NORTHWEST AIDS EDUCATION AND TRAINING CENTER

2012 HIV Update

David Spach, MD Clinical Director, Northwest AETC Professor of Medicine, Division of Infectious Diseases University of Washington
Presentation Prepared by: David Spach, MD Last Updated: April 16, 2012

2012 HIV Clinical Update: Topics

Acute (Primary) HIV Infection 2012 HHS Antiretroviral Therapy Guidelines Recognizing Common Clinical Manifestations

Healthcare Postexposure Prophylaxis

HIV 2012 UPDATE

Acute HIV

A 22-Year-Old Man with a Flu-Like Illness

A 22-year-old man is seen in the urgent care clinic with a 3day history of fever, sore throat, headache, myalgias, and fatigue. In addition, for one day he has a diffuse maculopapular, erythematous rash. He had anonymous sex with 2 men about 3 weeks ago.

Morbilliform Rash

Photograph from David Spach, MD

A 22-Year-Old Man with a Flu-Like Illness

What is in your differential diagnosis? What tests would you order?

PRIMARY (ACUTE) HIV

Clinical Manifestations of Primary HIV Infection

Fever Lethargy Myalgias Rash Headache Pharyngitis Adenopathy

0 10 20 30 40

86

74
59 57 55 52 44
50 60 70 80 90 100

N =160

Patients %
From: Vanhems P, et al. AIDS. 2000;14:375-81.

Acute (Primary) HIV: Eclipse Phase

Eclipse Phase 10,000,000

HIV RNA (copies/ml)

1,000,000 100,000 10,000 1,000

100
10 1 0 5 10 15 20

HIV RNA Limit of Detection

25

30

35

40

45

50

Days following HIV Acquisition

Eclipse Phase = Time between infection and detectable HIV RNA

Acute (Primary) HIV: Window Period

Window Period

Antibody Titer
0

10

15

20

25

30

35

40

45

50

Days following HIV Acquisition

Window Period = Time between infection and detectable HIV antibodies

PRIMARY (ACUTE) HIV

Acute (Primary) HIV: Symptomatic Disease

Acute Illness 10,000,000 30

HIV RNA (copies/ml)

1,000,000

10,000 20 1,000

100
10 1 0 5 10 15 20 25 30 35 40 45 50

15

10

Days following HIV Tansmission

Symptomatic Disease Often Precedes Positive Antibody Test

Antibody Titer

100,000

25

Transmission of HIV

HIV

Transmission of HIV
Chronic HIV infection Quasispecies HIV-Negative

Transmission of HIV: Founder Virus

Chronic HIV infection Quasispecies New Infected with HIV Founder Virus

Acute (Primary) HIV

High Transmission Risk

Acute (Primary) HIV

Factors Associated with High Transmission Risk

Unaware of HIV status High viral load Homogeneity of transmission-capable viral variants Low titer of neutralizing antibodies

+ -

HIV 2012 UPDATE

HHS Antiretroviral Therapy Recommendations

US Health and Human Services (HHS)

March 27, 2012 Antiretroviral Therapy Guidelines

Source: 2012 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

Case History
A 28-year-old man was diagnosed with HIV about 18 months ago. She is seen in the clinic for follow up. His CD4 counts have been 770, 710, 640, and 610 cells/mm3. He has no active medical, mental health, or substance abuse issues. He is sexually active with other men and uses condoms most of the time. Would you recommend starting antiretroviral therapy?

ANTIRETROVIRAL THERAPY: HHS GUIDELINES

HHS Antiretroviral Therapy Guidelines: March 2012

Initiating Therapy in Treatment-Nave Patients

1000

CD4 Cell Count

800

Recommend: Moderate (BIII)

600

500
400

Recommend: Strong (AII)

350

200

Recommend: Strong (AII)

Source: 2012 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

ANTIRETROVIRAL THERAPY: HHS GUIDELINES

Initiating Antiretroviral Therapy in Treatment-Nave Patients Change in CD4 Threshold in HHS Guidelines
1000

CD4 Cell Count

800

2012
600

500
400

2009 2007

350
200

200

2003

ANTIRETROVIRAL THERAPY: HHS GUIDELINES

HHS Antiretroviral Therapy Guidelines: March 2012

Initiating Therapy in Treatment-Nave Patients

Earlier Therapy

Later Therapy

Initiating Antiretroviral Therapy

Why are we treating earlier with antiretroviral therapy?

ANTIRETROVIRAL THERAPY: HHS GUIDELINES

HHS Antiretroviral Therapy Guidelines: March 2012

Factors Affecting Decision on When to Initiate Therapy

More effective regimens More convenient regimens Better tolerated therapy Less long-term toxicity Better immune recovery Lower rates of resistance More treatment options Concerns for uncontrolled viremia Decrease HIV transmission Lack of RCT data supporting early Rx Potential drug toxicity Drug and monitoring cost Potential negative impact on QOL

PREVENTION OF OPPORTUNISTIC INFECTIONS

CD4 Cell Progression (without Antiretroviral Therapy)

1000 800 600

CD4 Cell Count

400
200

AIDS
0
0
Year 1

4 5 6 Years

9 10 11 12 13 14 15

Chronic Immune Activation and Inflammation

1000 800 600

CD4 Cell Count

Immune Activation & Inflammation

400
200

0
0

1 0 0 Year 0 0 (expanded)

4 5 6 Years

9 10 11 12 13 14 15

ANTIRETROVIRAL THERAPY

Attributable Risk Factors Associated with Cardiovascular Disease Events HOPS Study, January 2002September 2009
Cox Proportional Hazards: Relationship of Baseline CD4 and Risk of Subsequent Cardiovascular Events

2.5 2.0 Hazard Ratio

N = 2,005

1.58

1.5 1.0 0.5 0.0

1.00

1.29

CD4 500 cells/l

CD4 350-499 cells/l

CD4 <350 cells/l

Baseline CD4 Cell Count

Source: Lichtenstein KA, et al. Clin Infect Dis. 2010;51:435-47.

ANTIRETROVIRAL THERAPY: DHHS GUIDELINES

Attributable Risk Factors Associated with Cardiovascular Disease Events HOPS Study, January 2002September 2009
Baseline Factor Associated with Incident Cardiovascular Disease Events

Diabetes Male gender HDL < 40 male HLD < 50 female LDL/nonHDL > goal CD4 < 500 cells/l Tobacco Smoking Hypertension Age 42 years (median)

2.4 13.3 20.9 21.5 25.6 26.7 34.4

N = 2,005

49.2 0 10 20 30 40 50 60

Attributable Risk (%)

Source: Lichtenstein KA, et al. Clin Infect Dis. 2010;51:435-47.

Chronic Inflammation Impact on HIV-Infected Persons

Increased risk of heart disease Increased risk of stroke Increased risk of cancer

HIV Prevention Trials Network (HPTN) Study 052

1,763 HIV Serodiscordant Couples (97% heterosexual)

n = 872

n = 853

n = 37

n=1

Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

ANTIRETROVIRAL THERAPY: DHHS GUIDELINES

HIV Prevention Trials Network (HPTN) Study 052

1000

CD4 Cell Count

800

600

550 Early Therapy

400 CD4 350-550 cells/mm3

350 Deferred Therapy

CD4 < 250 cells/mm3 or AIDS Related Event

250

200

Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

HIV Prevention Trials Network (HPTN) Study 052

96% Reduction
Early Therapy (n = 886)

P < 0.001

Deferred Therapy (n = 877)

27

10

15

20

25

30

Linked Transmissions

Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

DHHS Antiretroviral Therapy Guidelines: October 2011

Preferred Regimens for ARV-Nave Patients: Pill Burden

Class Therapy Pill Burden

NNRTI-Based Efavirenz-Tenofovir-Emtricitabine

Ritonavir + Atazanavir + Tenofovir-Emtricitabine PI-Based Darunavir + Ritonavir + Tenofovir-Emtricitabine

INSTI-Based

Raltegravir + Tenofovir-Emtricitabine

Source: 2011 DHHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

ANTIRETROVIRAL THERAPY: HHS GUIDELINES

HHS Antiretroviral Therapy Guidelines: March 2012

Preferred Regimens for ARV-Nave Patients: Pill Burden

Class Therapy *AWP (Monthly)
$2081

NNRTI-Based Efavirenz-Tenofovir-Emtricitabine

Ritonavir + Atazanavir + Tenofovir-Emtricitabine PI-Based Darunavir + Ritonavir + Tenofovir-Emtricitabine

$2860

$2925

INSTI-Based

Raltegravir + Tenofovir-Emtricitabine

$2562

*AWP = average wholesale price

Source: 2012 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

2011: New FDA-Approved HIV Medications (or New Preparations of Older Medications)
Nevirapine XR (Viramune XR): 400 mg tablet

Etravirine (Intelence): 200 mg tablet

Rilpivirine (Edurant): 25 mg tablet

Tenofovir-Emtricitabine-Rilpivirine (Complera): 1 pill qd

Case History
A 30-year-old woman with asymptomatic HIV infection is seen for follow-up in the clinic to discuss starting antiretroviral therapy. She states she really wants to take the the one pill a day regimen. She has no other medical problems.

Most recent labs show a CD4 cell count of 375 cells/mm3 and CD4% = 16. Most recent HIV RNA is 65,300 copies/ml. A baseline genotype shows no mutations. Which one pill once a day regimen to give her?

Atripla versus Complera

Atripla Complera

Tenofovir-Emtricitabine-Efavirenz
NRTI NRTI NNRTI

Tenofovir-Emtricitabine-Rilpivirine
NRTI NRTI NNRTI

Image Source: AIDS Info.org

Rilpivirine vs. Efavirenz in ARV-Naive ECHO and THRIVE Pooled Data: Study Design
Study Features
Protocol - Randomized, double-blind trial - Phase 3 - N = 690 (ECHO) and 678 (THRIVE) - Age > 18 - ARV-nave - HIV RNA > 5,000 copies/ml - No baseline NNRTI mutations - Randomized to one of 2 arms - All given 2 NRTIs* Rilpivirine: 25 mg qd + TDF/FTC (n = 346)

ECHO

1x

Efavirenz: 600 mg qd + TDF/FTC (n = 344)

Rilpivirine: 25 mg qd + 2NRTIs (n = 340)

THRIVE

1x

Efavirenz: 600 mg qd + 2NRTIs (n = 338)

*2 NRTIs: ECHO: Tenofovir + Emtricitabine (TDF/FTC) THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine;

Abacavir + Lamivudine

Source: Cohen C, et al. JAIDS. 2012:Feb 16 [Epub ahead of print].

Rilpivirine vs. Efavirenz in ARV-Naive ECHO and THRIVE Pooled Data: Week 48 Results
Virologic Response ( ITT-TLOVR) over 48 Weeks
100 Patients with Virologic Response

80
2NRTIs+ Rilpivirine (n = 686)

84% 82%
2NRTIs+ Efavirenz (n = 682)

60

40

20

0 0 2 4 8 12 16 24 32 40 48

Time (weeks)
Source: Cohen C, et al. JAIDS. 2012:Feb 16 [Epub ahead of print].

Rilpivirine vs. Efavirenz in ARV-Naive ECHO and THRIVE: Virologic Failure Results
Virologic Failure 48 Week Data
20
Virologic Failure 15 10 5 0 Rilpivirine: 25 mg Efavirenz: 600 mg 17

10
6

7
5 5

All

100K

> 100K

Baseline HIV RNA Level (copies/ml)

All regimens included 2 NRTIs Source: Rimsky L, et al. JAIDS. 2012;59:39-46.

2012 HIV UPDATE

Recognizing Clinical Manifestations

Cutaneous Manifestations

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

Oral Manifestations

CLINICAL MANIFESTATIONS

Case History

OPPORTUNISTIC INFECTIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

CLINICAL MANIFESTATIONS

Case History

HIV 2012 UPDATE

Postexposure Prophylaxis

Question
What is the risk of acquiring HIV from a needlestick injury when all following are present: - HIV-infected source patient not on antiretroviral therapy - Needlestick involved venipuncture needle - Skin on hand punctured - No antiretroviral postexposure prophylaxis given

Estimated Risk of Seroconversion with Percutaneous Injury

60 50 40 30 30 20 10 50

Seroconversion (%)

0.3
HIV

2
Hepatitis C HBsAg+ HBeAg-

0
HBsAg+ HBeAg-

Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

Case History

HIV Exposure in a Health Care Worker

A 29-year-old nurse sticks herself in the finger with a needle when drawing blood from a patient. The source patient is HIV-positive and HCV-negative. The nurse is immune to hepatitis B. The source patient has never been on antiretroviral therapy and has a HIV RNA level of 96,000 copies/ml. In addition to washing the wound, what PEP would you recommend for this nurse? A. No antiretroviral therapy B. Basic Regimen (2-drugs) C. Expanded (3-drugs)

Logistic-Regression Analysis of Risk Factors for HIV Transmission after Percutaneous Exposure to HIV-Infected Blood
Risk Factors for HIV Seroconversion in Health Care Workers Risk Factor Deep Injury Visible Blood on Device Terminal Illness in Source Patient Needle in Source Vein/Artery PEP with Zidovudine (AZT) Adjusted Odds Ratio 15.0 6.2 5.6

4.3
0.19

Source: Cardo DM, et al. N Engl J Med. 1997;337:1485-90.

Recommended HIV PEP after Percutaneous Exposure Known Source HIV Status
Percutaneous Exposure Type
Source Infection Status HIV+ Class 1* Recommend Basic 2-drug PEP Recommend Expanded 3-drug PEP HIV+ Class 2^ Recommend Expanded > 3-drug PEP Recommend Expanded > 3-drug PEP

Less Severe

More Severe#

Less Severe: e.g., solid needle or superficial injury # More Severe: e.g., large-bore hollow needle, deep puncture, visible blood on device, or needle used in patients artery or vein *HV+ Class 1: Asymptomatic HIV infection or low viral load (e.g., <1,500 copies/mL) ^HIV+ Class 2: Symptomatic HIV, AIDS, acute seroconversion, or known high viral load

Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2005;54(RR-9):1-17.

Recommended HIV PEP after Percutaneous Exposure Known Source HIV Status
Percutaneous Exposure Type
Source Infection Status HIV+ Class 1* Recommend Basic 2-drug PEP Recommend Expanded 3-drug PEP HIV+ Class 2^ Recommend Expanded > 3-drug PEP Recommend Expanded > 3-drug PEP

Less Severe

More Severe#

Less Severe: e.g., solid needle or superficial injury # More Severe: e.g., large-bore hollow needle, deep puncture, visible blood on device, or needle used in patients artery or vein *HV+ Class 1: Asymptomatic HIV infection or low viral load (e.g., <1,500 copies/mL) ^HIV+ Class 2: Symptomatic HIV, AIDS, acute seroconversion, or known high viral load

Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2005;54(RR-9):1-17.

ANTIRETROVIRAL THERAPY: DHHS GUIDELINES

2005 Recommended PEP Antiretroviral Therapy Preferred Basic and Expanded Regimens
Drugs for Basic Regimens (28 days) Preferred Regimens Zidovudine-Lamivudine (Combivir) Lopinavir-Ritonavir (Kaletra) Tenofovir + Emtricitabine (Truvada) Alternative Regimens Stavudine (Zerit) + Lamivudine (Epivir) Atazanavir (Reyataz) + Ritonavir (Norvir) Drugs for Expanded Regimen (28 days) Basic Regimen Plus:

Stavudine (Zerit) + Emtricitabine (Emtriva)

Didanosine (Videx) + Lamivudine (Epivir) Didanosine (Videx) + Emtricitabine(Emtriva)

Fosamprenavir (Lexiva) + Ritonavir (Norvir)

Saquinavir (Invirase) + Ritonavir (Norvir) Nelfinavir (Viracept) Efavirenz (Viracept)

Source: AIDS Info (www.aidsinfo.nih.gov)

Questions?