes
status, blood pressure, and glucose should be assessed and medications reviewed
for appropriate dosing. An ACE inhibitor or ARB may be started in patients with
HIVAN or patients with significant albuminuria. Statins may be initiated as indi-
cated by ASCVD scores to lower CV risk. Low-dose aspirin may also be considered
as clinically appropriate.
Generally, pharmacists should estimate GFR based on creatinine clearance
(e.g., Cockcroft-Gault equation) because medication dosing is based on creatinine
clearance estimates. Performance of other kidney function estimators such as the
Modification of Diet in Renal Disease (MDRD) equations or the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equations have been assessed in
comparison to direct measures of GFR in various HIV+ cohorts. Although there is
no specific equation identified as the optimal one to use for assessment in HIV, the
CKD-EPI calculator, which incorporates both cystatin C and creatinine, appears to
provide a more accurate GFR assessment.39
For all patients with CKD, the pharmacist should perform a regular medi-
cation review to ensure that both ART and other medications are appropriately
renally dosed and that use of concomitant nephrotoxic agents is minimized.
Selected recommendations for renal medication adjustment include the
following:
• Nucleoside/tide reverse transcriptase inhibitors (with the exception of
abacavir) and maraviroc must be renally dosed in the setting of reduced
GFR (Table 11-2).
• Renal dose adjustment of ART may require breaking up combina-
tion tablets or single-tablet regimens into their separate components.
Increased pill counts may be a barrier to patient adherence.
• Monitoring renal dysfunction when ART contains TDF, which causes
renal dysfunction via mitochondrial toxicity of the proximal renal
tubules and may present as Fanconi’s syndrome, marked by dehydra-
tion, polyuria, polydipsia, dilute urine, hypokalemia, hypophospha-
temia, hypocalcaemia, proteinuria, and metabolic acidosis.
• TDF may be dose-adjusted in renal dysfunction; however, KDIGO guide-
lines recommend using alternative ART if GFR declines >25% from base-
line and is <60 mL/min/1.73 m2. The prodrug TAF provides less systemic
and renal proximal tubule exposure to tenofovir and is therefore less
likely to cause renal toxicity. Switch studies from TDF to TAF saw very
ERRNVPHGLFRVRUJ
TABLE 11-2. Antiretrovirals Requiring Dose Adjustment in Renal Dysfunction

Drug Class Drug Usual Dose Adjustment for Renal Dysfunction
Nucleoside/ Didanosine EC 250–400 mg orally CrCl 30–59 = 200 mg (if >60 kg) or
Nucleotide daily 125 mg (<60 kg) daily
Reverse CrCl 10–29 = 125 mg daily
Transcriptase
CrCl <10 or dialysis = 125 mg (>60 kg)
Inhibitors
or 125 mg (< 60 kg) daily
Emtricitabine 200 mg orally CrCl 30–49 = 200 mg every 48 hours

daily CrCl 15–29 = 200 mg every 72 hours
CrCl <15 or dialysis = 200 mg every
96 hours
Lamivudine 300 mg orally CrCl 30–49 = 150 mg daily

daily CrCl 15–29 = 150 mg × 1 then
100 mg daily
CrCl 5–14 = 150 mg × 1 then
50 mg daily
CrCl <10 or dialysis = 50 mg × 1 then
25 mg daily
Stavudine 30–40 mg orally CrCl 26–50 = 20 mg BID (if ≥60 kg) or

twice daily 15 mg BID (<60 kg)
CrCl 10–25 or dialysis = 20 mg daily
(>60 kg) or 15 mg daily (<60 kg)
Tenofovir 25 mg/200 mg CrCl ≥30 = standard dose

Alafenamide/ orally daily CrCl <30 or dialysis = not
Emtricitabine recommended
(Descovy®)
Tenofovir 300 mg orally CrCl 30–49 = 300 mg every 48 hours

Disoproxil daily CrCl 10–29 = 300 mg every 72–96
Fumarate hours
CrCl <10 and NO dialysis = no data
Dialysis = 300 mg once weekly
Tenofovir 300 mg/200 mg CrCl 30–49 = 300 mg/200 mg every

Disoproxil orally daily 48 hours
Fumarate/ CrCl <30 = not recommended
Emtricitabine
(Truvada®)
Zidovudine 300 mg orally <15 or dialysis = 100 mg orally three

twice daily times daily or 300 mg daily
(continued)
ERRNVPHGLFRVRUJ

(continued)
Protease Atazanavir 400 mg orally Dialysis = not recommended
Inhibitors and daily
Pharmacokinetic
Boosters
300 mg boosted Dialysis = not recommended for those
with 100 mg who are treatment experienced
ritonavir orally
daily
Atazanavir/ 300 mg/150 mg CrCl <70 and used with tenofovir

Cobicistat orally daily disoproxil = not recommended
Darunavir/ 800 mg/150 mg CrCl <70 and used with tenofovir

Cobicistat orally daily disoproxil = not recommended
Lopinavir/ 400 mg/100 mg Dialysis = avoid using once daily

Ritonavir orally twice dosing (800 mg/200 mg once daily)
daily
CCR5 Inhibitor Maraviroc 300 mg orally CrCl <30 or dialysis = can reduce
twice daily to 150 mg orally twice daily
if hypotension occurs. Not
recommended for use if concurrent
CYP3A4 inhibitor or inducer.
Multiclass Efavirenz/ 600 mg/300 mg/ CrCl <50 = not recommended, use
Combination Tenofovir 200 mg orally separate components
Tablets Disoproxil daily
Fumarate/
Emtricitabine
(Atripla®)
Elvitegravir/ 150 mg/150 mg/ CrCl <30 = not recommended

Cobicistat/ 10 mg/200 mg
Tenofovir orally daily
Alafenamide/
Emtricitabine
(Genvoya®)
Elvitegravir/ 150 mg/ CrCl <70 = do not initiate

Cobicistat/ 150 mg/ CrCl <50 = if patient currently on
Tenofovir 300 mg/200 mg therapy, discontinue when CrCl
Disproxil orally daily declines <50
Fumarate/
Emtricitabine
(Stribild®)
(continued)
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(continued)
Rilpivirine/ 25 mg/25 mg/ CrCl <30 = not recommended
Tenofovir 200 mg orally
Alafenamide/ daily
Emtricitabine
(Odefsey®)
Rilpivirine/ 25 mg/300 mg/ CrCl <50 = not recommended, use

Tenofovir 200 mg orally separate components
Disoproxil daily
Fumarate/
Emtricitabine
(Complera®)
CrCl: creatinine clearance
modest improvement in GFR but more substantial improvements in

proteinuria.
• Cobicistat, dolutegravir, and rilpivirine inhibit proximal tubular secre-
tion of creatinine without affecting glomerular function. Elevations in
serum creatinine (mean 0.1 for rilpivirine; 0.15 mg/dL for dolutegravir;
<0.4 mg/dL for cobicistat) typically occur within the first 4 weeks of
therapy and plateau. Changes in serum creatinine above these levels or
that occur later during therapy should be further evaluated.
• Patients with a clinically significant decline in GFR (>25%), albuminuria
>300 mg/day, hematuria with albuminuria, proteinuria, or high blood
pressure and those with GFR <30 mL/min/1.73 m2 should be referred to
a nephrologist for further evaluation.
Bone Health and HIV

It is challenging to assess the epidemiology of fractures in HIV+ persons due to the
heterogeneity of studied populations and the influence of traditional risk factors
such as age, gender, race, alcohol and tobacco use, and use of non-antiretroviral
medications. A systematic review and meta-analysis did find an increased risk of
any type of fracture in HIV+ individuals (IRR 1.58, 95% CI 1.25–2.00).41 In addi-
tion to traditional risk factors, HIV-associated factors can influence development
of osteoporosis and fractures: low testosterone (in men) or low growth hormone
levels, chronic inflammation from circulating HIV virus, low CD4+ cell counts,
other chronic disease comorbidities such as viral hepatitis, and substance use
can all play a role. ART has an evolving impact on bone mineral density (BMD),
with a typical course consisting of an initial decrease in BMD after ART initiation
that stabilizes or potentially increases with improving health. Although there is
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an increased incidence of fractures in HIV+ persons, the relative contribution of

ART-mediated bone loss to fracture risk is unclear as it is variably associated with
fractures in studies.
TDF is implicated in bone loss via proposed mechanisms of secondary
hyperparathyroidism, phosphate wasting, and increased bone turnover. Studies
comparing TDF versus TAF regimens found smaller losses in BMD with TAF in both
spine (−1.3% versus −2.86%) and hip (−0.66% versus −2.86%).42 PIs and the NNRTI
efavirenz can impact vitamin D metabolism, which may also be contributory. At
present there are no strong recommendations to switch ART in patients at high
risk of falls or fractures, although this strategy can be considered if TDF, efavirenz,
or PIs are in the regimen.
Screening and treatment recommendations include the following43:
• For those with HIV disease, baseline bone densitometry (DXA) is recom-
mended for postmenopausal women, men >50 years, any history of
fragility fracture, persons at high risk of falls, or persons on long-term
oral steroids (>5 mg prednisone for >3 months). Optimal intervals for
repeating DXA are unknown; every 1 to 5 years may be appropriate
depending on the severity of osteopenia.
• HIV+ women >40 years and men aged 40 to 49 should be assessed for
10-year risk of developing major fracture using FRAX scores.44 Calcula-
tions may underestimate risk in HIV; some experts recommend counting
HIV disease as a secondary cause for osteoporosis when computing
FRAX. Patients scoring >10% for major fractures should undergo sub-
sequent DXA. Otherwise, FRAX calculation should be repeated every
2 to 3 years or upon development of new any risk factors.
• In patients with a history of fracture, low BMD, insufficient diet, obesity,
malabsorption, CKD, efavirenz-containing regimens, dark skin, or low
sun exposure 25-hydroxy vitamin D levels should be drawn. Supple-
mentation should be given to those with vitamin D levels <30 ng/mL.
Higher doses of ergocalciferol 50,000 International Units weekly for 8 to
12 weeks can be used in persons with more severe deficiencies of <20 ng/
mL. Target vitamin D level should be achieved prior to bisphosphonate
initiation to maximize response.
• Men aged 50 to 70 years should have 1,000 mg of calcium intake daily.
Women >51 years and men >71 years should have 1,200 mg calcium
daily. Integrase inhibitors should be given 2 hours before or 6 hours after
calcium supplements; alternatively, dolutegravir may be given simulta-
neously with calcium with food.
• Treatment for osteoporosis should follow guidelines for HIV-negative
persons. Both alendronate 70 mg orally weekly and zoledronic acid 5 mg IV
annually have been evaluated in persons with HIV and are preferred agents.
• Pharmacists should evaluate the medication list for other agents that
cause bone loss such as proton pump inhibitors, thiazolidinediones,
corticosteroids, and antiepileptic drugs.
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• Pharmacists should encourage patients to perform weight-bearing

exercises and reduce risk for bone loss by reducing alcohol intake and
cigarette smoking and preventing falls.
ROLE OF THE PHARMACIST IN HIV PRIMARY CARE

Pharmacists across all settings can play an integral role in improving chronic conditions
for all patients living with HIV. The pharmacist should ensure that a thorough medi-
cation history is recorded for each patient that includes both antiretrovirals and other
medications taken for comorbid conditions and should facilitate the communication of
this medication history across all of the patient’s primary care and specialty providers.
Pharmacists may assist in the management of chronic conditions by either providing
direct patient care (assessing patients, ordering laboratory tests, providing referrals, and
prescribing therapies) via expanded scope of practice protocols or by providing recommen-
dations to care providers via consultation. The pharmacist holds particular expertise on
the nuances of selecting or altering ART to reduce impact on comorbidities, in ensuring
proper dosing in the setting of kidney disease, and in ensuring that adjunctive therapies
are appropriately prescribed to minimize drug interactions, minimize toxicity, and opti-
mize chronic disease outcomes.
KEY RESOURCES
• Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management
of persons infected with HIV: 2013 update by the HIV Medicine Association of the
Infectious Diseases Society of America. Clin Infect Dis. Jan 2014;58(1):e1-e34. Avail-
able at http://www.ncbi.nlm.nih.gov/pubmed/24235263.
o This document provides an overview of primary care topics for HIV-infected
individuals as endorsed by the Infectious Diseases Society of America and the
American Academy of HIV Medicine.
• Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management
of bone disease in HIV. Clin Infect Dis. 2015;60:1242-1251.
o This expert consensus guideline on bone disease was created via a collaboration
of 34 HIV clinicians from different countries. It provides helpful algorithms and
guidance on screening and treatment.
• Hadigan C, Kattakuzhy S. Diabetes mellitus type 2 and abnormal glucose metabolism
in the setting of human immunodeficiency virus. Endocrinol Metab Clin North Am.
2014;43(3):685-696.
o This article provides an overview of what is currently known and unknown
regarding HIV and diabetes mellitus.
• Lamarca K, García Sarasola A, Vidal F, Domingo P. Drug therapies for HIV-related
metabolic disorders. Expert Opin Pharmacother. 2016 Jul;17(10):1327-1338.
o This article provides a review of studies and suggested management strategies for
hyperlipidemia and diabetes in HIV.
• Llibre JM, Hill A. Abacavir and cardiovascular disease: A critical look at the data. Anti-
viral Res. May 31 2016;132:116-121.
o This article reviews the data on the impact of abacavir on CVD, which is an
often-debated topic when selecting a regimen.
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• Lucas GM, Ross MJ, Stock PG, et al. Clinical Practice Guideline for the Management
of Chronic Kidney Disease in Patients Infected with HIV: 2014 Update by the HIVMA
of the IDSA. Clin Infect Dis. 2014;59(9):e96-e138.
o This guideline provides an evidence-based discussion of strategies ranging from
evaluation, to treatment, to ART selection for the management of chronic
kidney disease in HIV-infected individuals.
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infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases
Society of America. Clin Infect Dis. 2014;58(1):e1-e34.
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Services: Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.
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3. Gunthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention
of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA
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4. Ahn JY, Boettiger D, Law M, et al. Implementation and operational research: Effects of CD4
monitoring frequency on clinical end points in clinically stable HIV-infected patients with viral
suppression. J Acquir Immune Defic Syndr. 2015;69(3):e85-e92.
5. Kagina BM, Wiysonge CS, Lesosky M, et al. Safety of licensed vaccines in HIV-infected persons:
A systematic review protocol. Syst Rev. 2014;3:101.
6. Kim DK, Bridges CB, Harriman KH. Advisory Committee on Immunization Practices recom-
mended immunization schedule for adults aged 19 years or older: United States, 2016. Ann
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7. Martin-Iguacel R, Negredo E, Peck R, et al. Hypertension is a key feature of the metabolic
syndrome in subjects aging with HIV. Curr Hypertens Rep. 2016;18(6):46.
8. Seaberg EC, Munoz A, Lu M, et al. Association between highly active antiretroviral therapy and
hypertension in a large cohort of men followed from 1984 to 2003. AIDS. 2005;19(9):953-960.
9. Thiebaut R, El-Sadr WM, Friis-Moller N, et al. Predictors of hypertension and changes of blood
pressure in HIV-infected patients. Antivir Ther. 2005;10(7):811-823.
10. Butt AA, Chang CC, Kuller L, et al. Risk of heart failure with human immunodeficiency virus in
the absence of prior diagnosis of coronary heart disease. Arch Intern Med. 2011;171(8):737-743.
11. Cerrato E, D’Ascenzo F, Biondi-Zoccai G, et al. Cardiac dysfunction in pauci symptomatic
human immunodeficiency virus patients: A meta-analysis in the highly active antiretroviral
therapy era. Eur Heart J. 2013;34(19):1432-1436.
12. Llibre JM, Hill A. Abacavir and cardiovascular disease: A critical look at the data. Antiviral Res.
2016;132:116-121.
13. Rhew DC, Bernal M, Aguilar D, et al. Association between protease inhibitor use and increased
cardiovascular risk in patients infected with human immunodeficiency virus: A systematic
review. Clin Infect Dis. 2003;37(7):959-972.
14. Ofotokun I, Na LH, Landovitz RJ, et al. Comparison of the metabolic effects of ritonavir-boosted
darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG
5257. Clin Infect Dis. 2015;60(12):1842-1851.
15. Santos JR, Saumoy M, Curran A, et al. The lipid-lowering effect of tenofovir/emtricitabine: A
randomized, crossover, double-blind, placebo-controlled trial. Clin Infect Dis. 2015;61(3):403-408.
16. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fuma-
rate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment
of HIV-1 infection: Two randomised, double-blind, phase 3, non-inferiority trials. Lancet.
2015;385(9987):2606-2615.
17. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for
initial HIV-1 therapy. N Engl J Med. 2009;361(23):2230-2240.
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18. Nelson M, Hill A, van Delft Y, et al. Etravirine as a switching option for patients with HIV RNA
suppression: A review of recent trials. AIDS Res Treat. 2014;2014:636584.
19. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two
background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive
adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet.
2011;378:229–237.
20. Rockstroh JK, DeJesus E, Henry K, et al. A randomized, double-blind comparison of coformu-
lated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus
coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: Analysis of
week 96 results. J Acquir Immune Defic Syndr. 2013;62(5):483-486.
21. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmaco-
enhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV
type 1-infected patients: Week 48 results. J Infect Dis. 2013;208(1):32-39.
22. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir
versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS.
2008;22(12):1389-1397.
23. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation
of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia
(SWITCHMRK 1 and 2): Two multicentre, double-blind, randomised controlled trials. Lancet.
2010;375(9712):396-407.
24. Helleberg M, May MT, Ingle SM, et al. Smoking and life expectancy among HIV-infected individ-
uals on antiretroviral therapy in Europe and North America. AIDS. 2015;29(2):221-229.
25. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med.
2011;62:141-155.
26. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of
cardiovascular risk: A report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2935-2959.
27. Friis-Moller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-
infected patients: The data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc
Prev Rehabil. 2010;17(5):491-501.
28. Feinstein MJ, Achenbach CJ, Stone NJ, et al. A systematic review of the usefulness of statin
therapy in HIV-infected patients. Am J Cardiol. 2015;115(12):1760-1766.
29. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment
of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the
American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Circulation. 2014;129(25 suppl 2):S1-45.
30. Beltran S, Lescure FX, Desailloud R, et al. Increased prevalence of hypothyroidism among
human immunodeficiency virus-infected patients: A need for screening. Clin Infect Dis.
2003;37(4):579-583.
31. Bongiovanni M, Adorni F, Casana M, et al. Subclinical hypothyroidism in HIV-infected subjects.
J Antimicrob Chemother. 2006;58(5):1086-1089.
32. Chen F, Day SL, Metcalfe RA, et al. Characteristics of autoimmune thyroid disease occurring as
a late complication of immune reconstitution in patients with advanced human immunodefi-
ciency virus (HIV) disease. Medicine (Baltimore). 2005;84(2):98-106.
33. Hadigan C, Kattakuzhy S. Diabetes mellitus type 2 and abnormal glucose metabolism in the
setting of human immunodeficiency virus. Endocrinol Metab Clin North Am. 2014;43(3):685-696.
34. De Wit S, Sabin CA, Weber R, et al. Incidence and risk factors for new-onset diabetes in
HIV-infected patients: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study.
Diabetes Care. 2008;31(6):1224-1229.
35. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association
of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type
2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22(1):84-113.
36. Standards of medical care in diabetes—2016: Summary of revisions. Diabetes Care. 2016;39(suppl
1):S4-5.
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37. Choi A, Rodriguez R. Renal manifestations of HIV. HIV Insite Knowledge Base Chapter. Available at
http://www.hivinsite.com. Accessed June 20, 2016.
38. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney
disease. Kidney Int. Supp. 2013. Available at http://www.kdigo.org/clinical_practice_guidelines/
pdf/CKD/KDIGO_2012_CKD_GL.pdf. Accessed June 15, 2016.
39. Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic
kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of
the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(9):e96-e138.
40. Foy MC, Estrella MM, Lucas GM, et al. Comparison of risk factors and outcomes in HIV immune
complex kidney disease and HIV-associated nephropathy. Clin J Am Soc Nephrol. 2013;8(9):1524-
1532.
41. Shiau S, Broun EC, Arpadi SM, et al. Incident fractures in HIV-infected individuals: A systematic
review and meta-analysis. AIDS. 2013;27(12):1949-1957.
42. Cao H, Fordyce M, Saag M, et al. Renal and bone safety of tenofovir alafenamide vs tenofovir
disoproxil fumarate. Program and abstracts of the 2015 Conference on Retroviruses and Oppor-
tunistic Infections; February 23−26, 2015; Seattle, Washington. Abstract 143LB.
43. Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone
disease in HIV. Clin Infect Dis. 2015;60(8):1242-1251.
44. Kanis JA, Oden A, Johansson H, et al. FRAX and its applications to clinical practice. Bone.
2009;44(5):734-743.
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12
Neuropsychiatric Disorders, Mental
Health, Pain, and Substance Use
Jennifer E. Thomas, PharmD, AAHIVP,
and Joshua Caballero, PharmD, BCPP, FCCP
INTRODUCTION
The ability to properly treat mental health and substance use disorders in our
human immunodeficiency virus (HIV) population is a major concern. A recent
study stated that providers reported deferring the use of antiretroviral therapy
(ART) over 30% of the time due to mental health or substance use concerns.1
Unfortunately, there is a lack of studies and cogent guidelines on the treatment
of mental illnesses among HIV/acquired immunodeficiency syndrome (AIDS)
patients. As a result, healthcare practitioners must rely on targeting symptoms
when prescribing therapeutic options.
NEUROPSYCHIATRIC DISORDERS AND MENTAL HEALTH
Depression
Depression affects approximately 20% to 36% of patients with HIV.2 Depression
presents with symptoms of an increase or decrease in sleep and/or appetite, loss of
interest, increase in guilt, decrease in energy and concentration, reduced psycho-
motor activity, and an increase in suicidal thoughts. Risk factors that contribute
to depression in HIV include female gender, older age, elevated HIV1 RNA levels,
homelessness/unemployment, active drug use, and lack of social support. Before
initiating treatment, providers should rule out conditions that may cause depres-
sive symptoms, including infection (e.g., mononucleosis, syphilis), hypothy-
roidism, hypogonadism (low testosterone), anemia, diabetes, or electrolyte imbal-
ance. Ruling out HIV medications such as efavirenz that may cause depressive
symptoms are also encouraged. Treatment may be necessary when these symptoms
begin to interfere with functions of daily life (e.g., work, personal relationships,
adherence). Healthcare providers should assess depressive symptoms when initi-
ating ART and periodically every 6 to 12 months or if symptoms of depression are
noted. Depression can be assessed using several different scales (e.g., Patient Health
Questionnaire [PHQ-2, PHQ-9] and Center for Epidemiologic Studies Depression
Scale [CES-D]). The PHQ-2 can be used as a quick screening tool during visits. If
a patient scores a 3 or above, the PHQ-9 should be administered within the same
day. The PHQ-9 questionnaire is a screening tool in which a score greater than 9
243
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is positive for depression. The CES-D is a 20-item questionnaire in which scores

greater than 15 are indicative for depression. Persons with HIV and depression
tend to have lower adherence to medications, which may lead to a lower CD4+
cell count and an increase in morbidity and mortality.2,3 Studies show treatment
of depression can improve adherence and health outcomes. The use of psycho-
therapy (e.g., “talk therapy,” cognitive behavioral therapy, interpersonal) may be
useful as well as exercise and massage therapy. However, severe depression should
be treated with pharmacologic agents. The use of antidepressants along with ART
has shown positive outcomes (e.g., >2 greater odds of achieving viral suppression)
in patients with HIV compared to those not taking any antidepressant therapy.
Selecting an appropriate antidepressant for the patient depends on drug inter-
actions and side effect profile. Importantly, the patient’s ability to tolerate the anti-
depressant can affect adherence. The two antidepressant drug classes most used
among patients with HIV/AIDS include tricyclic antidepressants (TCAs) and selec-
tive serotonin reuptake inhibitors (SSRIs). Among TCAs, imipramine has shown
comparable response rates in patients with and without HIV infection (74% to
89%).4 However, TCAs as a class are associated with more anticholinergic (e.g.,
constipation, urinary retention, dry mouth), antihistaminic (e.g., sedation, weight
gain, orthostatic hypotension), and cardiovascular (e.g., arrhythmias, slowing of
conduction that can lead to heart block) side effects.5-7 The anticholinergic effects,
specifically dry mouth, have been reported to be the most common side effects
that patients experience.8 Patients who experience dry mouth, especially among
those with advanced AIDS, may be at an increased risk of getting oral infections
such as thrush and other opportunistic infections.9 However, HIV patients may
benefit from some side effects. For example, TCAs may increase appetite and aid
in weight gain.6 The sedating effects may help with insomnia.6 Patients taking
protease inhibitors (e.g., ritonavir) and cobicistat can have increased TCA concen-
trations.5 Therefore, it would be beneficial for the patient to start on the lowest
TCA dose and slowly titrate to an effective dose while monitoring for any side
effects (e.g., sedation, dizziness). Patients with cardiovascular comorbidities may
be at a higher risk for adverse reactions while on TCAs.
The SSRIs may be better tolerated than TCAs due to fewer anticholinergic and
cardiovascular side effects.6 However, the SSRIs are more likely to cause diarrhea,
anhedonia, and akathisia, while sedation varies between the SSRIs.5,6,10 Among the
SSRIs, paroxetine is more sedating and can help with insomnia, whereas fluoxe-
tine and sertraline are more activating and may help those experiencing sedation.
Dry mouth has been reported in patients taking fluoxetine, which may cause an
increase in oral complications.6,8,10
There is less data on the use of serotonin norepinephrine reuptake inhibi-
tors (SNRIs) and other antidepressants in the HIV population. One study showed
greater adherence to SNRIs (i.e., venlafaxine) compared to SSRIs (i.e., citalopram,
escitalopram, fluoxetine, paroxetine) or TCAs (i.e., amitriptyline).11 Venlafaxine
and duloxetine may be useful in treating depression and neuropathic pain among
people with HIV infection.7 However, venlafaxine may cause an increase in blood
pressure.7 Other antidepressants such as mirtazapine may be safer and better toler-
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CHAPTER 12 Neuropsychiatric Disorders, Mental Health, Pain, and Substance Use 245
ated than TCAs. Mirtazapine may be beneficial because it can cause weight gain
and sedation, which may help patients who experience poor appetite or insomnia.6
It is important to take into consideration which CYP enzymes affect the
metabolism of the antidepressants and which enzymes can be induced and/
or inhibited by ART or cobicistat (see Chapter 3).8 Among the most commonly
used SSRIs, fluoxetine and paroxetine may be the medications which will
have the most CYP interactions. Fluoxetine is metabolized by CYP2C9, 2C19,
3A4, and partially by 2D6. Paroxetine is also partially metabolized by 2D6.
When fluoxetine is given with protease inhibitors (PIs), fluoxetine levels may
increase, causing a patient to have a higher risk of experiencing serotonin
syndrome, whereas concomitant use of nevirapine and fluoxetine can lead to
decreased levels of fluoxetine.8,12 Fosamprenavir/ritonavir dosed at 700 mg/
100 mg twice daily for 10 days with paroxetine 20 mg once daily has also been
evaluated among healthy subjects. The results showed that paroxetine levels
decreased (~55% lower), possibly due to protein binding.8 Overall, among the
SSRIs, it appears citalopram and escitalopram (and possibly sertraline) have fewer
drug interactions with ART because they show weaker inhibition of CYP enzymes
as compared to other antidepressant medications.8
CYP2B6 metabolizes bupropion. The concomitant use of efavirenz and bupro-
pion revealed that concentrations of bupropion were reduced due to induction
of CYP2B6.8 When ritonavir is given with bupropion, the decrease in bupropion
levels depends on the dose of ritonavir.8 However, bupropion can decrease the
seizure threshold, which may cause problems in those with seizure disorders.
Although venlafaxine is metabolized by CYP3A4 and 2D6, it does not appear to
interact with some antiretrovirals (e.g., indinavir).8,13
Some in vitro studies have explored the impact of antidepressants on
preventing progression of HIV/AIDS. One study showed the effect of citalopram
in strengthening the cytolytic function of natural killer cells (NK).14 Another study
employing similar methods showed citalopram preventing HIV from infecting
macrophages.15 The study also suggests citalopram enhances the functions of
NK cells and CD8 T-cells that help in preventing HIV replication. However, these
results need to be studied in patients.
Anxiety and Anxiety-Like Disorders

Along with depression, anxiety is also highly prevalent in HIV-positive patients.
The prevalence of anxiety and anxiety-like disorders may affect a third or more of
the HIV population. Females and minorities are at higher risks. Some of the more
common disorders include generalized anxiety disorders, panic attacks, and post-
traumatic stress disorder (PTSD). Anxiety symptoms include somatic/autonomic
complications (e.g., heart palpitations, sweating, shortness of breath, trembling,
nausea, dizziness, muscle tension, sleep disturbances) and cognitive/psychological
disturbances (e.g., difficulty concentrating, excessive worrying, fear, avoidance).
Some frequently used tools to assess anxiety include the Hamilton Anxiety Rating
Scale (HAM-A), State-Trait Anxiety Inventory (STAI), Zung Self-Rated Anxiety Scale
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(SAS), and Hospital Anxiety & Depression Scale-Anxiety (HADS-A).16 Trained phar-
macists can administer some of these scales. If anxiety symptoms are present,
referral to a specialist is strongly encouraged.
Studies suggest that patients with higher anxiety levels tend to experience
ART failure, drug resistance, and possible progression of disease.17 These patients
may also have a higher incidence of intravenous drug use. A cohort study of
HIV-positive patients treated with methadone for opioid addiction showed those
diagnosed with panic disorder were less adherent to ART.18
PTSD may affect approximately 50% of HIV-positive patients. It has been
suggested that patients with HIV who develop PTSD may experience avoidance
symptoms and become nonadherent to ART.19 Additionally, one study found that
HIV-positive gay and bisexual men with PTSD were more likely to engage in risky
sexual behavior that increases transmission of HIV.20 However, those with either
social anxiety or panic disorder showed no increased HIV transmission behavior.
Even though anxiety, in general, is a common neuropsychiatric disorder
among the HIV/AIDS population, studies are lacking on its assessment and treat-
ment. Therefore, the management of anxiety disorders in patients with HIV should
mirror that of the general population, including the use of antidepressants with or
without psychotherapy.
Benzodiazepines are primarily used to treat acute episodes of anxiety disor-
ders; however, they may be used long term when needed. Studies are lacking that
evaluate the efficacy of benzodiazepines in anxiety in HIV patients. Although
there are studies on drug interactions with some of the older antiretrovirals,
studies are needed to assess potential drug interactions between benzodiazepines
and newer antiretrovirals and the impact of benzodiazepine side effects in the
HIV-positive population. Overall, the use of benzodiazepines in anxiety (similar
to antidepressants above) should mimic guidelines used in non-HIV populations.
Dosing of benzodiazepines should be started with care and titrated slowly. If there
is worry about drug–drug cytochrome P450 interactions, lorazepam, temazepam,
and oxazepam are recommended. Of these, lorazepam would be the preferred
benzodiazepine. Temazepam may be an option for those who also experience
insomnia; oxazepam is seldom used and may be difficult to fill at a pharmacy
due to availability. The 2016 Department of Health and Human Services (DHHS)
HIV treatment guidelines state that the use of triazolam with protease inhibitors
should be avoided.21 The guidelines also state that alternative benzodiazepines
(i.e., lorazepam, oxazepam, temazepam) should be considered in patients taking
alprazolam, clonazepam, and diazepam when using a protease inhibitor. However,
while there are data to avoid alprazolam, studies are lacking with other agents
(i.e., clonazepam, diazepam). Some patients may be stable on these combinations.
If the patient has been responding to the benzodiazepine (e.g., low-dose clonaz-
epam) and reports no side effects, the patient can remain on the current treat-
ment. However, if considering adding a protease inhibitor for a patient currently
on a benzodiazepine (e.g., considering adding ritonavir when a patient is taking
ERRNVPHGLFRVRUJ
alprazolam), then the pharmacist must assess the interaction and determine if a
change in the benzodiazepine is warranted.
Data show HIV-positive men were more likely to fill a benzodiazepine prescrip-
tion compared to HIV-negative men, whereas there was no difference of filling
a benzodiazepine prescription between HIV-positive women and HIV-negative
women.22 Caution is warranted as there may be an increased risk in mortality in
patients with HIV who are taking benzodiazepines and/or opioids long term (≥90
consecutive days).23
Delirium
It has been suggested that HIV/AIDS patients with untreated delirium have an
increased risk of mortality.24 The ability to differentiate between delirium and
dementia is important to provide appropriate treatment. Delirium can occur in
those who have a more severe HIV infection and is the most common neuro-
psychiatric disorder of hospitalized patients who have progressed to AIDS.9 The
symptoms of delirium are the same as in those who do not have HIV and include
difficulty in focusing or paying attention, disorganized thinking, altered level
of consciousness, and changes in mood and memory. Delirium can be assessed
among HIV/AIDS patients by using either the Folstein Mini Mental Status Exam-
ination, the Delirium Rating Scale, and/or the Memorial Delirium Assessment
Scale. Moreover, the occurrence of delirium in AIDS patients can occur not only
in adults or the elderly but in children as well. The cause of delirium can include
several factors, such as bacterial or fungal systemic infections, toxicity associ-
ated with polypharmacy, withdrawal or intoxication of psychoactive drugs, and/
or HIV-related cerebrovascular disease. Central nervous system (CNS) infections
should always be ruled out regardless of age and appropriate pharmacotherapy
initiated, if warranted.
Limited data suggest haloperidol (mean daily dose [mg]: 2.8 for acute; 1.4 for
maintenance) and chlorpromazine (mean daily dose [mg]: 50 for acute, 36 for
maintenance) were effective in treating the symptoms of delirium among patients
with AIDS. Lorazepam (mean daily dose [mg]: 3 for acute, 4.6 for maintenance)
worsened symptoms and declined cognitive function.25 Patients with AIDS are
more sensitive to extrapyramidal symptoms and may respond to much lower
doses of antipsychotics. A case study involving an adolescent girl with HIV diag-
nosed with delirium had a more favorable response to haloperidol (0.5 mg twice a
day) than to risperidone (1 mg twice a day).26
HIV-Associated Neurocognitive Disorders

Those who have HIV/AIDS may experience HIV-associated neurocognitive disor-
ders (HAND), which encompass a variety of cognitive impairment conditions
caused by the person’s immune response to HIV/AIDS within the nervous system.
The development of HAND may occur as a result of pro-inflammatory cytokines
and the release of other neurotoxic products within the nervous system as a result
of the immune system trying to fight HIV/AIDS infection. The different condi-
ERRNVPHGLFRVRUJ
tions of HAND are mild neurocognitive disorder, asymptomatic neurocognitive

impairment, HIV-associated dementia, AIDS dementia complex (ADC), and HIV
encephalopathy.9 General HAND symptoms include slower thought process and
poor memory resulting in poor adherence and progression of disease. As such, it is
important to assess and monitor the mental states of HIV/AIDS patients through
the use of the Mini Mental Status Examination (MMSE), Montreal Cognitive
Assessment (MoCA), or International HIV Dementia Screen (IHDS).27
At this time, the CNS Penetration-Effectiveness (CPE) rank is used to assess
the ability for ART to cross the blood-brain barrier. Overall, the higher the CPE,
the lower the viral load in the CNS.28 However, whether antiretrovirals that pene-
trate the CNS cause more neurotoxicity or if they may be more neuroprotective
(regardless of viral suppression) has been debated. Use of ART that targets the
CNS compared to therapy that does not, showed no difference in cognitive func-
tion improvement among patients with HAND.29 The study suggested some of the
antiretrovirals used in the group that targeted the CNS (e.g., zidovudine, abacavir)
had more CNS toxicity compared to the group that did not target the CNS (e.g.,
tenofovir, raltegravir), but this appeared to be nonsignificant. However, other data
suggest antiretrovirals with a lower CNS penetration effectiveness score correlated
with higher prevalence of neurocognitive impairment. At this time, more research
is needed in this area. A study in a limited sample size (n = 17) showed rivastig-
mine, a cholinesterase inhibitor, produced improvements in psychomotor speed
and executive functioning in patients with HAND.30 However, patients experi-
enced side effects (e.g., nausea, vomiting, unsteadiness), and approximately 25%
of patients withdrew because of intolerability of the side effects (e.g., nausea,
nightmares, anxiety, cutaneous rash). The study suggests rivastigmine was the
preferred cholinesterase inhibitor instead of donepezil and galantamine because
rivastigmine is not metabolized by CYP450 and may be less likely to interact with
ART.30 However, other agents such as donepezil may be used if there are no inter-
actions noted since it is a once-a-day dosing and may provide less nausea than
rivastigmine (as seen in non-HIV populations).
Other potential pharmacologic options studied for the treatment of HAND
include memantine and minocycline. Memantine (maximum dose 40 mg), an
N-methyl-D-aspartate (NMDA) receptor antagonist, for the treatment of ADC
showed improved cognitive function for 12 weeks compared to placebo.31 The
study did not mention the dose of memantine given to the patients at the start
of the study and/or if the dose was gradually increased to 40 mg/day. Another
potential therapeutic option for the treatment of HAND may be minocycline.
In vitro data have shown minocycline inhibits viral replication in macrophages
and lymphocytes, which may serve as a proposed biological pathway to delay the
progression of HAND.32-34
Severe Mental Illness

The presence of severe mental illness (e.g., schizophrenia, bipolar disorder) in
HIV/AIDS may decrease adherence, increase the likelihood of engaging in risky
ERRNVPHGLFRVRUJ
behaviors (e.g., unprotected sex, substance use), and increase HIV transmission.
However, patients who have routine access to health care and mental health
services can achieve similar adherence and mortality to those with HIV and no
mental illness.35 The assessment of mental health and provision of appropriate
therapy in HIV-positive patients is vital because studies show that those who fill
prescriptions and are adherent to psychiatric medications are just as likely to do
the same for ART.36 Therefore, the possible integration of mental health services
within HIV clinics can aid in the identification and monitoring of severe mental
illnesses, leading to improvement in health outcomes. Before starting a mood
stabilizer or antipsychotic, careful review of current ART should be noted since
some antiretrovirals may cause psychiatric complications. For example, efavirenz
has neuropsychiatric side effects (e.g., depression, suicidal ideation, anxiety, para-
noia, hostility) that can induce or worsen the patient’s psychiatric symptoms.8,37
In the treatment of schizophrenia, second-generation antipsychotics are
preferred due to the lower incidence of extrapyramidal symptoms.5,38 Risperidone,
olanzapine, and quetiapine have been studied in HIV patients. Doses described in
the literature have varied greatly; therefore, starting low and titrating to effect is
recommended. Of note, olanzapine and quetiapine are highly sedating and can
cause weight gain. Other antipsychotics may be considered; however, data are
lacking.5 Long-acting antipsychotic injections may be used in patients with HIV
and may be an option for patients who experience adherence issues. Information
on dosing of these agents and side effect profiles for the long-acting injections
in HIV is lacking; therefore, following guidelines for the general population is
recommended, with a couple of caveats. First, remember that HIV patients may
be more sensitive to side effects and require lower doses to treat symptoms, so
starting at lower doses and titrating slowly is encouraged. Additionally, some HIV
patients may be cachectic and have lower muscle volume; therefore, the use of
long-acting antipsychotics may not be possible since a dose-dumping effect may
occur, causing severe side effects and hospitalization. Of note, there have been
successful reports of using clozapine.38 However, caution is warranted as clozapine
can cause interactions with multiple antiretrovirals or cobicistat. Additionally,
decreases in absolute neutrophil count (ANC) and white blood cells (WBCs) may
be possible with clozapine, placing HIV patients at risk.
There is a lack of information on the use of psychotropic medications for
bipolar disorder in HIV/AIDS patients. Limited data state that lithium may be a
favorable option due to low interactions with ART since it is renally excreted and
may also have antidepressant effects.39 However, lithium can cause side effects
such as nausea, diarrhea, weight gain, and tremor, which may limit its use.5
Valproate may be another option, but it can interact with ART by glucuronida-
tion.39 The use of lamotrigine for maintenance therapy may be beneficial as well;
however, interaction with ART is also possible.39 For example, lamotrigine may
interact with ritonavir by glucuronidation, leading to lower levels of lamotrigine.
Carbamazepine can be another option but is an inducer of CYP3A enzymes, and
increased levels of carbamazepine may occur with concomitant use of efavirenz
and/or ritonavir.39
ERRNVPHGLFRVRUJ
Insomnia
Insomnia can present as difficulty falling asleep, difficulty maintaining sleep, or
awakening too early.40 Although insomnia is common in the general population, the
prevalence in HIV-positive patients is higher, with over 70% of patients reporting
sleep disturbances, often associated with co-occurring depression or anxiety.41
Insomnia may result in poor disease outcomes (e.g., reduced medication adher-
ence, adverse effects on immune function); therefore, insomnia screening should be
included in routine care plans.42 Common screening tools used to assess insomnia
include the Pittsburgh Sleep Quality Index and the Insomnia Severity Index.43
Factors contributing to insomnia should be assessed, including medication
regimens. Among antiretrovirals, efavirenz has been associated most frequently
with insomnia and other sleep disturbances. Adverse effects associated with
efavirenz often resolve within 3 months; however, these effects may require treat-
ment until that time to prevent nonadherence to therapy.
First-line therapy for treatment of insomnia is cognitive-behavioral therapy.
Patients should also be educated on the principles of sleep hygiene, including
setting a regular sleep schedule, only using the bedroom for activities related to
sleep, and avoiding caffeine, tobacco, and alcohol in the evening. If nonpharma-
cologic therapy is not effective, pharmacotherapy may be initiated.44 Initial phar-
macotherapy options for treatment of insomnia include short–intermediate-acting
benzodiazepines, benzodiazepine receptor agonists (BzRAs), or the melatonin
receptor agonist ramelteon. Short–intermediate-acting benzodiazepines include
temazepam, quazepam, and flurazepam; BzRAs include zaleplon, zolpidem, and
eszopiclone. Caution should be used when selecting treatment for a patient
with a history of substance use disorder, as both benzodiazepines, and to a lesser
extent BzRAs, carry a risk for abuse. Ramelteon may be a preferred option in this
patient population because it is not associated with this risk. Alternate treatment
options for chronic insomnia include low doses of sedating antidepressants, such
as doxepin, trazodone, mirtazapine, or amitriptyline.44 Another option that may
be beneficial for some patients is melatonin. A meta-analysis evaluating 19 studies
comparing melatonin to placebo in the treatment of primary sleep disorders in
the general adult and pediatric populations found melatonin has modest effects
on decreasing sleep onset latency, increasing total sleep time, and improving sleep
quality.45 Melatonin also appears to have immunomodulatory effects and has been
studied for its potential role as an immunostimulant.46
Many medications used in the treatment of insomnia are metabolized by
CYP3A4, and caution should be exercised when prescribing these medications
to patients taking antiretroviral regimens containing protease inhibitors or the
boosting agent cobicistat. Dose reductions may be necessary with certain insomnia
medications (e.g., zolpidem, eszopiclone, quazepam, flurazepam) when used in
combination with these agents. It is important to note that triazolam is contra-
indicated in combination with protease inhibitors or cobicistat. In addition to
drug interactions, it is essential to assess renal and kidney function when selecting
a regimen for insomnia. The majority of agents require dose adjustment for hepatic
ERRNVPHGLFRVRUJ
impairment, although safer options include lower doses of temazepam, zaleplon,

and zolpidem.47 For patients with renal impairment, safer options include zolp-
idem, zaleplon, ramelteon, and doxepin.47
PAIN
Patients with HIV frequently report pain, with studies in various settings reporting
rates ranging from 30% to 70%.48 An association between increased pain and
decreased CD4 counts has been described in several studies; however, pain may
present in any patient.49,50 Pain associated with HIV can negatively impact quality
of life and should be routinely assessed. Pain conditions which present in HIV can
be divided into three general categories:
1. pain directly related to HIV infection
2. pain related to HIV therapy
3. pain unrelated to HIV51
These pain conditions may overlap; however, it is important to identify the type
of pain, as treatment may vary.
HIV-related neuropathy is a common neurologic complication, which may
affect up to 50% of persons with HIV. Studies have found prevalence of symptoms
of neuropathy ranging from approximately 30% to 60%, with rates increasing
with age.52,53 Neuropathy in HIV generally presents as a distal symmetric polyneu-
ropathy (DSP). The exact pathophysiology is unknown; however, it is thought to
be related to either direct toxicity of the virus or indirect neurotoxicity through
inflammation and viral proteins.54 Neuropathy may also be associated with certain
antiretrovirals, which will be addressed later in this section. Although DSP can
be asymptomatic in some patients, many patients experience symptoms such
as numbness, tingling, burning, or pain, typically in the distal lower extremi-
ties. These symptoms may gradually spread and, in some cases, affect the upper
extremities as well. Patients may also exhibit reduced sensation to pinpricks and
vibrations in the extremities and decreased reflexes. It is important to assess for
other causes of neuropathy, including diabetes mellitus and alcoholism.
Although there have been many studies assessing pharmacologic therapy in
other types of neuropathic pain, trials in patients with HIV-related neuropathy are
limited. One of the most promising therapies in HIV-related DSP is topical capsa-
icin. One randomized controlled trial found a single application of a capsaicin 8%
transdermal patch resulted in significant improvement in neuropathic pain for up
to 12 weeks.55 Other studies demonstrated the efficacy of capsaicin for HIV DSP,
while another found a nonsignificant trend toward pain improvement.56-58 Other
studies evaluating topical therapies, including capsaicin 0.075% cream and lido-
caine 5% gel, did not find these agents to be effective.59,60 One limitation of topical
capsaicin is the high incidence of application site reactions, including erythema,
pain, maculopapular rash, and pruritis.
Oral medications are often successfully used in patients with other types of
neuropathic pain; however, they often do not have positive results in HIV neurop-
ERRNVPHGLFRVRUJ
athy. One small randomized controlled study found gabapentin (at doses starting
at 400 mg/day and titrated up a maximum of 2,400 mg/day) resulted in significant
improvement in pain when compared with placebo.61 A randomized controlled
trail of pregabalin (150–600 mg/day) did not find the agent to be more effective
than placebo.62 A couple of small placebo-controlled trials assessing the efficacy
of lamotrigine for the treatment of DSP associated with HIV found a significant
reduction in pain symptoms in participants who were taking neurotoxic antiretro-
virals (e.g., stavudine, didanosine); however, there was no significant reduction in
pain for participants taking ART that did not include these drugs.63,64 Because these
neurotoxic antiretrovirals are rarely used today, this treatment is likely not to be
useful, although it is interesting to note these results suggest a possible difference
in the neurotoxicity mechanism between the virus and neurotoxic medications.
Antidepressants have been used successfully in the treatment of diabetic
neuropathies; however, studies in HIV-associated DSP have been less promising.
Two studies evaluating the efficacy of the TCA amitriptyline found no statistically
significant improvement in pain scores when compared to placebo, although one
of the studies did report a trend toward improvement with amitriptyline (dose
range 25–100 mg/day).65,66 One study that evaluated the efficacy of the SNRI
duloxetine also failed to find a significant reduction in pain; however, this study
was limited with a very small sample size, and further studies may be warranted.67
Other recent studies have investigated therapies based on more recent patho-
physiologic models of HIV-associated DSP; however, these treatments have not
been shown to be effective. These therapies include acetyl-L-carnitine, vicriviroc,
memantine, peptide T, and mexilitine.54 Smoked cannabis has demonstrated effi-
cacy in a couple of studies; however, marijuana, as noted below, may cause other
deleterious and unwanted complications.68,69
Pain disorders may also be associated with HIV treatment, although this is rare
with current therapies. Neuropathy has been associated with ART, most notably
with the nucleoside reverse transcriptase inhibitors didanosine and stavudine, for
which use has significantly declined with the approval of better-tolerated agents.
Some studies suggested an association between protease inhibitors and neurop-
athy, but an evaluation that adjusted for other risk factors determined the associa-
tion is small, if it exists at all.70 Although it can be difficult to differentiate between
ART-induced and HIV-mediated neuropathies, a change in treatment regimen is
recommended if the neuropathy is believed related to ART, for symptoms may
improve once the agent is discontinued.
Individuals with HIV may also present with pain unrelated to the virus. The
most common of the many available pain assessment scales is the numerical
rating scale patients use to rate the intensity of their pain from 0 (no pain) to 10
(worst pain). Guidelines for the treatment of pain in patients with HIV are lacking,
and treatment is generally adapted from guidelines for cancer-related and chronic
nonmalignant pain. Treatment recommendations are based on the World Health
Organization’s stepwise approach, based on pain severity.71
Recommended pharmacologic options for mild pain are acetaminophen or a
nonsteroidal anti-inflammatory drug (NSAID). Caution should be exercised when
ERRNVPHGLFRVRUJ
using acetaminophen in patients who regularly drink alcohol or those with liver
disease. NSAIDs have been found to be more effective than acetaminophen for
pain related to knee and hip osteoarthritis; however, they should be used with
caution in patients at risk for renal, cardiac, or gastrointestinal complications or
patients with bleeding disorders. There is no evidence that any one NSAID is more
effective than others.
For patients with moderate pain, whose pain is not relieved with acetamin-
ophen or NSAIDS, the recommended next-line therapy has traditionally been a
combination of opioids and acetaminophen, while the treatment of severe pain
has consisted of opioids with or without adjunctive pain medications. Opioid
therapy has been shown to be effective for both nociceptive and neuropathic
pain in the short-term, but caution is advised when using these agents due to the
high risk of abuse, particularly in patients with a history of substance use disor-
ders. Although these agents may be considered for short-term use, chronic opioid
therapy for treatment of chronic pain (pain lasting longer than 3 months or past
the time of normal tissue healing) has not been shown to be effective in treatment
of HIV patients and should not be recommended at this time.72 Additionally, the
opioids methadone and oxycodone have the potential to interact with ART (see
“Substance Use” section).
SUBSTANCE USE
Substance use disorders are highly prevalent in HIV-positive individuals, with
multiple studies finding high rates of alcohol and drug use and dependence in this
population.73 One study in a multicenter cohort of HIV-positive patients reported
24% of patients with recent marijuana use, 9% recent use of amphetamines, 8.5%
crack cocaine use, 2.8% recently injecting drugs, and 2% recent use of opiates.
This study also found that over 10% of individuals reported polydrug use in the
previous 3 months.73 Substance use is a known risk factor for transmission of HIV,
through both direct and indirect mechanisms. Use of parenteral drugs is associated
with increased risk of HIV transmission through shared injection paraphernalia,
and nonparenteral drug and alcohol use is associated with lowered inhibitions
and increased probability of participating in high-risk behaviors (e.g., unprotected
sex). Substance use is also associated with other medical problems (e.g., hepatic
disease, infection, cardiovascular disease), which can complicate the treatment of
HIV infection.
Screening for substance use disorders should be included as part of routine
care in patients with HIV. Several short screening tools are available for practi-
tioners to screen for substance use. Common rating scales include the three-item
Alcohol Use Disorders Identification Test–Consumption (AUDIT-C) and four-item
CAGE (Cut down, Annoyed, Guilty, Eye-opener) scales for alcohol use disor-
ders, and CAGE-Adapted to Include Drugs (CAGE-AID). Pharmacists can play an
important role in recognizing signs of substance use disorders and linking patients
to the appropriate providers for treatment.
ERRNVPHGLFRVRUJ
Alcohol is one of the most commonly used substances by individuals with

HIV, with approximately 53% of those surveyed in one study reporting any alcohol
consumption in the past month and 8% of the sample meeting criteria for heavy
drinking (defined in this study as consumption of 5 or more drinks on at least 4 days
during the past 4 weeks).74 Heavy alcohol use may lead to hepatic impairment and
cirrhosis, in which case ART containing abacavir may require dose adjustment. Phar-
macotherapy may be used along with concurrent psychosocial therapy in the treat-
ment of alcohol use disorders. First-line pharmacotherapy for alcohol use disorder is
naltrexone or acamprosate; disulfiram is considered a second-line option.75 Disulfiram
cannot be used in combination with antiretroviral formulations that contain alcohol,
including tipranavir/ritonavir capsules and ritonavir-containing oral solutions.
Marijuana is a substance highly used by HIV-infected individuals, with one
study finding 24% of patients reporting use in the past 3 months and another
study finding 38% reporting use in the past year.73,76 Marijuana is not known to
have any clinically significant interactions with ART; however, as with other illicit
drugs, marijuana use has been associated with reduced medication adherence in
patients with HIV.
Opioid use disorder, including the use of heroin and misuse of prescription
opioids, is also highly prevalent among the HIV-positive population. One study in
HIV-positive individuals found that over the past year, 14.4% of participants used
heroin and 17.1% used a prescription opioid obtained without a prescription.76
There are no known interactions between heroin and ART; however, any prescrip-
tion opioids metabolized via the CYP3A4 enzyme may interact with ART. Oxyco-
done is metabolized by the CYP enzyme system, and combination with protease
inhibitors or the boosting agent cobicistat may result in higher than expected
concentrations of oxycodone, increasing the risk of overdose. Medication adher-
ence has been found to be negatively impacted by opioid misuse, and treatment of
opioid dependence with opioid substitution therapy has been shown to increase
ART adherence.77 First-line pharmacotherapy for treatment of opioid use disorder
is buprenorphine or methadone.75 Pharmacists should be aware of clinically signifi-
cant interactions between these agents and ART. Buprenorphine is metabolized via
CYP3A4, and when used with certain antiretrovirals, buprenorphine concentra-
tions may increase. Particular caution should be used if initiating ART containing
atazanavir, darunavir, or cobicistat in a patient using buprenorphine, as buprenor-
phine doses may need to be decreased. Methadone also has several significant
interactions with ART. When methadone is used in combination with zidovudine,
there may be an increase in zidovudine levels, making it necessary to monitor
more closely for zidovudine toxicity. Efavirenz and ritonavir decrease methadone
levels, potentially leading to opiate withdrawal symptoms and a need to adjust
the methadone dose if withdrawal occurs. Lastly, ART containing cobicistat may
increase methadone levels. Methadone is associated with a risk of QTc prolon-
gation and torsade de pointes; therefore, caution should be used if prescribing
ART that could increase methadone. A baseline electrocardiogram (ECG) should
be recommended in this situation, and the patient’s medication profile should be
evaluated for other medications that could prolong the QT interval.
ERRNVPHGLFRVRUJ
Methylenedioxymethamphetamine (MDMA) is frequently used in the general

population, but studies evaluating the prevalence of use in HIV-positive popula-
tions are lacking. MDMA is metabolized by the CYP2D6 isoenzyme, and interac-
tions may occur when combined with 2D6 inhibitors. Ritonavir has been shown to
interact with MDMA via inhibition of CYP2D6, which has led to MDMA toxicity
and at least one reported fatality. Ritonavir, even in low boosting doses, should
not be prescribed for patients who report use of MDMA, and patients suspected of
using MDMA should be advised of this potential interaction.
Cocaine use is also commonly seen in HIV-positive individuals, with one study
reporting that 40% of participants used the drug in the past year and another
reporting 9% crack cocaine use in the past 3 months.73,76 Metabolism of cocaine
is partly through the CYP3A enzymes, including CYP3A4; therefore, antiretrovi-
rals that inhibit or induce CYP3A4 may interact with cocaine. CYP3A4 inhibitors,
including protease inhibitors and cobicistat, could potentially increase the risk of
cocaine toxicity. When inducers of CYP3A4, including nevirapine and efavirenz,
are combined with cocaine, there may be an increase in the levels of hepatotoxic
cocaine metabolites, such as norcocaine.78 Although the clinical significance of
this interaction has not been determined, caution should be used when selecting
ART for a patient who uses cocaine.
Amphetamine use is highly prevalent in patients with HIV, with one study
finding that almost 10% of participants reported recently using amphetamines.73
Methamphetamine in particular has been shown to have a day-specific effect on
medication adherence, with patients less likely to be adherent on days they used
methamphetamine.79 Peripheral toxicity and neurotoxicity have been associated
with methamphetamine use, and these effects are more likely in HIV-positive
patients compared to the general population.80 Methamphetamine is metabolized
by CYP2D6, and to a smaller degree by CYP3A4, and could be expected to poten-
tially interact with ARTs that inhibit or induce these enzymes. Because studies
assessing these interactions are lacking, caution should be used when selecting
ART for a patient who uses amphetamines.

The role of the pharmacist in the treatment of neuropsychiatric disorders, pain, and
substance use within the HIV population can be very complex. The pharmacist’s exper-
tise in appropriate selection of ART and agent(s) for neuropsychiatric disorders are keys
to promoting both safety and efficacy. Those treating psychiatric or neurologic disorders
should be cognizant that such conditions may decrease adherence and health outcomes.
Scales and inventories used to monitor efficacy are encouraged. Patients should be treated
for pain and monitored for efficacy; however, careful consideration is needed when
choosing an agent or determining length of treatment. Pharmacists should also assess
substance use in this patient population due to higher rates of use in light of the fact
that taking such substances (e.g., alcohol, marijuana, amphetamines) may consequently
decrease ART adherence. Equally important for pharmacists is to identify any potential
drug interactions between psychotropics and ART. It is crucial for pharmacists to counsel
ERRNVPHGLFRVRUJ
patients with HIV regarding their psychotropic medications, specifically reminding them
how the medication will help (e.g., improve mood, feel better, maintain adherence to HIV
medications), discussing common side effects, and making them feel they can discuss
any medication-related issue with the pharmacist. Pharmacists can serve as liaisons and
direct patients to other services within the health care team (e.g., social worker).
KEY RESOURCES
There is a paucity of data regarding the use of psychotropic agents in
patients with HIV; however, there are some resources that may assist the
pharmacist or other health care provider to determine appropriate pharma-
cotherapy for patients. These include:
• CNS Penetration Effectiveness (CPE) Ranks 2010. https://hnrp.hivresearch.ucsd.edu/
index.php/research/investigator-resources/resources-offered/laboratory-pharmacolo-
gy-a-biomarkers-resources-242/cns-penetration-effectiveness-ranks-2010.
• Ellis RJ, Letendre S, Vaida F, et al. Randomized trial of central nervous system—
Targeted antiretrovirals for HIV-associated neurocognitive disorder. Clin Infect Dis.
2014;58(7):1015–1022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952601/.
• HIV Clinical Resource by the Office of the Medical Director, New York State Depart-
ment of Health AIDS Institute in collaboration with Johns Hopkins University Divi-
sion of Infectious Diseases. http://www.hivguidelines.org.
• Kemppainen JK, MacKain S, Reyes D. Anxiety symptoms in HIV-infected individuals.
J Assoc Nurses AIDS Care. 2013;24(1 suppl):S29-39.
• Mental Health Screening: A Quick Reference Guide for HIV Primary Care Clinicians.
http://cdn.hivguidelines.org/wp-content/uploads/20160816144754/mental-health-
screening-06-21-2012.pdf.
• Predicted Interactions between Psychotropics and Antiretrovirals http://www.
hivclinic.ca/main/drugs_interact_files/psych-int.pdf.
• Predicted Interactions between Antiretrovirals, Medications Used in Treatment
of Substance Abuse, and Recreational Drugs. http://www.hivguidelines.org/
substance-use/drug-drug-interactions/.
Pharmacists may also play a role in identifying patients with neuropsychi-
atric disorders. A few commonly used screening tools include:
• Insomnia Severity Index. http://www.depressiontoolkit.org/download/insomniasever-
ityindex_blank.pdf.
• Patient Health Questionnaire (PHQ-9). http://www.cqaimh.org/pdf/tool_phq9.pdf.
• Zung Self-Rated Anxiety Scale. https://www.mnsu.edu/comdis/isad16/papers/
therapy16/sugarmanzunganxiety.pdf.
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13
Care of the Transgender Patient
INTRODUCTION
Transgender individuals are a patient population with distinct barriers to care
and unique treatment considerations.1 Transgender individuals are those whose
gender identity differs from their biological sex. A full list of definitions important
in transgender health is provided in Table 13-1.1,2 Using these phrases and words
correctly can greatly enhance patient comfort and engagement in care processes.
Additionally, it is important to avoid using incorrect terms (such as tranny) and to
avoid making incorrect assumptions (such as assuming sexual orientation on the
basis of gender). Promoting inclusiveness and demonstrating cultural competency
of the health and social issues facing transgender populations is paramount when
caring for transgender patients.
It is estimated that the prevalence of transsexual men is anywhere from 1:30,400
up to 1:200,000, and the prevalence of transsexual women is anywhere from 1:11,900
up to 1:45,000.3 This 1:3 ratio of transsexual men to transsexual women has been
observed in epidemiological studies in multiple Western countries.4
TRANSGENDER HEALTH ISSUES

Transgender individuals, like other minorities, have unique health and social
issues. These issues include high rates of mental illness, substance abuse, human
immunodeficiency virus (HIV), and an increased risk of chronic conditions and
cancer.5
The most common mental health disorders encountered in transgender individ-
uals are depression and anxiety. Additionally, suicide ideation and suicide attempts
are both more prevalent in transgender individuals than in control populations.6
There are high rates of alcohol, nicotine, and illicit substance abuse in transgender
populations. Self-reported abuse of alcohol, cocaine, amphetamine, methamphet-
amine, and opiate use has been anywhere from 4 to 10 times higher in transgender
populations compared to the general population.7 The source of mental health disor-
ders and substance abuse disorders is thought to be a result of internalized stigma
(inwardly and self-directed transphobia), enacted stigma in the forms of discrimina-
tion (either overt or subversive), or psychological or physical abuse by others.7
HIV and its sequelae, acquired immunodeficiency syndrome (AIDS), are major
medical issues in the transgender community. Transgender individuals were not
261
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TABLE 13-1. Definitions Related to Gender and Sexuality

Term Definition
Sex Biological genotype and phenotype without regard of self
Gender identity (or “affirmed Inherent sense of being male or female regardless of sex
gender”)
Gender expression Characteristics in appearance, personality, and behavior

culturally defined as masculine or feminine
Gender role conformity The extent to which an individual’s gender expression adheres to
cultural norms for his or her sex
Gender role nonconformity Nonconformity with prevailing norms of gender expression
Coming out (or “coming out of Figure of speech for disclosure of one’s sexual orientation and/or
the closet”) gender identity
Transgender individual Individual whose gender identity is different from his or her
biological sex
Transsexual Individual who makes his or her body congruent with his or her
gender identity, either through medical or surgical means
Transvestite (crossdresser) Individual who dresses in the clothes of the opposite sex while
typically retaining a gender identity consistent with his or her
biological sex
Genderqueer Individual whose gender identity does not conform to the binary
categories of male or female
Sexual orientation The sex that a person is attracted to without regard to gender
Gender dysphoria Individual whose gender at birth is contrary to the one with
which he or she identifies; replaces “gender identity disorder”
in DSM-V
Female-to-male (FtM) individual Individual assigned female at birth who has changed the gender
role and/or body image to a more masculine role or image
Male-to-female (MtF) individual Individual assigned male at birth who has changed the gender
role and/or body image to a more feminine role or image
Transition Period during which a transgender or transsexual person is

learning to cross-live as a member of the sex category opposite
his or her biological sex or is beginning hormonal therapy
DSM-V: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
originally considered in initial federal surveillance efforts, so the pervasiveness

of HIV in the transgender community was not evaluated until the mid-1990s.1 A
meta-analysis found an HIV prevalence of 21.7% among transgender women in the
United States and an estimated prevalence of 19.1% among 15 pooled countries
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CHAPTER 13 Care of the Transgender Patient 263
(five Latin America, six Asia-Pacific, three European, and the United States).8 Risk
factors for HIV infection among transgender females include multiple male sex
partners, casual sex, and sex while under the influence of alcohol and/or drugs.9
Compounding this higher risk of infection is that transgender individuals face
significant barriers to receiving appropriate care, including poverty, lack of health
insurance, lack of provider knowledge, and fear that prevents finding medical care.1
Principles that healthcare workers should consider when providing care for
transgender individuals are
• promoting inclusiveness (affirming their gender identity, exploring
different options for gender identity expression, and assisting with
medical care decisions that will help alleviate gender dysphoria)
• avoiding stigmas and bias (either overt biases such as discriminatory
practices or verbal abuse or subversive biases including inadvertent
use of inappropriate or offensive terms or making assumptions about
someone based on gender)
TREATMENT OF TRANSGENDER PATIENTS

There are two major guidelines for the treatment of transgender individuals under-
going transition therapy: the World Professional Association for Transgender
Health (WPATH)4 and The Endocrine Society, which concerns the use of hormones
for transition therapy.10 Some or all of the modalities discussed in these guidelines
should be used to successfully treat gender dysphoria. Alleviating gender dysphoria
often involves multi-modal therapy that may include psychotherapy, hormone
therapy to facilitate gender reassignment, and surgical gender reassignment. The
recommendation for the individual living as their identified gender (either full-
time or part-time) has been shown to be beneficial for gender dysphoria. Psycho-
therapy (individual, couple, family, and/or group) can help with exploring gender
identity, role, and expression. Psychotherapy can also help with exploring the
impact of gender dysphoria as well as any experienced stigmas. Ideally, psycho-
therapy will foster and enhance social and peer support structures, improve body
image, and promote resilience. Other important nonmedical support structures
can include in-person or on-line peer support resources for both the individual as
well as peers and family, voice and communication therapy to promote comfort
in gender identity, hair removal, and changes in name and gender on identity
documents (where able).4
The types of hormone therapy used in the treatment of gender dysphoria are
puberty suppression and hormone replacement therapy for the purpose of gender
reassignment. A list of medications used for puberty suppression and transition
therapy is found in Table 13-2.2,10 There are two goals when deciding to suppress
puberty. First, it allows young adolescents to explore their gender dysphoria
before making any permanent decisions regarding potentially permanent physical
changes. Second, it prevents the onset of sex characteristics that are permanent
and potentially difficult to change or conceal. The first-line agents for suppression
of puberty are gonadotropin-releasing hormone (GnRH) analogs. These agents
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TABLE 13-2. Medications Used in the Treatment of Transgender Patients

Medication Class and Effect Dosing
Goserelin GnRH analog; suppresses sub-Q implant; 3.6 mg q4
pituitary gonadotropin and weeks or 10.8 mg q12 weeks
sex steroid production
Histrelin sub-Q implant; 50 mg q12
months releases ~65 mcg/
day
Leuprolide IM depot injection q4 weeks

<25 kg: 7.5 mg
26–37 kg: 11.25 mg
>37 kg: 15 mg
Triptorelin IM depot injection q4 weeks

<20 kg: 1.875 mg
20–30 kg: 2.5 mg
>30 kg: 3.75 mg
Letrozole Aromatase inhibitor; inhibits 2.5 mg orally once/day

estrogen production
Anastrozole 1 mg orally once/day
Tamoxifen Selective estrogen receptor 20 mg orally once/day

modulator; partial estrogen
receptor agonist/antagonist
Spironolactone Antiandrogen; inhibits 25–50 mg orally twice/day

testosterone production
Finasteride 5α-reductase inhibitor; inhibits 1–10 mg orally once/day

testosterone production
Medroxyprogesterone Progestin; suppresses pituitary 2.5 mg orally once/day

gonadotropin and thus sex
steroid production
Estradiol, oral Estradiol 2–6 mg/day
Estradiol valerate, oral 2–6 mg/day
Estradiol valerate, IM 5–20 mg every 2 weeks
Estradiol cypionate, IM 2–10 mg every 1 week
Estradiol, transdermal patch 0.1–0.4 mg/24 hours; patch

applied twice weekly
(continued)
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TABLE 13-2. Medications Used in the Treatment of Transgender Patients

(continued)
Medication Class and Effect Dosing
Testosterone enanthate, IM Testosterone 100–200 mg every 2 weeks (or
50% of the dose weekly)
Testosterone cypionate, IM 100–200 mg every 2 weeks (or

50% of the dose weekly)
Testosterone, transdermal gel 2.5–10 mg/day
Testosterone, transdermal 1–8 mg/day

patch
GnRH: gonadotropin-releasing hormone; IM: intramuscular; sub-Q: subcutaneous
suppress pituitary gonadotropin, thus leading to a halt of sex steroid production.

These agents are well tolerated and their effects are reversible upon discontinua-
tion. However, these agents can be expensive, which limits their use. Alternative
agents would include high-dose progestin (i.e., medroxyprogesterone), estrogen
blockers (i.e., letrozole, tamoxifen), and anti-androgens (i.e., spironolactone,
finasteride). These agents are less efficacious at arresting puberty and are associ-
ated with significantly more side effects. Monitoring when using these agents for
puberty suppression should consist of: monitoring for growth impairment at every
visit, sex steroid levels every 3 months (with subsequent dose adjustments), yearly
laboratory tests (kidney function, liver function, lipid panel, insulin and hemo-
globin A1c), and dual-energy x-ray absorptiometry to test bone density.
Hormone therapy is also utilized to facilitate transition therapy to the patient’s
identified gender. Several studies have shown long-term hormone therapy to
generally be safe in transgender patients.11 The purpose of hormone therapy in
this setting is two-fold. First, it stops endogenous hormone production. Second, it
uses the principles of hormone replacement therapy in hypogonadal patients to
provide exogenous hormone of the identified gender, thus promoting a change in
physical appearance. The same principles of puberty suppression should be used
to suppress endogenous hormone production (even if the patient is beyond the
age of puberty), with a GnRH analog being preferred. Estradiol is the preferred
feminizing hormone over conjugated estrogens because of the ability to measure
serum estradiol levels as well as the variety of dosage forms. Transdermal estrogen
is recommended for patients with risk factors for venous thromboembolism (VTE).
Patients with comorbid conditions that can be affected by estrogen should avoid
oral estrogen if possible. Monitoring during estrogen therapy should include
signs of feminization (e.g., body fat redistribution, decreased spontaneous erec-
tions, breast growth) at every visit, serum testosterone and estradiol levels every
3 months (to ensure normal physiologic levels are being achieved while attaining
desired physical changes), signs and symptoms of VTE, and bone mineral density
ERRNVPHGLFRVRUJ
at baseline if risk factors for osteoporosis exist. Smoking cessation should be initi-
ated, if necessary and if the patient is willing, because of the risk of VTE. If spirono-
lactone is being used to suppress testosterone production, then serum electrolytes
should be monitored.
Testosterone is the preferred agent to elicit masculinizing effects in transi-
tioning transgender men. Intramuscular or transdermal testosterone can be used,
and the goal of therapy is to achieve a serum testosterone level at the physio-
logic concentration that would be found in a biologic male. Higher levels are
associated with an increased rate of adverse effects, including erythrocytosis, liver
dysfunction, and acne. Monitoring should include appropriate signs of masculin-
ization (e.g., fat redistribution, cessation of menses, facial and body hair growth)
at every visit, serum testosterone levels every 3 months with corresponding dose
adjustments, blood count and liver function at baseline and every 3 to 6 months,
annual pap smear if cervical tissue is present, and mammograms as recommended
if mastectomy is not performed.
Some transitioning patients may desire the option of surgery. Not all patients
have surgeries, and the type of surgeries used will vary depending on the indi-
vidual patient. For a patient to be eligible for surgery, certain criteria should be met
beforehand, including having used hormone therapy continuously and respon-
sibly for at least 12 months, successful and continuous real-life experience in their
desired gender role for at least 12 months, participation in psychotherapy during
their transition, demonstrated knowledge of the issues surrounding surgery, and
demonstrated progress in dealing with any family, work, and social issues. Surgeries
that may be used in a transitioning patient include removal of the gonads (orchi-
ectomy and oophorectomy), total hysterectomy, mammoplasty, penectomy, vagi-
noplasty, clitoroplasty, vulvoplasty, mastectomy, scrotoplasty, facial feminization/
masculinazation, liposuction/lipofilling, voice surgery, and hair reconstruction.
OTHER CONSIDERATIONS
Other factors that should be considered when caring for transgender patients
include demonstrating cultural competency and sensitivity and working around
gender-related roadblocks in standard care processes (electronic medical record
systems, medical calculations incorporating gender, gender-driven cancer
screening, and risk evaluation and mitigation strategy [REMS] programs).
Pharmacists, as well as other healthcare practitioners, can promote inclusive-
ness toward transgender patients through several means. Being nonjudgmental
and providing the level and type of care one would provide any patient is first and
foremost. Open communication regarding preferred pronouns and name can help
patients feel comfortable in the healthcare setting. Someone’s preferred name may
be different from the legal name. Make sure all staff are aware of how to be inclu-
sive, as one bad experience can break trust between patient and provider. Consider
modifying forms to be inclusive toward transgender patients. In addition, evaluate
how the electronic medical systems are designed to handle names and gender.
ERRNVPHGLFRVRUJ
A working group from WPATH issued recommendations on data collection and

presentation in these systems.12,13 Take-away points are that gender identity should
be collected first to emphasize the importance of gender identity to the patient
and biologic/birth sex should be collected second. There should be an area for
“preferred name,” and both gender identity and preferred name should be easily
visible to all staff to prevent confusion and mislabeling. Additionally, the collected
biologic sex can be used to drive any automatic calculations (i.e., creatinine clear-
ance) and drug screening (i.e., teratogens).
A common question pharmacists ask when caring for transgender patients
is which gender should be used for physiologic or risk calculations, such as the
Framingham Score or Cockcroft-Gault equation for creatinine clearance. The
answer is that it depends on a number of factors. If a patient is living only as the
affirmed gender and has not begun any medical therapy for transitioning, then
using biologic sex is justified. If a patient has spent multiple years on hormone
therapy and has accompanying changes in muscle mass and fat distribution, then
using the affirmed gender is justified. It ultimately comes down to clinical judg-
ment and individual patient evaluations.2,14 An example would be performing a
renal dose calculation for a renally dosed antiretroviral such as emtricitabine in
a patient with chronic kidney disease. This dosing decision should be based on
the medical history, biologic sex, duration of hormone therapy, and any other
individual patient characteristics one would normally consider when evaluating
a patient.
Cancer screening is another concern in transgender patients. It is important
to know what is recommended to ensure vital cancer screenings are not missed as
well as to explain to the patient why certain cancer screenings are important. A
general rule is that if an organ or body part is present that meets criteria for cancer
screening (i.e., cervix, breasts, testicles), then screening should be carried out. This
makes it paramount to have an accurate and complete medical and surgical history
for all transgender patients. Both chronic estrogen and testosterone therapy have
been linked to increased cardiovascular outcomes, so monitoring and counseling
on VTE and the potential for increased cardiovascular risk is also prudent. Coun-
seling on methods to reduce cardiovascular risk (i.e., smoking cessation or weight
loss) should also be considered.
Another issue important to pharmacists is how to handle gender-based REMS
programs, as these can have limited ability to accurately register transgender
patients. Understanding the complete patient profile (hormone therapy status
and duration, surgical history, age, and sexual history) is vital to understand what
potential risks, if any, exist when administering a potentially teratogenic agent to
a patient.15
HIV CARE IN TRANSGENDER PATIENTS

The general screening, prevention, and treatment guidelines for HIV do not differ
for transgender patients. However, clinicians should take care to address the
ERRNVPHGLFRVRUJ
unique biological, psychological, and social needs of this vulnerable population.

A straight adaptation of HIV programs developed for nontransgender men who
have sex with men or for nontransgender women can fail to consider high rates
of trauma, poverty, incarceration, unemployment, involvement in sex work, and
substance abuse that can be seen in the transgender women population.
Daily, oral pre-exposure prophylaxis (PrEP) with fixed-dose tenofovir diso-
proxil fumarate (TDF), 300 mg, and emtricitabine (FTC), 200 mg, have been
shown to be effective at preventing HIV transmission in transgender women who
have sex with men.16 There are no known drug–drug interactions between this
PrEP regimen and the medications used for hormone therapy. Infection with HIV
is not a contraindication to receiving hormone therapy, and studies suggest that
continuing hormone therapy along with antiretroviral therapy (ART) improves
patient engagement in care processes and can improve adherence of antiretro-
viral medications.17,18 It is known that metabolism of estrogen occurs via the cyto-
chrome P450 enzyme system (CYP3A4). However, with the exception of ampre-
navir and fosamprenavir, antiretroviral drugs can be safely used in combination
with estrogen therapy. Both amprenavir and fosamprenavir have had decreased
serum amprenavir levels when co-administered with estrogen. CYP3A4 inducers
such as the nonnucleoside reverse transcriptase inhibitors efavirenz or nevirapine
or the entire protease inhibitor class would be expected to decrease estrogen levels,
thus requiring dose increases. Additionally, upon the interruption or cessation
of ART one would expect estrogen levels to increase, thus necessitating a dosage
decrease.19 Information on drug–drug interactions between antiviral medications
and agents used for hormone therapy are sparse. Most drug–drug interaction
studies evaluating estrogen are evaluating formulations used as contraception in
nontransgender individuals, thus extrapolation of evidence should be done with
caution. Many available drug–drug interaction studies are in vitro; thus, the clin-
ical significance of the interaction may be unknown.19
One co-therapy that may be seen in a patient with HIV is sulfamethoxazole-
trimethoprim. Pharmacists should be aware when this agent is used in a trans-
gender patient treated with spironolactone (used as an antiandrogen) given the
risk of hyperkalemia. Regular monitoring of renal function and serum potassium
levels should be considered. Similarly, regular monitoring of liver function should
be considered in patients taking testosterone along with antivirals that increase
the risk of hepatotoxicity, such as efavirenz, nevirapine, tipranavir, darunavir, and
ritonavir. Other medications that may commonly be seen in patients with HIV
such as rifampin, and antifungals (itraconazole or fluconazole) can also affect cyto-
chrome P450 enzymes; similar caution with estrogen therapy should be observed.

An engaged and properly trained pharmacist should play an important role in the care
of transgender patients. A major area in which pharmacists can contribute is access to
medication, namely GnRH analogs that have considerable costs associated with them.
ERRNVPHGLFRVRUJ
By working with the patient, insurance companies, and other members of the healthcare
team, pharmacists can ensure consistent access to these medications. Pharmacists should
also play a role in counseling patients starting these medications, which can include topics
like product selection (oral versus transdermal versus intramuscular) and administration
technique (such as with intramuscular testosterone). The pharmacist can provide a clear
expectation of what changes the patients might encounter and when they will encounter
them as well as counsel them on possible adverse effects. A highly engaged pharma-
cist could also assist with long-term drug monitoring of these agents by performing any
adverse-effect mitigation or necessary dose adjustments.2
Transgender patients are a unique patient population with significant healthcare dispari-
ties and barriers. Being culturally competent is paramount when providing care to trans-
gender patients, as it promotes inclusiveness and engagement in the care process and
discourages falling out of the healthcare system.
KEY RESOURCES
• National Center for Transgender Equality
o Leading social justice advocacy organization for transgender people that
promotes equality through various educational and advocacy efforts.
o http://www.transequality.org/
• National LGBT Health Education Center
o Resource center for education resources related to lesbian, gay, bisexual, and
transgender (LGBT) health. Part of a federally qualified LGBT-focused health
center.
o http://www.lgbthealtheducation.org/
• Transgender men
o Website that covers topics more specific to transgender men.
o http://www.ftmi.org/
• Transgender women
o Website with forums, chat, and personal accounts related to topics concerning
transgender individuals.
o https://www.susans.org/
• Additional resources related to transgender health issues relevant to patients, family,
and healthcare providers.
o http://transhealth.phsa.ca/
o http://www.wpath.org/
o http://www.tsroadmap.com/
• University of California at San Francisco Center of Excellence for Transgender Health
o Leading academic resource for medical providers caring for transgender patients.
Dedicated faculty and staff that have years of experience specific to transgender
patients’ needs and issues.
o http://www.transhealth.ucsf.edu/
o http://www.transgendercare.com/
ERRNVPHGLFRVRUJ
REFERENCES
1. Institute of Medicine Committee on Lesbian GB, Transgender Health I, Research G, Opportuni-
ties. The National Academies Collection: Reports funded by National Institutes of Health. The
Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Under-
standing. Washington, DC: National Academies Press, National Academy of Sciences; 2011.
2. Bishop BM. Pharmacotherapy considerations in the management of transgender patients: A
brief review. Pharmacotherapy. 2015;35:1130-1139.
3. De Cuypere G, Van Hemelrijck M, Michel A, et al. Prevalence and demography of transsexu-
alism in Belgium. Eur Psychiat. 2007;22:137-141.
4. Coleman E, Bockting W, Botzer M, et al. Standards of care for the health of transsexual, trans-
gender, and gender-nonconforming people, Version 7. Int J Transgenderism. 2012;13:165-232.
5. Mayer KH, Bradford JB, Makadon HJ, et al. Sexual and gender minority health: What we know
and what needs to be done. Am J Public Health. 2008;98:989-995.
6. Clements-Nolle K, Marx R, Katz M. Attempted suicide among transgender persons: The influ-
ence of gender-based discrimination and victimization. J Homosexual. 2006;51:53-69.
7. Ramirez-Valles J, Garcia D, Campbell RT, et al. HIV infection, sexual risk behavior, and
substance use among Latino gay and bisexual men and transgender persons. Am J Public Health.
2008;98:1036-1042.
8. Baral SD, Poteat T, Stromdahl S, et al. Worldwide burden of HIV in transgender women: A
systematic review and meta-analysis. Lancet Infect Dis. 2013;13:214-222.
9. Herbst JH, Jacobs ED, Finlayson TJ, et al. Estimating HIV prevalence and risk behaviors of trans-
gender persons in the United States: A systematic review. AIDs Behav. 2008;12:1-17.
10. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endocrine treatment of
transsexual persons: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab.
2009;94:3132-3154.
11. Asscheman H, Giltay EJ, Megens JAJ, et al. A long-term follow-up study of mortality in transsex-
uals receiving treatment with cross-sex hormones. Eur J Endocrinol. 2011;164:635-642.
12. Deutsch MB, Buchholz D. Electronic health records and transgender patients—practical recom-
mendations for the collection of gender identity data. J Gen Intern Med. 2015;30:843-847.
13. Deutsch MB, Green J, Keatley J, et al. Electronic medical records and the transgender patient:
Recommendations from the World Professional Association for Transgender Health EMR
Working Group. J Am Med Inform Assoc. 2013;20:700-703.
14. Leach C, Bishop B. Pharmacotherapy considerations in the management of transgender
patients: An alternative viewpoint. Pharmacotherapy. 2016;36:E28-E29.
15. Katz KA. Transgender patients, isotretinoin, and US Food and Drug Administration-mandated
risk evaluation and mitigation strategies: A prescription for Inclusion. JAMA Dermatol.
2016;152:513-514.
16. Deutsch MB, Glidden DV, Sevelius J, et al. HIV pre-exposure prophylaxis in transgender women:
A subgroup analysis of the iPrEx trial. Lancet HIV. 2015;2:E512-E519.
17. Sevelius JM, Carrico A, Johnson MO. Antiretroviral therapy adherence among transgender
women living with HIV. J Assoc Nurse AIDS Care. 2010;21:256-264.
18. Sevelius JM, Patouhas E, Keatley JG, Johnson MO. Barriers and facilitators to engagement and
retention in care among transgender women living with human immunodeficiency virus. Ann
Behav Med. 2014;47:5-16.
19. Radix A, Sevelius J, Deutsch MB. Transgender women, hormonal therapy and HIV treatment: A
comprehensive review of the literature and recommendations for best practices. J Int AIDS Soc.
2016;19:20810.
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14
Women’s Health
INTRODUCTION
In the early years of the epidemic, very few women were diagnosed with human
immunodeficiency syndrome (HIV). Current statistics indicate that HIV infection is
increasingly affecting women—comprising approximately 20% of all new infections
in the United States each year and 25% of all people living with HIV.1 The growing
incidence in women has been linked to an increase in high-risk heterosexual behav-
iors.2,3 Worldwide, however, women comprise nearly 50% of adults living with HIV
infection, with the most concerning rates in sub-Saharan Africa (59%).4 According
to the World Health Organization, young women (aged 15–24) account for 4 out of
10 new HIV infections in sub-Saharan Africa.5 African American women are dispro-
portionately affected. Women are a special population in that a woman’s respon-
sibilities for children and family care may be perceived as a higher priority than
medical care. Counseling should emphasize the importance of retention in care and
attempts made to identify and address any barriers to routine follow-up visits.
GENDER DIFFERENCES
The current HIV guidelines do not differentiate between men and women in the
recommendations for initiating antiretroviral therapy (ART) or goals of therapy.
The only distinction in treatment selection is that utilization of efavirenz is highly
discouraged in women of childbearing potential due to teratogenic effects observed
in animal studies.6 Clinical responses to therapy do not appear to be different
between men and women.7 Of note, lower viral loads have been observed (~2- to
6-fold) in women as compared to men in epidemiologic studies.8 Gender differ-
ences have also been apparent in the incidence and severity of ART adverse effects,
including hepatotoxicity, dyslipidemia, fat redistribution, and lactic acidosis.
The greater severity of adverse effects observed in women may negatively affect
treatment adherence. Adherence research in women indicates that antiretroviral
adherence rates are lower, related, in part, to HIV-related stigma, with the African
American patients at highest risk.9,10
PRECONCEPTION COUNSELING
Current statistics estimate that 68% of women newly diagnosed with HIV infec-
tion are of childbearing potential (ages 15–44).1 Women with HIV should receive
271
ERRNVPHGLFRVRUJ
comparable support from healthcare providers and pharmacists regarding their

reproductive choices. Preconception counseling with HIV care providers should
occur as part of routine patient care to evaluate a woman’s pregnancy desires as
well as provide education about effective contraception methods and safe repro-
ductive options. Preventing unintended pregnancy is an important strategy to
reduce perinatal HIV transmission. Rates of unplanned pregnancies in women
who are HIV positive have been reported as high as 85%, and most adolescent
pregnancies are unplanned.11,12
Preconception counseling with patients should include information about
safe sex practices to prevent HIV transmission to noninfected partners, potential
risk of acquiring more resistant strains of HIV infection, risk of acquiring sexually
transmitted diseases, and effects of smoking and substance abuse in pregnancy
and health outcomes. Early in the HIV epidemic, women with HIV infection
were largely discouraged from becoming pregnant due to the real possibility of
orphaning their children and not surviving them through adulthood. However,
the advancements of ART have dramatically impacted survival and longevity for
women well beyond their childbearing years.
Preconception counseling should assess a woman’s intentions to become preg-
nant as well as provide information on the risks of mother-to-child transmission
(MTCT) during pregnancy and current management strategies to reduce perinatal
infection.6 Patients should be made aware that select antiretroviral regimens are
preferred in pregnancy based on the teratogenicity and clinical evidence and that
modifications in ART may be necessary when she becomes pregnant. The woman’s
overall health should be optimized prior to conception, including achievement of
virologic suppression, control of comorbid conditions such as hypertension, and
receipt of medically indicated immunizations, such as hepatitis B and influenza.
Those women not desiring pregnancy should be counseled on the importance of
consistent use of effective contraceptive methods.
CONTRACEPTION METHODS
It is critical that a barrier method such as condoms, male or female, be used for
prevention of HIV transmission. Current guidelines recommend women with HIV
infection use any contraceptive method.13 However, there are clinically relevant
drug–drug interactions to consider between hormonal contraceptives and ART.
The mechanism by which most interactions occur is mediated by cytochrome
P450 enzymes, resulting in reduced efficacy of the contraceptive therapy.
In terms of oral contraceptives, protease inhibitors (PIs) and nonnucleoside
reverse transcriptase inhibitors (NNRTIs) have the greatest potential for induced
metabolism of steroid hormones and suboptimal contraceptive efficacy. See Table
14-1 for a list of interactions between ART and hormonal contraceptives and
recommendations for management.14
There do not appear to be clinically significant drug interactions between
ART and depot medroxyprogesterone acetate (DMPA). There are limited clinical
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CHAPTER 14 Women’s Health 273
TABLE 14-1. Management of Drug Interactions Between Antiretroviral

Therapy and Hormonal Contraceptives
Contraceptive
Impact on Contraceptive Management
Contraceptive Therapy Antiretroviral Therapy Therapy (AUC) Recommendations
Safe Contraceptive Combinations with Antiretroviral therapy
Combination Etravirine
hormonal therapy or Rilpivirine Additional
progestin-only oral
Atazanavir (without Not clinically significant contraceptive
contraceptives methods not needed
ritonavir)
Or
Etonogestrel Implants Indinavir
Raltegravir
Dolutegravir
Elvitegravir/cobicistat
Maraviroc
DMPA All antiretroviral Not clinically significant Additional

therapy contraceptive
methods not needed
Clinically Relevant Contraceptive Drug Interactions

Ethinyl Estradiol Ritonavir-boosted ↓ 16% to 55% Dual methods of
protease inhibitors contraception or an
alternative method
Atazanavir without ↑ 48% Lower dose of ethinyl

ritonavir estradiol (≤30
mcg) or alternative
contraceptive
Fosamprenavir without ↑ levels Alternative

ritonavir contraceptive is
recommended due to
lower antiretroviral
concentrations
Nelfinavir ↓ 47% Dual methods of

contraception or an
alternative method
Norgestimate Efavirenz ↓ metabolites Dual methods of

(83% levonorgestrel, contraception or an
64% norelgestromin) alternative method
(continued)
ERRNVPHGLFRVRUJ
TABLE 14-1. Management of Drug Interactions Between Antiretroviral

Therapy and Hormonal Contraceptives (continued)
Contraceptive
Impact on Contraceptive Management
Contraceptive Therapy Antiretroviral Therapy Therapy (AUC) Recommendations
Norethindrone Ritonavir-boosted ↓ 14% to 34% Dual methods of
protease inhibitors contraception or an
alternative method
Atazanavir without ↑ 110% Additional

ritonavir contraceptive
methods not needed
Fosamprenavir ↑ levels Alternative

contraceptive is
recommended due to
lower antiretroviral
concentrations
Etonogestrel Implants Ritonavir-boosted Clinical data lacking Additional method

protease inhibitors but preliminary data of contraception
suggest ↑ levels (including barrier
method) or
an alternative
contraceptive may be
considered
Efavirenz ↓ etonogestrel Dual methods of

contraception or an
alternative method
Nevirapine No studies but similar Additional method

PK interactions as of contraception
efavirenz (including barrier
method) or
an alternative
contraceptive may be
considered
See reference 14 for more information.
ERRNVPHGLFRVRUJ
pharmacokinetic data pertaining to drug interactions with alternative dosage

forms such as transdermal patches, intravaginal rings, and long-acting reversible
contraception such as intrauterine contraceptive devices (IUDs). Patients should
be advised against the use of spermicides as a form of contraception. The spermi-
cide nonoxynol-9, for example, has facilitated HIV transmission by altering the
cervical mucosa and increasing viral shedding.15
SAFE CONCEPTION FOR WOMEN IN SERODISCORDANT

RELATIONSHIPS
It is not uncommon for couples desiring to become pregnant to be in a serodiscor-
dant relationship where one person is HIV-negative. Each year new HIV infections
occur resulting from serodiscordant couples attempting to conceive. Serodiscor-
dant couples should be counseled on the best strategies to safely conceive while
minimizing the risk of HIV transmission to the uninfected partner and fetus.
There are several strategies for reducing the risk of HIV transmission that
should be discussed with serodiscordant couples prior to attempting to conceive
(Figure 14-1). The first, and one of the most effective strategies, is for the HIV-
infected partner to achieve virologic suppression on ART. Studies have demon-
strated HIV transmission risk was reduced 92% to 96% when the HIV-infected
partner was treated with ART.16,17 A more recent observational study demonstrated
a zero HIV transmission risk in serodiscordant couples reporting condomless sexual
activity with the HIV-infected partner virologically suppressed on ART.18 Although
these are significant achievements, it is important to emphasize to couples that
although the HIV-infected partner is virologically suppressed on ART, risk is not
fully eliminated for HIV transmission during unprotected intercourse and more
research is needed in high-risk serodiscordant couples. As a result, couples should
be advised to use condoms at all times around the periovulatory time. A second
strategy is that both the HIV-infected and uninfected partners should be screened
and receive treatment for genital tract infections. The inflammation that arises
from these infections can increase HIV genital shedding and may increase the risk
of HIV transmission.14
The safest option for conception in women who are HIV-positive is artifi-
cial (self-insemination) with the HIV-negative partner’s sperm.14 If the woman is
HIV-negative in the discordant relationship, safe options include artificial insem-
ination with donor sperm from HIV-uninfected men, sperm washing plus insem-
ination from the HIV-infected partner, or in vitro fertilization. Due to the chal-
lenges for most patients to utilize these more expensive reproductive methods
or identify fertility clinics working with HIV-infected patients, another option to
lower the risk is the use of pre-exposure prophylaxis (PrEP). This strategy provides
ART to the HIV-negative partner while trying to conceive. Tenofovir disoproxil
fumerate/emtricitabine (TDF/FTC) has received U.S. Food and Drug Administra-
tion (FDA) approval for PrEP for prevention of HIV infection in uninfected high-
risk individuals, although not explicitly in the context of conception with serodis-
cordant couples. To be maximally effective, the Centers for Disease Control and
ERRNVPHGLFRVRUJ
PRECONCEPTION
Achieve virologic
suppression OPTIONAL:
Initiate pre-exposure
prophylaxis (PrEP)
with TDF/FTC 1 month
before conception
Screen for genital tract infections
and treat
CONCEPTION STRATEGIES
HIV-Positive Male HIV-Positive Female
Timed unprotected
• Artificial
intercourse with PrEP Artificial
insemination with
during peri-ovulatory insemination
donor sperm
period.
• Sperm washing
with intrauterine
insemination or
in vitro fertilization
FIGURE 14-1. Safe conception considerations for serodiscordant couples.
Prevention (CDC) recommends that PrEP should be initiated 1 month before and
continued for 1 month after attempting pregnancy.19 HIV-negative partners have
two options when using PrEP for conception. They may use PrEP continuously
during the months they are trying to conceive or intermittently only around the
periovulatory phase each month.
Although continuous use of PrEP offers the greatest consistency of drug levels
and protection, there is also the potential for side effects with therapy. In general,
however, TDF/FTC is well tolerated. Intermittent use of PrEP to minimize medi-
cation side effects could contribute to inadequate exposure based on the patient’s
timing of drug therapy. Pharmacists can play a role in counseling patients on the
timing between periovulatory and ovulation phases for conception for patients
selecting this option.
For more information on dosing, safety monitoring, and HIV testing related
to the use of PrEP, please refer to Chapter 6.
ERRNVPHGLFRVRUJ
PREGNANCY CARE
One of the landmark trials in HIV medicine, the Pediatric AIDS Clinical Trials
Group (PACTG 076) in 1994 demonstrated reduced perinatal transmission of
HIV with the use of ART in pregnancy.20 The MTCT risk during pregnancy in the
absence of ART is approximately 25%. This trial and subsequent trials with combi-
nation ART during pregnancy observed reduced perinatal transmission rates of less
than 2% with prevention efforts during delivery and postpartum.14
Women who are pregnant should be counseled on risks and benefits of treat-
ment for both the mother’s health and prevention of perinatal transmission, poten-
tial adverse effects of ART in pregnancy, and the importance of strict adherence to
achieve these outcomes. The Antiretroviral Pregnancy Registry (www.APRegistry.
com) was formed with the intent of evaluating pregnancy outcomes associated
with antiretroviral medication use throughout pregnancy and especially in the
first trimester.21 In an effort to better understand the teratogenicity potential with
ART, healthcare professionals are urged to contribute pregnancy exposure data to
the registry for ongoing monitoring of safety. Pharmacists can play an important
role in informing healthcare prescribers and patients of the benefits of enrolling in
this registry and facilitating the process.
Antepartum Management
Reducing mother-to-child HIV transmission in pregnancy with ART occurs as a
result of two primary mechanisms. First, suppressing and maintaining control of
the maternal viral load in blood and genital secretions is a major component.
Second, providing PrEP with ART significantly reduces transmission to the fetus in
utero and following delivery.
Prior to initiation of ART, it is critical to obtain a complete ART history and
perform a genotypic resistance test to determine baseline susceptibility and direct
therapeutic options. In antiretroviral-naïve patients, it is generally recommended
to begin ART prior to the results of the genotype due to transmission concerns with
viremia with fewer weeks of ART.14 If necessary, alterations to the empiric regimen
should be implemented based on the resistance results to achieve and maintain
virologic suppression. In women already receiving ART, the regimen should be
continued (including efavirenz) unless it is not achieving virologic suppression
or is poorly tolerated. Research indicates that interrupting ART during pregnancy
increases the risk of MTCT, especially in the third trimester.22 If the woman was
previously treated for HIV infection but is currently not taking ART, informa-
tion regarding previous therapies should be obtained to determine drug-induced
adverse effects or prior resistance on therapy.
When selecting an antiretroviral regimen for a patient, several factors must be
considered. These include tolerability, susceptibility based on genotypic resistance
testing, pill burden, dosing frequency, drug–drug interactions, comorbidities, and
information regarding safety and efficacy in pregnancy. In general, the therapies
ERRNVPHGLFRVRUJ
offered to treatment-naïve, HIV-infected pregnant women are very similar to the

nonpregnant population. The Department of Health and Human Services (DHHS)
perinatal guidelines recommend combination therapy that may include two nucle-
oside reverse transcriptase inhibitors (NRTIs) and either a ritonavir-boosted PI or
integrase inhibitor.14 Table 14-2 provides a list of the recommended therapies. The
primary distinction is that dolutegravir and elvitegravir/cobicistat-based regimens
are not currently recommended in ART-naïve pregnant women due to a lack of
available clinical and pharmacokinetic evidence. The DHHS perinatal guidelines
are updated regularly, so they should be consulted for guidance on the most current
recommended pregnancy regimens and individual agents.
Because a major mechanism to preventing MTCT is providing pre-exposure
prophylaxis, antiretroviral regimens in pregnancy typically include at least one
agent that achieves good placental transfer. Among the antiretroviral classes,
NRTIs, NNRTIs, and integrase strand transfer inhibitors (INSTIs) cross the placenta
effectively to provide drug concentrations in the fetus. PIs, however, have low
placental transfer due to placental efflux transporter mechanisms and high protein
binding.14 The preferred NRTIs that are well studied in pregnancy include teno-
fovir disoproxil fumerate, emtricitabine, lamivudine, and abacavir.
Prior to the use of abacavir, an HLA-B*5701 test should be performed to eval-
uate risk of hypersensitivity. PIs should be boosted with ritonavir when used in
pregnancy. Preferred PIs are atazanavir and darunavir due to experience in preg-
nancy, once-daily dosing administration with atazanavir, and overall tolerability
of both compared to others in the class. Cobicistat has not been studied in preg-
nancy and, therefore, is not recommended at this time as a pharmacokinetic
enhancer in treatment-naïve pregnant patients. Raltegravir is currently the only
TABLE 14-2. 2016 Recommended Therapies in Pregnancy for Prevention of

Mother-to-Child Transmission
Preferred Antiretroviral Therapy Regimens
NRTI Backbone Options:
Tenofovir disoproxil fumerate/emtricitabine
Tenofovir disoproxil fumerate/lamivudine
Abacavir/lamivudine*
PLUS one of the following options from the drug classes below:
Protease Inhibitors INSTIs

Atazanavir/ritonavir Raltegravir
Or
Darunavir/ritonavir
INSTIs: integrase strand transfer inhibitors; NRTI: nucleoside/tide reverse transcriptase inhibitor
See reference 14 for more information.
* Not recommended with atazanavir/ritonavir or with efavirenz if pretreatment HIV RNA is >100,000 copies/mL.
ERRNVPHGLFRVRUJ
integrase inhibitor recommended for treatment-naïve pregnant patients based on

experience in pregnancy. NNRTIs efavirenz and rilpivirine are alternative therapy
recommendations. In animal studies, birth defects have been observed with
efavirenz. The potential for fetal safety concerns compared to treatments without
teratogenic effects have shifted efavirenz to an alternative treatment in pregnancy.
Rilpivirine is also an alternative due to less experience (data) in pregnancy. For
optimal efficacy, it is recommended only for use in patients with a baseline viral
load <100,000 copies/mL or CD4 >200 cell/mm3. Tenofovir alafenamide efficacy
and safety in pregnancy has not been studied at this time.
Teratogenicity research on use of ART in first-trimester pregnancy has gener-
ally revealed similar rates of birth defects as in the general population.14 However,
in primate animal studies with efavirenz used at human doses, congenital malfor-
mations involving the eyes, brain, and cleft palate were observed. There have been
neural tube defects reported in women taking efavirenz, but current evidence
does not conclusively support a causal relationship between efavirenz and first-
trimester human birth defects. The effects of tenofovir disoproxil fumerate on
bone development in pregnancy have been studied. Although lower fetal bone
density was observed in animal studies, reversible, first-trimester experience in
human studies has revealed incidence rates comparable to the general popula-
tion. A small study in Africa observed no major effects of tenofovir disoproxil
fumerate on serum creatinine and phosphorus levels in infants in the first year of
life following use during pregnancy and breastfeeding.23
Pharmacokinetic research of antiretroviral dosing in HIV-infected pregnant
women indicate the therapeutic concentrations of NRTIs, NNRTIs, and raltegravir
are not changed clinically compared to the nonpregnant population; however,
some PIs had lower concentrations particularly in the second and third trimesters.
Atazanavir requires a higher dose in the second and third trimester (atazanavir 400
mg with ritonavir 100 mg), and raltegravir and darunavir should be dosed twice
daily during pregnancy. Data from pharmacokinetic studies are lacking at this
time to guide dosing in pregnancy with newer integrase inhibitors such as dolute-
gravir and elvitegravir as well as etravirine, maraviroc, and enfuvirtide. Research
is continuously evolving with safety and drug disposition of alternative ARTs in
pregnancy. As a result, consulting with an HIV expert may be helpful in providing
information on clinical evidence with the newer therapies.
The maternal viral load should be followed closely in pregnant women until
virologic suppression is achieved on therapy. Then viral load monitoring is recom-
mended every 3 months and evaluation approximately 2 weeks prior to delivery
to direct the most appropriate method of delivery. Adherence to ART is critical to
maintaining virologic suppression throughout pregnancy and should be empha-
sized at each visit. One special population that is increasing in numbers, which
should be closely monitored, is perinatally infected pregnant women. Due to the
long duration of treatment experienced over their lifetime, they generally have
more extensive baseline resistance, and adherence could be a greater challenge.
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Intrapartum Management
The greatest risk of mother-to-child HIV transmission occurs during labor and
delivery. As a result, the woman should continue to take ART up to and through
delivery if possible. Additionally, the maternal viral load should be assessed
between 34 and 36 weeks. In the PACTG 076 study, intravenous (IV) zidovudine
was administered during delivery as prophylaxis. Recent studies have demon-
strated that in women with lower viral loads just prior to delivery, IV zidovu-
dine during labor and delivery provided no additional benefit in HIV transmission
rates.14 However, women with a viral load >1,000 copies/mL or with an unknown
viral load should receive zidovudine to further reduce the risk of perinatal trans-
mission, regardless of the mother’s susceptibility to zidovudine.
The mode of delivery also has a substantial impact on perinatal transmis-
sion rates in high-risk patients. The exposure of the fetus to the mother’s blood
and genital tract during contractions and delivery increases the risk of infection.
Therefore, for pregnant women who do not achieve a viral load ≤1,000 copies/mL,
it is recommended to schedule a cesarean delivery at 38 weeks gestation prior to
rupture of membranes.14 Women who are virologically suppressed do not have a
higher risk of HIV transmission with a vaginal delivery; therefore, the data do not
support cesarean delivery in these patients.
The pharmacist can provide assistance to those hospitals that do not have
an intrapartum treatment protocol in place. A helpful resource for intrapartum
management protocols is found at www.hiveonline.org.24 This organization has
developed and published protocols intended to be shared and adopted by hospi-
tals in need of such order sets. These example order set templates and protocols
may be found in the Provider Resources section on this website.
Postpartum Management
During counseling, pregnant women should be informed that HIV is transmitted
through breast milk and that infant formula must be used for feeding the newborn.
Guidelines also advise against premastication of food to prevent HIV transmis-
sion.14 Additional preventive measures in the care of the newborn are discussed in
Chapter 15, “Pediatric HIV Infection.”
Following delivery, the provider should discuss the mother’s interest in and
feasibility of continuing the pregnancy ART regimen or interest in other regimen
options. If the pregnancy regimen is continued and includes PIs, adjustments back
to the standard doses should be made following delivery.
Childbirth represents a challenging time for HIV-positive women with respect
to maintaining virologic suppression. Postpartum viral rebound is not uncommon
and usually reflects reduced adherence to ART and neglecting their personal needs
while providing care for the newborn. In addition to the negative effects of viremia
on the woman’s health, she is at high risk of transmitting HIV to an HIV-negative
partner and developing antiretroviral resistance. Women should also be evaluated
for postpartum depression, which may affect ART adherence and virologic control.
ERRNVPHGLFRVRUJ
As a result, this is a critical period for retention in clinical care, so it is essential

for the pharmacist to provide counseling on the importance of close monitoring.
CERVICAL CANCER SCREENING

Women with HIV infection have higher rates of cervical cancer and human papil-
lomavirus (HPV) co-infection than uninfected women.25,26 This is believed to be
due to lowered immune system responses and failure to effectively clear HPV
infection.25 Some data suggest that treating HIV infection reduces the progression
of precancerous cervical lesions.27 In light of the cervical cancer statistics, HIV
guidelines recommend women with HIV be closely monitored, beginning with
a baseline Pap smear at the time of diagnosis.28 If the first result is normal, some
experts recommend Pap smear tests every 6 months until three consecutive tests
are normal and then testing every 3 years.
HPV types 16 and 18 are high-risk types that lead to most cases of cervical
dysplasia and cancer, and all current HPV vaccines protect against these types.28
Immunogenicity of the HPV vaccine in HIV-positive women has been demon-
strated with the best results in those with higher CD4 counts (CD4 >200 cells/
mm3).29 In women, the HPV vaccine is recommended for ages 13 to 26 who have
not been previously vaccinated or completed the series. It is a three-dose series
with the second dose at 1 to 2 months and the third dose at 6 months.30 For more
information on HIV and cancer, please refer to Chapter 16.
ROLE OF THE PHARMACIST IN WOMEN’S HEALTH

Pharmacists have unique opportunities to positively influence women’s health outcomes
in a number of ways. First, the influence of counseling on health behaviors, including
medication adherence, cannot be overstated. Perinatal outcomes in pregnancy are contin-
gent on maternal medication adherence. Pharmacists can reinforce the educational points
to pregnant women about the risks and benefits of ART in pregnancy and the importance
of treatment adherence. The success of current strategies on reducing vertical transmission
risk is reassuring to women with HIV.
Although adherence to ART is a standard discussion with most HIV patients, pharma-
cists can emphasize the benefits of virologic control in reducing HIV transmission during
pregnancy as well as to their partners (if HIV negative). Additionally, achieving treatment
goals improves the woman’s health and reduces the risk of HIV-associated sequelae. One
study of HIV-positive women in the Women’s Interagency HIV Study noted underutiliza-
tion of pharmacist counseling but observed a positive trend toward better adherence rates
and improvements in CD4 cell count in pharmacist-counseled women.31
Pharmacists play a critical role in identifying clinically relevant drug interactions with
antiretroviral regimens. Drug interactions with combination hormonal contraceptives may
necessitate additional methods of contraception and need for further counseling. Phar-
macists are also important to the review of antiretroviral medication dosing in pregnancy
ERRNVPHGLFRVRUJ
when dosing adjustments are warranted to ensure adequate levels, especially in the third
trimester. Hospital pharmacists play a key role in maintaining supply of needed ARTs for
intrapartum management (such as zidovudine), especially in smaller hospital settings.
Pharmacists can convey heightened sensitivity to the additional challenges of family
care facing women with HIV and encourage retention in medical care. Vaccine-prevent-
able disease is another aspect of care where pharmacists are well positioned to have an
impact. Educating patients about vaccinations and improving HPV vaccine rates in this
more vulnerable population is an important opportunity for pharmacists. At a time in
our country when rates of HIV infection in women are growing, attention to the special
considerations and needs of these women is paramount.
KEY RESOURCES
• CDC HIV Surveillance Report
o The report provides statistics of new cases of HIV infection and AIDS in the
United States by demographics, transmission category, and geographic region.
http://www.cdc.gov/hiv/library/reports/surveillance/.
• CDC Pre-exposure Prophylaxis Clinical Practice Guideline
o This resource provides guidance recommendations on indications for PrEP
therapy, monitoring therapy, and follow-up HIV testing. Additionally, it provides
risk reduction outcomes observed in clinical trials. http://www.cdc.gov/hiv/
guidelines/preventing.html.
• DHHS Pregnancy and Perinatal Transmission Guidelines
o This resource offers information on guidance of the use of ART in pregnancy and
is updated as new information becomes available. This is a helpful resource in
the care of the HIV-positive woman during pregnancy for a variety of scenarios,
including infant care after birth. https://aidsinfo.nih.gov/guidelines/html/3/peri-
natal-guidelines/0#.
• HIVE
o This website provides resources to hospitals and providers in the form of proto-
cols and order sets for antepartum, intrapartum, and postpartum management
as well as resources for breastfeeding and reproductive topics. http://www.
hiveonline.org.
Example Intrapartum order set: http://www.hiveonline.org/wp-content/
uploads/2015/02/MDXOrdersXMaternalXIntrapartumXHIVEXAugX2015.pdf.
• National Perinatal HIV Consultation and Referral Service
o This hotline provides a team of specialists to answer questions on perinatal HIV
management, including complex patient treatment issues as well as clinicians
experienced in reproductive health services. http://nccc.ucsf.edu 1-888-448-8765.
REFERENCES
1. Centers for Disease Control and Prevention. HIV Surveillance Report, 2014; vol. 26. http://www.
cdc.gov/hiv/library/reports/surveillance/. Published November 2015. Accessed June 22, 2016.
2. Moore RD. Epidemiology of HIV infection in the United States: Implications for linkage to care.
Clin Infect Dis. 2011;52(S2):S208-213.
3. Hodder SL, Justman J, Hughes JP, et al. HIV acquisition among women from selected areas of the
United States. Ann Intern Med. 2013;158(1):10-18.
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4. WHO. Global health observatory (GHO) data. Number of women living with HIV, WHO; 2014.
Available at: http://www.who.int/gho/hiv/epidemic_status/cases_adults_women_children_text/
en/.
5. AVERT. Global information and advice on HIV & AIDS. HIV and AIDS in Sub-Saharan Africa
Regional Overview, AVERT; 2013. Available at: http://www.avert.org/professionals/hiv-around-
world/sub-saharan-africa/overview.
Services. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Accessed May 31, 2016.
7. Floridia M, Giuliano M, Palmisano L, et al. Gender differences in the treatment of HIV infection.
Pharmacol Res. 2008;58(3-4):173-182.
8. Gandhi M, Bacchetti P, Miotti P, et al. Does patient sex affect human immunodeficiency virus
levels? Clin Infect Dis. 2002;35(3):313-322.
9. Nicastri E, Leone S, Angeletti C, et al. Sex issues in HIV-1-infected persons during highly active
antiretroviral therapy: A systematic review. J Antimicrob Chemother. 2007;60(4):724-732.
10. Puskas CM, Forrest JI, Parashar S, et al. Women and vulnerability to HAART non-adherence:
A literature review of treatment adherence by gender from 2000 to 2011. Curr HIV/AIDS Rep.
2011;8(4):277-287.
11. Sutton MY, Patel R, Frazier EL. Unplanned pregnancies among HIV-infected women in care—
United States. J Acquir Immune Defic Syndr. 2014;65(3):350-358.
12. Koenig LJ, Espinoza L, Hodge K, et al. Young, seropositive, and pregnant: Epidemiologic and
psychosocial perspectives on pregnant adolescents with human immunodeficiency virus infec-
tion. Am J Obstet Gynecol. 2007;197(3 Suppl):S123-S131.
13. Centers for Disease Control and Prevention. Update to CDC’s U.S. Medical Eligibility Criteria
for Contraceptive Use, 2010: Revised recommendations for the use of hormonal contraception
among women at high risk for HIV infection or infected with HIV. MMWR Morb Mortal Wkly
Rep. 2012;61(24):449-452.
14. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmis-
sion. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for
Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.
Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed June 25,
2016.
15. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR
Recomm Rep. 2015;64(RR-03):1-137.
16. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral
therapy. N Engl J Med. 2011;356(6):493-505.
17. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of anti-
retroviral therapy: A prospective cohort analysis. Lancet. 2010;375(9731):2092-2098.
18. Rodger AJ, Cambiano V, Bruun T, et al. Sexual activity without condoms and risk of HIV trans-
mission in serodifferent couples when the HIV-positive partner is using suppressive antiretro-
viral therapy. JAMA. 2016;316(2):171-181.
19. Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV
infections in the United States—2014: A clinical practice guideline. Atlanta, GA: US Department
of Health and Human Services, CDC, US Public Health Service; 2014. Available at: http://www.
cdc.gov/hiv/pdf/guidelines/ PrEPProviderSupplement2014.pdf.
20. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human
immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group
Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180.
21. Antiretroviral Pregnancy Registry. Available at: http://www.APRegistry.com.
22. Galli L, Puliti D, Chiappini E, et al. Is the interruption of antiretroviral treatment during preg-
nancy an additional major risk factor for mother-to-child transmission of HIV Type 1? Clin Infect
Dis. 2009;48(9):1310-1317.
23. Floridia M, Liotta G, Andreotti M, et al. Serum phosphate and creatinine levels in the first year
of life in infants born to HIV-positive mothers receiving tenofovir-based combination regimens
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during pregnancy and prolonged breastfeeding in an Option B+ program in Malawi. J Acquir

Immune Defic Syndr. 2016;73(5):e90-91.
24. HIVE. Available at: http://www.hiveonline.org.
25. Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with
human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl
Cancer Inst. 2000;92(18):1500-1510.
26. Ahdieh L, Klein RS, Burk R, et al. Prevalence, incidence, and type-specific persistence of human
papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. J
Infect Dis. 2001;184(6):682-690.
27. Ahdieh-Grant L, Rui L, Levine AM, et al. Highly active antiretroviral therapy and cervical squa-
mous intraepithelial lesions in human immunodeficiency virus-positive women. J Natl Cancer
Inst. 2004;96(14):1070-1076.
Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed June 24,
2016.
29. Kojic EM, Kang M, Cespedes MS, et al. Immunogenicity and safety of the quadrivalent human
papillomavirus vaccine in HIV-1-infected women. Clin Infect Dis. 2014;59(1):127-135.
30. Kim DK, Bridges CB, Harriman KH. Advisory Committee on Immunization Practices. Advisory
Committee on Immunization Practices recommended immunization schedule for adults aged
19 years or older: United States, 2016. Ann Intern Med. 2016;164:184-194.
31. Cocohoba JM, Althoff KN, Cohen M, et al. Pharmacist counseling in a cohort of women with
HIV and women at risk for HIV. Patient Pref Adherence. 2012;6:457-463.
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15
Pediatric HIV Infection
Kathleen K. Graham, PharmD, and Ana M. Puga, MD
INTRODUCTION
Human immunodeficiency virus (HIV) infection is one of the most devastating
pediatric diseases in history. At the end of 2015, approximately 1.8 million chil-
dren (<15 years old) worldwide were living with HIV/acquired immunodeficiency
syndrome (AIDS); in 2015 alone, there were 150,000 children newly infected and
110,000 deaths.1 The majority were infected through perinatal mother-to-child
transmission (MTCT) by their HIV-positive mothers during pregnancy, childbirth,
or breastfeeding and are living in resource-poor countries.1
Perinatally Acquired Pediatric HIV Infection

Since the first case reports of perinatally acquired HIV infection in the early 1980s,
significant progress has been made in the prevention of mother-to-child trans-
mission (PMTCT). In the early 1990s, the landmark Pediatric AIDS Clinical Trials
Group (PACTG) 076 protocol demonstrated that antiretroviral (ARV) prophy-
laxis given antepartum and intrapartum to the mother, and immediately to the
neonate, could significantly reduce transmission by 68%.2 Implementation of the
PMTCT protocol in the United States has decreased MTCT to <2%, compared to
rates of 30% to 40% without prophylaxis (Figure 15-1A).3
Worldwide progress toward the elimination of MTCT is now emerging (http://
www.unaids.org/en/resources/campaigns/HowAIDSchangedeverything/factsheet).
In 2015, 77% of pregnant women living with HIV globally were accessing anti-
retroviral therapy (ART) to avoid transmission of HIV to their children, and new
HIV infections among children were reduced by 58% from 2000 to 2014.1 The 2016
UNAIDS Prevention Gap report found that the provision of antiretroviral medi-
cines to women living with HIV during pregnancy or breastfeeding has averted
1.6 million new child HIV infections globally (Figure 15-1B).4 Future global plans
including the Start Free, Stay Free, AIDS Free initiative to prevent MTCT, ensure
that children stay HIV-free through life, and prevent progression to AIDS in chil-
dren and adolescents living with HIV.4
Nonperinatally Acquired Pediatric HIV Infection

In contrast to the low rate of new perinatally acquired HIV infection in the United
States, the rate of nonperinatally acquired HIV infection (acquired through sexual
transmission or injection drug use) in U.S. adolescents is on the rise. Youth aged
285
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1,000
Number 800
600
400
200
0
1985 1987 1989 1991 1993 1995 1997 1999 2001 2003
Year
*Acquired immunodeficiency syndrome.

† Data adjusted for reporting delays and for estimated proportional
redistribution of cases in persons reported without an identified risk factor.
FIGURE 15-1A. Estimated number of cases of perinatally acquired AIDS,* by year of diagnosis —
United States, 1985–2004.†
Source: Centers for Disease Control and Prevention (CDC) Achievements in public health.
Reduction in perinatal transmission of HIV infection— United States, 1985-2005. MMWR Morb
Mortal Wkly Rep. 2006;55(21):592–597 pmid:16741495.
600
500
Number (thousand)
400
1.6 million new child HIV
300 infections averted
200
100
0
1995 2000 2005 2010 2015
New child HIV infections without the provision of antiretroviral medicines New child HIV infections
to prevent mother-to-child transmission
FIGURE 15-1B. New HIV infections among children (aged 0–14 years) with and without the
provision of antiretroviral medicines to prevent mother-to-child transmission, global, 1995–2015.
Source: Centers for Disease Control and Prevention (CDC) Achievements in public health.
Reduction in perinatal transmission of HIV infection—United States, 1985-2005. MMWR Morb
Mortal Wkly Rep. 2006;55(21):592–597 pmid:16741495.
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CHAPTER 15 Pediatric HIV Infection 287
13 to 24 accounted for more than 1 in 5 new HIV diagnoses in 2014. Among youth
aged 13 to 24 diagnosed with HIV in 2014, 80% (7,828) were gay and bisexual
males. Of those newly diagnosed young gay and bisexual males, 55% (4,321) were
black, 23% (1,786) were Hispanic/Latino, and 16% (1,291) were white.5
Globally, nonperinatally acquired transmission is also on the rise, with 26
adolescents (15 to 19 years) newly infected with HIV every hour in 2014 (220,000
total). Adolescent girls and young women are disproportionately affected by HIV
in sub-Saharan Africa where 7 out of every 10 new infections occur in girls 15 to
19 years of age.6
Challenges in HIV Pediatric Infection

Management of pediatric HIV infection has presented many challenges through the
years as pediatric-based research lagged behind research in the adult population.
Due to delays in developing pediatric ARV formulations and dosing guidelines, the
NIH-based PACTG was founded. It has conducted numerous clinical trials and has
facilitated the approval of many current pediatric ARV formulations. The PACTG has
now expanded to become the International Maternal Pediatric and Adolescent AIDS
Clinical Trials (IMPAACT) group. Current international and domestic protocols are
evaluating new pediatric formulations, drug interactions, PMTCT, vaccines, mono-
clonal antibodies, and cure strategies. The Adolescent Trials Network (ATN) was also
formed to specifically address the needs of adolescents regarding testing, treatment,
adherence, and psychosocial issues.
The detection and management of pediatric and adolescent HIV infection
continues to present various challenges that are also unique practice opportuni-
ties for pharmacists. In this chapter we will review each of these challenges in the
management of pediatrics and adolescents living with HIV, and focus on the phar-
macist’s role on the healthcare team to provide expertise in care and treatment.
Testing for Perinatal HIV Exposure and HIV Diagnosis

The initial postnatal management of the HIV-exposed infant is outlined in Table
15-1. Testing in neonates to detect perinatal HIV infection at <18 months requires
the use of direct nucleic acid testing. Antibody tests should not be used due to
the possible transfer of maternal antibodies.7 Because the HIV quantitative RNA
assay could potentially be affected by the maternal or neonatal ARV prophylaxis,
the HIV DNA assay is preferred and is more specific with 100% identification at 3
months and 6 months.7
Virologic diagnostic testing at birth should be considered for HIV-exposed
infants at high risk of perinatal HIV transmission. All HIV-exposed infants require
virologic testing at 14 to 21 days, 1 to 2 months, and 4 to 6 months. A positive
virologic test should be confirmed as soon as possible by a repeat virologic test on
a second specimen.7 Diagnostic testing at 18 to 24 months requires direct nucleic
acid testing and HIV antibody (or antigen/antibody) testing. Diagnostic testing in
children with nonperinatal exposure or children with perinatal exposure aged >24
months relies primarily on the use of HIV antibody (or antigen/antibody) tests.8
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TABLE 15-1. Recommendations for Initial Postnatal Management of the

HIV-Exposed Neonate
• A complete blood count and differential should be performed on newborns as a baseline
evaluation (BIII).
• If hematologic abnormalities are identified in infants receiving prophylaxis, decisions on whether
to continue infant antiretroviral (ARV) prophylaxis need to be individualized. Consultation
with an expert in pediatric HIV infection is advised if early discontinuation of prophylaxis is
considered (CIII).
• Decisions about the timing of subsequent monitoring of hematologic parameters in infants
depend on baseline hematologic values, gestational age at birth, clinical condition of the
infants, the zidovudine dose being administered, receipt of other ARV drugs and concomitant
medications, and maternal antepartum therapy (CIII).
• Hemoglobin and neutrophil counts should be remeasured 4 weeks after initiation of prophylaxis
for infants who receive combination zidovudine/lamivudine-containing ARV prophylaxis
regimens (AI).
• Routine measurement of serum lactate is not recommended. However, measurement can be
considered if an infant develops severe clinical symptoms of unknown etiology (particularly
neurologic symptoms) (CIII).
• Virologic tests are required to diagnose HIV infection in infants aged <18 months and should be
performed at 14 to 21 days of life and at ages 1 to 2 months and 4 to 6 months (AII).
• To prevent Pneumocystis jirovecii pneumonia (PCP), all infants born to HIV-infected women should
begin PCP prophylaxis at ages 4 to 6 weeks, after completing their ARV prophylaxis regimen,
unless there is adequate test information to presumptively exclude HIV infection (see the
Pediatric Opportunistic Infections Guidelines) (AII).
• Healthcare providers should routinely inquire about breastfeeding and premastication; instruct
HIV-infected caregivers to avoid these practices, and advise on safer feeding options (AII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II
= One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes;
III = Expert opinion
Source: Panel on Antiretroviral Therapy and Medical Management of HIV-Infection. Recommendations for Use of
Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal
HIV Transmission in the United States. (Last updated: October 26, 2016, last reviewed: October 26, 2016.) Accessed
January 20, 2017. Available at: https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0.
Neonatal Post-Exposure Prophylaxis

Management of the HIV-exposed neonate starts with rapid testing and diagnosis of
HIV infection, followed by ARV prophylaxis postpartum to prevent HIV infection,
and rapid treatment of neonates with confirmed HIV infection following delivery.
Table 15-2 outlines the PMTCT protocol with dosing guidelines. Neonates should
be initiated on zidovudine (ZDV) as soon as possible, preferably within 6 hours. A
6-week neonatal ZDV prophylaxis regimen is recommended for all HIV-exposed
neonates; however, a 4-week neonatal ZDV regimen can be considered for full-
term infants when the mother has received standard combination ART during
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TABLE 15-2. Neonatal Dosing for Prevention of Perinatal HIV Transmission

HIV-Exposed Infants
Initiated as soon after delivery as possible
Regimen Dosing Duration
ZDV ≥35 Weeks’ Gestation at Birth: Birth through 4–6 weeksa
Note: Birth to Age 6 Weeks:
Twice-daily dosing • 4 mg/kg orally twice daily
prophylaxis should
be started as soon Simplified Weight-Band Dosing
after birth as possible, for Infants ≥35 Weeks:
preferably within 6–12
Weight Band (kg) *Volume (mL)
hours of delivery
ZDV 10 mg/mL
For infants unable to
Oral Syrup
tolerate oral agents,
Twice Daily
the IV dose is 75% of
the oral dose while 2 to <3 kg 1 mL
maintaining the same 3 to <4 kg 1.5 mL
dosing interval. 4 to <5 kg 2 mL
≥30 to <35 Weeks’ Gestation at Birth: Birth through 6 weeks

Birth to Age 2 Weeks:
• 2 mg/kg orally twice daily
Age 2 Weeks to 4–6 Weeks:
<30 Weeks’ Gestation at Birth: Birth through 6 weeks

Birth to Age 4 Weeks:
Age 4 Weeks to 6 Weeks:
Additional Antiretroviral Prophylaxis Agents for HIV-Exposed Infants

Who Are at High Risk of HIV Acquisition
NICHD-HPTN 040/PACTG 1043 Study Regimen
NVP Birth Weight 1.5–2 kg: Three Doses in the First

In addition to ZDV as • 8 mg dose PO Week of Life:
shown above Birth Weight >2 kg: 1. Within 48 hours of
birth
• 12 mg dose PO
2. 48 hours after first
dose
3. 96 hours after second
dose
(continued)
ERRNVPHGLFRVRUJ
TABLE 15-2. Neonatal Dosing for Prevention of Perinatal HIV Transmission

(continued)
HIV-Exposed Infants
Regimen Dosing Duration
Three-Drug Infant Combination Antiretroviral Prophylaxis Regimen
This regimen is under investigation, but is already used in clinical practice by some experts
3TC ≥32 Weeks’ Gestation at Birth: Birth through 2–6 weeks

In addition to ZDV as Birth to Age 4 Weeks:
shown above • 2 mg/kg PO twice daily
Age 4 Weeks to 6 Weeks:
• 4 mg/kg PO twice daily
NVP ≥37 Weeks’ Gestation at Birth: Birth through 2–6 weeksb

In addition to ZDV as Birth to Age 6 Weeks:
shown above • 6 mg/kg PO twice daily
34 to <37 Weeks’ Gestation at Birth:

Birth to Age 1 Week:
Age 1 Week to 6 Weeks:
a
A 4-week neonatal ZDV prophylaxis regimen may be used when the mother has received standard ART during
pregnancy with sustained viral suppression and there are no concerns related to maternal adherence. All other infants
should receive a 6-week course of ZDV.
b
The optimal duration of NVP is unknown. Some experts recommend continuation of NVP for a 6-week course, while
others recommend discontinuation after 2 weeks of life if HIV nucleic acid amplification test is negative.
3TC: lamivudine; BSA: body surface area; IV: intravenously; NVP: nevirapine; PO: orally; ZDV: zidovudine
Source: Panel on Antiretroviral Therapy and Medical Management of HIV-Infection. Recommendations for Use of
Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV
Transmission in the United States. (Last updated: October 26, 2016, last reviewed: October 26, 2016.) Accessed January
20, 2017. Available at: https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0.
pregnancy with consistent viral suppression and there are no concerns related to
maternal adherence.7
Infants at high risk of HIV acquisition with no maternal antepartum ARV
are recommended to receive prophylaxis with ZDV given for 6 weeks combined
with three doses of nevirapine in the first week of life (i.e., at birth, 48 hours later,
and 96 hours after the second dose), begun as soon after birth as possible.7 An
investigational three-drug infant combination antiretroviral prophylaxis regimen
of zidovudine, lamivudine, and nevirapine is also outlined in Table 15-2 as it is
currently used in clinical practice by some experts. In addition to ARV, it is recom-
ERRNVPHGLFRVRUJ
mended that all HIV-infected or HIV-indeterminate infants from age 4 to 6 weeks

to 12 months also receive primary prophylaxis for Pneumocystis jirovecii pneu-
monia regardless of CD4 cell count/percentage.9
In the United States, mothers should be instructed not to breastfeed or to
premasticate food for their babies.7 Globally, due to the importance of breast-
feeding for the survival of the infant, the WHO has adopted guidelines that
support breastfeeding among mothers with HIV infection while on combination
antiretroviral therapy (cART) and fully supported for adherence.10
MANAGEMENT OF PEDIATRIC AND ADOLESCENT HIV INFECTION
Special Considerations in Neonates, Children, and Adolescents with

HIV Infection
Pediatrics encompasses a broad age range spanning from neonate/infant, to child,
to adolescent. During this time, significant growth and development occurs, and
one must be aware of special considerations in pediatrics compared to adults,
leading to the expression, “children are not little adults.” Table 15-3 compares
age-related special considerations in neonates, infants, children, and adolescents
with HIV infection.
Neonates, Infants, and Children

Special considerations in neonates, infants, and children include physical and
developmental differences from adults. The growing child is a constantly changing
“moving target” and therefore requires frequent evaluation.
As the child grows and develops, important special considerations for phar-
macists are
• frequent weight-based dosage calculations
• appropriate formulation selection
• adherence
• knowledge of the age-related differences in pharmacokinetics (PK)
Table 15-3 outlines the PK parameters and the differences in absorption, distri-
bution, metabolism, and excretion from birth to adolescence.11 These age-related
PK differences can impact the bioavailability and dosing of ARV and other medi-
cations that are dependent on the PK parameters, which is why pediatric doses
cannot be simply extrapolated from adult doses.
Adolescents
Once children are older than 12 years of age and sexually mature, they enter the
stage of adolescence (generally considered as 13 to 24 years of age). Although the
physical and pharmacokinetic characteristics of adolescents are generally consid-
ered to be equivalent to adults, the mental, behavioral, and cognitive developments
may not have reached adult levels. Adolescence is a time of rebellion, sexual debut,
ERRNVPHGLFRVRUJ
TABLE 15-3. Special Considerations in Neonates, Infants, Children, and

Adolescents with HIV Infection
0–2 years 3–12 years 13–24 years
Neonates, Infants Children Adolescents
Sources of Exposure Perinatal Late perinatal Late perinatal
at Time of Breastfeeding Breastfeeding Sexual transmission-
Diagnosis abuse or voluntary
Premasticated food Sexual abuse
from HIV-infected parenteral
caregiver exposure—IV drug
use or accidental
needlesticks
Diagnostic Tests HIV DNA—most specific HIV RNA HIV RNA

HIV RNA ELISA antibody ELISA antibody
CD4 Counts Higher CD4 absolute Adult values Adult values

Higher CD4 % (0–5 yr)
Viral Loads Untreated >100,000 copies/mL Adult values
Pharmacokinetics
Absorption
Gastric emptying Decreased until Adult values
6–8 months
Distribution
Plasma protein binding Decreased until 1 year Adult values
Metabolism
CYP 3A4, 1A2, 2C9 Decreased until Adult values
1–2 years
CYP 2C19, 2D6 Decreased until 10–12 years Adult values

Decreased until 7–10 years
UGTs Adult values
First pass Decreased until 14 days Adult values
Excretion
Creatinine clearance Decreased until Adult values
6 months
Tubular secretion Decreased until Adult values

7 months
Tubular reabsorption Decreased until Adult values

1–3 years
(continued)
ERRNVPHGLFRVRUJ
TABLE 15-3. Special Considerations in Neonates, Infants, Children, and

Adolescents with HIV Infection (continued)
0–2 years 3–12 years 13–24 years
Neonates, Infants Children Adolescents
Dosing Change Check every visit, Check every visit, Adult dosing
Requirements mg/kg and mg/m2 mg/kg
dosing Weight-band dosing
Medication Limited liquids and Liquids, chewable, small Adult formulations

Formulations dosing guidelines or dispersible tablets Single-tablet regimens
Adherence Issues Caregiver responsible— Caregiver responsible— Transition from

Too busy, forgetting, Too busy, forgetting, caregiver to
illness or instability illness, instability, adolescent—Pill
Neonate, Infant— allows child self- burden, regimen
Palatability, toxicity, administration fatigue, stigma,
refusal—G-tube Child—Palatability, rebellion, denial,
toxicity, refusal— substance use,
G-tube, pill incarceration,
swallowing, pill disclosure,
burden, regimen behavioral, mental
fatigue health, family, job,
housing
Sexual Debut and Not applicable Begins at 10–12 years Continues through
HIV Disclosure Perinatally infected— adolescence,
diagnosis disclosure diagnosis, disclosure
to partners
Resistance Transmitted Transmitted Nonadherence

from mother, from mother, Perinatals—past
nonadherence, nonadherence, incomplete (mono,
0–1 class resistance most 1–2 class resistance most dual) therapy—
likely likely multiclass resistance
most likely
Source: Data from Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for
the use of antiretroviral agents in pediatric infection. (Last updated: April 27, 2017, last reviewed: April 27, 2017.)
Available at: https://aidsinfo.nih.gov/guidelines/html/2/pediatric-treatment-guidelines/0#. Section accessed August 28,
2017 and Fernandez E, Perez R, Hernandez A, et al. Factors and mechanisms for pharmacokinetic differences between
pediatric population and adults. Pharmaceutics. 2011;3:53-72.
ERRNVPHGLFRVRUJ
risk taking, and experimentation—all of which can lead to challenges in adherence

to medications, engagement in medical care, safe sex, and partner notification.8
The adolescents living with HIV are now a mixed group of perinatally
acquired HIV pediatrics who are treatment-experienced who have survived into
their adolescent years and newly diagnosed nonperinatally acquired HIV adoles-
cents. Special considerations in both adolescent groups include addressing psycho-
social needs and adherence to cART. Among youth aged 18 to 24 who were living
with HIV in 2012, 21% were prescribed HIV medicines (ART), and 16% had a
suppressed viral load—the lowest rates of any age group.4 Factors implicated in
poor levels of adherence in adolescents living with HIV include poverty, inad-
equate food access, unstable housing, limited education, lack of stable employ-
ment, substance abuse, denial, stigma, homophobia, and discrimination.12 HIV
diagnosis disclosure to friends corresponded with reduced medication hiding and
ultimately yielded better immune functioning in children and adolescents living
with HIV.13 It is important for pharmacists to address these issues when meeting
with the adolescent and to select cART regimens that will meet their needs to
provide optimal adherence support and age-specific patient care.
When to Treat?
Immune System Staging and Viral Load

Evaluating when to start cART begins with recognition of age-specific staging.
Neonates are born with higher CD4 cell count and percentages, and these levels
decline and reach adult levels at age 6 years or greater. Table 15-4 describes the
Centers for Disease Control and Prevention (CDC) staging of HIV infection based
on age-specific CD4 counts or percentages.14 Infants in the first year of life expe-
rience higher risks of progression or death than older children for any given CD4
TABLE 15-4. HIV Infection Stage Based on Age-Specific CD4 Cell Count or
Percentage
Age on Date of CD4 Test
<1 Year 1 to <6 Years ≥6 Years
Stage Cells/µL % Cells/µL % Cells/µL %
1 ≥1,500 ≥34 ≥1,000 ≥30 ≥500 ≥26
2 750–1,499 26–33 500–999 22–29 200–499 14–25
3 <750 <26 <500 <22 <200 <14

Note: The stage is based primarily on the CD4 cell count; the CD4 cell count takes precedence over the CD4
percentage, and the percentage is considered only if the count is missing. If a Stage 3-defining opportunistic illness
has been diagnosed, then the stage is 3 regardless of CD4 test results.
Source: Centers for Disease Control and Prevention: Revised Surveillance Case Definition for HIV Infection—United
States, 2014. MMWR. 2014;63(No. RR-3):1-10.
ERRNVPHGLFRVRUJ
stratum.8 The pattern of change in plasma viral load in untreated perinatally

infected infants is higher and more prolonged compared to infected adults and
adolescents.8
HIV-Related Symptoms
The majority of HIV-related symptoms including stage 3—defining opportu-
nistic illnesses—are similar among pediatrics, adolescents, and adults living with
HIV. Early mild clinical symptoms encountered in pediatric and adolescent HIV
infection include lymphadenopathy, hepatomegaly, splenomegaly, dermatitis,
parotitis, recurrent or persistent upper respiratory tract infections, sinusitis, or
otitis media.8
The National Institutes of Health Panel on the Guidelines for the Use of ARV
Agents in Pediatric Infection recommend cART for all HIV-infected children,
regardless of clinical symptoms, viral load, or CD4 T lymphocyte (CD4) count.
The strength of the recommendation to treat varies based on age and the pretreat-
ment CD4 count and severity of HIV-related symptoms.8 This recommendation was
based on data from the START randomized clinical trial that provided evidence of
benefit with initiation of ART in asymptomatic adults with CD4 cell counts >500
cells/mm3 and the CHER trial, which demonstrated evidence of improved outcomes
with initiation of ART in asymptomatic infants between 6 and 12 weeks of age.15,16
Please check the latest iteration of the guidelines for updated recommendations
and levels of evidence as they accumulate.
What to Start?
Baseline Assessments
Prior to selection of cART, it is important to obtain baseline assessments including
CD4 count and CD4%, HIV-RNA, resistance test (genotype), clinical history and
physical exam, complete blood count (CBC) with differential, chemistries, lipid
panel, urinalysis, HLA-B*5701 (abacavir), and hepatitis B virus (HBV) screening.8
Initial Preferred Regimens

Initial preferred cART in pediatrics includes a backbone of two nucleoside/nucle-
otide reverse transcriptase inhibitors (NRTIs), plus a third agent from either the
integrase strand transfer inhibitor (INSTI), nonnucleoside reverse transcriptase
(NNRTI), or boosted-protease inhibitor (PI) classes.8 Table 15-5 outlines the 2017
Pediatric Panel guideline recommendations for preferred cART regimens for treat-
ment-naïve pediatrics with HIV from birth through adolescence.8,17 The preferred
agents were selected using criteria on the safety, efficacy, and ease of adminis-
tration. Due to life-threatening cardiovascular, renal, and central nervous system
toxicity, lopinavir/ritonavir oral solution is no longer recommended in premature
infants until 14 days after their due date, or in full-term infants younger than 42
weeks postmenstrual age.8 Table 15-6 (page 298) outlines the dosing guidelines for
the preferred ARV in infants and children, and Table 15-7 (page 300) outlines the
ERRNVPHGLFRVRUJ
TABLE 15-5. Preferred cART Regimens for Initial Treament of Neonates,

Infants, Children, and Adolescents with HIV
Preferred Two NRTI Backbone Preferred Third Agent
Children: Birth to <14 days ZDV plus (3TC or FTC) NVP*
Children Aged: ZDV plus (3TC or FTC) LPV/r**

≥14 Days to <3 Months
Children Aged: ZDV plus (3TC or FTC) or LPV/RTV or RAL

≥3 Months and <3 Years ABC plus (3TC or FTC)
Children Aged: ZDV plus (3TC or FTC) or ATV/RTV or DRV/RTV

≥3 Years to <6 Years ABC plus (3TC or FTC) twice daily or RAL
Children Aged: ZDV plus (3TC or FTC) or ATV/RTV or DTG

≥6 Years to <12 Years ABC plus (3TC or FTC)
Adolescents Aged ≥12 Years and ABC plus (3TC or FTC) or ATV/RTV or
Not Sexually Mature (SMR I-III) TAF/FTC DTG or
Once daily DRV/RTV or
EVG/COBI
Source: Data from Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines
for the use of antiretroviral agents in pediatric infection. (Last updated: April 27, 2017, last reviewed: August 15, 2017.)
Available at: https://aidsinfo.nih.gov/guidelines/html/2/pediatric-treatment-guidelines/0# Section accessed: August 15,
2017.
*Currently, no FDA-approved treatment dosing for nevirapine in this age group. Refer to DHHS guidelines for dosing.
**Lopinavir/r only indicated after 42 weeks postmenstrual age and >14 days postnatal.
3TC: lamivudine; ABC: abacavir; ATV: atazanavir; cART: combination antiretroviral therapy; COBI: cobicistat; DRV:
darunavir; DTG: dolutegravir; EVG: elvitegravir; FTC: emtricitabine; LPV/r: lopinavir/ritonavir; NRTI: nucleoside/
nucleotide reverse transcriptase inhibitor; RAL: raltegravir; RTV: ritonavir; TAF: tenofovir alafenamide; TDF: tenofovir
disoproxil; ZDV: zidovudine
dosing guidelines for the preferred ARV in adolescents.8 Treatment recommenda-

tions are subject to change; therefore, clinicians should regularly consult current
pediatric guidelines for the most up-to-date information on preferred and alterna-
tive treatment regimens.8,17
Initiating Treatment and Supporting Adherence
Antiretroviral Considerations
The selection of a pediatric cART regimen is based on the child’s age, results of
viral drug-resistance testing, drug efficacy and adverse events, barrier to resis-
tance, potential for drug interactions, child and family preference, pill size or
liquid palatability, and dosing frequency.8 Infants and children living with HIV
have a limited availability of treatment options based on palatability, tolerance,
and optimal dosing guidelines. Over the years, simplified weight-band–based
ERRNVPHGLFRVRUJ
dosing guidelines using weight ranges that correspond to specific doses to elim-
inate dosage calculations have become available. More pediatric-friendly dosage
forms have also become available, including oral granules, oral powders, chewable
tablets, dispersible tablets, and smaller-sized tablets. The fixed-dose combination
(FDC) tablets have also greatly improved ARV options for adolescents. However,
given the overall limitations in treatment options for children living with HIV, the
selection of cART should include considerations for preserving future treatment
options. This means that while a potent and effective regimen should be used for
initial therapy, the clinician should also keep in mind what ARV agents might
still be available that would remain effective should the first regimen fail. This
sequencing of first- and second-line regimens can be useful in preserving future
ART and maximizing the long-term benefit of therapy through the child’s life-
time.8 Table 15-8 (page 302) reviews the treatment considerations in each of the
preferred ARV agents, including advantages and disadvantages.
Adherence Support
Maintaining adherence in pediatrics from birth through adolescence is especially
challenging as the responsibility of medication taking changes from primarily
caregiver, to child, to adolescent. Pharmacists can support adherence to prescribed
regimens to prevent subtherapeutic levels of ARV medications, reduce the risk
of development of drug resistance, and reduce the likelihood of virologic failure.
The guidelines recommend that clinicians assess, discuss, and address adher-
ence issues with a child’s caregiver and the child (when age appropriate), assess
adherence barriers, and resolve any issues before therapy is initiated. In addition,
frequent follow-up is important to assess virologic response to therapy, drug intol-
erance, viral resistance, and adherence.8 Table 15-9 (page 304) outlines the recom-
mended initial, medication, and follow-up strategies that pharmacists can use to
improve pediatric and adolescent adherence to cART. A recent meta-analysis of
the evidence base for ART adherence-enhancing interventions for adolescents
and young adults 13 to 24 years of age revealed that top interventions included
individual sessions and the use of technology such as cell phones, pagers, Skype,
telephones, computers, and “smart” wristwatches. Other interventions included
parent sessions, motivational interviewing, other family members, group sessions,
and financial incentives. Although improvement in adherence was noted, prog-
ress in the area of adherence in adolescents and young adults lagged behind the
evidence base for adherence in adults and more research was necessary.18
Monitoring for Efficacy, Toxicity, and Comorbidities

After starting or changing cART, adherence and side effects of cART should be eval-
uated in 1 to 2 weeks, followed by laboratory testing for toxicity and viral load
response in 2 to 4 weeks. Children and adolescents should have routine clinical
visits every 3 to 4 months to assess adherence, efficacy, and toxicities. Efficacy
goals include the restoration and preservation of immune function to the age-
appropriate levels of CD4 counts and achieving durable viral load suppression
of HIV-RNA.8 Toxicity monitoring includes both clinical and laboratory moni-
ERRNVPHGLFRVRUJ
TABLE 15-6. Dosing Guidelines for Preferred Antiretroviral Agents for the
Treatment of Infants and Children with HIV
Abacavir Lamivudine Emtricitabine Darunavir

ZiagenR EpivirR EmtrivaR PrezistaR + Ritonavir
(ABC) (3TC) (FTC) (DRV/RTV)
Solution 20 mg/mL 10 mg/mL 10 mg/mL 100 mg/mL
Tablets, Tablet: 300 mg Tablets: Capsules: Tablets:
Capsule, 150, 300 mg 200 mg 75 mg, 150 mg, 600 mg, 800 mg
Powder,
Granules
AGE: ≥3 months: Birth–<4 weeks: Birth–<3 ≥3 years Twice Daily w/

<12 years 8 mg/kg/dose 2 mg/kg/dose months: Weight: Food:
TWICE daily TWICE daily 3 mg/kg once daily 10–<11 kg DRV 200 mg
(600 mg max ≥4 weeks: ≥3 months–17 (2.0 mL) +
total dose) 4 mg/kg/dose years: RTV 32 mg
TWICE daily 6 mg/kg once daily (0.4 mL) BID
(300 mg max total (240 mg max 11–<12 kg DRV 220 mg
dose) solution) (2.2 mL) +
(200 mg max RTV 32 mg
capsule) (0.4 mL) BID
12–<13 kg DRV 240 mg
(2.4 mL) +
RTV 40 mg
(0.5 mL) BID
13–<14 kg DRV 260 mg
(2.6 mL) +
RTV 40 mg
(0.5 mL) BID
14–<15 kg DRV 280 mg
(2.8 mL) +
RTV 48 mg
(0.6 mL) BID
15–<30 kg DRV 375 mg tabs
(or 3.8 mL)
+RTV 48 mg
(0.6 mL) BID
30–<40 kg DRV 450 mg
Tabs (or 4.6 mL)
+RTV 100 mg
Tab (or 1.25 mL)
BID
DRV 600 mg
≥40 kg Tab (or 6 mL)
RTV 100 mg
Tab (or 1.25 mL)
BID
BID: twice daily; tsp: teaspoon

Adapted from the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the
use of antiretroviral agents in pediatric infection. (Last updated: April 27, 2017, last reviewed: April 27, 2017.) Available at:
https://aidsinfo.nih.gov/guidelines/html/2/pediatric-treatment-guidelines/0#. Section accessed August 28, 2017.
ERRNVPHGLFRVRUJ
Atazanavir Lopinavir/
ReyatazR + Zidovudine Dolutegravir Ritonavir Raltegravir
Ritonavir RetrovirR TivicayR KaletraR IsentressR
(ATV/RTV) (ZDV) (DTG) (LPV/r) (RAL)
None 10 mg/mL None 80 mg/20 mg/mL None
Powder: 50 mg/packet Capsules: 100 mg Tablets: Tablets: Granules:
Capsules: 150 mg, Tablets: 300 mg 10 mg, 25 mg 100/25 mg LPV/r 100 mg/packet
200 mg, 300 mg 50 mg 200/50 mg LPV/r Chew tab: 100 mg,
25 mg
Tab: 400 mg
Once Daily Powder: >35 weeks >12 years and Not Receiving Granules for Oral
≥3 months: Postconception: not sexually nevirapine, Suspension:
Birth–4 weeks: mature efavirenz, ≥4 weeks and
5 kg–<15 kg: 4 mg/kg/dose q 12 hrs (SMR I-III) fosamprenavir, ≥3 kg–<20 kg:
ATV 200 mg >4 weeks: or nelfinavir: 3–<4 kg:
30–40 kg:
(4 packets) + 4 kg–<9 kg: 1 mL (20 mg) BID
RTV 80 mg (1 mL) oral 12 mg/kg/dose q 12 hrs 10 mg + 14 days–12 mos: 4–<6 kg:
solution 9 kg–<30 kg: 25 mg once daily 300 mg/75 mg 1.5 mL (30 mg) BID
once daily with food 9 mg/kg/dose q 12 hrs >40 kg: LPV/RTV per m2 6–<8 kg:
15 kg–<25 mg: ≥30 kg: BSA BID 2 mL (40 mg) BID
50 mg once daily
ATV 250 mg 300 mg tablet BID 8–<11 kg:
(5 packets) + Naïve: 3 mL (60 mg) BID
RTV 80 mg (1 mL) oral ≥30–<35 weeks 12 mos–18 years: 11–<14 kg:
solution Postconception 230 mg/57.5 mg 4 mL (80 mg) BID
once daily with food Birth to 2 wks: LPV/RTV per m2 14–<20 kg:
2 mg/kg/dose q 12 hrs BSA BID 5 mL (100 mg) BID
Mix with 1 tablespoon 2 wks–6-8 wks: Experienced: Mix packet in 5 mL
of food, or 30 mL 3 mg/kg/dose q 12 hrs 300 mg/75 mg water for
liquid, or 10 mL >6–8 weeks: LPV/RTV per m2 20 mg/mL conc.
formula 12 mg/kg/dose q 12 hrs BSA BID
Chewable Tablets:
Once Daily <30 weeks Naïve and 11–<14 kg:
Capsules Experienced 3 × 25 mg BID
Postconception:
≥6–<18 years Patients 14–<20 kg:
Birth–4 weeks: receiving
2 mg/kg/dose q 12 hrs 1 × 100 mg BID
<15 kg: nevirapine,
4 wks–8-10 wks: 20–28 kg:
not recommended efavirenz,
3 mg/kg/dose q 12 hrs fosamprenavir, 1.5 × 100 mg BID
15–<20 kg: 28–<40 kg:
>8–10 weeks: or nelfinavir:
ATV 150 mg + 2 × 100 mg BID
12 mg/kg/dose q 12 hrs
RTV 100 mg
>12 mos–18 years: ≥40 kg:
once daily with food 3 × 100 mg BID
Body Surface Area: 300 mg/75 mg
20–<40 kg:
Oral: 180–240 mg/m2 LPV/RTV per m2
ATV 200 mg + Film-Coated Tablet
q 12 hrs BSA BID
RTV 100 mg for ≥25 kg:
once daily with food 400 mg BID
≥40 kg:
ATV 300 mg +
RTV 100 mg
once daily with food
BID: twice daily; tsp: teaspoon
Adapted from the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the
use of antiretroviral agents in pediatric infection. (Last updated: April 27, 2017, last reviewed: April 27, 2017.) Available at:
ERRNVPHGLFRVRUJ
TABLE 15-7. Dosing Guidelines for Preferred Antiretroviral Agents for the Treatment of Adolescents with HIV
Elvitegravir Elvitegravir
Dolutegravir/
Abacavir/ TAF/FTC/ TDF/FTC/
Abacavir + Darunavir Atazanavir Lamivudine Tenofovir Cobicistat Tenofovir Cobicistat
R R R R
Abacavir Lamivudine Lamivudine Emtricitabine Prezista + Reyataz + Dolutegravir Triumeq TAF/FTC Genvoya TDF/ FTC StribildR
ZiagenR EpivirR Epzicom EmtrivaR Ritonavir Ritonavir TivicayR (DTG/ABC/ DescovyR (EVG/TAF/ TruvadaR (EVG/TDF/
AGE (ABC) (3TC) (ABC/3TC) (FTC) (DRV/RTV) (ATV/RTV) (DTG) 3TC) (F/TAF) FTC/COBI) (TDF/FTC) FTC/COBI)
Tablet: Tablets: Tablet: Capsule: Tablets: Capsules: Tablets: Tablet: Tablet: Tablet: Tablet: Tablet:
300 mg 150 mg, Fixed dose: 200 mg 75 mg, 150 mg 10 mg, Fixed dose: Fixed dose: Fixed dose: Fixed dose: Fixed dose:
300 mg ABC 600 mg/ 150 mg, 200 mg 25 mg DTG 50 mg/ TAF 25 mg/ EVG 150 mg/ TDF 300 mg/ EVG 150 mg/
600 mg 300 mg 50 mg
3TC 300 mg 800 mg ABC 600 mg/ FTC 200 mg TAF 10 mg/ FTC 200 mg TDF 300 mg/
3TC 300 FTC 200 mg/ FTC 200 mg/
mg
COBI 150 mg COBI 150 mg
>12 years ≥25 kg: ≥25 kg: ≥25 kg: 200 mg Naïve ≥40 kg: 30–40 kg: >40 kg: ≥35 kg: ≥35 kg: ≥35 kg:
and not 300 mg 150 mg 1 tablet once 1 capsule 30–<40 kg: ATV 300 mg 10 mg + 1 tablet once 1 tablet once 1 tablet once 1 tablet each
sexually daily once daily 25 mg daily daily daily once daily
1 tablet 1 tablet BID DRV 600 mg RTV 100 mg
ERRNVPHGLFRVRUJ
mature once daily
BID or or + DRV 75 mg 1 tablet each
(SMR I-III)
600 mg 300 mg + RTV 100 mg once daily >40 kg:
1 tablet once 50 mg once
1 tablet once 1 tablet each daily
daily daily once daily
>40 kg:
DRV 800 mg
RTV 100 mg
1 tablet each
once daily

TABLE 15-7. Dosing Guidelines for Preferred Antiretroviral Agents for the Treatment of Adolescents with HIV (continued)
Elvitegravir Elvitegravir
Dolutegravir/
Abacavir/ TAF/FTC/ TDF/FTC/
Abacavir + Darunavir Atazanavir Lamivudine Tenofovir Cobicistat Tenofovir Cobicistat
R R R R
Abacavir Lamivudine Lamivudine Emtricitabine Prezista + Reyataz + Dolutegravir Triumeq TAF/FTC Genvoya TDF/ FTC StribildR
ZiagenR EpivirR Epzicom EmtrivaR Ritonavir Ritonavir TivicayR (DTG/ABC/ DescovyR (EVG/TAF/ TruvadaR (EVG/TDF/
AGE (ABC) (3TC) (ABC/3TC) (FTC) (DRV/RTV) (ATV/RTV) (DTG) 3TC) (F/TAF) FTC/COBI) (TDF/FTC) FTC/COBI)
≥12 years ≥25 kg: ≥25 kg: ≥25 kg: 200 mg Naïve ≥40 kg: 30–40 kg: >40 kg: ≥35 kg: ≥35 kg: ≥35 kg: ≥35 kg:
and 300 mg 150 mg 1 tablet once 1 capsule 30–<40 kg: ATV 300 mg 10 mg + 1 tablet once 1 tablet once 1 tablet once 1 tablet once 1 tablet once
sexually daily once daily 25 mg daily daily daily daily daily
mature 1 tablet 1 tablet BID DRV 600 mg RTV 100 mg
or once daily
(SMR IV-V) BID or + DRV 75 mg 1 tablet each
600 mg 300 mg + RTV 100 mg once daily >40 kg:
1 tablet once 50 mg once
1 tablet once 1 tablet each daily
daily daily once daily
>40 kg:
DRV 800 mg
ERRNVPHGLFRVRUJ
RTV 100 mg
1 tablet each
once daily
BID: twice daily
= No recommended dose is available.

Source: Adapted from the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the use of antiretroviral agents in pediatric infection. (Last updated:
April 27, 2017, last reviewed: April 27, 2017.) Available at: https://aidsinfo.nih.gov/guidelines/html/2/pediatric-treatment-guidelines/0#. Section accessed August 28, 2017.
TABLE 15-8. Antiretroviral Treatment Considerations in Infants, Children,

and Adolescents with HIV
FDA-Approved Pediatric Formulation
Age Range and Storage Advantages Disadvantages
Abacavir ≥3 months Oral solution (20 mg/ Palatable liquid HSR, perform
(Ziagen, ABC) mL) Food allowed HLA-B*5701
Room temperature
Emtricitabine ≥Birth Oral solution (10 mg/ Palatable liquid Skin discoloration
(Emtriva, FTC) mL) Once daily
Refrigerate
Lamivudine ≥Birth Oral solution (10 mg/ Palatable liquid BID in infant and
(Epivir, 3TC) mL) young child
Room temperature
Tenofovir ≥2 years Oral powder (40 mg/1 g) Once daily Renal toxicity,
Disoproxil Fixed-dose tablet: Food allowed bone mineral
density
(Viread, TDF) Truvada—TDF/FTC Slow resistance
decreased
Tenofovir ≥12 years No pediatric formulation Less renal and Not indicated for
Alafenamide, ≥35 kg Fixed-dose tablet: bone toxicity <12 yrs
(TAF) Descovy—TAF/FTC Once daily
Zidovudine ≥Birth Oral syrup (10 mg/mL) Extensive pediatric Bone marrow
(Retrovir, ZDV) Room temperature experience toxicity
Lopinavir/r >14 days and Oral Solution Co-formulated Poor bitter

(Kaletra, LPV/r) >42 weeks (80 mg LPV/20 mg RTV) With RTV palatability
Postmenstrual Food allowed Drug interactions
Atazanavir ≥3 months Powder Packet Once daily No liquid, food

(Reyataz, ATV) ≥5 kg (50 mg/packet) Powder, Food Elevated bilirubin
Darunavir ≥3 years Oral Suspension Liquid available Multiple tablets,
(Prezista, DRV) ≥10 kg (100 mg/mL) 75 mg, Once daily >12 yrs Food, Sulfa moiety
150 mg, 600 mg,
800 mg tabs
Raltegravir ≥4 weeks Oral Suspension (100 Granules, chew tabs Rash, CK elevation
(Isentress, RAL) ≥3 kg mg/pkt) Chew tabs Food
25, 100 mg
Dolutegravir ≥30 kg 10 mg, 25 mg, 50 mg Once daily Interactions with
(Tivicay, DTG) tabs Fixed-dose tablets CYP inducers
(continued)
ERRNVPHGLFRVRUJ
TABLE 15-8. Antiretroviral Treatment Considerations in Infants, Children,

and Adolescents with HIV (continued)
FDA-Approved Pediatric Formulation
Age Range and Storage Advantages Disadvantages
Elvitegravir, No pediatric Once daily COBI
EVG ≥12 years formulation drug
>35 kg Stribild-TDF/FTC/EVG/ Food, fixed
COBI interactions
Genvoya-TAF/FTC/EVG/ Dose tablets
COBI
BID: twice daily; COBI: cobicistat; CYP: cytochrome; HSR: hypersensitivity reaction
Source: Adapted from the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV.
Guidelines for the use of antiretroviral agents in pediatric infection. (Last updated: April 27, 2017, last reviewed: April
27, 2017.) Available at: https://aidsinfo.nih.gov/guidelines/html/2/pediatric-treatment-guidelines/0#. Section accessed
August 28, 2017.
toring for ARV side effects. Mild-to-moderate transient side effects such as nausea,
vomiting, or diarrhea can be treated symptomatically using appropriate age-based
antiemetics and antidiarrheal agents. Severe or life-threatening reactions require
stopping all ARVs immediately and then once the toxicity has resolved, restarting
cART with a substitution for the suspected offending agent(s). Dosage reduction is
not recommended for ARV toxicity management.8
Comorbidities in pediatric HIV infection tend to develop over time and can
be caused by cART and/or chronic inflammation due to long-term HIV infection.
Potential comorbidities in infants, children, and adolescents include renal insuffi-
ciency, bone mineral density loss, metabolic syndrome, hyperlipidemia, and lipo-
dystrophy. Older ARVs with mitochondrial toxicities have mostly been replaced by
newer, less toxic ARVs, which may help to reduce future pediatric comorbidities.
Management of Treatment Failure and Resistance

Virologic failure is often defined as repeated or persistent plasma viral load detec-
tion above 200 copies/mL (especially if >500 copies/mL) after having achieved
virologic suppression; immunologic failure is defined as a suboptimal immuno-
logic response to therapy.8 Determining the etiology of virologic treatment failure
in infants, children, and adolescents is challenging and may be a result of poor
adherence, drug resistance, poor drug absorption, inadequate dosing, and drug–
drug interactions.8 Careful investigation into each possible etiology is important
before making a treatment decision.
Multiclass Resistance
Children and adolescents with perinatally acquired HIV are often heavily treat-
ment experienced and may have received mono and dual therapy in the 1990s
ERRNVPHGLFRVRUJ
TABLE 15-9. Strategies to Improve Adherence to Antiretroviral Medications

Initial Intervention Strategies
• Establish trust and identify mutually acceptable goals for care.
• Obtain explicit agreement on the need for treatment and adherence.
• Identify depression, low self-esteem, substance abuse, or other mental health issues for the child/
adolescent and/or caregiver that may decrease adherence. Evaluate and initiate treatment for
mental health issues before starting ARV drugs, if possible.
• Identify family, friends, health team members, and others who can support adherence.
• Educate patient and family about the critical role of adherence in therapy outcome including (1)
the relationship between partial adherence and resistance; and (2) resistance and potential impact
on future drug regimen choices. Develop a treatment plan that the patient and family understand
and to which they feel committed.
• Work with the patient and family to make specific plans for taking medications as prescribed and
supporting adherence. Assist them to arrange for administration in day care, school, and other
settings, when needed. Consider home delivery of medications.
• Establish readiness to take medication through practice sessions or other means.
• Schedule a home visit to review medications and determine how they will be administered in the
home setting.
• Consider a brief period of hospitalization at start of therapy in selected circumstances for patient
education and to assess tolerability of medications chosen.
Medication Strategies
• Choose the simplest regimen possible, reducing dosing frequency and number of pills.
• When choosing a regimen, consider the daily and weekly routines and variations in patient and
family activities.
• Choose the most palatable medicine possible (pharmacists may be able to add syrups or flavoring
agents to increase palatability).
• Choose drugs with the fewest AEs; provide anticipatory guidance for management of AEs.
• Simplify food requirements for medication administration.
• Prescribe drugs carefully to avoid adverse drug–drug interactions.
• Assess pill-swallowing capacity and offer pill-swallowing training.
(continued)
and, as a result, can harbor multiclass-resistant virus. This presents a challenge in

constructing viable regimens that will be durable through the years. Phenotypic
resistance testing is recommended (usually in addition to genotypic resistance
testing) in children with known or suspected complex drug resistance mutation
patterns as a result of virologic failure of successive ART regimens.8
Because resistance mutations may not always be detected after discontinuing
the ARV, evaluation of resistance requires a cumulative review of all current and
past resistance tests and past ARV regimens to determine which ARVs are available
to construct a new regimen. Regimens should contain at least two, but prefer-
ably three, fully active drugs for durable, potent virologic suppression.8 In very
complex multiresistant cases, the use of multiple partially acting agents may be
ERRNVPHGLFRVRUJ
TABLE 15-9. Strategies to Improve Adherence to Antiretroviral Medications

(continued)
Follow-Up Intervention Strategies
• Have more than one member of the multidisciplinary team monitor adherence at each visit and
in between visits by telephone, e-mail, text, and social media, as needed.
• Provide ongoing support, encouragement, and understanding of the difficulties associated with
maintaining adherence to daily medication regimens.
• Use patient education aids, including pictures, calendars, and stickers.
• Encourage use of pill boxes, reminders, alarms, pagers, and timers.
• Provide follow-up clinic visits, telephone calls, and text messages to support and assess adherence.
• Provide access to support groups, peer groups, or one-on-one counseling for caregivers and
patients, especially for those with known depression or drug use issues that are recognized to
decrease adherence.
• Provide pharmacist-based adherence support, such as medication education and counseling,
blister packs, refill reminders, automatic refills, and home delivery of medications.
• Consider DOT at home, in the clinic, or in selected circumstances, during a brief inpatient
hospitalization.
• Consider gastrostomy tube use in selected circumstances.
• Information on other interventions to consider can be found at http://www.cdc.gov/hiv/
prevention/research/compendium/ma/complete.html.
AE: adverse effect; ARV: antiretroviral; DOT: directly observed therapy
Source: Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the use
of antiretroviral agents in pediatric infection. (Last updated: April 27, 2017, last reviewed: April 27, 2017.) Available at:
required to construct a durable regimen in addition to alternative classes of ARVs

such as the entry inhibitors maraviroc and enfuvirtide.6 This becomes even more
challenging as some of the alternative ARV agents may still not be indicated or
have dosing guidelines for children.
Prevention of Vaccine-Preventable Diseases and Opportunistic

Infections
The CDC recommends that HIV-infected and HIV-exposed children be protected
from vaccine-preventable diseases and that all inactivated vaccines—whether
killed whole organism or recombinant, subunit, toxoid, polysaccharide, or poly-
saccharide protein-conjugate—can be administered safely to individuals with
altered immune competence. Children with severe cell-mediated immunodefi-
ciency should not receive live-attenuated vaccines; however, based on limited data,
the CDC does recommend that the live varicella vaccine and measles, mumps,
and rubella (MMR) can be considered for use in HIV-infected children who are
not severely immune suppressed (i.e., children with CD4 T lymphocyte [CD4] cell
percentages >15% and those aged >5 years with CD4 cell counts ≥200 cells/μL).19
ERRNVPHGLFRVRUJ
Table 15-10 outlines the CDC recommended vaccinations. Additional information

regarding pediatric vaccine schedules and recommendations can be found at the
CDC website (www.cdc.gov/hiv).
Pediatrics with low age-specific CD4 counts and CD4 percentages may also
require primary prophylaxis for opportunistic infections. Table 15-10 includes
primary prophylaxis recommendations for Pneumocystis pneumonia, toxoplas-
mosis, and Mycobacterium avium complex (MAC).9 Additional information on the
prophylaxis and treatment of opportunistic infections in pediatric patients may be
found in the DHHS Guidelines for the Prevention and Treatment of Opportunistic
Infections in HIV-Exposed and HIV-Infected Children.9
TESTING AND PREVENTION OF HIV TRANSMISSION

The CDC recommends routine HIV testing of all adolescents and adults aged 13 to
64 in all healthcare settings, regardless of stated risk factors, to identify early HIV
infection.5 At the end of 2012, 44% of youth ages 18 to 24 years living with HIV
did not know they had HIV.4 An ATN study found that HIV testing and rapid care
referral and linkage to care in newly diagnosed adolescents with HIV resulted in
90.8% engagement in care.20
Pre-exposure prophylaxis (PrEP) for HIV-negative partners with tenofovir/
emtricitabine (TruvadaTM) is currently approved for adults by the U.S. Food and
Drug Administration. At this time, since the original PrEP trials did not include
persons under the age of 18, the CDC recommends that clinicians weigh the
PrEP risks and benefits in persons under 18 years of age.21 A recent demonstration
project, ATN 113, studied the safety and adherence to PrEP in adolescent males
having sex with males ages 15 to 17 in the United States and found a seroconver-
sion rate per 100 person-years of 6.41 (95% CI: 4.90–25.87). The majority achieved
protective drug levels, yet adherence decreased over time and the HIV incidence
was still high.22 Studies are also underway to evaluate tenofovir alafenamide/
emtricitabine (DescovyTM) as PrEP.
ERRNVPHGLFRVRUJ

TABLE 15-10. Pediatric Vaccine Preventable Diseases and Primary Prophylaxis for Pneumocystis Pneumonia, Toxoplasma
Encephalitis, and Mycobacterium avium complex
Vaccine Preventable
Diseases Pneumocystis Pneumonia (PCP) Toxoplasma Encephalitis (TE) Mycobacterium avium complex (MAC)
Hepatitis A 1st choice: TMP-SMX 1st choice: TMP-SMX 1st choice: Clarithromycin daily or
Hepatitis B Alternatives: Dapsone, Atovaquone Alternatives: Dapsone plus Pyrimethamine/ Azithromycin weekly
Rotavirus Leucovorin or Atovaquone +/- Alternatives: Azithromycin daily or Rifabutin
Pyrimethamine /Leucovorin daily
Diptheria, Primary Prophylaxis Indicated for: Primary Prophylaxis Indicated for: Primary Prophylaxis Indicated for
Tetanus, • All HIV-infected or HIV-indeterminate IgG Antibody to Toxoplasma and Severe Children:
Pertusis infants from aged 4–6 weeks to <12 months. Immunosuppression: • Aged <1 year with CD4 count
Regardless of CD4 cell count/percentage • HIV-infected children aged <6 years with CD4 <750 cells/mm3;
H. influenza • HIV-infected children aged 1 to <6 years percentage <15%; HIV-infected children aged • Aged 1 to <2 years with CD4 count
type B with CD4 count <500 cells/mm3 or CD4 ≥6 years with CD4 count <100 cells/mm3 <500 cells/mm3;
percentage <15%; HIV-infected children aged • Aged 2 to <6 years with CD4 count
Pneumococcal ≥6 years with CD4 count <200 cells/mm3 or <75 cells/mm3;
CD4 percentage <15% • Aged ≥6 years with CD4 count <50 cells/mm3
ERRNVPHGLFRVRUJ
Inactivated Criteria for Discontinuing Primary Criteria for Discontinuing Primary Criteria for Discontinuing Primary
Poliovirus Prophylaxis: Prophylaxis: Prophylaxis:
• Note: Do not discontinue in HIV-infected Note: Do not discontinue in children aged • Do not discontinue in children age <2 years.
Influenza children aged <1 year <1 year • After ≥6 months of cART and:
After ≥6 Months of cART: • After ≥6 months of cART, and • Aged 2 to <6 years with CD4 count
Measles, Mumps, • Aged 1 to <6 years; CD4 percentage ≥15% or • Aged 1 to <6 years; CD4 percentage is ≥15% >200 cells/mm3 for >3 consecutive months
Rubella CD4 count is ≥500 cells/mm3 for for >3 consecutive months • Aged ≥6 years with CD4 count
>3 consecutive months, or • Aged ≥6 years; CD4 count >200 cells/mm3 for >100 cells/mm3 for >3 consecutive months
• Aged ≥6 years, CD4 percentage ≥15% or CD4 >3 consecutive months
count is ≥200 cells/mm3 for >3 consecutive
months (continued)
TABLE 15-10. Pediatric Vaccine Preventable Diseases and Primary Prophylaxis for Pneumocystis Pneumonia, Toxoplasma
Encephalitis, and Mycobacterium avium complex (continued)
Vaccine Preventable
Diseases Pneumocystis Pneumonia (PCP) Toxoplasma Encephalitis (TE) Mycobacterium avium complex (MAC)
Varicella Criteria for Restarting Primary Criteria for Restarting Primary Criteria for Restarting Primary
Prophylaxis: Prophylaxis: Prophylaxis:
Meningococcus • Aged 1 to <6 years with CD4 percentage • Aged 1 to <6 years with CD4 percentage • Aged 2 to <6 years with CD4 count
<15% or CD4 count <500 cells/mm3 <15% <200 cells/mm3
Human • Aged ≥6 years with CD4 percentage <15% or • Aged ≥6 years with CD4 count <100 to • Aged ≥6 years with CD4 count
Papillomavirus CD4 count <200 cells/mm3 200 cells/mm3 <100 cells/mm3

Source: Adapted from the Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed
and HIV-Infected Children. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf. (Last updated: November 6, 2013,
last reviewed: November 6, 2013.) Section accessed June 25, 2016. Adapted from the Centers for Disease Control and Prevention Vaccination Guidelines, 2016. Available at: http://www.cdc.gov/
vaccines/schedules/hcp/child-adolescent.html.
ERRNVPHGLFRVRUJ

The role of the pharmacist in the management of pediatric HIV infection is multifaceted
and requires broad knowledge of the special considerations with regard to the developing
child from birth to adolescence. The pharmacist’s role in caring for adult patients with
HIV/AIDS has been well described in the literature.23 However, there are few publications
describing the role of the pharmacist in caring for the pediatric HIV population.
One report documents how HIV pharmacists can start programs that provide adherence
education and pharmacotherapy evaluation to children and adolescents along with their
adult caregivers. The pharmacist meets with caregivers and children and adolescents who
are starting or changing their regimen and provides HIV education, reviews the goals and
benefits of ARV therapy, then provides individualized age-specific strategies to overcome
barriers to adherence before starting therapy to ensure success. In the case of resistance,
the pharmacist constructs an optimal regimen for viral suppression. The pharmacist then
follows all patients, providing frequent weight-based dosing calculations, orders follow-up
laboratory tests, and monitors for side effects and drug interactions to ensure that patients
reach viral suppression successfully.24
A pharmacist-based antiretroviral stewardship program was developed and implemented
in a pediatric HIV clinic to evaluate ARV regimens and make recommendations for opti-
mization when indicated. The pharmacist-based antiretroviral stewardship team (AST)
developed a screening assessment tool, then evaluated and made recommendations to
optimize clinical outcomes. The results showed the following recommendation frequen-
cies: suboptimal regimens based on genotypic resistance (35.4%), switching to safer ARVs
(33.3%), and virologic and averting drug–drug interactions (10.4%). Clinical outcomes
were evaluated and of the patients who had recommendations implemented within 6
months, there was a 7-fold higher probability of a significant reduction in viral load by
6 months. The authors conclude that the pharmacist-based ARV stewardship program
improved clinical outcomes and can be considered a core strategy in continuous quality
improvement in the management of HIV-infected children and adolescents.25
The pediatric literature review demonstrates that the pharmacist has an integral part-
nership with the healthcare team to provide age-specific care to infants, children, and
adolescents living with HIV in the following areas:23-25
• assisting in the selection of age-specific regimens
• performing dosage calculations
• assessing drug interactions
• monitoring for side effects and assessing comorbidities
• assisting with insurance challenges, co-pays, and acquisition of ARVs
• performing medication reconciliation to prevent medication errors
• monitoring response to therapy
• assessing for treatment failure, managing resistance, and selecting new treat-
ment regimens
ERRNVPHGLFRVRUJ
• serving as a resource for drug information for patients and providers, including
drug interactions, drug formulations, dosing, side effects, current clinical trials,
investigational drug therapies, and study protocols
• providing adherence education, including meeting with the patient and care-
giver before initiating therapy to provide education regarding the ARV medi-
cations, goals of therapy, administration methods for liquid medications, pill
swallowing techniques, pill reminder techniques (pill boxes, alarms, cell phone
texting), missed doses, and ordering refills
• promoting HIV testing, PrEP education, and HIV prevention methods in
adolescents
KEY RESOURCES
• Centers for Disease Control HIV website: www.cdc.gov.
o Provides the most updated federal statistics and guidelines.
• Department of Health and Human Services Treatment Guidelines. Available at: www.
AIDSinfo.nih.gov.
o Provides the most updated federal guidelines on management of HIV infection.
• National Resource for information on youth and HIV. Available at: https://whatwork-
sinyouthhiv.org.
o Provides resources on youth and HIV.
• The National Perinatal HIV Hotline (1-888-448-8765)
o Provides free clinical consultation on all aspects of perinatal HIV, including
infant care.
• United Nations AIDS website: www.unaids.org.
o Provides the most updated global statistics and global plan.
REFERENCES
1. World Health Organization Global summary of the AIDS epidemic, December 2015. Available
at: http://www.who.int/hiv/data/epi_core_2016.png?ua=1.
2. Conner EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human
immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group
Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180; pmid:7935654.
3. Centers for Disease Control and Prevention (CDC). Achievements in public health. Reduction
in perinatal transmission of HIV infection—United States, 1985–2005. MMWR Morb Mortal Wkly
Rep. 2006;55(21):592-597; pmid:16741495.
4. UNAIDS Prevention Gap report (http://www.unaids.org/sites/default/files/media_asset/2016-pre-
vention-gap-report_en.pdf).
5. Centers for Disease Control and Prevention HIV Surveillance Fast Facts, 2014: Available at:
http://www.cdc.gov/hiv/group/age/youth/index.html.
6. UNICEF Data. HIV/AIDS. Updated June 2016. Available at: www.data.unicef.org.
7. Panel on Antiretroviral Therapy and Medical Management of HIV-Infection. Recommendations
for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and
Interventions to Reduce Perinatal HIV Transmission in the United States. (Last updated: October
26, 2016, last reviewed: October 26, 2016.) Accessed: January 20, 2017. Available at: https://
aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0.
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8. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guide-
lines for the use of antiretroviral agents in pediatric infection. (Last updated: April 27, 2017,
last reviewed: April 27, 2017.) Available at: https://aidsinfo.nih.gov/guidelines/html/2/pediat-
ric-treatment-guidelines/0#. Section accessed August 28, 2017.
9. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for
the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected
Children. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/
contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf. (Last updated: November 6, 2013, last
reviewed: November 6, 2013.) Section accessed June 25, 2016. Updates on HIV and infant
feeding guideline. Available at: www.who.int.
10. Updates on HIV and infant feeding guideline. Available at: www.who.int.
11. Fernandez E, Perez R, Hernandez A, et al. Factors and mechanisms for pharmacokinetic differ-
ences between pediatric population and adults. Pharmaceutics. 2011;3:53-72.
12. Martinez J, and Chakraborty R and the Committee on Pediatric AIDS. Psychosocial Support for
Youth Living With HIV. Pediatrics. 2014;133(3):558-562.
13. Calabrese SK, Martin S, Wolters PL, et al. Diagnosis disclosure, medication hiding, and medical
functioning among perinatally infected, HIV-positive children and adolescents. AIDS Care.
2012;24(9):1092-1096.
14. Centers for Disease Control and Prevention: Revised Surveillance Case Definition for HIV infec-
tion—United States, 2014. MMWR. 2014;63(No. RR-3):1-10.
15. Insight Start Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV
infection. N Engl J Med. 2015;373(9):795-807. Available at: http://www.ncbi.nlm.nih.gov/
pubmed/26192873.
16. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-
infected infants. N Engl J Med. 2008;359(21):2233-2244. Available at: http://www.ncbi.nlm.nih.
gov/pubmed/19020325.
17. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Adults and
Adolescents. Adult and Adolescent Treatment Guidelines: Considerations for Antiretro-
viral Use in Special Patient Populations HIV-Infected Adolescents and Young Adult. (Last
updated: January 28, 2016, last reviewed: January 28, 2016.) Available at: https://aidsinfo.
nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/21/hiv-infected-adoles-
cents-and-young-adults.
18. Shaw S, Amico K. Antiretroviral therapy adherence enhancing interventions for adolescents and
young adults 13–24 years of age: A review of the evidence base. JAIDS. 2016;72(4):387-399.
19. Centers for Disease Control and Prevention Vaccination Guidelines, 2016. Available at: http://
www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html.
20. Philbin MM, Tanner AE, DuVal A, et al. HIV testing, care referral, and linkage to care intervals
affect time to engagement in care for newly diagnosed HIV-infected adolescents in 15 adoles-
cent medicine clinics in the United States. JAIDS. 2016;72(2):222-229.
21. Centers for Disease Control and Prevention. Pre-exposure Prophylaxis for HIV Prevention in the
United States—2014. A Clinical Practice Guideline. Available at: http://www.cdc.gov/hiv/pdf/
guidelines/PrEPguidelines2014.pdf.
22. Hosek S, Landovitz R, Rudy B, et al. An HIV pre-exposure prophylaxis (PrEP) demonstration
project and safety study for adolescent MSM ages 15–17 in the United States (ATN 113).
Programme and abstracts of the International AIDS Conference, Durban, South Africa, 2016.
23. Tseng A, Foisy M, Hughes C, et al. Role of the pharmacist in caring for patients with HIV/AIDS:
Clinical practice guidelines. Can J Hosp Pharm. 2012 Mar-Apr;65(2):125-145.
24. Scott JD, Abernathy KA, Diaz-Linares M, et al. HIV clinical pharmacists—The US perspective.
Farm Hosp. 2010;34(6):303-308.
25. Hsu AJ, Neptune A, Adams C, et al. Antiretroviral stewardship in a pediatric HIV clinic: Develop-
ment, implementation and improved clinical outcomes. Ped Inf Dis J. 2016;35(6):642-648.
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16
HIV and Cancer
Karim Ibrahim, BPharm, DClinPharm, AACPA, MSHP,
and Alison Yi Jin Wong, BPharm, MSc, AAHIVP
INTRODUCTION
Human immunodeficiency virus (HIV) and malignancies have been linked since
the early 1980s, when Kaposi’s sarcoma (KS) was described in young men who also
had concomitant symptoms of severe immunosuppression, a condition that was
subsequently known as acquired immunodeficiency syndrome (AIDS). In addi-
tion to KS, people living with HIV (PLHIV) are at an increased risk of developing
high-grade B-cell non-Hodgkin’s lymphoma (NHL) and invasive carcinoma of
the cervix. Hence, KS, NHL, and invasive carcinoma of the cervix are known as
AIDS-defining cancers.1,2
Other cancers such as Hodgkin’s lymphoma (HL) anal, colorectal, and liver
carcinoma, although not classified as AIDS-defining cancers, occur at increased
frequency in PLHIV.3 They are referred to as non–AIDS-defining cancers (NADC).
The cumulative incidence of developing certain NADCs, including anal, colorectal,
and liver, continue to increase over the years, partially due to the prolonged
survival of PLHIV.4
MANAGEMENT OF AIDS-DEFINING CANCERS
Kaposi’s Sarcoma
KS, one of the earliest manifestations of severe immunosuppression as a result of
HIV infection, is generally associated with severe immunosuppression but can also
occur at any CD4+ cell count. The advent of combination antiretroviral therapy
(cART) has led to a dramatic decrease in the incidence of KS in PLHIV.1
KS is an endothelial cell tumor that is associated with human herpes virus 8
(HHV-8) infection, also known as KS-associated herpes virus (KSHV).5 Therefore,
HIV patients with HHV-8 co-infection are at high risk of developing KS. Transmis-
sion of HHV-8 in endemic areas can occur through saliva, whereas in epidemic KS,
sexual transmission appears to be the major mode of acquisition.
KS typically manifests as pigmented lesions involving skin, mucous membranes
of the mouth, eyes, nose, and anus. Skin lesions occur as reddish, purple, or bluish-
brown nodules, lesions, or patches. Skin lesions can lead to very painful swelling,
especially when lower limbs are affected. Internal organs like lungs and the gastro-
313
ERRNVPHGLFRVRUJ
TABLE 16-1. Cumulative Cancer Incidence by 75 Years Old (Data from

2005–2009)
Cancer Type People Living with HIV HIV-Uninfected People
Kaposi 4.1 0
Non-Hodgkin’s lymphoma 4 0.5
Lung 3.7 2.3
Anal 1.7 0.1
Liver 1.4 0.4
Colorectal 1.3 1.3
Hodgkin’s lymphoma 0.8 0.1

Data from: Silverberg M, Lau B, Achenbach CJ, et al. Cumulative incidence of cancer among persons with HIV in North
America. Ann Intern Med. 2015;163:507-518.
intestinal (GI) tract can also be affected. In addition to physical symptoms, there
may be significant psychological impact associated with KS as a result of the visible
skin lesions.
The most important step in the treatment of KS in PLHIV is the start of cART.
This leads to the control of HIV replication and subsequent immune reconsti-
tution, which in turn stabilizes KS or leads to regression in most patients.6 In
addition to cART, the addition of systemic treatment may be necessary in some
patients with persistent disease. Single-agent liposomal doxorubicin at a dose of
20 mg/m2 every two to three weeks is the most commonly used agent for HIV-
related KS. Liposomal doxorubicin has demonstrated efficacy and is generally well
tolerated with overall responses up to 80%.7 Main side effects include neutropenia
and hypersensitivity reactions.
Paclitaxel is a very effective second-line agent in patients who have failed
liposomal doxorubicin. Doses between 100 and 135 mg/m2 have been used with
response rates of up to 60%.8 Paclitaxel has more potential for myelosuppression as
compared to liposomal doxorubicin, and peripheral neuropathy is common. Pacli-
taxel can also have significant drug interactions via the cytochrome P450 enzymes
with ART, particularly with protease inhibitor (PI)-based ART. Other agents like
etoposide and vinorelbine have been used in patients who fail liposomal doxoru-
bicin and paclitaxel. Other currently studied experimental agents as potential KS
therapies include imatinib, sirolimus, and bevacizumab.
HIV-Associated Non-Hodgkin’s Lymphoma

NHL remains the second most common AIDS-defining cancer in HIV-infected
patients after KS (Table 16-1). PLHIV have at least a 100-fold increased incidence
ERRNVPHGLFRVRUJ
CHAPTER 16 HIV and Cancer 315
of NHL compared to HIV-negative individuals, and the disease is usually wide-

spread and aggressive.9 Furthermore, central nervous system (CNS) involvement
with lymphoma occurs in up to 20% of patients. The introduction of cART has
reduced the incidence of HIV-associated NHL, although it remains a major cause
of morbidity and mortality in PLHIV. Diffuse large B-cell lymphoma (DLBCL) and
Burkitt lymphoma are the most common forms of HIV-associated NHL, accounting
for about 90% of cases.
Since the advent of cART, significant improvements in the overall survival (OS)
of HIV-infected patients undergoing chemotherapy for NHL have been reported.10
Although it may be argued that the improvements in outcomes are multifactorial
(e.g., the availability of granulocyte colony stimulating factor [G-CSF] and broad
spectrum anti-infective agents), ultimately cART with its effect on preserving the
immune function has led to dramatic improvements in the performance status of
HIV patients diagnosed with NHL.
The use of cART has also led to increased use of high-dose chemotherapy and
allowed the optimal delivery of chemotherapy, which are important factors when
treating aggressive lymphomas in the HIV-negative setting. The role of cART in
controlling HIV replication has been reported to be independently associated with
improvements in OS in patients with HIV-associated lymphomas.11
Different chemotherapy regimens have been tested for HIV-associated NHL.
Both CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and
the infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide,
and doxorubicin) chemotherapy regimens have proven very effective therapeutic
options.
More recently, rituximab, an anti-CD20 monoclonal antibody, has been a
common addition to CHOP and EPOCH chemotherapy regimens for HIV-asso-
ciated NHL. This is partly due to excellent results achieved with these combina-
tions in HIV-negative patients as well as the fact that most cases of HIV-associated
NHL are CD20 positive. When patients receive rituximab in addition to CHOP
and EPOCH, additional monitoring may be considered, especially in patients with
CD4 cell counts below 100 cells/µL. Additional monitoring includes screening for
potential increased infectious complications and prolonged or delayed neutro-
penic events post rituximab. Patients should be counseled regarding the risks of
treatment, and the importance of urgent presentation for care in case of occur-
rence of febrile neutropenia. Results for some studies using rituximab with chemo-
therapy for HIV-associated NHL are listed in Table 16-2.
Invasive Cervical Cancer

Women living with HIV have an increased risk of cervical cancer. The incidence
of cervical cancer is four to five times higher in women living with HIV (WLHIV)
compared to HIV-negative women, and continues to increase.12 Unlike other AIDS-
defining cancers, the introduction of cART has not reduced the incidence of inva-
sive cervical cancer among women living with HIV.13
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TABLE 16-2. Rituximab Combined with Chemotherapy for Patients with

HIV-Associated NHL
Author Intervention Sample Size CR (%) 2-year OS (%)
Boue et al., 2006 R-CHOP 61 67 75
Kaplan et al., 2005 R-CHOP vs. CHOP 150 58 vs. 47 55
Ribera et al., 2008 R-CHOP 81 69 59
Sparano et al., 2010 R-EPOCH vs. 106 73 vs. 55 70 vs. 67

EPOCH then R
CR: complete remission; NHL: non-Hodgkin’s lymphoma; OS: overall survival
Boue F, Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated
non-Hodgkin’s lymphoma. J Clin Oncol. 2006;24(25):4123-4128.
Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase 3 trial
of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies
Consortium Trial 010. Blood. 2005;106(5):1538-1543.
Ribera JM, Oriol A, Morgades M, et al. Safety and efficacy of cyclophosphamide, adriamycin, vincristine, prednisone
and rituximab in patients with human immunodeficiency virus-associated diffuse large B-cell lymphoma: Results of a
phase II trial. Br J Haematol. 2008;140(4):411-419.
Sparano JA, Lee JY, Kaplan LD, et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in
HIV-associated B-cell non-Hodgkin lymphoma. Blood. 2010;115(15):3008-3016.
Human papillomavirus (HPV) infection is critical to developing cervical

intraepithelial neoplasia (CIN). Therefore, screening for HPV infection is of utmost
importance for women infected with HIV. CIN is common in HIV-infected women
as both HPV and HIV are sexually transmitted. HIV may also influence the nature
of HPV infection, and women with HIV are likely to be infected with the onco-
genic HPV subtypes (e.g., HPV16 and HPV18).
Cervical cancer could take several years to develop after the initial HPV infec-
tion. However, this period appears to be shorter in WLHIV as compared to HIV-neg-
ative women. Persistent HPV infection initially leads to grade-1 CIN (CIN1), also
known as low-grade squamous intraepithelial lesion (LSIL), which could resolve
without treatment in the majority of cases (up to 70%). However, regression rates
are higher in HIV-negative patients when compared to WLHIV. In some women
with HPV infection who develop CIN1, lesions may progress to moderate grade
(CIN2) or severe grade (CIN3) or to a precancerous lesion involving cervical glan-
dular cells, called atypical squamous cells of undetermined significance (ASCUS). If
untreated, CIN2/3 has a high probability of progressing to squamous cell cancer,
and ASCUS has a high probability of progressing to advanced cervical cancer.
Two HPV vaccines are licensed for use in the United States:
1. Quadrivalent vaccine (HPV4) against HPV 6, 11, 16, and 18 (Gardasil®),
which has been approved for the prevention of HPV in females and
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males aged 9 through 26 years for prevention of cervical, vulvar, vaginal

cancer, and anal cancers.
2. Bivalent vaccine (HPV2) against HPV 16 and 18 (Cervarix®) licensed for
HPV prevention in females aged 9 through 25 years.
Several studies have shown the HPV vaccines to be safe and immunogeneic in
PLHIV. The Advisory Committee on Immunization Practices (ACIP) recommends
vaccination with HPV4 or HPV2 for females aged 11 or 12 years. Vaccination also
is recommended for females aged 13 through 26 years who were not vaccinated
previously, including those with HIV infection.14
The Papanicolaou (Pap) test is the most effective cervical cancer screening
method in WLHIV. Centers for Disease Control and Prevention (CDC) guidelines
recommend that screening should commence within 1 year of the onset of sexual
activity for HIV-infected women under the age of 30 years, but not later than 21
years old. If the Pap test for newly diagnosed patients is normal, the next Pap test
should be repeated in 12 months, with some experts recommending a Pap test at
6 months after baseline test. The Pap test should be performed annually thereafter
provided that it is normal. If the Pap test is positive, then referral for colposcopy
should be considered. Cervical screening should continue for women above the
age of 30 years throughout their lifetime.15
Precancerous lesions identified via screening tests should be managed
according to the severity and grade of lesions. CIN1 lesions are generally observed
first, then surgical excision of these lesions could be considered if they persist after
1 or 2 years or progress to CIN 2/3. Surgical excision of lesions is associated with
high success rates in the general population, especially in the early stages; however,
results are not as good in WLHIV and high rates of disease recurrence have been
reported in many studies. Recurrence rates of up to 87% have been reported in
women with severe immunosuppression. cART has been associated with lower
rates of disease recurrence in patients undergoing surgery. Cisplatin-based chemo-
therapy is the mainstay of treatment for more advanced disease. A combination
of chemotherapy plus pelvic radiotherapy may be required in some patients to
reduce chances of recurrence.
MANAGEMENT OF NON–AIDS-DEFINING CANCERS

The increase in NADCs in PLHIV may be partially due to increased prevalence of
risk factors in this population, although HIV-related immune dysfunction may
also be a contributing factor. Unlike AIDS-defining cancers like KS and NHL, there
is a weaker association between having a low CD4 cell count and the risk of devel-
oping a non–AIDS-defining cancer.
Anal Cancer
Similar to cervical cancer, the cumulative incidence of invasive anal cancer
among patients with HIV infection in North America increased from 0.6 to 1.7
between the time periods of 1996–1999 and 2005–2009, despite the introduction
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of cART.4 HIV infection is considered to be an independent risk factor for anal

cancer. HPV vaccination as a means of anal cancer prevention has been shown to
be effective in the HIV-negative population.16 Vaccination has been shown to be
safe and highly immunogenic in HIV-infected men; however, clinical efficacy in
preventing HPV-related infections has not yet been demonstrated.17 Nonetheless,
HPV vaccination for anal cancer prevention is highly recommended in all HIV-
infected patients due to potential burden of disease.14
Although recommendations vary regarding the screening for anal dysplasia
in PLHIV, the rationale for routine anal Pap smears is evident and screening could
be beneficial in early anal cancer detection and management. The HIV Medical
Association/Infectious Diseases Society of America HIV Primary Care Guidelines
and the New York State Department of Health recommend that clinicians consider
anal Pap testing for PLHIV for those at risk of developing anal cancer (e.g., men
who have sex with men, patients with a history of anogenital condylomas, and
women with abnormal cervical and/or vulvar histology). Conversely, the CDC and
the American Cancer Society do not recommend routine anal cytology screening.
If patients are screened and found to have abnormal anal cytology, they should
be referred for further evaluation with high-resolution anoscopy and/or biopsy of
abnormal tissue.
Combined chemo-radiotherapy is the preferred method of treatment for anal
squamous cell cancers and consists of 5 fluorouracil (5-FU) combined with either
mitomycin or cisplatin. In the modern era, overall survival rates between HIV-
positive and HIV-negative patients appear to be similar and range between 43%
to 100%, although certain studies report decreased tolerability in PLHIV. Indeed,
certain studies report an increased risk of skin and GI side effects, thereby requiring
dose adjustments and/or cessation of radiotherapy. This should be avoided if
possible, however, as lower effective radiotherapy doses historically have been
associated with lower rates of local anal cancer control and lower overall survival
in PLHIV.18
HIV-Associated Hodgkin’s Lymphoma

Although HL is not considered an AIDS-defining cancer, population-based studies
have shown a significant increase in the incidence of HIV-associated HL.19 The risk
of HL in PLHIV is markedly increased, with a standard incidence ratio of 11.03 (see
Table 16-1). In a large prospective cohort study of PLHIV, the incidence for HL was
14 times higher compared to the general population.20
In contrast to some types of NHL associated with HIV, HL seems to occur at
higher CD4 counts. Although the incidence rates of AIDS-defining malignancies
like KS and NHL have fallen in the post-cART era, the incidence of HL in PLHIV
appear to have increased. HIV-associated HL is more likely to present as advanced-
stage disease with bone marrow involvement.
Before the introduction of cART, the outcomes of HIV-associated HL were
poor, with studies reporting low complete response (CR) rates of 58% and short
median OS of 13 months only.21
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In the post-cART era, five-year OS rates are approaching 80%, which now
parallel outcomes observed in the HIV-negative population. The treatment
regimen consisting of adriamycin/doxorubicin, bleomycin, vinblastine, and
dacarbazine (ABVD) appears to have the best balance between efficacy and
safety. More intense regimens that include bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) have
yielded impressive results but are generally associated with more treatment-
related toxicities.22
Colorectal Cancer
Colorectal cancer is the fifth most common cancer in PLHIV in the cART era.
Overall incidence of colorectal cancer appears to be similar between HIV-infected
and uninfected patients. Screening recommendations are also similar to those for
the general population, but screening rates in PLHIV are often suboptimal despite
this population having a higher prevalence of known colon cancer risk factors
such as smoking.
Surgical resection of colorectal cancer and its metastasis (if limited) plays a
large role in curative treatment. Adjuvant chemo-radiotherapy may also be recom-
mended to eradicate micrometastases to reduce recurrence or to treat metastatic
disease in a palliative setting. Survival outcomes for HIV-positive patients are
generally reported as similar to those of the general population.
In regard to the choice of ART and monitoring of HIV care in the context of
colorectal cancer, considering the importance of surgical resection in colorectal
cancer, several precautions are necessary. There is little evidence with regard to
the impact of surgical resection on absorption of ART. However, it is possible
that decreased absorption may result in decreased treatment efficacy. As a result,
certain experts recommend avoiding extended-release formulation tablets (e.g.,
nevirapine extended-release formulation) in patients with colorectal cancer and
those who are status-post treatment. Therapeutic drug monitoring is recom-
mended for verification of antiretroviral absorption and may be helpful to guide
dose adjustments.
Non-Small Cell Lung Cancer

Overall lung cancer incidence has been reported to be higher in PLHIV than in
the general population and may be due to the higher prevalence of cigarette
smoking and preexisting lung disease. HIV-related immune dysfunction may also
be a contributing factor. Mortality from lung cancer also appears to be higher
in PLHIV compared to HIV-negative individuals despite the similar occurrence of
lung cancer subtypes in each population (i.e., adenocarcinomas, non-small cell
carcinomas, squamous cell carcinoma).23
Despite a higher incidence rate of lung cancer in PLHIV compared to unin-
fected people (129 versus 45 per 100,000 person-years, respectively), screening
recommendations with low-dose computed tomography (CT) chest scans for
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PLHIV are similar to those for uninfected people. A study in HIV-positive smokers
(median age 48 years, 34 pack-years smoked) was inconclusive, as only one lung
cancer was detected in 678 patient-years despite a high rate of active smoking.24
Additional studies in PLHIV are necessary to determine adequate PLHIV screening
recommendations. Current prevention strategies should focus on smoking cessa-
tion and optimal control of other lung diseases (asthma, chronic obstructive
pulmonary disease, etc.) while managing drug–drug interactions with cART.25
Hepatocellular Carcinoma
The incidence of liver cancer in PLHIV is higher than for those uninfected with
HIV. This may be due to the greater proportion of PLHIV who are also co-infected
with hepatitis B virus and/or hepatitis C virus. Furthermore, other risk factors such
as alcohol abuse are also much more prevalent in the HIV-infected population.
Of note, patients with controlled hepatitis B virus still remain at a higher risk of
hepatocellular carcinoma than those who are not HIV/HBV co-infected. Similarly,
patients with previously treated or cleared HCV infection also remain at higher
risk of hepatocellular carcinoma compared to those who were never co-infected.
Regular hepatocellular carcinoma abdominal ultrasound screening may, therefore,
be recommended in PLHIV with viral hepatitis (please refer to Chapter 8 for more
information on viral hepatitis and recommendations for hepatocellular carci-
noma screening in co-infected patients). Radiofrequency ablation, resection, or
liver transplantation are generally recommended for curative treatment of hepa-
tocellular carcinoma. Noncurative treatments include chemoembolization or use
of sorafenib. Drug–drug interactions are common with sorafenib and should be
assessed prior to co-administration with cART.25
IMPORTANT MANAGEMENT CONSIDERATIONS FOR

HIV PATIENTS WITH CANCER
Concomitant ART and Chemotherapy

In the case of AIDS-defining cancers, HIV is often diagnosed simultaneously
or shortly after the diagnosis of the cancer. It is also possible that HIV-positive
patients not on ART, or one who is nonadherent to cART, may also be diagnosed
with an AIDS-defining cancer. Patients diagnosed with non–AIDS-defining cancers
are generally patients who are already known to be HIV-positive.
Initiating cART in Patients with Cancer

If not already on medication, initiation of cART is recommended as soon as
possible. Confirmation of HIV diagnosis and genotype results often requires a
minimum of 2 weeks, and it is recommended not to delay chemotherapy, regard-
less of whether the patient has started ART or not. Oftentimes, the CD4 count will
be available prior to viral load and genotype information. Initiation of opportu-
nistic infection prophylaxis, if required, is recommended while waiting for addi-
ERRNVPHGLFRVRUJ
tional information. This allows the clinician to establish adequate tolerability of

opportunistic infection prophylaxis prior to initiating ART.
In patients with no known resistance, some experts recommend the initia-
tion of a raltegravir-based regimen with tenofovir alafenamide/emtricitabine. This
would avoid most pharmacokinetic interactions and potential additive toxicities.
If twice-daily dosing with raltegravir is problematic, dolutegravir can be used.
Dolutegravir is generally very well tolerated with limited drug interactions but,
due to limited clinical experience, raltegravir remains the first choice. Use of teno-
fovir alafenamide may be limited due to access/reimbursement limitations. There-
fore, tenofovir disoproxil fumarate is an alternative. Due to potential additive
nephrotoxicity with certain chemotherapies, it is necessary to have an alternative
regimen available. Ordering an HLA-B*5701 test can help the clinician evaluate
whether abacavir/lamivudine is a possible alternative in case of toxicity. Because
this test often requires several weeks for results to return, it should be ordered at
the baseline evaluation.
Continuing cART During Chemotherapy

cART use during chemotherapy is associated with better complete response rates
and survival outcomes due to the improved immune status of HIV-infected patients
undergoing chemotherapy. If the patient is already on cART, it is suggested to
continue cART during chemotherapy due to the favorable clinical outcomes and
immune reconstitution post chemotherapy.
In some situations, interruption of cART during chemotherapy is inevi-
table due to significant GI toxicities observed with chemotherapy, such as severe
nausea, vomiting, diarrhea, and mucositis. If necessary, antiretroviral cessation
should occur in collaboration between HIV physicians and HIV/infectious diseases
pharmacists to prevent drug resistance. This is particularly relevant for certain
antiretrovirals with a long half-life like efavirenz (40–55 hours) that may remain
in the plasma several weeks after cessation, whereas other agents, such as tenofovir
and emtricitabine, have a short half-life.
Managing Potential cART and Chemotherapy Drug Interactions

One of the main challenges facing clinicians is the high likelihood of cART and
chemotherapy drug interactions.
The choice of an appropriate cART regimen is essential when treating HIV-
associated cancers to
• minimize potential pharmacokinetic and pharmacodynamic drug
interactions
• ensure full efficacy of the chemotherapy drugs
Certain drug–drug interactions between cART and chemotherapy agents
have been described in the literature, primarily in the context of HIV-associated
lymphoma. Protease inhibitors (PIs) and cobicistat inhibit CYP3A4. The concomi-
tant administration of these agents and some of the CYP3A4- metabolized chemo-
therapy agents such as vinca alkaloids, taxanes, and etoposide may result in
ERRNVPHGLFRVRUJ
these agents’ decreased clearance, which in turn could lead to life-threatening

toxicities and treatment delays. Nonnucleoside reverse transcriptase inhibitors
(NNRTIs) nevirapine and efavirenz are both potent inducers of CYP3A4, which
may result in faster clearance of chemotherapy drugs metabolized by this enzyme
and may in turn reduce chemotherapy efficacy and hence compromise treatment
outcomes. See Table 16-3 for some potential antiretroviral agents and chemo-
therapy interactions.
On the other hand, chemotherapy is often unlikely to influence antiretroviral
concentrations but remain possible. For example, long-term use of dexametha-
sone may induce CYP3A4, thereby decreasing plasma concentrations of certain
antiretrovirals. Also, capecitabine and 5-fluorouracil are strong CYP2C9 inhibitors
and may increase etravirine concentrations.
Finally, concomitant administration of antiretrovirals and chemotherapy
agents may result in additive toxicity. For example, both zidovudine and chemo-
therapy may cause anemia; similarly, stavudine and vinca-alkaloids may cause
peripheral neuropathy. These combinations are, therefore, not recommended.
The HIV treating physician and/or pharmacist should then assess the ART agents
before or immediately after initiation of chemotherapy.
TABLE 16-3. Examples of Some Potential Antiretroviral Agents and

Chemotherapy Interactions
Interactions with PIs Interaction with NNRTIs
Drug Metabolism (more with ritonavir) (efavirenz and nevirapine)
Cyclophosphamide CYP2B6, 2C19 (active) ↑ Via CYP2B6 induction ↑ Via CYP2B6 induction
CYP 3A4 (inactive, ↑ CYP3A4 inhibition
toxic)
Etoposide CYP3A4 ↑ Via CYP3A4 inhibition ↓ Via CYP3A4 induction
Vincristine/vinblastine CYP3A4 ↑↑ Via CYP3A4 ↓ Via CYP3A4 induction

inhibition
Doxorubicin CYP450 involved May ↑ reduction via May ↑ reduction via

in free radical CYP2B6 induction CYP2B6 induction to
generation in vitro to free radical and free radical and hence
hence ↑ antineoplastic ↑ antineoplastic
properties properties
Docetaxel CYP3A4 ↑↑ Via CYP3A4 ↓ Via CYP3A4 induction

inhibition
Prednisolone CYP3A4 ↑ Via CYP3A4 inhibition ↓ Via CYP3A4 induction

↑: increase in the concentration of the active metabolite, ↓: decrease in the concentration of active metabolite;
NNRTIs: nonnucleoside reverse transcriptase inhibitors; PIs: protease inhibitors
ERRNVPHGLFRVRUJ
Antiretroviral agents no longer recommended. The use of the following

antiretroviral agents is no longer recommended due to lower efficacy or unac-
ceptable toxicities: delavirdine, didanosine, fosamprenavir, indinavir, nelfinavir,
saquinavir, and stavudine. If the patient presents for chemotherapy and is on one
of the above antiretroviral agents, then a change in ART should be recommended
(Table 16-4).
Favorable antiretroviral agents with low risk of drug–drug interactions.
Raltegravir, dolutegravir, and rilpivirine are at low risk of drug–drug interactions
according to their metabolic and safety profile. Drug–drug interactions remain
possible, however, and should still be assessed. Of note, rilpivirine needs to be
taken with a meal with approximately 390–533 kcal to ensure adequate absorp-
tion. This may not always be possible in the context of chemotherapy or radio-
therapy; use of this agent should then be reassessed (Table 16-4).
Ritonavir- or cobicistat-containing cART. Several studies have shown that
ritonavir containing cART regimens may be associated with increased toxicities
due to potentiation of chemotherapy, particularly with chemotherapy regimens
containing vinca alkaloids. These data could be extrapolated to cobicistat, which
is also a strong pharmacokinetic inhibitor. The use of these agents in combination
with chemotherapy is best avoided if possible. If the patient presents for chemo-
TABLE 16-4. Summary of Antiretroviral Therapy Choice During

Chemotherapy
Recommendation Antiretroviral Agents Rationale
Antiretrovirals no longer Delavirdine, didanosine, Lower efficacy and/or
recommended fosamprenavir, indinavir, unacceptable toxicities
nelfinavir, saquinavir,
stavudine, zidovudine
Acceptable under special Cobicistat (pharmacokinetic Increased risk of drug–drug

circumstances enhancer), atazanavir, interactions or drug toxicities;
darunavir, etravirine, however, these agents may be
lopinavir, maraviroc, recommended due to prior
ritonavir, tenofovir disoproxil HIV resistance
fumarate, tipranavir
Favorable antiretroviral agents Raltegravir, dolutegravir, Low risk of drug–drug

rilpivirine*, tenofovir interactions and toxicities
alafenamide, abacavir**,
lamivudine, emtricitabine
*Rilpivirine requires 390–533 kcal of food for adequate absorption. This may be difficult to achieve in the context of
chemotherapy.
**HLA-B*5701 test should be done prior to treatment initiation. Abacavir is contraindicated in patients with a positive
HLA-B*5701 test.
ERRNVPHGLFRVRUJ
therapy and is on a ritonavir- or cobicistat-containing regimen, a change in ART

should be considered. This may not always be possible depending on the patient’s
antiretroviral history and HIV-resistance profile. If switching to a non-PI regimen
is not suitable, then chemotherapy dose reductions according to emerging treat-
ment toxicities may need to be considered according to usual recommendations.
No empiric dose adjustments are recommended, however.
Efavirenz-, nevirapine-, etravirine-containing cART. These agents are asso-
ciated with increased hepatotoxicity and may increase the metabolism of certain
chemotherapy agents, thereby decreasing efficacy. These interactions are primarily
theoretical, and their clinical significance is unknown. Therefore, a change in ART
should be considered to avoid potential drug interactions with these agents when
possible.
Maraviroc-containing cART. This agent does not typically affect the metab-
olism of other drugs and has a good safety profile. However, certain supportive
therapies given concurrently during chemotherapy (e.g., azole antifungals) may
influence its concentrations, and dose adjustments may be necessary.
Tenofovir. Due to the potential for additive renal toxicity, tenofovir disoproxil
fumarate (TDF) should be used with caution in patients receiving nephrotoxic
regimens such as high-dose methotrexate or cisplatin/carboplatin-based chemo-
therapy regimens. If the patient presents for a chemotherapy regimen that has
nephrotoxic potential, then the pharmacist may consider consulting with the
HIV team/physician to request substitution of TDF. If switching to another agent
is not suitable, then consider close monitoring of renal function during treat-
ment. Tenofovir alafenamide (TAF) currently has no contraindication for use with
chemotherapy. This agent has a preferred toxicity profile compared to TDF, and we
recommend this as the best alternative to TDF if available and reimbursed.
Zidovudine. This agent should be avoided if possible as additive hematological
toxicity and bone marrow suppression with chemotherapy are possible (anemia
and neutropenia). If the patient presents for chemotherapy and is on zidovudine,
then a change in ART should be considered. If zidovudine is an acceptable choice
because the patient’s virus is resistant to other antiretrovirals, close monitoring of
the patient’s complete blood count is warranted.
Switching ART before or during chemotherapy. Pharmacists should be partic-
ularly thoughtful when recommending or switching ART in patients who are
already stable on cART. Indeed, maintenance of virological suppression is para-
mount, and efficacy of certain antiretrovirals may be compromised according to
the patient’s virus resistance profile. Furthermore, although current antiretroviral
agents are generally very well tolerated, patients may experience drug toxicities
when changing to a new agent, and these toxicities may further delay or compli-
cate treatment.
Supportive Therapy and cART During Chemotherapy

The pharmacist must also be aware of pharmacokinetic (PK) and pharmacody-
namic (PD) interactions between supportive care medications and cART. Acid
ERRNVPHGLFRVRUJ
suppressants commonly used as part of supportive therapy in patients undergoing

chemotherapy can reduce the absorption of atazanavir and rilpivirine and subse-
quently lead to HIV virologic failure. Dexamethasone used as an antiemetic is
a CYP3A4 inducer, and long-term use can reduce the concentrations of certain
antiretrovirals. Azole antifungal agents like itraconazole and voriconazole are
substrates and inhibitors of the CYP3A4 and can lead to two-way drug interac-
tions with cART.
Evaluation of Comorbidities
The prevalence of tuberculosis and hepatitis B co-infection is higher in the HIV-
infected population than the uninfected population, and these other comorbidities
may influence ART management in the setting of cancer. Prior to chemotherapy
administration, it is important to assess the possibility of occult hepatitis B or the
risk of hepatitis B reactivation in patients with HIV. It is therefore advisable to
evaluate if hepatitis B treatment or reactivation prophylaxis is necessary in patients
prior to administering chemotherapy. As tenofovir, emtricitabine, and lamivudine
are generally active against both HIV and hepatitis B virus (HBV), it is often possible
to provide HBV treatment or prophylaxis without additional pill burden.
In regard to tuberculosis, patients with latent disease should be treated to
prevent re-activation during chemotherapy. Please refer to Chapter 10 on tuber-
culosis, for further details regarding treatment of latent and active tuberculosis.
HIV Follow-Up Plan

An HIV follow-up plan should be established between the HIV treating team and
oncology treatment team to ensure adequate monitoring. The HIV treating team
should establish the frequency of HIV viral load and CD4 count monitoring.
Notably, CD4 cell counts may decrease rapidly with chemotherapy and/or radio-
therapy. CD4 cell counts may increase again following the completion of chemo-
therapy and/or radiotherapy, although it may take several years before reaching
pre-chemotherapy/radiotherapy levels. Monitoring of HIV viral load and CD4
count is recommended to be performed on a monthly basis during the duration of
chemotherapy to add antimicrobial prophylactic agents on a timely basis.
Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) is recommended for
those who have a CD4 cell count of <200 cells/µL and should be considered in
individuals with an AIDS diagnosis with a CD4 cell count above this level. Most
HIV-infected patients are at risk of reaching a CD4 cell count of <200 cells/µL
with chemotherapy. The use of sulfamethoxazole/trimethoprim also confers cross-
protection against cerebral toxoplasmosis. Although one double-strength sulfame-
thoxazole/trimethoprim (800/160 mg) tablet daily is the preferred dose, other doses
include the use of a single-strength tablet daily and/or a double-strength tablet 3
times weekly. Cerebral toxoplasmosis prophylaxis is recommended in patients with
a CD4 cell count <100 cells/µL with a positive toxoplasmosis IgG or IgM.
Mycobacterium avium complex (MAC) prophylaxis should be initiated for
HIV-infected patients with a CD4 cell count of <50 cells/µL, as well as for patients
ERRNVPHGLFRVRUJ
who are at risk of achieving a CD4 count below this level during chemotherapy.
The treatment of choice is azithromycin 1,200 mg once a week.
PLHIV undergoing chemotherapy should also be monitored for cytomegalo-
virus (CMV) infection via CMV serology/polymerase chain reaction (PCR), espe-
cially in those with a CD4 cell count of <100 cells/µL and those with previous
CMV infection. Patients who are at high risk of CMV infection should receive
prophylaxis with oral valganciclovir or intravenous ganciclovir. Patients under-
going chemotherapy for hematological malignancies may require adequate fungal
prophylaxis due to longer periods of neutropenia expected with some chemo-
therapy regimens.
The use of primary G-CSF prophylaxis should be considered in HIV patients
receiving chemotherapy in accordance with the local guidelines. This is of partic-
ular importance in patients with severe immunosuppression with low CD4 cell
counts and in patients receiving high-dose chemotherapy. Administration of
primary G-CSF support with chemotherapy has proven effective in minimizing
or preventing prolonged neutropenia and in allowing for the administration of
subsequent cycles of chemotherapy on time without delays.

The advent of cART has completely changed the picture for HIV-associated malignan-
cies, and major improvements in outcomes for some HIV-associated malignancies have
been reported. Outcomes of some of these cancers are now parallel to those observed in
HIV-negative patients.
Current evidence supports concurrent use of cART with chemotherapy for HIV-associated
lymphoma. If appropriate, regimens should be constructed to avoid ritonavir and cobi-
cistat during chemotherapy, particularly for vinca alkaloids and taxane-based chemo-
therapy regimens to minimize treatment-related toxicities. Zidovudine use should be
avoided in patients treated with chemotherapy due to the significant increase in the risk
of hematological toxicities.
The management of HIV-infected patients with cancer is frequently complicated by
treatment-induced immunosuppression (e.g., prolonged neutropenia, comorbid diseases,
opportunistic infections, drug interactions between chemotherapy and ART). Multidisci-
plinary cooperation between oncologists, HIV physicians, and clinical pharmacists with
expertise in oncology and HIV would be the best approach to ensure that HIV patients
with malignancies are suitably managed.
Pharmacists are best suited to provide advice regarding the optimal choice of ART during
chemotherapy; minimize or prevent risk of ART–chemotherapy drug–drug interactions;
provide counseling regarding cART initiation; and lead interventions for cancer risk reduc-
tion (e.g., smoking cessation advice) as well as recommend and administer HPV vaccina-
tions to reduce risk of cervical and anal cancer.
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KEY RESOURCES
• Comprehensive HIV/HCV drug therapy and interaction guide. UHN-Toronto General
Hospital, Immunodeficiency Clinic; 2016 [2016 June 30th]. Available from: http://
app.hivclinic.ca/.
• Torres HA, Mulanovich V. Management of HIV infection in patients with cancer
receiving chemotherapy. Clin Infect Dis. 2014;59(1):106–114.
o This is a very useful review that focuses on the selection of the most appropriate
ART regimens for patients receiving chemotherapy.
• Wong A, Tseng AL. Antiretroviral Interactions with Chemotherapy Regimens. 2014 HIV
Oncology Handbook. Available from: http://hivclinic.ca/drug-information/antiretrovi-
ral-interactions-with-chemotherapy-regimens.
o This is a comprehensive resource for antiretroviral and chemotherapy drug inter-
actions. The reader can also search for drug interactions by a specific chemo-
therapy regimen.
REFERENCES
1. Spano JP, Atlan D, Breau JL, Farge D. AIDS and non-AIDS-related malignancies: A new vexing
challenge in HIV-positive patients —Part I: Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and
Hodgkin’s lymphoma. Eur J In Med. 2002;13(3):170-179.
2. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with
HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis. Lancet.
2007;370(9581):59-67.
3. Pantanowitz L, Dezube BJ. Evolving spectrum and incidence of non-AIDS-defining malignan-
cies. Curr Opin HIVAIDS. 2009;4(1):27-34.
4. Silverberg M, Lau B, Achenbach CJ, et al. Cumulative incidence of cancer among persons with
HIV in North America. Ann Intern Med. 2015;163:507-518.
5. Dezube BJ. Clinical presentation and natural history of AIDS-related Kaposi’s sarcoma. Hematol
Oncol Clin North Am. 1996;10:1023.
6. Bourboulia D, Aldam D, Lagos D, et al. Short- and long-term effects of highly active anti-retro-
viral therapy on Kaposi sarcoma-associated herpes virus immune response and vireamia. AIDS.
2004;18:485-493.
7. Cooley T1, Henry D, Tonda M, et al. A randomized, double-blind study of pegylated liposomal
doxorubicin for the treatment of AIDS-related Kaposi’s sarcoma. Oncologist. 2007;12(1):114-123.
8. Gill PS, Tulpule A, Espina BM, et al. Paclitaxel is safe and effective in the treatment of advanced
AIDS-related Kaposi’s sarcoma. J Clin Oncol.1999;17:1876-1883.
9. Stebbing J. Antiretroviral treatment regimens and immune parameters in the prevention of
systemic AIDS-Related Non-Hodgkin’s lymphoma. J Clin Oncol. 2004;22(11):2177-2183.
10. Besson C, Goubar A, Gabarre J, et al. Changes in AIDS-related lymphoma since the era of highly
active antiretroviral therapy. Blood. 2001;98(8):2339-2344.
11. Hoffmann C, Wolf E, Fatkenheuer G, et al. Response to highly active antiretroviral therapy
strongly predicts outcome in patients with AIDS-related lymphoma. AIDS. 2003;17(10):1521-1529.
12. Ellerbrock TV, Chiasson MA, Bush TJ, et al. Incidence of cervical squamous intraepithelial
lesions in HIV-infected women. JAMA. 2000;283:1031.
13. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and
incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst.
2000;92:1823.
14. Human Papillomavirus Vaccination: Recommendations of the Advisory Committee on Immuni-
zation Practices (ACIP). Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6305a1.
htm. Accessed August 27, 2016.
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15. Panel on opportunistic Infections in HIV-Infected Adults and Adolescents. Guideline for the
Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed June 30,
2016.
16. Wells JS, Holstad MM, Thomas T, Bruner DW. An integrative review of guidelines for anal cancer
screening in HIV-infected persons. AIDS Patient Care STDs; 2014:28(7):350-357.
17. Wilkin T. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in
HIV-1-infected men. JID. 2010;202(8):1246-1253.
18. Fraunholz IB, Haberl A, Klauke S, et al. Long-term effects of chemoradiotherapy for anal cancer
in patients with HIV infection: Oncological outcomes, immunological status, and the clinical
course of the HIV disease. Dis Colon Rectum. 2014;57:423-431.
19. Clifford GM, Rickenbach M, Lise M, et al. Hodgkin lymphoma in the Swiss HIV Cohort Study.
Blood. 2009;113(23):5737-5742.
20. Powles T, Robinson D, Stebbing J, et al. Highly active antiretroviral therapy and the incidence of
non-AIDS-defining cancers in people with HIV infection. J Clin Oncol. 2009;27(6):884-890.
21. Tirelli U, Errante D, Dolcetti R, et al. Hodgkin’s disease and human immunodeficiency virus
infection: Clinicopathologic and virologic features of 114 patients from the Italian Cooperative
Group on AIDS and Tumors. J Clin Oncol. 1995;13(7):1758-1767.
22. Montoto S, Shaw K, Okosun J, et al. HIV status does not influence outcome in patients with clas-
sical hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine,
and dacarbazine in the highly active antiretroviral therapy era. J Clin Oncol. 2012; October 8.
23. Suneja G, Shiels MS, Melville SK, et al. Disparities in the treatment and outcomes of lung cancer
among HIV-infected individuals. AIDS. 2013;27(3):459-468.
24. Hulbert A, Hooker CM, Keruly JC, et al. Prospective CT screening for lung cancer in a high-risk
population: HIV-positive smokers. J Thorac Oncol. 2014;9(6):752–759.
25. Spano JP, Poizot-Martin I, Costagliola D, et al. Non-AIDS-related malignancies: Expert consensus
review and practical applications from the multidisciplinary CANCERVIH Working Group. Ann
Oncol. 2016; 27(3):397-408.
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17
Transplant and HIV
Melissa Badowski, PharmD, MPH, BCPS, AAHIVP; Sarah E. Pérez,
PharmD, BCACP, AAHIVP; and Elizabeth Hetterman, PharmD, BCPS
INTRODUCTION
Human immunodeficiency virus (HIV) was previously considered a contra-
indication to solid organ transplantation (SOT). This contraindication was based
on data collected prior to the availability of combination antiretroviral therapy
(cART) when many patients experienced mortality from opportunistic infections
and acquired immunodeficiency syndrome (AIDS)-defining cancers. Because HIV-
infected patients are living longer as a result of ART, interest in SOT in this popu-
lation has increased. This chapter will review the epidemiology, outcomes, medi-
cation management considerations, and the essential role of the pharmacist in
caring for individuals with HIV requiring SOT.
EPIDEMIOLOGY
It is estimated that up to 10% of HIV-positive patients have chronic kidney disease
(CKD), and progression to end-stage renal disease (ESRD) is more rapid compared
to those without HIV.1 Although patients with HIV only account for up to 2% of
the ESRD population in the United States and Europe, the prevalence of ESRD
has increased more than 14-fold from 1999 to 2010 in this group.2 The incidence
of ESRD due to HIV-associated nephropathy has decreased secondary to ART,
yet the rate of CKD and ESRD is increasing in this population due to traditional
factors such as poorly controlled hypertension and diabetes. Five-year survival for
patients undergoing dialysis is 63% for HIV-positive patients compared to 94%
in matched counterparts.3 The same is true for HIV-positive patients living with
end-stage liver disease (ESLD) where the median survival without transplanta-
tion is 1.5 years. Liver disease ranks among the top three causes of death in HIV-
positive patients due to cirrhosis and hepatocellular carcinoma secondary to hepa-
titis B virus (HBV) and hepatitis C virus (HCV) co-infections.
Organ transplantation not only improves patient survival but also quality of
life. Rates of success are highly dependent on transplant center experience, patient
characteristics, and comorbidities. For example, in HIV-positive patients receiving
liver transplantation due to HCV co-infection, higher rates of acute rejection, graft
loss, and mortality have occurred. However, as clinical experience increases, data
continue to emerge on improved transplant outcomes among HIV-positive patients.
Currently, experience with renal and liver transplantation in HIV-positive patients
329
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is well documented. Simultaneous pancreas-kidney, combined liver-kidney, heart,

and lung transplantation have also been described in this population, but the data
are limited.
Currently, there are 116,789 individuals on the organ transplantation wait-
list with another individual added every 10 minutes in the United States.4 Wait-
ing-list time depends on various factors, such as organ to be transplanted, blood
type, and human leukocyte antigen (HLA). In 2016, 33,611 SOTs were performed
with 27,630 transplants made possible through deceased donors.5 It is anticipated
that by expanding access for HIV-positive patients to receive organs from others
with HIV through the HIV Organ Policy Equity (HOPE) Act, an estimated 1,000
additional SOTs may occur annually.6 Although passed in 2013, the HOPE Act
was not implemented until November 2015. This act will expand research eval-
uating SOTs from HIV-positive donors to HIV-positive recipients. Currently, only
kidney and liver transplants fall within the scope of the HOPE Act because there
is substantial evidence supporting transplantation from HIV-negative donors to
HIV-positive recipients.7
CONSIDERATIONS FOR SOT IN PATIENTS WITH HIV

The main objectives of SOTs are to promote graft and patient survival while mini-
mizing the risk of rejection, infectious complications, and drug toxicities. Prior to
transplantation, most protocols require stable ART, an undetectable HIV viral load,
and good immunologic function as manifested by CD4 count to optimize patient
outcomes and decrease the risk of delayed graft function, acute rejection, and
infections that can compromise the graft and patient survival. Donor and recip-
ient criteria for transplantation, as outlined by the HOPE Act, are summarized in
Table 17-1.8 ART and immunosuppression should be initiated carefully and based
upon shared decision making between HIV and SOT clinicians. Drug–drug inter-
actions between immunosuppressants and antiretrovirals can negatively impact
drug concentrations, especially with immunosuppressants. Identifying drug–drug
interactions prior to transplantation may prevent or minimize adverse outcomes
due to subtherapeutic or supratherapeutic levels of immunosuppressants as well
as allow clinicians to tailor medication regimens to optimize HIV treatment and
minimize risk of drug toxicities.
Immunosuppression
When selecting immunosuppression, one must consider the recipients’ risk for
rejection, toxicities of the medication, as well as drug–drug interactions. Immuno-
suppression protocols may vary according to transplant center and type of organ
transplanted. The primary goal is to prevent rejection while minimizing the risk of
infection, malignancy, and drug toxicity. To date, the majority of literature avail-
able regarding immunosuppression in patients with HIV is in HIV-positive kidney
transplant recipients. Most regimens consist of induction and maintenance immu-
nosuppression with either triple or dual drug therapy.
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CHAPTER 17 Transplant and HIV 331
TABLE 17-1. HOPE Act Donor and Recipient Criteria for HIV-Positive to
HIV-Positive Transplantation
Recipient Living Donor Deceased Donor
CD4 Count OI History: ≥200 ≥500 b
No requirement
(cells/mm3)a
No OI History:
≥200 (kidney)
≥100 (liver)
HIV Viral Load (copies/mL) <50c <50 No requirement
OI No active OI or history of CNS No invasive No invasive OI

lymphoma or PML OI
CNS: central nervous system; OI: opportunistic infection; PML: progressive multifocal leukoencephalopathy
a
Measurement must occur within 16 weeks prior to transplantation.
b
For at least 6 months prior to transplantation
c
If recipient is unable to tolerate ART due to organ failure or if recipient recently started ART and viral load is
detectable, he or she may be considered for transplantation if medical team is confident the patient will be able to
resume ART post-transplantation.
Source: Data from reference 8.
Induction
Controversy exists as to which induction agent provides the most optimal outcomes
for HIV-positive transplant recipients. Compared to their HIV-negative counter-
parts, HIV-positive kidney transplant recipients have a 2- to 4-fold increased risk of
acute rejection.9 Although commonly used in the HIV-negative kidney transplant
population, the use of induction in the HIV-positive population poses a signifi-
cant challenge as centers weigh the risk of serious infection post-transplant versus
the well-documented increased risk of acute rejection post-transplant. The two
most commonly used induction agents in the HIV-positive population are basilix-
imab, a monoclonal anti-interleukin 2 receptor antibody, and rabbit antithymo-
cyte globulin (rATG), a lymphocyte-depleting polyclonal antibody. Some centers
avoid the use of lymphocyte-depleting agents due to significant and prolonged
CD4 depletion and increased infection risk.9 Because no relevant drug–drug inter-
actions are expected to occur with basiliximab or rATG and ART, either would be
acceptable for administration.
Maintenance
As seen with induction, maintenance regimens are most often center-specific,
based upon experience and patient outcomes. The literature most often cites
an initial maintenance immunosuppression regimen consisting of a calcineurin
inhibitor (CNI) (cyclosporine or tacrolimus) plus an antiproliferative agent (myco-
phenolate mofetil [MMF] or mycophenolic acid [MPA]) with a glucocorticoid.10
Although tacrolimus is available as an extended-release product, no data currently
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exist regarding this product’s drug interactions with ART and clinical outcomes
in the HIV-positive transplant population. Azathioprine is an alternative agent to
MMF; however, data regarding its use in HIV recipients is not well documented.
Less commonly, mammalian target-of-rapamycin inhibitors (mTORi), such as
sirolimus or everolimus, have been used as alternative therapy when patients do
not tolerate CNIs or antimetabolites. Belatacept, a selective T-cell co-stimulation
blocker, was approved in 2011 for maintenance immunosuppression in kidney
transplant recipients. Unlike CNIs, belatacept does not carry a risk of nephrotox-
icity nor does it interact with ART. However, literature regarding its use in HIV-
positive transplant recipients is scarce and no data currently exist regarding long-
term outcomes in HIV-positive recipients. Common immunosuppressant adverse
effects are listed in Table 17-2.
TABLE 17-2. Characteristics of Adverse Effects with Maintenance

Immunosuppressive Agents
Adverse Effects
Cyclosporine • Neurotoxicity (tremor, headache, seizure)
• Nephrotoxicity
Modified: • Hirsutism
Gengraf® • Diabetes mellitus
Neoral®
• Hypercholesterolemia
• Electrolyte abnormalities (hyperkalemia, hypomagnesemia)
Non-modified: • Hyperuricemia
SandIMMUNE ®
• Gingival hyperplasia
Tacrolimus • Neurotoxicity (tremor, headache, seizure)

• Nephrotoxicity
Prograf® • Alopecia
• Diabetes mellitus
• Hypercholesterolemia
• Electrolyte abnormalities (hyperkalemia, hypomagnesemia)
Mycophenolate mofetil • Diarrhea

• Nausea
Cellcept® • Vomiting
Myfortic ®
• Bone marrow suppression (leukopenia, anemia,
thrombocytopenia)
Azathioprine • Bone marrow suppression (leukopenia, anemia,

thrombocytopenia)
• Hepatotoxicity
• Pancreatitis
(continued)
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TABLE 17-2. Characteristics of Adverse Effects with Maintenance

Immunosuppressive Agents (continued)
Adverse Effects
Sirolimus • Proteinuria
• Hyperlipidemia
Rapamune ®
• Impaired wound healing
• Mouth ulcers
• Pneumonitis
• Anemia
• Thrombocytopenia
Everolimus • Proteinuria
Zortress ®
• Hyperlipidemia
• Mouth ulcers
• Pneumonitis
• Anemia
• Thrombocytopenia
Corticosteroids • Impaired glucose tolerance

• Hypertension
• Increased appetite
• Mood disturbances
• Osteoporosis
• Hyperglycemia
• Weight gain
• Hyperlipidemia
DRUG–DRUG INTERACTIONS BETWEEN cART AND

IMMUNOSUPPRESSANTS
Due to complex pharmacokinetic interactions, immunosuppression dose adjust-
ments may be required as well as therapeutic drug monitoring.11,12 Common drug
interactions are listed in Table 17-3.11 It is imperative that immunosuppression
drug levels are closely monitored post-transplant to avoid subtherapeutic levels
that may result in rejection or supratherapeutic levels, leading to drug toxicity or
increased risk of infection due to overimmunosuppression. Goal trough levels of
maintenance immunosuppression vary according to the transplant center, organ
ERRNVPHGLFRVRUJ
TABLE 17-3. Drug–Drug Interactions

BAS rATG TAC CsA MPA AZA SRL EVR CS BELA
NRTIs ABC ◊ ◊ ◊ ◊ • ◊ ◊ ◊ ◊ ◊
ddI ◊ ◊ ◊ ◊ ◊ • ◊ ◊ ◊ ◊
FTC ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊
3TC ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊
d4T ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊
TAF ◊ ◊ ◊ • ◊ ◊ ◊ ◊ ◊ ◊
TDF ◊ ◊ • • • ◊ • ◊ ◊ ◊
AZT ◊ ◊ ◊ ◊ • • ◊ ◊ ◊ ◊
NNRTIs DLV ◊ ◊ • • • ◊ • • ◊ ◊
EFV ◊ ◊ • • • ◊ • • ◊ ◊
ETR ◊ ◊ • • ◊ ◊ • • ◊ ◊
NVP ◊ ◊ • • • ◊ • • ◊ ◊
RPV ◊ ◊ • • ◊ ◊ ◊ • ◊ ◊
PIs ATV ◊ ◊ • • • ◊ • • • ◊
DRV ◊ ◊ • • • ◊ • • • ◊
FPV ◊ ◊ • • • ◊ • • • ◊
IDV ◊ ◊ • • • ◊ • • • ◊
LPV/r ◊ ◊ • • • ◊ • • • ◊
NFV ◊ ◊ • • • ◊ • • • ◊
SQV ◊ ◊ • • • ◊ • • • ◊
TPV ◊ ◊ • • • ◊ • • • ◊
INSTIs DTG ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊
EVG/c ◊ ◊ • • ◊ ◊ • • • ◊
RAL ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊
PK RTV ◊ ◊ • • • ◊ • • • ◊
Enhancers
COBI ◊ ◊ • • ◊ ◊ • • • ◊
(continued)
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TABLE 17-3. Drug–Drug Interactions (continued)

BAS rATG TAC CsA MPA AZA SRL EVR CS BELA
Entry T20 ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊ ◊
Inhibitors
MVC ◊ ◊ ◊ • ◊ ◊ ◊ • ◊ ◊
◊ = no interaction expected, • = potential interaction
3TC: lamivudine; ABC: abacavir; ATV: atazanavir; AZA: azathioprine; AZT: zidovudine; BAS: basiliximab; BELA:
belatacept; COBI: cobicistat; CS: corticosteroids; CsA: cyclosporine; d4T: stavudine; ddI: didanosine; DLV: delavirdine;
DRV: darunavir; DTG: dolutegravir; EFV: efavirenz; ETR: etravirine; EVG/c: elvitegravir/cobicistat; EVR: everolimus; FPV:
fosamprenavir; FTC: emtricitabine; IDV: indinavir; INSTIs: integrase strand transfer inhibitors; LPV/r: lopinavir/ritonavir;
MPA: mycophenolic acid; MVC: maraviroc; NFV: nelfinavir; NNRTIs: nonnucleoside reverse transcriptase inhibitors;
NRTIs: nucleoside reverse transcriptase inhibitors; NVP: nevirapine; PI: protease inhibitor; PK: pharmacokinetic; RAL:
raltegravir; rATG: rabbit antithymocyte globulin; RPV: rilpivirine; RTV: ritonavir; SQV: saquinavir; SRL: sirolimus; T20:
enfuvirtide; TAC: tacrolimus; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil fumarate; TPV: tipranavir
Source: Data from references 11 and 12.
transplanted, time from transplant, rejection risk, and current clinical status. It
is important to work in close collaboration with the HIV and transplant medical
teams when making alterations to ART or immunosuppression. Pre-transplant
evaluation of the patient’s current ART regimen can assist in identifying drug
interactions that may arise post-transplant. If appropriate and feasible, the HIV
clinician may choose to convert the patient to a noninteracting ART regimen prior
to transplant. An attempt should be made to implement any changes in the ART
regimen well in advance of transplant to stabilize and assess efficacy and tolera-
bility of the new regimen. Appropriate management of these drug interactions
is crucial to prevent graft rejection as well as infections, promote graft survival,
control the patient’s HIV, prevent the development of HIV resistance, and avoid
any patient-experienced toxicities.
Drug Interactions with Nucleoside Reverse Transcriptase Inhibitors

First-line recommended cART regimens include two nucleoside reverse transcrip-
tase inhibitors (NRTIs) along with an agent from another drug class.13 The most
common backbones consist of lamivudine or emtricitabine plus abacavir, teno-
fovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF). Lamivudine and
emtricitabine undergo minimal metabolism and are mostly excreted renally as
unchanged drug. Therefore, there are no expected drug–drug interactions with
immunosuppressive agents.
The majority of immunosuppressants are not expected to interact with
abacavir with the exception of mycophenolate. The prodrug mycophenolate
mofetil undergoes glucuronidation to become the active form of mycophenolic
acid. As abacavir also undergoes glucuronidation, it is possible for abacavir to alter
the levels of mycophenolate, which has a synergistic effect with abacavir against
HIV. The clinical impact of this interaction is not known. There are no recommen-
dations for dose adjustment, but mycophenolate levels should be monitored.
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Currently, two tenofovir formulations are commercially available that include

TDF and the newer formulation of TAF. There are more concerns with drug inter-
actions between TDF and immunosuppressants with the potential additive impact
on renal function. For this reason, it may be prudent to avoid TDF if a patient
has undergone kidney transplantation due to increased nephrotoxic effects when
compared to abacavir or TAF. Both TDF and cyclosporine (CsA) can impair renal
function. CsA is also expected to increase plasma concentrations of TDF through
P-glycoprotein (Pgp) inhibition, increasing the possibility of TDF-associated
adverse effects. Frequent renal monitoring is recommended if these drugs are used
concomitantly. Mycophenolate and TDF can compete for active tubular secretion,
which can possibly lead to increased concentrations of both drugs. Renal function
should be closely monitored if both drugs are given. No interaction is expected
between sirolimus and TDF that results in changes in the concentration of either
drug; however, both have the potential to cause renal tubular toxicity. Tacrolimus
can also cause renal impairment. If sirolimus or tacrolimus is used in combination
with TDF, close monitoring of renal function is recommended.
TAF is a new prodrug formulation of tenofovir that results in much lower
plasma concentrations compared to TDF, resulting in less renal toxicity. Therefore,
the drug interactions discussed with TDF and immunosuppressants are much less
concerning with TAF. There is a possible drug interaction between TAF and CsA via
the same mechanism as the interaction with TDF and CsA. The clinical impact of
this interaction is uncertain but is less likely to cause renal impairment compared
to the interaction between CsA and TDF. Renal function should still be monitored
if these drugs are co-administered.
Stavudine, didanosine, and zidovudine are other NRTIs used less frequently
due to their side effect profiles. Interactions between these drugs and immuno-
suppressants are described in Table 17-3.
Drug Interactions with Nonnucleoside Reverse Transcriptase Inhibitors

The majority of nonnucleoside reverse transcriptase inhibitors (NNRTIs) are
CYP3A4 inducers, resulting in drug–drug interactions that can cause decreased
immunosuppressant levels.12 Because rilpivirine is neither an inducer nor inhibitor
of CYP, interactions are unlikely to occur.12 Efavirenz, etravirine, nevirapine, and
delavirdine can cause decreased serum concentration of tacrolimus, cyclosporine,
sirolimus, and everolimus. Specifically, efavirenz has been shown to increase the
metabolism of CsA and, therefore, a higher dose of CsA is necessary to achieve
therapeutic concentrations.14 Although case reports with tacrolimus and efavirenz
or nevirapine did not result in any changes in these medication levels, the dose
of tacrolimus may need to be increased.15 Drug levels of these immunosuppres-
sants should be monitored when concomitantly receiving NNRTIs, with closer
monitoring occurring during these agents’ initiation or discontinuation. Myco-
phenolate can cause decreased nevirapine concentrations; however, the clinical
significance of this is unknown.
Proton pump inhibitors (PPIs) are often prescribed to patients post-transplant.
The administration of rilpivirine and PPIs are contraindicated as PPIs can decrease
ERRNVPHGLFRVRUJ
the absorption and serum concentration of rilpivirine.12,13 Patients on rilpivir-

ine-containing regimens that require a PPI should be switched to a more appro-
priate regimen based on their previous treatment history, resistance pattern, other
comorbidities, and medications. It is ideal to make these switches prior to the
transplant if possible to ensure the new ART regimen is tolerable and efficacious.
Drug Interactions with Protease Inhibitors

Protease inhibitors (PIs), as a class of drugs, have drug–drug interactions with the
majority of immunosuppressants. PIs and their pharmacokinetic boosters, ritonavir
and cobicistat, inhibit CYP3A4. Therefore, concentrations of immunosuppressants
(with the exception of azathioprine) will be increased if given in combination with
a PI. This interaction can significantly increase drug concentrations of CNIs and
sirolimus, leading to drug toxicity and increasing the risk for significant adverse
effects. Most often, CNI toxicity manifests as a headache, tremor, and, in severe
cases, seizure. Case reports have consistently demonstrated the need to reduce the
starting dose of tacrolimus (by a minimum of 50%) or increase the dosing interval
of tacrolimus (0.5 mg weekly) when given with PIs.16-19 The same holds true for CsA
(dose reduction of 5% to 20%).20 Therefore, it is necessary to closely monitor trough
levels of CNIs and sirolimus in these patients and adjust accordingly to meet goal
levels. Increased steroid-associated side effects are expected if corticosteroids are
given concomitantly with PIs. If these interactions between immunosuppressants
cannot be avoided, dose adjustments of the immunosuppressants and frequent
drug level and side effect monitoring is required.
If patients are initiated on a PPI post-transplant, caution should be exercised
if the patient is taking atazanavir. This combination should be avoided in ART
treatment-experienced patients.12,13 In treatment-naïve patients, no more than an
equivalent dose of omeprazole 20 mg should be administered 12 hours apart from
boosted atazanavir.
Drug Interactions with Integrase Strand Transfer Inhibitors

All three integrase strand transfer inhibitors (INSTIs) are considered recommended
antiretroviral agents for initial therapy when given in combination with an NRTI
backbone.13 There are no drug–drug interactions expected between raltegravir or
dolutegravir and immunosuppressants, so they are an optimal choice in the setting
of transplantation.12,13 Elvitegravir is used in combination with the pharmaco-
kinetic booster cobicistat. As cobicistat is a strong CYP3A4 inhibitor, it may
increase the levels of several immunosuppressants, including tacrolimus, CsA,
sirolimus, everolimus, and corticosteroids. Therapeutic drug monitoring of the
immunosuppressants is recommended. If cobicistat is given in combination with
corticosteroids, patients should be monitored for corticosteroid-related adverse
effects such as weight gain, hyperglycemia, and osteoporosis. Co-administration
of everolimus and strong CYP3A4 inhibitors is not recommended, and there are
no recommendations for adjustments. There are no expected drug interactions
between cobicistat and mycophenolate or azathioprine.
ERRNVPHGLFRVRUJ
Drug Interactions with Entry Inhibitors

Maraviroc, a CCR5 antagonist entry inhibitor, is a substrate of CYP3A4. As inhib-
itors of CYP3A4, CsA and everolimus can potentially increase the concentration
of maraviroc.12,13 Although no data or clinical recommendations currently exist,
standard doses of maraviroc or immunosuppressants are recommended along with
close monitoring. In addition, there are no expected drug interactions between
immunosuppressants and the fusion inhibitor enfuvirtide.
INFECTIOUS COMPLICATIONS
Infection prophylaxis is as essential as immunosuppression post-transplantation.
Various sources for infection can arise and may include community-acquired or
nosocomial pathogens as well as reactivation of infection by donor or recipient.
Most infectious complications occur within the first 6 months of transplantation.
A nonrandomized study followed 150 HIV-positive kidney transplant recipients
for up to 3 years and reported that 140 severe infections occurred in 57 patients
(38%) requiring hospitalization. Of these severe infections, 60% occurred within 6
months of transplantation.21 Refer to Chapter 7 for a detailed discussion of oppor-
tunistic infections.

In consultation with the transplant team, the transplant recipient’s ART and immuno-
suppression should be managed collaboratively with the patient’s HIV healthcare team.
Although the Centers for Medicare & Medicaid Services (CMS) does not require pharma-
cists in HIV management, it requires a transplant pharmacist as a part of the interdisci-
plinary medical team. Clinical pharmacists are the cornerstone of educating patients on
their medications, recognizing and managing drug–drug interactions and adverse effects,
and assisting with gaining access to these specialized medications. If possible, pretrans-
plantation evaluation of ART and immunosuppression should be discussed in collabo-
ration with both teams in an attempt to minimize drug–drug interactions preemptively.
If ART is going to be initiated, changed, or temporarily discontinued, the change and
potential effect should be communicated to the transplantation team to anticipate any
therapeutic changes in the degree of immunosuppression.
KEY RESOURCES
• Blumberg EA, Rogers CC. AST Infectious Diseases Community of Practice.
Human Immunodeficiency virus in solid organ transplantation. Am J Transplant.
2013;13(Suppl 4):169-178. Available at: http://onlinelibrary.wiley.com/doi/10.1111/
ajt.12109/epdf.
o Provides criteria for transplantation of various organs in HIV-infected individ-
uals, treatment considerations, and preventative measures (opportunistic infec-
tion prophylaxis, and vaccination recommendations).
ERRNVPHGLFRVRUJ
• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department
of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/
lvguidelines/AdultandAdolescentGL.pdf. Accessed August 1, 2017.
o These guidelines provide comprehensive information of the management of
treatment-naïve and experienced patients in terms of preferred and alternative
antiretroviral regimens. There are various tables provided to outline necessary
monitoring parameters, potential adverse effects, and drug–drug interactions.
• University of Liverpool. HIV Drug Interactions. Available from: http://www.hiv-dru-
ginteractions.org/checker. Accessed August 1, 2017.
o An interactive, up-to-date database that provides free color-coded drug interac-
tion charts to identify clinically significant drug–drug interactions.
REFERENCES
1. Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic
kidney disease in patients infected with HIV: 2014 Update by the HIV Medicine Association of
the Infectious Diseases Society of America. Clin Infect Dis. 2014; 59:e96–e138.
2. Boyarsky BJ, Durand CM, Palella FJ Jr, Segev DL. Challenges and clinical decision-making in
HIV-to-HIV transplantation: Insights from the HIV literature. Am J Transplant. 2015;15(8):2023-
2030.
3. Trullas JC, Cofan F, Barril G, et al. Outcome and prognostic factors in HIV-1-infected patients
on dialysis in the cART era: A GESIDA/ SEN cohort study. J Acquir Immune Defic Syndr. 2011;57:
276–283.
4. HRSA. Organ Procurement and Transplantation Network. Available at: https://optn.transplant.
hrsa.gov/. Accessed August 14, 2017.
5. United Network for Organ Sharing. Annual Report. Available from: https://www.unos.org/
about/annual-report/2016-annual-report/. Published July 31, 2017. Accessed August 1, 2017.
6. Mesiwala A, Barbero R, Erickson J. Saving Lives and Giving Hope by Reducing the Organ
Waiting List. Available at: https://obamawhitehouse.archives.gov/blog/2016/06/13/saving-lives-
and-giving-hope-reducing-organ-waiting-list. June 13, 2016. Accessed August 1, 2017.
7. HRSA. Organ Procurement and Transplantation Network. Hope Act. Available at: https://optn.
transplant.hrsa.gov/learn/professional-education/hope-act/. Accessed August 1, 2017.
8. National Institutes of Health. Final Human Immunodeficiency Virus (HIV) Organ Policy Equity
(HOPE) Act Safeguards and Research Criteria for Transplantation of Organs Infected with HIV.
Available at: https://www.federalregister.gov/documents/2015/11/25/2015-30172/final-human-
immunodeficiency-virus-hiv-organ-policy-equity-hope-act-safeguards-and-research-criteria.
November 25, 2015. Accessed August 1, 2017.
9. Kucirka LM, Durand CM, Bae S, et al. Induction immunosuppression and clinical outcomes in
kidney transplant recipients infected with human immunodeficiency virus. Transplantation.
2016;16:2368–2376.
10. Chadban SJ Barraclough KA, Campbell SB, et al. KHA-CARI guideline: KHA-CARI adaptation of
the KDIGO clinical practice guideline for the care of kidney transplant recipients. Nephrology
(Carlton). 2012;17:204–214.
11. Van Maarseveen EM, Rogers CC, Frofe-Clark J, et al. Drug-drug interactions between anti-
retroviral and immunosuppressive agents in HIV-infected patients after solid organ transplanta-
tion: A review. AIDS Patient Care STDS. 2012; 26:568-581.
12. University of Liverpool. HIV Drug Interactions. Available at: http://www.hiv-druginteractions.
org/checker. Accessed August 1, 2017.
13. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiret-
roviral agents in HIV-1-infected adults and adolescents. Department of Health and Human
Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.
pdf. Accessed August 1, 2017.
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14. Frassetto LA, Browne M, Cheng A, et al. Immunosuppressant pharmacokinetics and dosing
modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant.
2007;7:2816-2820.
15. Teicher E, Vincent I, Bonhomme-Faivre L, et al. Effect of highly active antiretroviral therapy on
tacrolimus pharmacokinetics in hepatitis C virus and HIV co-infected liver transplant recipients
in the ANRS HC-08 study. Clin Pharmacokinet. 2007;46:941-952.
16. Schonder KS, Shullo MA, Okusanya O. Tacrolimus and lopinavir/ritonavir interaction in liver
transplantation. Ann Pharmacother. 2003;37:1793-1796.
17. Jain AK, Venkataramanan R, Shapiro R, et al. The interaction between antiretroviral agents and
tacrolimus in liver and kidney transplant patients. Liver Transpl. 2002;8:841-845.
18. Mertz D, Battegay M, Marzolini C, Mayr M. Drug-drug interaction in a kidney transplant recip-
ient receiving HIV salvage therapy and tacrolimus. Am J Kidney Dis. 2009;54:e1-4.
19. Tsapepas DS, Webber AB, Aull MJ, et al. Managing the atazanavir-tacrolimus drug interaction in
a renal transplant recipient. Am J Health-Syst Pharm. 2011;68:138-142.
20. Vogel M, Voigt E, Michaelis HC, et al. Management of drug-to-drug interactions between
cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected
patients. Liver Transpl. 2004;10(7):939-944.
21. Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipi-
ents. N Engl J Med. 2010;363:2004-2014.
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18
Care Transitions for Persons
Living with HIV
INTRODUCTION
The widespread use of antiretroviral therapy (ART) has successfully increased the
life span of individuals living with human immunodeficiency virus (HIV) infec-
tion.1,2 In the United States, in 2012 it was estimated that about one-quarter of
people living with HIV were at least 55 years old.1 As a result, new challenges have
arisen in this aging population including treating multiple comorbidities,2 the pres-
ence of polypharmacy,2 the use of multiple caregivers and community pharmacies
to manage a patient’s health conditions, and an increased potential for admissions
to institutional care (e.g., hospitals, addiction recovery centers, long-term care and
correctional facilities). Given these factors and the complexity of ART, there is a
high potential for medication errors in this population, particularly as individuals
transition between outpatient and institutionalized care.3,4 Pharmacists in all prac-
tice settings are ideally positioned to assist with coordinating care for HIV-positive
patients, particularly during care transitions to minimize medication errors and
optimize health outcomes.
TYPES OF MEDICATION ERRORS

Over the past decade there have been numerous reports of high rates of medica-
tion errors in hospitalized HIV patients, mostly involving ART. A recent review of
the literature reported error rates as high as 86% in this population.3,5 In general,
most medication errors occurred on admission at the time of prescribing; however,
errors were also found during hospitalization and upon discharge.
The most common errors involved:
• drug interactions
• errors in the ART regimen itself (missing more than one drug)
• incorrect dose
• complete omission of ART or opportunistic infection (OI) prophylaxis
• drug scheduling3
Subsequent studies have reported similar findings.6-8 For instance, in a retrospec-
tive chart review performed at a large urban medical center, a 38% medication
error rate (1.44 errors/patient) involving both ART and OI medications in the
inpatient setting was observed. Drug omissions were the most common type of
341
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ART error (30%), while omitting OI prophylaxis accounted for 79% of total errors
involving OI medications. Only 24% of medication errors were corrected before
discharge within a median time of 36 hours.6
Differences in electronic health records (EHRs) between hospital, clinic, and
community pharmacies can also lead to medication errors during care transitions
because the systems are often not shared. Medication reconciliation can be chal-
lenging to perform and document within various EHR systems, and smooth trans-
mission of the reconciled list to the next care provider may be limited.9 There are
also issues with duplicate medications prescribed by different clinicians and the
potential to prescribe the incorrect ART regimen.
Likewise, in the community setting, ART errors have been reported.10,11 For
instance, one study examined the frequency of ART prescribing errors in 12,226
privately insured patients with HIV in the United States. Overall, ritonavir boosting
errors were the most common, and patients from the 2005 cohort were 3 times
more likely to have an ART error than patients from 1999 or 2000 (5.9% versus
1.9%).10 Key points involving medication errors in the hospital setting are summa-
rized in Table 18-1.3,6-8,12
CONSEQUENCES OF MEDICATION ERRORS

The consequences of medication errors can be significant and may involve the
following:
• ART failure—omission of ART, underdosing of ART (i.e., missing doses,
underdosing drugs, drug interactions leading to low concentrations of
ART), or giving only a partial ART regimen may lead to drug resistance,
treatment failure, progression of disease, and possibly death.7,12-14 If drug
resistance occurs, a more complex and potentially toxic regimen with
increased pill and cost burden may be required for salvage treatment.
This may increase the chance of pill fatigue and nonadherence.
• ART toxicity—drug toxicity may occur due to an overdose of medica-
tion secondary to drug interactions, failure to adjust dosing for renal or
hepatic dysfunction, and errors in dosing or dosing frequency.7,12,13
• Increased morbidity from HIV and non-HIV–related condi-
tions—if treatment is indicated but omitted for OIs, OI prophylaxis, or
other comorbidities, there is the potential for suboptimal management
of these conditions and increased patient morbidity.
SOLUTIONS TO MINIMIZE MEDICATION ERRORS
Hospital Setting
More recently, ART stewardship programs have demonstrated a significant
decrease in medication error rates.7,8,12,13,15-17 Initiatives have included a variety
of interventions such as involvement of an HIV/infectious disease (ID) pharma-
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CHAPTER 18 Care Transitions for Persons Living with HIV 343
TABLE 18-1. Medication Errors in the Hospital Setting3,6-8,12

• Errors can occur at any time during hospitalization and are most common at the time of
admission and prescribing.
• Errors not corrected during hospitalization may persist in the community setting after discharge.
• Common drug errors involve drug interactions with ART, complete or partial omission of ART,
incorrect ART drugs ordered, ART dosing errors (e.g., dose not adjusted for underlying organ
dysfunction, incorrect dose prescribed), incorrect ART scheduling (e.g., food considerations,
timing of medications), and failure to prescribe OI prophylaxis.
Examples of potential drug errors include:

S Mixing up drug names (e.g., ritonavir and Retrovir®; Viracept® and Viramune®; nevirapine and
nelfinavir).
S Failure to prescribe ritonavir as a PI booster or failure to prescribe the main PI and only give
low-dose ritonavir.
S Prescribing the wrong dose of ART (e.g., ritonavir 600 mg daily instead of 100–200 mg daily for
boosting other PIs; ART prescribed once daily instead of BID [half the dose given]).
S Duplication of ART in FDC tablets (e.g., prescribing lamivudine tablets with Epzicom® [abacavir
+ lamivudine FDC tablet]).
S Prescribing FDC ART tablets in patients with significant renal dysfunction. Since many of
the nucleoside antiretrovirals require dosage adjustment in renal dysfunction, single-drug
formulations are recommended to adjust drug doses properly.
S Prescribing the tenofovir formulation of TDF instead of TAF. TAF dose differs from TDF.
• Pharmacokinetic boosters such as ritonavir and cobicistat, other PIs, and enzyme inducers such as
efavirenz and the rifamycins are commonly involved in drug interactions.
• Common drug classes that may lead to significant interactions with ART are gastric acid
suppressants, statins, antimycobacterials, antifungals, anticoagulants, antimicrobials
(e.g., macrolides), anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine), narcotics,
psychotropics, and inhaled/intranasal medications (e.g., fluticasone, budesonide, salmeterol).
ART: antiretroviral therapy; BID: twice daily; FDC: fixed-dose combination; OI: opportunistic infection; PI: protease
inhibitor; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil fumarate
cist or trained resident7,13,15,17; optimization of the computer order entry system

(COES), including alerts to notify pharmacists of drug interactions or incorrect
ART doses8,12,15-17; physician and pharmacist education8,15,17; the distribution of
educational pocket cards among staff17; and collaboration with the ID department
to evaluate prescribed ART regimens of newly admitted HIV patients.17 In one
study, customization of the COES and staff education yielded a modest decrease
in the rate of inpatient ART errors from 45% to 37%, including a decrease in ART
errors on discharge from 38% to 12%.8 While this approach is beneficial, the
most impressive reduction in ART error rates involved a multifaceted approach,
including trained HIV/ID pharmacists performing prospective audits and daily
review of ART and OI regimens.7,13,15,17 In a retrospective observational study, there
was a 73.9% decrease in the number of errors when this approach was used.7 Like-
wise, other studies have reported similar results when multiple interventions,
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including daily review of medications, were implemented simultaneously.15,17

Key points involving solutions to minimize drug error in the hospital setting are
outlined in Table 18-2. 3,4,7-9,12,13,15-19
Community/Ambulatory Setting
Although continuity of care in the hospital setting is critical, transition of care
from the hospital back to the community setting is equally important. One
report recently described a model of integrated outpatient pharmacy services
for HIV patients.14 The program outlines the roles of clinical pharmacists, resi-
dents/students, and technicians. Clinical pharmacy services aim to integrate care
between the outpatient clinic and dispensing specialty pharmacy and include
TABLE 18-2. Solutions to Minimize Medication Errors in the Hospital

Setting3,4,7-9,12,13,15-19
• A multifaceted approach to minimizing medication errors in the hospital setting is required.
• A consistent method to identify and report hospital admissions of persons living with HIV to
pharmacy services in a timely fashion is recommended.
• A trained HIV/ID pharmacist, when available, preferably should perform medication
reconciliation for HIV patients on admission within 24 hours, daily while in hospital, and
at discharge. Pay particular attention to the accuracy of the ART regimen, indications for OI
prophylaxis, medications used to treat comorbidities, the presence of drug interactions, and
dosage adjustments in organ dysfunction.
• Communicating discharge information (e.g., current medication and medical conditions) with
the patient’s caregivers (e.g., HIV/ID physician, family physician, clinic/community pharmacist)
is critical for a smooth transition back into the community setting. Providing a hard copy of
the medication list to the patient and encouraging patients to use patient-centered technology
(smartphone applications) may also be useful.
• Staff education and training are also beneficial, along with consultation with the HIV/ID service
as required.
• Customization of the COES through order-entry sets to guide ART prescribing and the addition of
extra notes, alerts, and pop-ups provide a proactive approach to preventing medication errors at
the time of prescribing.
• Having adequate ART stock on site to avoid missed doses is important. For smaller centers that do
not routinely stock ART, patients should be encouraged to bring in their own ART. Smaller centers
might also establish a system to borrow stock the same day from larger surrounding hospitals. If
a temporary ART substitution is required due to lack of stock, consultation with the ID service or
the HIV/ID pharmacist is recommended.
• The addition of co-formulated ART products to the formulary and bi-annual formulary review
to include new ART formulations may be beneficial. However, caution is required in patients
with significant renal dysfunction, as many co-formulated products should be avoided in this
population.
• Periodic audits to check for ART errors may be helpful to identify problem areas and also to
highlight successes.
ART: antiretroviral therapy; COES: computer order entry system; ID: infectious diseases; OI: opportunistic infection
ERRNVPHGLFRVRUJ
filling prescriptions, providing medication/adherence counseling, assisting with

drug access, monitoring monthly treatment, and facilitating seamless care.
Documentation in the patient’s EHR allows for continuity of care among
interdisciplinary team members. When patients are admitted to the hospital,
the clinic pharmacist also provides daily review of ART orders and works with
the inpatient team to resolve any discrepancies proactively. An advanced nurse
practitioner assists with coordinating discharge-related needs and involves the
outpatient pharmacist if the patient has medication-related needs such as prior
authorization required for drug access.14 Figure 18-1 provides a summary of the
model of integration used between the ID clinic services and the specialty phar-
macy services in this program.14
Another study addressed barriers that community pharmacists encounter
when providing medication reconciliation for recently discharged patients in
the general population.20 Although all pharmacists recognized the importance of
medication reconciliation in recently discharged patients, many felt it was time-
consuming and reimbursement was lacking for this service. Pharmacists stated
that having established relationships with other caregivers and patients, access
to EHRs, adequate technician support, and organization-level support were key
factors in reconciling medications. In addition, the assistance of a post-discharge
care coordination team was beneficial. In this model, the community pharmacist
was informed of the patient discharge and the medication prescriptions were faxed
in advance along with an inpatient’s contact phone number. This allowed the
pharmacist to work on the medication reconciliation process prior to the patient’s
arrival at the pharmacy.20 Key points involving solutions to facilitating continuity
of care in the outpatient setting are found in Table 18-3.10,11,14,19-21
Correctional Facilities
Pharmacists are key members of the healthcare team in correctional facilities and
can assist in reducing gaps in ART.22 As described in one model of care, on admis-
sion to a correctional facility, clinical pharmacists assessed all individuals with HIV
to ensure ART was continued when appropriate. If the patient was not on ART,
but was eligible, a referral was made to the ID physician for further assessment.
Pharmacists also screened patients for suspected ART toxicity, lack of ART efficacy,
and significant nonadherence, and referred to the ID physician when required.
A liaison HIV pharmacist attended the ID physician clinics and ensured that any
problems identified were addressed. The HIV pharmacist provided ongoing moni-
toring and follow-up throughout the course of incarceration. Close to the release
date, the pharmacist assisted with coordinating care in the community for complex
patients. This involved communicating regimen changes to care providers, iden-
tifying new drug interactions, facilitating drug coverage issues, and coordinating
adherence support, including the provision of directly observed therapy (DOT).
Upon release, patients were given a 2-week bridging supply of ART and a follow-up
appointment with the prescribing outpatient physician.22
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NM ID Clinic NM Specialty Pharmacy
Clinic APPE
Clinic pharmacist
student meets
meets with
patient to perform
patient to provide
medication
education on new
history and
(or change in)
provide
ART and provide
information on
information on
NM specialty
NM specialty
pharmacy
pharmacy
If patient is interested in using NM specialty NM specialty pharmacy submits prior-

pharmacy, prescription is transferred to NM authorization requests and helps to apply
specialty pharmacy for patient assistance, as needed
Prescription is filled and delivered to clinic

or mailed to patient (if unable to fill
prescription, NM specialty pharmacy
facilitates prescription transfer to another
pharmacy)
Call at 1 week to confirm patient is

taking and tolerating ART
Patient receives follow-up care in NM ID

Monthly call to assess adherence, tolerability
clinic, with repeated medication history-
of regimen, and need for refill
taking on each visit and pharmacist
involvement as needed
FIGURE 18-1. Integration of infectious diseases clinic services and specialty pharmacy services.
APPE: advanced pharmacy practice experience; ART: antiretroviral therapy; NM: Northwestern
Medicine
Source: Originally published in Gilbert EM, Gerzenshtein L. Integration of outpatient infectious
diseases clinic pharmacy services and specialty pharmacy services for patients with HIV
infection. Am J Health-Syst Pharm. 2016;73(11):757-763 © 2016, American Society of Health-
System Pharmacists, Inc. All rights reserved. Used with permission.
ERRNVPHGLFRVRUJ
TABLE 18-3. Solutions to Facilitating Continuity of Care in the Outpatient

Setting10,11,14,19-21
• Medication reconciliation should be performed at every clinic visit. This should include a
record of medical conditions and all forms of drugs used (i.e., oral, injectable, topical, inhaled,
nonprescription, supplements, complementary medications, recreational substances, temporary/
seasonal agents [e.g., allergy and PRN medications]).
• It is important to verify all of the patient’s prescribers and pharmacies. In order to minimize drug
error, encourage the patient to consolidate care at one community pharmacy and to minimize the
number of prescribers.
• If a patient has been recently discharged from institutional care, an accurate medication history
during that time period should be obtained and any discrepancies in the outpatient setting should
be resolved. Ideally, information to provide to a community pharmacy upon discharge may
include discharge diagnosis, drug allergies/intolerances, medication prescriptions and updated list
with drug names, doses, directions and indications (includes drug changes or discontinuations
post-discharge and rationale), pertinent laboratory values, insurance plan coverage, follow-up
appointment information, caregiver contact information, and any outstanding follow-up issues.20
• If a patient is admitted to an institution, seamless transition should involve consultation with the
institutional pharmacist or caregiver, particularly in complex cases.
• Prescriptions for ART and other medications should be screened carefully in clinic and at the
time of dispensing for any dosing errors, drug interactions, duplication of therapies (when
multiple prescribers are involved), ongoing indications (e.g., need for ongoing OI prophylaxis
medications), and adherence challenges.
• Changes in a patient’s ART or other medications should be communicated to other caregivers,
with special attention to proactively avoiding high-risk drugs that may cause future interactions
(e.g., avoid prescribing fluticasone in an asthmatic patient on ritonavir- or cobicistat-boosted ART
regimens).
• Maintaining accurate and detailed records on a patient’s ART history, including resistance testing,
allergies, toxicities, and adherence challenges, is critical. If the patient requires a change in ART or
care is transferred to another setting, such records are invaluable and will facilitate future care of
the patient.
• Facilitating drug access and coverage is an essential part of coordinating care and avoiding gaps in
ART.
• Documentation in the healthcare record is an important part of ongoing communication with
team members.
ART: antiretroviral therapy; OI: opportunistic infection; PRN: as needed
In summary, some important principles to consider in the corrections popu-

lation include an emphasis on medication reconciliation and ensuring continuity
of ART and any other medications on admission. Planning for institutional release
should address overall patient stability with a focus on housing, social factors,
and any ongoing mental health disorders and/or addiction issues. When possible,
a supply of ART should be given to the patient with instructions for follow-up
(e.g., which pharmacy to attend for ongoing ART and date of outpatient medical
appointment). Medication coverage issues and adherence issues (e.g., imple-
ERRNVPHGLFRVRUJ
menting DOT at a community pharmacy) should be addressed prior to release

when possible. Communication with the patient’s outpatient healthcare provid-
er(s) and community pharmacy is an essential component to a seamless transition
to the community. Tables 18-2 and 18-3 provide additional information on facili-
tating transitions of care that may be applicable to the correctional setting.
ROLE OF THE PHARMACIST IN COORDINATING PATIENT CARE

Pharmacists in all areas of practice are well-positioned members of the healthcare team to
assist in coordinating transitions in patient care. Recent American and Canadian guide-
lines on the role of the pharmacist in HIV care outline several key roles that pharmacists
have in this area, including:
• performing medication reconciliation
• identifying and preventing drug errors
• being involved to ensure seamless care19,21
Inpatient pharmacists (and pharmacists in other institutional settings) can play a
significant role in minimizing medication errors in persons living with HIV. It is recom-
mended that medication reconciliation should be performed on all patient admissions,
with a particular focus on ART regimen accuracy, OI prophylaxis, and drug interactions.
Ongoing monitoring during the course of hospitalization and seamless care at discharge
are also required. A clinician’s guide to assessing inpatient ART was recently published in
response to the significance of medication errors in the HIV population and the need for
education among healthcare providers.18 This evidence-based guide provides an assess-
ment framework aimed at identifying and managing the most common medication errors
in the inpatient setting reported in the literature.18
Outpatient pharmacists in ambulatory HIV clinics and community pharmacies are also
key members of the healthcare team and should be actively involved in reducing medica-
tion errors. An emphasis on maintaining accurate ART histories and a current list of other
medications from all prescribers is useful. Pharmacists can assist and encourage patients
to keep a current medication list and also record any medication issues such as side
effects. Newer technology (e.g., Smartphone applications23) can be employed for patients
to record and track their medication information. In addition, pharmacists can also assist
with drug coverage, monitor for drug toxicity and interactions, and facilitate adherence.
Documentation and communication of care are also essential to all relevant caregivers in
the community—especially as the patient transitions from various care settings.
KEY RESOURCES
Guidelines
• Schafer JJ, Gill TK, Sherman EM, et al. ASHP guidelines on pharmacist involvement in
HIV care. Am J Health-Syst Pharm. 2016;73(7):468-494.
• Tseng A, Foisy M, Hughes CA, et al. Role of the pharmacist in caring for patients with
HIV/AIDS: Clinical Practice Guidelines. Can J Hosp Pharm. 2012;65(2):125-145. http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC3329905/. Accessed September 1, 2016.
ERRNVPHGLFRVRUJ
o Both the American and Canadian HIV pharmacist guidelines provide some guid-
ance on the role of the pharmacist in coordinating the care of HIV patients.
Reviews/Studies
• Li EH, Foisy MM. Antiretroviral and medication errors in hospitalized HIV-positive
patients. Ann Pharmacother. 2014;48(8):998-1010.
o Provides a comprehensive literature review on medication errors in persons
living with HIV with proposed solutions to reduce errors in this population.
• Mekonnen AB, McLachlan AJ, Brien JA. Pharmacy-led medication reconciliation
programmes at hospital transitions: A systematic review and meta-analysis. J Clin
Pharm Ther. 2016;41(2):128-144.
o Systematic review and meta-analysis showing that pharmacy-initiated medi-
cation reconciliation is an effective strategy in reducing medication errors and
discrepancies in the inpatient setting.
Practice Guides and Tools
Hospital Practice
• Fernandes O, Toombs K, Pereira T, et al. Canadian consensus on clinical pharmacy
key performance indicators: knowledge mobilization guide. Canadian Society of
Hospital Pharmacists (CSHP), Ottawa, ON, 2015. https://www.cshp.ca/sites/default/
files/files/CSPH-Can-Concensus-cpKPI-Knowledge-Mobilization-Guide.pdf. Accessed
September 8, 2017.
o This national guide contains information on clinical pharmacy key performance
indicators (cpKPIs) with a focus on medication safety and includes resources on
medication reconciliation on admission and discharge.
• Medication safety tool and resources. Institute for Safe Medication Practice (ISMP).
Horsham, PA, 2016. http://www.ismp.org/tools/. Accessed September 1, 2016.
o Includes a variety of resources to assist healthcare workers on the safe use of
medications and in preventing medication errors both in hospital and commu-
nity practice. Examples include guidelines on (1) root cause analysis (RCA), which
serve to assist institutions investigate medical errors and adverse effects after
an incident occurs; and (2) the failure mode and effects analysis (FMEA), which
is a proactive quality improvement process used by multidisciplinary teams to
examine the points of potential failure of new products or services prior to an
error actually occurring.
• Pittman ES, Li EH, Foisy MM. Addressing medication errors involving HIV-positive
inpatients: Development of a clinician’s guide to assessing antiretroviral therapy.
Can J Hosp Pharm. 2015;68(6):470-473. http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC4690673/. Accessed September 1, 2016. Pocket card version of guide
(available for order): http://hivclinic.ca/wp-content/uploads/2014/09/Antiretroviral-
Assessment-CDN-Web_2-secured.pdf. Accessed July 19, 2017. Complete version of
guide: http://bugsanddrugs.ca/documents/HIVARVGuide.pdf. Accessed July 19, 2017.
o This educational tool provides an evidence-based framework for pharmacists to
assess ART in hospitalized patients living with HIV with the goal of identifying
and minimizing drug error. It provides ART assessment sections on admission,
during the course of hospitalization, and on discharge with an emphasis on
facilitating care transitions.
• Safer Healthcare Now. Medication reconciliation in acute care getting started kit.
Canadian Patient Safety Institute (CPSI). Version 3.0, September 2011. http://
www.patientsafetyinstitute.ca/en/toolsResources/Documents/Interventions/
Medication%20Reconciliation/Acute%20Care/MedRec%20(Acute%20Care)%20
Getting%20Started%20Kit.pdf. Accessed September 1, 2016.
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o This national getting started kit provides guidance on providing medication

reconciliation with the goals of improving quality and safety in the hospital
setting. Sample medication reconciliation tools are included.
Community Practice
• The Canadian HIV/AIDS Pharmacists Network. Meds Rec Form. http://hivclinic.ca/
chap/downloads/MedsRec%20Form_English_2015.pdf. Accessed September 1, 2016.
o The Canadian HIV/AIDS Pharmacists (CHAP) Network developed this medica-
tion reconciliation tool aimed at community pharmacists. The form focuses on
medication reconciliation and identifying drug-related problems in the persons
living with HIV. It also serves as a communication tool between pharmacists and
other healthcare providers.
REFERENCES
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medication errors in hospitalized patients with human immunodeficiency virus infection. Infect
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ERRNVPHGLFRVRUJ
ERRNVPHGLFRVRUJ
Index
Acute renal failure, 110

A Acyclovir, 140, 156
Abacavir (ABC), 29, 35, 335, 336 genital herpes treatment and, 194
adolescent dosing guidelines for, 300, 301 side effects, toxicities of, 157
adverse effects of, 36, 38 Adacavir, pediatric considerations and, 302
barriers to resistance and, 87 Adherence support, 74-75
CNS toxicity and, 248 importance of, 108
dosing of, 60 pediatric, 296-297, 304-305
lipid changes and, 228 Adolescent HIV
pediatric dosing guidelines for, 298 adherence support for, 297
pregnancy and, 278 baseline assessments, regimens for, 295,
296
Abacavir, lamivudine, 30
dosing guidelines for, 300-301
adolescent dosing guidelines for, 300, 301
management of, 291-294
chemotherapy and, 321
pre-exposure prophylaxis and, 306
dosing of, 66
nPEP and, 117
Abacavir, lamivudine, dolutegravir, 67
Adolescent Trials Network, 287
Abacavir, lamivudine, dolutegravir,
cobicistat, 31 Adriamycin, doxorubicin, bleomycin,
vinblastine, dacarbazine, 319
Abacavir, lamivudine, zidovudine, 30, 66
Adverse effects, 35-36. See also specific drugs.
Acamprosate, 254
maintenance immunosuppressive agents
Acetaminophen, 253
and, 332-333
Acid-suppressing therapy interactions, 39,
AIDS, 9
40-41
defining conditions of, 10
Acquired resistance, 86
AIDS Clinical Trials Group, 31, 35
Active tuberculosis, 204
AIDS Education & Training Center, 144
diagnosis of, 204-205
AIDSinfo, 143, 144, 145
treatment of, 207-208
Alcohol use, 253, 254
Acute HIV infection
Alprazolam, 246
disease progression and, 6-9
American Academy of HIV Medicine, 22
initial treatment for, 77-79
American Association for the Study of Liver
signs, symptoms, lab findings in, 8
Diseases, 176
typical disease progression of, 8
American Association of Clinical
Acute infection, 27 Endocrinologists, 230
353
ERRNVPHGLFRVRUJ
American Diabetes Association, 230 barriers to resistance and, 87

American Foundation for AIDS Research, 31 dosing of, 63
Amikacin, 207, 208 renal dysfunction dosing of, 235
Amiodarone, 173 Atazanavir, ritonavir (ATV/r)
Amitriptyline, 244, 250, 252 adolescent dosing guidelines for, 300, 301
Amphetamine use, 255 barriers to resistance and, 87
Amphotericin B, 129 lipid changes and, 228
side effects, toxicities of, 157 pediatric dosing guidelines for, 299
Amphotericin B deoxycholate, flucytosine, post-exposure prophylaxis, 116
133, 151 Atovaquone, 130
Amprenavir, 268 side effects, toxicities of, 157
Anal cancer, 317 Atripla, 28
Anidulafungin IV, 158 AVAC Global Advocacy for HIV Prevention,
Antibody testing, 18-19 120
Antiretroviral agents, 35 Azathioprine, 332, 337
Antiretroviral Pregnancy Registry, 277 Azithromycin, 153, 187, 189
Antiretroviral therapy (ART), 25-68, 85-86 side effects, toxicities of, 158
adherence to, 49-50 Azithromycin, ethambutol, 136-137, 154
discovery of, 28-29
failure of, 342 B
history of, 28-35
Bacterial vaginosis, 191, 192
history timeline for, 32-34
Badowski, Melissa, 329-340
initiating, 214
Bangkok Tenofovir Study, 107
switching, 79-80
Basiliximab, 331
toxicity of, 342
Belatacept, 332
Antiretroviral treatment
Benzathine benzylpenicillin, 198, 199
goals for, 69
Benzodiazepines, 246, 250
laboratory monitoring of, 72-74
Bias, Tiffany E., 69-83
pediatric considerations and, 302-303
Bipolar disorder, 249
Antoniou, Tony, 185-202
Bishop, Bryan M., 261-270
Anxiety/anxiety-like disorders, 245-247
Bivalent vaccine (HPV2), 317
Archived DNA genotypic assays, 89
Bleomycin, etoposide, doxorubicin,
Artificial self-insemination, 275 cyclophosphamide, vincristine,
ASPIRE, 111 procarbazine, prednisone, 319
Atazanavir, 29, 76, 176, 337 Bone health, 236-238
acid suppressing agents and, 40 Bone mineral density, 236-237
adverse effects of, 37-38 Bookstaver, P. Brandon, 25-68
chemotherapy and, 325 Boosted PI plus NRTI regimen failure, 97
dosing of, 63 British HIV Association, 143, 181
drug interactions and, 211 Buprenorphine, 254
pediatric considerations and, 302
pregnancy and, 278 C
renal dysfunction dosing of, 235
Caballero, Joshua, 243-260
Atazanavir, cobicistat (ATV/c), 29, 87
ERRNVPHGLFRVRUJ
INDEX 355
Cabotegravir, 112 Cephalosporin, macrolide, 188

Cancer incidence, 314 Cerebral toxoplasmosis, 134-135
Cancer(s), 313-328 clinical presentation, treatment of, 134
cART and chemotherapy, 320-322 primary prevention of, 135
cervical, 315-317 treatment of, 134-135, 152
colorectal, 319 Cervical cancer
comorbidities evaluation of, 325 invasive, 315-317
follow-up plan for, 325-326 screening, 281
hepatocellular, 320 Cervicitis, 185-186
Hodgkin’s lymphoma, 318-319 Cha, Agnes, 69-83
incidence of, 314 Chemokine receptor 5 (CCR5) antagonists,
Kaposi’s sarcoma, 313-314 28
non-AIDS-defining, 317-318 Chemotherapy, 320-324, 325-326
non-Hodgkins lymphoma, 314-315 ART choices for, 323-324
non-small cell lung, 319-320 CHER trial, 295
Capecitabine, 322 Chlamydia, 186-188
Capreomycin, 207, 208 Chlorpromazine, 247
Capsaicin, topical, 251 CHOP (cyclophosphamide, doxorubicin,
vincristine, prednisolone), 315
Carbamazepine, 249
Chronic infection, 27
Cardiovascular disease, 226-230
Chronic kidney disease, 232-236, 329
Care transitions, 341-351
Chronic pain, 253
Caspofungin, IV, 158
Cidofovir, 138, 140, 194-195
Caulder, Celeste R., 25-68
side effects, toxicities of, 158
CCR5 coreceptor inhibitors, resistance
associated with, 93-94 Cisplatin, 317, 324
Cefixime, 189 Citalopram, 244, 245
Ceftriaxone, 199 Clarithromycin, 153
Ceftriaxone, azithromycin, 187, 188 side effects, toxicities of, 158
Cellcept, 332 Clarithromycin, ethambutol, 136-137, 154
Centers for Disease Control and Prevention Clindamycin, 191, 192
(CDC), 17-18, 310 side effects, toxicities of, 159
age-specific staging and, 294 Clindamycin, primaquine, 130
HIV epidemiology and, 4-5 Clinical Consultation Center, 120
HIV Prevention, 120 Clofazimine, 208, 209
HIV Surveillance Report, 13, 282 Clonazepam, 246
Materials on Medication Adherence, 80 Clotrimazole, 129
National HIV Surveillance System and side effects, toxicities of, 159
Medical Monitoring Project, 22 Clozapine, 249
Pap screening test and, 317 CNS Penetration Effectiveness, 256
Pre-exposure Prophylaxis Clinical Practice Cobicistat, 30, 75, 176
Guideline, 275-276, 282
adverse effects of, 37
revised testing guidelines, 22
chemotherapy and, 321, 323-324
testing guidelines by, 19-20
creatinine secretion and, 236
tuberculosis, 203
dosing of, 66
ERRNVPHGLFRVRUJ
pregnancy and, 278 Cyclophosphamide, 322

Cocaine use, 255 Cycloserine, 208, 209
Cocohoba, Jennifer M., 221-241 Cyclosporine, 175, 331-332, 336-338
Cognitive behavioral therapy, 250 Cytomegalovirus disease, 137-139, 326
Colorectal cancer, 319 clinical presentation, diagnosis of,
Combination antiretroviral therapy (cART), 137-138
315, 317. See also specific therapies esophagitis or colitis and, 155
adolescents and, 291-294 neurological disease and, 155
breast feeding and, 291 primary prevention of, 139
cancer and, 317, 320-321 treatment for, 138, 154-155
chemotherapy and, 320-321, 324-325
HBV and stopping/changing, 169-170 D
immunosuppressant interactions with,
Daclatasvir, ribavirin, 177
333-334
Daclatasvir, sofosbuvir, 173, 174, 176
pediatric generally, 295-296
Daclatasvir, sofosbuvir, ribavirin, 174
pediatric initiation, adherence support
with, 296-297 Dapivirine, 111, 112
pediatric monitoring of, 297, 303 Dapsone, 131
pediatric regimens of, 296 side effects, toxicities of, 159
preventing mother-to-child transmission Dapsone, trimethoprim, 130
and, 105 Darunavir (DRV), 29, 76, 176
ritonavir or cobicistat containing, 323 adverse effects of, 37, 38-39
treatment as prevention, 103-105 dosing of, 63
Comprehensive HIV/HCV Drug Therapy and drug interactions and, 211
Interaction Guide, 326
pregnancy and, 278
Connolly, Kristina E. R., 25-68
testosterone therapy and, 268
Continuum of care, 9, 11
Darunavir, cobicistat (DRV/c), 29
antiretroviral therapy receipt and, 12
barriers to resistance and, 86
engagement in, 12
dosing of, 63
identifying new cases for, 11
renal dysfunction dosing of, 235
linkage to care and, 11
Darunavir, ritonavir (DRV/r)
minimizing medication errors and, 344,
345, 349-350
viral suppression and, 12-13
lipid changes and, 228
Contraception
pediatric dosing guidelines for, 298
methods, 272-275
post-exposure prophylaxis and, 116
safe, 275-276
Dasabuvir, 173, 175-176, 177
Coreceptor tropism, 90
Data Collection on Adverse Events of
Corticosteroids, 333, 337
Anti-HIV Drugs study, 163
Covalently closed circular DNA, 165
Delavirdine, 323, 336
Cryptococcal meningitis, 132-134
Delirium, 247-248
clinical presentation, diagnosis of,
Depot medroxyprogesterone acetate (DMPA),
132-133
272, 273
primary prevention of, 134
Depression, 243-245
treatment of, 133-134, 151
Desensitization protocol, 144
ERRNVPHGLFRVRUJ
INDEX 357
Dexamethazone, 322 opportunistic infection drugs and, 144

Diabetes, 231-232 updated assessments and, 45-46
Diagnosis, 17-23 Drug Resistance Mutation in HIV, 2017
Diagnostic testing, principles of, 18-19 Update, 99
Diazepam, 246 Drug therapy targets, HIV life cycle, 25-27
Didanosine (ddl), 29, 252, 323, 336 Drug-drug interactions, 39, 334-336
adverse effects of, 36 Drug-food interactions, 46-48
barriers to resistance and, 87 Duloxetine, 244, 252
dosing of, 60
renal dysfunction dosing of, 234 E
Digoxin, 173 Echinocandin, IV, 129
Direct-acting antivirals (DAAs), 171-173, 177, Efavirenz (EFV), 76, 336
180
adverse effects for, 36, 38
drug reaction management of, 178-179
Disulfiram, 254
-cART, 324
Docetaxel, 322
Dolutegravir (DTE), 30, 45, 76, 323
dosing of, 62
acid suppressing agents and, 41
drug interactions and, 210
estrogen therapy and, 268
insomnia and, 250
-containing regimen, barriers to
pregnancy and, 279
resistance, 87
creatinine secretion and, 236
Efavirenz, tenofovir disoproxil fumarate,
dosing of, 65
emtricitabine, 235
E44D mutation, 92
initial regimen advantages/disadvantages
Egelund, Eric F., 203-218
of, 78
Elbasvir, 173, 175, 177
Elbasvir/grazoprevir, 174
Elite controllers, 27
pediatric dosing guidelines for, 299
Elvitegravir (EVG), 30, 39, 76
transplants and, 337
Dolutegravir, abacavir, lamivudine, 300, 301
Donepezil, 248
Dong, Betty J., 221-241
initial regimen advantages/disadvantages
Dosing, 60-68
of, 78
Doxepin, 250
major resistance pathways of, 94
Doxorubicin, 314, 322
Doxycycline, 187, 196, 198, 199
Elvitegravir, cobicistat
Drug development, 50-52
Drug interactions, 45
ART and hormonal contraceptives,
273-274
transplants and, 335
chemotherapy, 321-324
Elvitegravir, cobicistat, tenofovir
ERRNVPHGLFRVRUJ
alafenamide, emtricitabine, 235 -cART, 324

Elvitegravir, cobicistat, tenofovir disoproxil dosing of, 62
fumarate, emtricitabine drug interactions and, 210
post-exposure prophylaxis and, 116 post-exposure prophylaxis and, 116
renal dysfunction dosing for, 235 weight factor for resistance-associated
Emtricitabine, 29, 35, 325, 335 mutations, 93
adolescent dosing guidelines for, 300, 301 European AIDS Clinical Society, 143-144
adverse effects of, 36 European AIDS Treatment Network, 180
dosing for, 61 Everolimus, 332, 333, 336, 338
hepatitis B and, 168
pediatric considerations and, 302 F
PrEP and, 106 Famciclovir, 140, 156
renal dysfunction dosing for, 234 genital herpes treatment and, 194
Emtricitabine, tenofovir disoproxil fumarate, side effects, toxicities of, 157
106-108, 109-110, 112
Fanconi’s syndrome, 110
Endocrine Society, The, 263
FEM-PrEP, 107-108
End-stage liver disease, 329
5-fluorouracil, 322
End-stage renal disease, 329 5-fluorouracil with mitomycin or
Enfuvirtide (T-20), 28, 338 cisplatin, 318
adverse effects of, 37, 39 FLAMINGO study, 76
barriers to resistance and, 87 Flaviviridae family, 170
dosing for, 65 Fluconazole, 129, 148
Entecavir, 168-169 high-dose, 133, 151
Enzyme immunoassays, 171 hormone therapy and, 268
EPOCH (etoposide, prenisone, vincristine, side effects, toxicities of, 159
cyclophosphamide, doxorubicin), 315 Flucytosine PO, side effects, toxicities of, 160
Erythromycin, 196 Fluoroquinolones, 189, 207
Escitalopram, 244, 245 Fluoxetine, 244, 245
Esophageal candidiasis, 127-129 Flurazepam, 250
clinical presentation, diagnosis of, Foisy, Michelle, 341-351
128-129 Food and Drug Administration, rapid testing,
primary prevention of, 129 21
treatment for, 129, 148 Fosamprenavir, 29, 323
Estradiol, 265 acid suppressing agents and, 40
Eszopiclone, 250 adverse effects of, 37, 38-39
Ethambutol, 207, 208 dosing of, 64
side effects, toxicities of, 159 estrogen therapy and, 268
Ethinyl estradiol, 273 Fosamprenavir, ritonavir, 245
Ethionamide, 207, 208, 209 Foscarnet, 138, 154
Etonogestrel implants, 273, 274 Foscarnet IV, 140, 194, 195
Etoposide, 322 side effects, toxicities of, 160
Etravirine (ETR) Foscarnet, topical, 194, 195
adverse effects of, 36, 38 Fourth generation HIV test, 19-20
barriers to resistance and, 87 Fusion inhibitors, 28
ERRNVPHGLFRVRUJ
INDEX 359
clinical presentation, treatment of, 164

G prevention of, 164
Gabapentin, 252 serology, diagnosis of, 164
Galantamine, 248 vaccine for, 164
Ganciclovir, IV, 138, 154, 155 Hepatitis B, 110, 165-170
side effects, toxicities of, 160 cART stopping/changing, 169-170
Garrett, Katy L., 103-123 clinical presentation, treatment of,
167-169
G-CSF prophylaxis, 326
core antibody, 165
Gender terminology, 262
core antigen, 165
Genetic barrier to resistance, 86-87
e antibody, 167
Gengraf, 332
e antigen, 166
Genital herpes, 192-194
IRIS and, 169
Genital ulcers, 192-195
prevention of, 168
GenoSure Archive, 89
serologic test results for, 166
Genotypic assays, 88-89
serology, diagnosis of, 165-167
Giguère, Pierre, 163-183
surface antibody, 166
Glecaprevir, 173, 175, 177
surface antigen, 165
Glecaprevir, pibrentasvir, 174, 177
treatment of, 168
Gonadotropin-releasing hormone (GnRH)
analogs, 263, 265 vaccine for, 168
Gonorrhea, 187, 188-189 virology, replication of, 165
Government of Canada, Drugs, 145 Hepatitis C, 170-178
Graham, Kathleen K., 285-311 ART treatment options and, 179-180
Gram stain, 191 chronic, treatment for, 172-174
Grazoprevir, 173, 175, 177 clinical presentation of, 171-172
Grochowski, Janet, 85-101 genotypes and, 170-171
Guidelines for Prevention and Treatment of monitoring of, 177-178
Opportunistic Infections in HIV-Infected prevention, reinfection prevention for,
Adults and Adolescents, 181 180
Guidelines for Use of ARV Agents in Pediatric reactivation of, 177-178
Infection, 295
serology, diagnosis of, 171
special populations and, 177
H transmission of, 170
HAART (highly active antiretroviral therapy), treatment factors with, 176-177
28 virology, replication of, 170
Haloperidol, 247 Hepatitis C On-line, 181
HBV DNA, 167 Hepatocellular cancers, 320
HCV Guidance, 182 Heroin use, 254
Health and Human Services, Department of Herpes zoster, 139-141
AIDSinfo HIV Drug Database, 80-81 clinical presentation, diagnosis of, 139
AIDS Info Website, 80 pre-exposure prevention for, 156
cART guidelines, 104 primary prevention for, 140
Hepatic enzyme effects, 39, 42-44 treatment of, 140, 156
Hepatitis A, 163-164 Hester, E. Kelly, 271-284
ERRNVPHGLFRVRUJ
Hetterman, Elizabeth, 329-340 Network, Toronto General Hospital, 144,

High-risk populations/patients, 18, 108, 109 145
HIV-1, 3 Immunologic failure, pediatric, 303
p24 antigen, 18, 19, 20 Immunosuppression, 330
RNA, 18, 19 Incomplete virologic response, 85

Indinavir, 323
HIV-2, 3
adverse effects of, 37, 38
HIV Drug Interactions, 339
dosing for, 64
HIV epidemiology, 3-5
Indinavir, ritonavir, 29
HIV French Resistance, 99
Induction agent, 331
HIV InSite, 216
Infectious Diseases Society of America, 176
HIV Medicine Association, 22, 140
herpes zoster and, 140-141
HIV Organ Policy Equity (HOPE) Act, 330,
331 Informed consent, general, 18
HIV overview, 3-15 INSIGHT START Study Group, 81
HIV Prevention Trials Network, 103-104, Insomnia, 250-251

112, 120 Insomnia Severity Index, 256
HIV strains, subtypes, 3 Integrase strand transfer inhibitors (INSTIs),
HIV/AIDS Medical Practice Guidelines, 121 28-29, 38, 87
on virologic failure, 85 drug interactions and, 45, 213

regimen selection and, 75-76
Pregnancy and Perinatal Transmission
Guidelines, 282 resistance associated with, 93
HIV/HCV Drug Therapy Guide, 144 transplantation and, 337
HIV-associated neurocognitive disorders International Advisory Panel on HIV Care
(HAND), 247-248 Continuum Optimization, 13-14
HIVE, 282 International Antiviral Society—USA, 144
Hodgkin’s lymphoma, 318-319 International Maternal Pediatric and
Adolescent AIDS Clinical Trials, 287
Home Access HIV-1 Test System, 21
IPERGAY study, 108
Hormonal contraceptives, 272-275
iPrEx, 106, 107
Hormone therapy, 265-266
Isoniazid, 206-207, 208
Huesgen, Emily C., 203-218
Itraconazole, 133, 151
Hughes, Christine A., 127-162
cART and, 325
Hypertension, 226
hormone therapy and, 268
oral, 129, 148
I side effects, toxicities of, 159
Ibrahim, Karin, 313-328 solution, 129
IgG antibodies, 18, 19
to hepatitis B core antigen, 165, 166 J
Imiquimod, topical, 194
Jarisch-Herxheimer reaction, 198
Immune reconstitution inflammatory
Joint United Nations Programme on HIV/
syndrome (IRIS), 127, 133, 134, 169
AIDS, 3, 14
tuberculosis and, 214-215
uveitis and, 138
K
Immunizations, primary care, 224-225
Immunodeficiency Clinic, University Health Kanamycin, 207, 208
ERRNVPHGLFRVRUJ
INDEX 361
Kaposi’s sarcoma, 313-314 L74V mutation, 91, 92

Kashuba, Angela DM, 103-123 Lymphogranuloma venereum, 195-196
Kelly, Deborah V., 185-202
K103N mutation, 91 M
Kreutzwiser, Denise, 163-183
Macrolides, 189
K65R mutation, 91, 92
Maraviroc (MVC), 28, 30
L barriers to resistance and, 87
Lamivudine (3TC), 28, 29, 35, 325, 335 cARTm 324
adolescent dosing guidelines for, 300, 301 dosing of, 65
adverse effects of, 36 interactions with, 45
barriers to resistance and, 87 renal dysfunction dosing of, 235
dosing of, 61 transplants and, 338
hepatitis B and, 168, 169 Marijuana, 252, 253, 254
pediatric considerations and, 302 Medication errors, 341-342
pediatric dosing guidelines for, 298 community/ambulatory setting
renal dysfunction dosing for, 234 minimization of, 344-345, 346-347,
350
Lamivudine, zidovudine, 66
correctional facilities minimization of,
Lamotrigine, 249, 252 345, 347-348
Latent tuberculosis infection, 204 hospital setting minimization of, 342-344
diagnosis of, 205-206 Melatonin, 250
screening for, 206 Memantine, 248
treatment of, 206 Mental health
Ledipasvir, 172-174 disorders in transgender patient, 261,
Ledipasvir/sofosbuvir, 174 263-264
Levofloxacin, 207, 208 neuropsychiatric disorders and, 243-251
side effects, toxicities of, 160 Mental illness, severe, 248-249
Lidocaine, 251 Metformin, 45
Linezolid, 209 Methadone, 254
Lithium, 249 Methotrexate, 324
Long-term nonprogressors, 27 Methylenedioxymethamphetamine (MDMA),
Lopinavir, 211 255
Lopinavir, ritonavir, 190 Metronidazole, 190, 191, 192
adverse effects of, 37, 38 Micafungin IV, side effect toxicities, 158
barriers to resistance and, 87 Miconazole mucoadhesive buccal tablets, 129
dosing of, 64 Microbicide Trials Network, 112, 120
lipid changes and, 228 Minocycline, 248
pediatric considerations for, 302 Mirtazapine, 244-245, 250
pediatric dosing guidelines for, 299 M184V mutation, 90-91, 92
post-exposure prophylaxis and, 116 Monoclonal antibodies, 51, 112
renal dysfunction dosing, 235 Morbidity increase, 342
Lorazepam, 246, 247 Mother-to-child transmission, 272, 277-278,
280, 285, 286
Low-level viremia, 86
ERRNVPHGLFRVRUJ
preventing, 105 barriers to resistance and, 87

Motivational interviewing, 74-75 cART and, 324
Moxifloxacin, 209 chemotherapy and, 322
side effects, toxicities of, 160 dosing of, 62
Multicenter AIDS Cohort Study, 167 estrogen therapy and, 268
Multiclass resistance, pediatric, 303-305 infant dosing of, 290
Multispot test, 20 testosterone therapy and, 268
Mycobacterium avium complex disease, New York State Department of Health
135-136, 325-326 AIDS Institute, 200
clinical presentation, diagnosis of, 136 HIV Testing Toolkit, 22
pediatric preventions for, 306, 307-308 Nitroimidazoles, 190
primary preventions for, 137 Non-AIDS-defining cancers, 317-318
treatment of, 136-137, 153-154 Non-Hodgkin’s lymphoma, 314-315
Mycophenolate mofetil, 331, 332 Nonnucleoside reverse transcriptase
solid organ transplantation and, 335 inhibitors (NNRTIs), 27, 29
Mycophenolic acid with glucocorticoid, 331 adverse effects of, 38
Myfortic, 332 drug interaction for, 209, 212
plus dual NRTI regimen failure, 97
N regimen selection for, 76
resistance associated with, 91
Naltrexone, 254
solid organ transplant and, 336-337
National Association of Crime Victim
Compensation Boards, 120 Nonoccupational exposure, 6
National Center for Transgender Equality, Non-occupational post-exposure prophylaxis
269 (nPEP), 114, 115-117, 119
National Clinician’s Consultation Center, evaluation/treatment algorithm for, 118
state laws, 22 Non-small cell lung cancer, 319-320
National Institute of Allergy and Infectious Nonsteroidal anti-inflammatory drug
Diseases, 31, 35 (NSAID), 252-253
National LGBT Health Education Center, 269 Norethindrone, 274
National Perinatal HIV Consultation and Norgestimate, 273
Referral Service, 282 Nucleic acid amplification tests (NAATs),
National Perinatal HIV Hotline, 310 186, 188
National Resource on Youth and HIV, 310 Nucleoside reverse transcriptase inhibitors
Nelfinavir, 323 (NRTIs), 27, 29
acid suppressing agents and, 40 adverse effects of, 35-36, 38
adverse effects of, 37, 38 barriers to resistance and, 87
dosing of, 64 drug interactions of, 212
Neoral, 332 solid organ transplant and, 335-336
Neurocognitive disorders, 247-248 regimen selection of, 75
Neuropathy, 251, 252 resistance associated with, 90-91, 92
Neuropsychiatric disorders, 243-260 Nystatin, 129
mental health and, 243-251 side effects, toxicities of, 160
Nevirapine (NVP), 28, 29, 210, 336
ERRNVPHGLFRVRUJ
INDEX 363
Patient assessment, baseline, 70-71

O Patient education, opportunistic infection
drugs, 146
Obitasvir, 173
Patient Health Questionnaire (PHQ-9), 256
Occupational exposure, 6, 114, 115
Patient management, failed first-line ARV
Office for Victims of Crime People, 120
regimen, 97
Olanzapine, 249
Pediatric AIDS Clinical Trials Group, 285, 288
Ombitasvir, 175-176, 177
Pediatric HIV, 285-311
Omeprazole, 337
adherence strategies for, 304-305
Opioid use disorder, 254
ART considerations in, 302
Opioids, 253
baseline assessments for, 295
Opportunistic infections, 127-162
challenges in, 287
drug access for, 146
dosing guidelines for, 298-299
patient education about, 146
immune system staging, viral load and,
pediatric prevention of, 305-306 294-295
therapy side effects, toxicities of, 157-162 management of, 291, 292-293
treatments for, 143-144 monitoring treatment, comorbidities,
Oraquick Advance Rapid HIV Test, 21 297-298
OraQuick In-Home HIV Test, 21 multiclass resistance in, 303-304
Oropharyngeal candidiasis, 127-128 neonatal post-exposure prophylaxis in,
clinical presentation, diagnosis of, 128 288
primary prevention for, 129 nonperinatally acquired, 285, 287
treatment of, 129, 148 nPEP and, 117
Oxazepam, 246 opportunistic infection preventions for,

305-308
Oxycodone, 254
perinatally acquired, 285, 286
symptoms of, 295
P testing neonates for, 287-288
Paclitaxel, 314 testing, transmission prevention of, 306
Pain, 251-253 treatment failure and, 303
Panel on Antiretroviral Guidelines for Adults treatment initiation, adherence support
and Adolescents, 216, 339 in, 296-297
Panel on Opportunistic Infections in vaccines and, 305-306
HIV-Infected Adults and Adolescents, 216
Peg-interferon alfa monotherapy, 169
Pap test, 315, 318
Pegylated interferon, ribavirin, 177
Para-aminosalicyclic acid, 209
Penicillin G, 199
Parenteral drugs, 253
Pentamidine IV/for inhalation, 161
Parenteral exposure, 7
Pérez, Sarah E., 329-340
risk of, 115
Perinatal transmission, 6
Paritaprevir, 173
Pharmacist’s role
Paritaprevir, ritonavir, 175, 177
for cancer patient, 326
Paritprevir, ritonavir, ombitascir, dasabuvir,
for transgender patient, 266-267, 268-269
175-176
for transplants, 338
Paroxetine, 244, 245
for viral hepatitis patients, 180-181
Partners PrEP, 106-107
in adherence, 75, 80
Partnership for Prescription Assistance, 121
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in ART, 53-54 successful program for, 110-111

in continuum of care, 13 Pregnancy, PrEP and, 110
in coordinating patient care, 348 PrEPWatch, 121
in HIV testing, diagnosis, 21-22 Prevention, 103-123
in neuropsychiatric disorders, 255-256 demographics of, 103-104
in opportunistic infections, 141-142 post-exposure prophylaxis and, 114-116
in pediatric HIV, 309-310 pre-exposure prophylaxis and, 106-113
in primary care, 238 preventing mother-to-child, 105, 106
in sexually transmitted infection prevention of, 103-123
screening, treatment, 199-200 treatment as prevention and, 103-105,
in transmission, 119-120 106
in tuberculosis treatment, 215 Primaquine PO, 161
in virologic failure management, 98-99 Primaquine, clindamycin, 130
in women’s health, 281-282 Primary care, 221-241
Pharmacokinetic enhancers, 39 immunizations and, 224-225
Phenotypic assays, 89 initial visit for, 221-223
Pibrentasvir, 173, 175, 177 of chronic comorbid conditions, 226-238
Picornavirus, 163 routine laboratory tests for, 223
PK enhancer interactions, 44 Progestin-only oral contraceptives, 273
Pneumocystis jirovecii pneumonia, 130, 325 Prograf, 332
clinical presentation, diagnosis of, 130 Protease inhibitors (PIs), 27-28, 175
pediatric prevention for, 306, 307-308 adverse effects of, 38-39
prevention, treatment in infants of, 291 chemotherapy and, 321
primary prevention for, 132 drug interactions and, 212-213, 337
treatment for, 130-131, 148-150 regimen selection and, 75
Polymerase chain reaction, 193 resistance associated with, 91
Posaconazole, 129, 133 Proton pump inhibitors, 336-337
Post-exposure prophylaxis (PEP), 114-116, Puga, Ana M., 285-311
117 Pyrazinamide, 207, 208, 209
preferred, alternative regimens for, 116, Pyrimethamine PO, 161
117
Pyrimethamine, clindamycin, leucovorin,
Preconception counseling, 271-272 135
Prednisolone, 322
Pre-exposure prophylaxis (PrEP), 106,
275-276
Q
adherence importance and, 108 Q151M complex mutation, 92
cost of, 111 Quadrivalent vaccine (HPV4), 316-317
development pipeline for, 113 Quazepam, 250
evidence for, 106 Quetiapine, 249
FTC/TDF alternatives and, 111-112
future studies for, 112 R
indications/target populations for, Rabbit antithymocyte globulin (rATG), 331
108-109
Raltegravir (RAL), 28, 30, 75, 76, 323
monitoring, 109-110
pediatric HIV and, 306
ERRNVPHGLFRVRUJ
INDEX 365
adverse effects of, 37 chemotherapy and, 325

barriers to resistance, 87 dosing of, 63
CNS and, 248 drug interactions and, 211
dosing of, 65 lipid changes and, 228
drug interactions of, 210 pregnancy and, 279
initial regimen advantages/disadvantages PrEP and, 112
for, 79 proton pump inhibitors and, 336-337
lipid changes and, 228 Rilpivirine, creatinine secretion and, 236
major pathways of resistance, 94 Rilpivirine, tenofovir alafenamide,
pediatric considerations and, 302 emtricitabine, 236
pediatric dosing guidelines for, 299 Rilpivirine, tenofovir disoproxil fumarate,
post-exposure prophylaxis, 116 emtricitabine, 236
pregnancy and, 278-279 Ring Study, The, 111
transplants and, 337 Risperidone, 249
Raltegravir, tenofovir disoproxil fumarate, Ritonavir, 28, 30, 75, 173, 175-177, 190
emtricitabine, 116 adverse effects of, 37
Rapamune, 333 -boosted atazanavir, 38
Rapid plasma reagin tests, 197 -boosted darunavir, 38
Rapid progressors, 27 -boosted lipid changes, 228
Rapid testing, 20-21 alprazolam and, 246-247
Recent infection, 77 bupropion and, 245
Recommendations on Treatment of Hepatitis chemotherapy and, 323-324
C, 182 dosing of, 66
Regimen selection, 75-77 testosterone therapy and, 268
Resistance Rituximab, 315, 316
by antiretroviral class, 90-94 Rivastigmine, 248
genetic barriers to, 86 Rosuvastatin, 173
mutations and, 87-88
principles of, 86
S
testing, 88-90, 95
Saberi, Parya, 85-101
R5-tropic strains, 93-94
SandIMMUNE, 332
Ribavirin, 176, 177
Saquinavir, 28, 323
Rifabutin, 208
PO, side effects, toxicities of, 161
dosing of, 64
Rifampin, 175
Schafer, Jason J., 17-23
drug interactions and, 209-213
Schizophrenia, 249
hormone therapy and, 268
Screening, opting in or out, 17-18
Rifamycin, 209
Selective serotonin reuptake inhibitors, 244
Rifapentine, 207, 208
Serotonin norepinephrine reuptake
drug interactions and, 209-213
inhibitors, 244-245
Rilpivirine (RPV), 323
Sexual exposure, 7
risk of, 115
Sexually Transmitted Diseases Treatment
barriers to resistance and, 87 Guidelines (CDC), 200
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Sexually transmitted infections, 185-202

routine screening for, 185 T
urethritis, cervicitis and, 185-189 Tacrolimus, 331-332, 336, 337
vaginal, urethral discharge and, 189-192 Temazepam, 246, 250, 251
Sherman, Elizabeth M., 3-15 TEMPRANO study, 69-70, 77
Simeprevir, 176 ANRS 12136 Study Group, 81
Simeprevir, sofosbuvir, 173, 176 Tenofovir, 173, 325
Sirolimus, 332, 333, 336 adolescent dosing guidelines for, 300, 301
Sofosbuvir, 172-175 -cART, 324
Sofosbuvir, ledipavir, 177 CNS and, 248
Sofosbuvir, ribavirin, 177 PrEP and, 106
Sofosbuvir, velpatasvir, 177 Tenofovir alafenamide (TAF), 29, 44-45,
Sofosbuvir, velpatasvir, voxilaprevir, 174 335-336
Solid organ transplantation, 329-340 adverse effects of, 36
cART and immunosuppressant barriers to resistance, 87
interactions in, 333-334 chemotherapy and, 321, 324
epidemiology of, 329-330 drug interactions and, 211
HIV patients and, 330 hepatitis B and, 168
immunosuppression and, 330 pediatric considerations for, 302
induction agent and, 331 Tenofovir alafenamide fumarate,
infections and, 338 emtricitabine, 30
maintenance and, 331-332 adolescent PrEP and, 306
Spironolactone, 268 dosing of, 66
Stanford University HIV Resistance Database, lipid changes and, 228
99 renal dysfunction dosing of, 234
Start Free, Stay Free AIDS Free Initiative, 285 Tenofovir alafenamide fumarate,
START trial, 69, 77, 104-105, 295 emtricitabine, rilpivirine, 31
STARTMARK study, 76 dosing, 67, 68
Statin interactions, 44 Tenofovir disoproxil fumarate (TDF), 29,
44-45, 335-336
Stavudine (d4T), 29, 252, 322, 323, 336
acute renal failure and, 110
dosing of, 61
renal dysfunction dosing for, 234
dosing of, 62
Streptomycin, 207, 208
Suboptimal CD4+ cell count response, 86
hepatitis B and, 168, 169
Substance use disorders, 253-255
Sulfadiazine, pyrimethamine, leucovorin,
134-135, 152, 162 pediatric considerations and, 302
Sulfamethoxazole/trimethoprim, 268, 325 pregnancy and, 278, 279
IV/PO, side effects, toxicities of, 162 PrEP and, 106-110
Supportive therapy, 325 Tenofovir disoproxil fumarate, emtricitabine,
31, 275-276
Suppression management, 89
adolescent PrEP and, 306
Syphilis, 196-199
dosing of, 67
ERRNVPHGLFRVRUJ
INDEX 367
lipid changes and, 228 prophylaxis, 307-308

post-exposure prophylaxis and, 116 Transgender patient care, 261-270
renal dysfunction dosing for, 234 health issues in, 261, 263-264
transgender patient and, 268 HIV care in, 267-268
Tenofovir disoproxil fumarate, emtricitabine, medications used for, 264-266
darunavir, 117 other considerations in, 266-267
Tenofovir disoproxil fumarate, emtricitabine, treatment and, 263
dolutegravir, 79, 117
Transmission prevention, 5-6, 17, 103-123
Tenofovir disoproxil fumarate, emtricitabine,
demographics of, 103-104
efavirenz, 28, 31
post-exposure prophylaxis and, 114-116
dosing of, 67
pre-exposure prophylaxis and, 106-113
Tenofovir disoproxil fumarate, emtricitabine,
elviregravir, cobicistat, 31 preventing mother-to-child, 105, 106
dosing of, 67 prevention of, 103-123
Tenofovir disoproxil fumarate, emtricitabine, treatment as prevention and, 103-105,
raltegravir, 117 106
Tenofovir disoproxil fumarate, emtricitabine, Transmitted resistance, 86
ritonavir, 117 Transplantation, 329-340. See also Solid
Tenofovir disoproxil fumarate, emtricitabine, Organ Transplantation
ritonavir-boosted darunavir, 79 cART and immunosuppressant
Tenofovir disoproxil fumarate, lamivudine, interactions in, 333-334
116 epidemiology of, 329-330
Terminal infection, 27 HIV patients and, 330
Testing, 17, 17-23 immunosuppression and, 330
at-home, 21 induction agent and, 331
rapid, 20-21 infections and, 338
repeat, 18 maintenance and, 331-332
Testosterone, 266, 268 Trazodone, 250
Therapeutic drug monitoring Treatment as prevention (TaSP), 103-105
laboratories and, 216 Treatment failure management
tuberculosis and, 213-214 first line, 97-98
Third-generation immunoassays, 19 new regimen introduction and, 96
Thomas, Jennifer E., 243-260 of multiple regimens, 98
Thymidine analogue associated mutations pediatric, 303
(TAMs), 90, 92
resistance and, 85-101
Thyroid dysfunction, 230-231
selecting new regimen for, 95-96
Tinidazole, 190, 191, 192
syphilis and, 197-198
Tipranavir, 30
terminology in, 85-86
Treatment history, 95
Treatment initiation, 69-74
dosing of, 64
pediatric, 296-297
prior to, 71
Toronto General Hospital & Ottawa Hospital
recommendations for, 69-70
HIV and HCV Drug Therapy Guide, 182
recommended regimens for, 76
Toxicity monitoring, 297, 303
regimen advantages/disadvantages in, 78
Toxoplasma encephalitis, pediatric
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Treatment regimen side effects, toxicities of, 160

follow-up, monitoring of, 96 oral, 138, 154, 155
patient management of failed first-line, Velpatasvir, 173-175
97 Velpatasvir, sofosbuvir, 173-174
Trichomoniasis, 189-190, 192 Venereal Disease Research Laboratory tests,
Tricyclic antidepressants, 244 197
Trimethoprim PO, 162 Venlafaxine, 244
Trimethoprim-sulfamethoxazole (TMP-SMX) Vinblastine, 322
39, 130, 131, 135, 149-150, 152 Vinca-alkaloids, 322
Tropism assays, 90 Vincristine, 322
Tseng, Alice L., 125, 163-183 Viral blips, 85, 97
T69 insertion, 92 Viral hepatitis, 163-183
Tuberculosis, 203-218 Viral Hepatitis Information, 181
drug interactions and, 209-212 Viral load
epidemiology of, 203 pediatric, 294-295
IRIS and, 214-215 suppressed, 103-104, 105
microbiology of, 204 Viral set point, 9
testing for, 206 Viral steady-state, 9
therapeutic drug monitoring and, Viremia, 97
213-214
Virologic failure, 85
transmission, infection control of, 204
causes of, 94-95
pediatric, 303
U Virtual phenotypes, 89-90
U.S. Preventive Services Task Force, 17-18 VOICE, 107-108, 111
Uni-Gold Recombigen HIV test, 21 V1181 mutation, 92
United Nations Voriconazole, 133
AIDS website, 310 cART and, 325
Programme on HIV/AIDS (UNAIDS), 104 IV/PO, 129, 159
University of Liverpool Voxilaprevir, 174-175
Hepatitis Drug Interaction Checker, 182 Voxilaprevir, velpatasvir, 174
HIV Pharmacology, 144 Voxilaprevir, velpatasvir, sofosbuvir, 176, 177
Urethral discharge, 189-192
Urethritis, 185-186 W
WAVES trial, 76
V Western blot test, 19
V1181 mutation, 92 Window period, 19
Vaccines, 51-53 Women’s health, 271-284
pediatric, 305-306 antepartum management for, 277-278
Vaginal discharge, STIs, 189-192 ART in pregnancy and, 278-279
Valacyclovir, 140, 156 cervical cancer screening and, 281
genital herpes treatment and, 194 gender differences and, 271
side effects, toxicities of, 157 intrapartum management for, 280
Valganciclovir PO postpartum management for, 280-281
ERRNVPHGLFRVRUJ
INDEX 369
preconception counseling for, 271-272 chemotherapy and, 322, 324

pregnancy care for, 277 CNS toxicity and, 248
safe conception for, 275-276 dosing of, 62
Wong, Alison Yi Jin, 313-328 neonatal dosing of, 288-290
World Health Organization (WHO), 144 pediatric considerations for, 302
cART guidelines by, 104 pediatric dosing guidelines for, 299
HIV link, 121 renal dysfunction dosing of, 234
on tuberculosis, 203 Zidovudine, emtricitabine, 116
World Professional Association for Zidovudine, lamivudine, darunavir, 117
Transgender Health, 263 Zidovudine, lamivudine, dolutegravir 117
Worley, Marylee, 3-15 Zidovudine, lamivudine, lopinavir, 117
Zidovudine, lamivudine, nevirapine, 290
Y Zidovudine, lamivudine, raltegravir, 117
Y181C mutation, 91 Zidovudine, lamivudine, ritonavir, 117
Yoong, Deborah, 127-162 Zolpidem, 250, 251
Zortress, 333
Zung Self-Rated Anxiety Scale, 256
Z
Zaleplon, 250, 251
Zidovudine (AZT), 28-29, 336
barriers to resistance, 87
ERRNVPHGLFRVRUJ
ERRNVPHGLFRVRUJ

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Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP

Elizabeth M. Sherman, PharmD, AAHIVP

Alice L. Tseng, PharmD, FCSHP, AAHIVP

Acquisitions, Special Publishing: Beth Campbell

Library of Congress Cataloging-in-Publication Data

© 2018, American Society of Health-System Pharmacists, Inc. All rights reserved.

To Cassie, Eamon, and Alida for always reminding me to

Many thanks to my husband Viet Vu and son Khai for

For Ben and Lily and my early mentor Betty.

Thanks to my husband Mark Pellar and wonderful daugh-

SECTION I: The Diagnosis and Pharmacologic Management of HIV-1

CHAPTER 1: HIV Infection Overview..........................................................................3

CHAPTER 2: HIV Testing and Diagnosis...................................................................17

CHAPTER 3: Antiretroviral Therapy..........................................................................25

CHAPTER 4: Initiating HIV Treatment and Supporting Adherence.........................69

CHAPTER 5: HIV Treatment Failure and Resistance.................................................85

CHAPTER 6: Preventing HIV Transmission with Antiretroviral Therapy..............103

SECTION II: The Pharmacologic Management of HIV Co-infections

CHAPTER 7: Opportunistic Infections....................................................................127

CHAPTER 8: Viral Hepatitis.....................................................................................163

CHAPTER 9: Sexually Transmitted Infections.........................................................185

CHAPTER 10: HIV and Tuberculosis........................................................................203

SECTION III: Primary Care and Special Populations with HIV

CHAPTER 11: HIV Primary Care..............................................................................221

CHAPTER 12: Neuropsychiatric Disorders, Mental Health, Pain, and

CHAPTER 13: Care of the Transgender Patient.......................................................261

CHAPTER 14: Women’s Health...............................................................................271

CHAPTER 15: Pediatric HIV Infection.....................................................................285

CHAPTER 16: HIV and Cancer................................................................................313

CHAPTER 17: Transplant and HIV..........................................................................329

CHAPTER 18: Care Transitions for Persons Living with HIV.................................341

Elizabeth M. Sherman, PharmD, AAHIVP

Alice L. Tseng, PharmD, FCSHP, AAHIVP

Melissa Badowski, PharmD, MPH, BCPS, AAHIVP

Tiffany Bias, PharmD, AAHIVP, BCPS (AQ-ID)

Bryan M. Bishop, PharmD, BCPS

P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVP

Joshua Caballero, PharmD, BCPP, FCCP

Celeste R. Caulder, PharmD

Agnes Cha, PharmD, AAHIVP, BCACP

Kristina E. R. Connolly, PharmD, BCPS

Mackenzie L. Cottrell, PharmD, MS, BCPS, AAHIVP

Betty J. Dong, PharmD, FCCP, FASHP, FAPhA, AAHIVP

Eric F. Egelund, PharmD, PhD, AAHIVE

Michelle M. Foisy, BScPharm, PharmD, ACPR, FCSHP, AAHIVP

Katy L. Garrett, PharmD

Pierre Giguère, BPharm, MSc, AAHIVP

Kathleen K. Graham, PharmD

Janet Grochowski, PharmD, BCPS, AAHIVP

E. Kelly Hester, PharmD, FCCP, BCPS, AAHIVP

Elizabeth Hetterman, PharmD, BCPS

Emily C. Huesgen, PharmD, BCACP, AAHIVP

Christine A. Hughes, BScPharm, PharmD, FCSHP

Karim Ibrahim, BPharm, DClinPharm, AACPA, MSHP

Angela DM Kashuba, PharmD, DABCP, FCP

Deborah V. Kelly, BScPharm, PharmD, FCSHP, AAHIVP

Denise Kreutzwiser, BScH, BScPharm, ACPR, AAHIVP

Sarah E. Pérez, PharmD, BCACP, AAHIVP

Parya Saberi, PharmD, MAS, AAHIVP

Jennifer E. Thomas, PharmD, AAHIVP

Alison Yi Jin Wong, BPharm, MSc, AAHIVP

Marylee Worley, PharmD, BCPS

Deborah Yoong, BScPharm, ACPR, PharmD

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