Human Immunodeficiency Virus and

Antiretroviral Therapy
Lucille Sanzero Eller, PhD, RN
Associate Professor
Rutgers, The State University of New Jersey
College of Nursing
Local Performance Site of the NY/NJ AETC
September 2009

Objectives
1. Discuss the epidemiology of HIV in the U.S.
2. Describe the HIV replication cycle.
3. Discuss ARV therapy.
4. Identify methods of evaluation of ART
effectiveness.

Age of persons with HIV/AIDS

diagnosed during 2007

CDC. HIV/AIDS in the United States. August 21, 2009. Accessed on

September 14, 2009 at:
http://www.cdc.gov/hiv/resources/factsheets/us.htm

Transmission categories: adults/ adolescents

with HIV/AIDS diagnosed in 2007

CDC. HIV/AIDS in the United States. August 21, 2009. Accessed on

September 14, 2009 at:
http://www.cdc.gov/hiv/resources/factsheets/us.htm

HIV VIRION

HIV Replication Cycle (1)

1. Binding and Fusion
Virions gp120 and gp41 proteins bind to

cell surface receptors (CD4 and either the

CCR5 or CXCR4 co-receptor)
Viral membrane fuses with cell
membrane
Viral contents released into cell

HIV Replication Cycle (2)

2. Reverse Transcription and Integration
Viral enzyme reverse transcriptase is used to
copy viral RNA into viral DNA
Viral DNA is transported into cell nucleus and
spliced into cells DNA by HIV enzyme integrase
Viral DNA persists in latent state until cell
activation

HIV Replication Cycle (3)

3. Transcription and Translation
Upon activation of infected cell, viral DNA

is transcribed into messenger RNA

(mRNA) and the genetic material for next
generation of HIV
mRNA is transcribed into viral proteins
and enzymes

HIV Replication Cycle (4)

4. Assembly, Budding and Maturation
HIV proteins/enzymes and viral RNA assemble

into new viral particles

Virus buds from the cell
Protease enzyme cleaves long protein strands
into small functional HIV proteins and enzymes
Mature HIV particles now able to infect other
cells and replicate

Antiretroviral Therapy (ART)

ART-

use of antiretroviral drugs to treat HIV

disease

Highly

Active Antiretroviral Therapy (HAART)regimens combining several antiretroviral

drugs
To be successful, antiretroviral regimens need to

contain at least two, and preferably three, active

drugs from multiple drug classes

Primary Goals of ART

Reduce

survival

HIV-related morbidity and prolong

Improve

quality of life

Restore

and preserve immunologic function

Maximally
Prevent

and durably suppress viral load

vertical HIV transmission

ART Drug Classes and Mechanisms

of Action: NRTIs
Nucleoside

Reverse Transcriptase Inhibitors

(NRTIs)
(Reverse transcriptase changes viral RNA to DNA)
Block RT before HIV genetic code combines

with infected cells genetic code

Mimic building blocks used by RT to copy HIV
genetic material, so disrupt copying of HIV
genetic code

ART Drug Classes and Mechanisms

of Action: NNRTIs
Nonnucleoside

Reverse Transcriptase
Inhibitors (NNRTIs)
Block RT before HIV genetic code

combines with infected cells genetic

code
Physically prevent RT from
working

ART Drug Classes and Mechanisms

of Action: PIs
Protease

Inhibitors (PIs)

Block protease enzyme that cuts long

protein strands into small functional

proteins and enzymes needed to
assemble mature virus
Prevent maturation of new viral
particles

ART Drug Classes and Mechanisms

of Action: FIs (Entry Inhibitors)
Fusion

Inhibitors (FIs)

Block fusion of HIV with cell

membrane preventing HIV s ability to

infect cells

ART Drug Classes and Mechanisms

of Action: CCR5 Antagonists
CCR5

Antagonists

Bind to and block the CCR5 co-receptor of

the immune cell, thereby preventing HIV

from entering and infecting the cell

ART Drug Classes and Mechanisms

of Action: Integrase Inhibitors
Integrase

inhibitors

Prevent integration of HIV DNA into

the nucleus of infected cells

ART Drugs in Clinical Trials: Classes and

Mechanisms of Action (1)
Gene

therapies- block HIV genes

Maturation

inhibitors- inhibit development

of HIVs internal structures in new virions

Zinc

finger inhibitors- break apart structures

holding HIV inner core together

ART Drugs in Clinical Trials: Classes and

Mechanisms of Action (2)
Antisense drugs- mirror HIV genetic code,
lock onto virus and block replication

Factors to Consider in Selecting Initial

ART Regimen (1)
Comorbidity
Patient

adherence potential

Convenience

(e.g., pill burden, dosing

frequency, and food and fluid
considerations)

Potential

adverse drug effects and drug

interactions with other medications

Factors to Consider in Selecting Initial

ART Regimen (2)
Pregnancy
Results

potential

of genotypic drug resistance testing

Gender

and pretreatment CD4 T-cell count if

considering nevirapine

HLA B*5701

abacavir

testing if considering

Regimen Simplification (1)

Regimen

simplification is a change in
established effective therapy to
reduce pill burden and dosing frequency,
enhance tolerability, or
decrease specific food and fluid

requirements

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Regimen Simplification (2)

Rationales

behind regimen
simplification are
to improve the patients quality of life
improve medication adherence
avoid long-term toxicities
reduce the risk of virologic failure
Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Regimen Simplification (3)

Potential candidates for regimen simplification:
1) are receiving treatments that are no longer
preferred or alternative choices for initial therapy
2) were prescribed a regimen in the setting of
treatment failure at a time when there was an
incomplete understanding of resistance or drugdrug interaction data, or
3) were prescribed a regimen prior to availability of
newer options that might be easier to administer
and/or more tolerable.

Indications for Initiation of ART (1)

All patients with a history of an AIDS-

defining illness or with a CD4 count <350

CD4+ T cells/mm3

data supporting this recommendation are

stronger for those with a CD4 T-cell count
<200 cells/mm3 and with a history of AIDS
than for those with CD4 T-cell counts between
200 and 350 cells/mm3

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Indications for Initiation of ART (2)

Regardless of CD4 count, ART should be

initiated in

Pregnant women
Patients with HIV-associated nephropathy
Patients co-infected with Hepatitis B when HBV

treatment is indicated (treat with fully

suppressive drugs active against both HIV and
HBV)

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Indications for Initiation of ART (3)

In patients with CD4 count >350 cells/mm 3

who do not meet any of the specific

conditions listed previously

Optimal time to initiate therapy is not well

defined
Patient scenarios and comorbidities should
be considered

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Benefits of Early ART (1)

Maintain

higher CD4 and prevent potential

irreversible damage to the immune system

Decrease

risk for HIV-associated

complications (Tb, non-Hodgkins
lymphoma,KS, peripheral neuropathy, HPVassociated malignancies, and HIVassociated cognitive impairment)

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Benefits of Early ART (2)

Decrease

risk of non-opportunistic
conditions (CVD, renal disease, liver
disease, and nonAIDS-associated
malignancies and infections)

Decrease

risk of transmission to others

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Risks of Early ART (1)

Development

of treatment-related side
effects/toxicities

Development

of drug resistance

Less

time to learn about HIV and its

treatment and less time to prepare for
adherence

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Risks of Early ART (2)

Increased

total time on medication, with

greater chance of treatment fatigue

Premature

use of ART before development

of more effective, less toxic, better studied
combinations

Transmission

of drug-resistant virus

Panel on Clinical Practices for Treatment of HIV Infection. (2008).

DHHS Categories for Initial ART

Preferred
Clinical data show optimal efficacy and durability
Acceptable tolerability and ease of use

Alternative
Clinical trial data show efficacy but also show

disadvantages in ARV activity, durability, tolerability, or

ease of use (compared to preferred components)
may be the best option in select individual patients

Other

possible options

Inferior efficacy or greater or more serious toxicities

Panel on Clinical Practices for Treatment of HIV Infection. (2008)

Current Antiretroviral Medications

NRTI

PI

Fusion Inhibitor

Abacavir

Atazanavir

Didanosine

Darunavir

Emtricitabine

Fosamprenavir

Lamivudine

Indinavir

Stavudine

Lopinavir

Tenofovir

Nelfinavir

Integrase Inhibitor

Zidovudine

Ritonavir

Enfuvirtide

CCR5 Antagonist

Maraviroc

Raltegravir

Saquinavir

NNRTI
Delavirdine
Efavirenz
Etravirine
Nevirapine

Tipranavir

Fixed-dose Combinations
Zidovudine/ lamivudine
Zidovudine/lamivudine/abacavir
Abacavir/lamivudine
Emtricitabine/tenofovir
Efavirenz/emtricitabine
/tenofovir

Initial ART
The

most extensively studied combination

antiretroviral regimens for treatment-nave
patients generally consist of:
two NRTIs plus one NNRTI, or
two NRTIs plus a PI (with or without ritonavir

boosting).

Initial ART: Preferred

NRTIs

NNRTI-based

Efavirenz*

+
OR

Tenofovir +
emtricitabine1,2
(coformulated)

PI-based (ritonavir-boosted)
Atazanavir + ritonavir qd
Darunavir + ritonavir qd
Fosamprenavir + ritonavir bid
Lopinavir/ritonavir (coform) qd or bid

NRTIs

Tenofovir +
emtricitabine1,2
(coformulated)

**Avoid Efavirenz in pregnant women and women with significant pregnancy

potential
1 Emtricitabine can be used in place of lamivudine and vice versa
2 Tenofovir + emtricitabine or lamivudine is preferred in patients with
HIV/HBV co-infection

Initial ART: Alternative

NNRTI-based
Nevirapine*

PI-based

+ Alternative Dual
NRTIs (see
slide)

next

Atazanavir

(unboosted) qd
Fosamprenavir (unboosted) bid
Fosamprenavir + ritonavir qd
Saquinavir + ritonavir

+ Alternative Dual
NRTIs (see
slide)

Nevirapine should not be initiated in women with CD4 counts >250 or men with
CD4 counts >400
Atazanavir must be boosted with ritonavir if used with tenofovir

next

Initial ART: Alternative Dual NRTIs

NRTIs:
abacavir/lamivudine (coformulated)
who have tested negative for HLA-B*5701

(for patients

didanosine + (lamivudine or emtricitabine*)

zidovudine/lamivudine* (coformulated)
* emtricitabine may be used in place of lamivudine or
vice versa

NNRTI Class Advantages

Save

PI options for future use

Long half-lives
Less metabolic toxicity
(hyperlipidemia, insulin resistance)
than with some PIs

NNRTI Class Disadvantages

Low

genetic barrier to resistance (single

mutation confers resistance): greater risk
for resistance with failure or treatment
interruption
Cross resistance among approved NNRTIs
Skin rash
Potential for CYP450 drug interactions
Transmitted resistance to NNRTIs more
common than resistance to PIs

PI Class Advantages
Save

NNRTI for future use

Higher genetic barrier to resistance
PI resistance uncommon with failure
(boosted PIs)

PI Class Disadvantages
Metabolic

complications
Gastrointestinal side effects
Liver toxicity
CYP3A4 inhibitors & substrates: potential
for drug interactions
PR interval prolongation
Absorption depends on food and low
gastric pH

Dual NRTIs Advantages and

Disadvantages
Advantages

Established backbone of combination

therapy
Minimal drug interactions
Disadvantages

Lactic acidosis and hepatic steatosis

(especially with stavudine, didanosine,

zidovudine )

Adverse Effects: Fusion

Inhibitor
Enfuvirtide

Injection-site reactions (subcutaneous

injection)
Hypersensitivity reaction
Increased risk of bacterial pneumonia in
clinical trials

Adverse Effects: CCR5 Antagonist

Maraviroc
Abdominal pain
Upper respiratory tract infections
Cough
Hepatotoxicity
Musculoskeletal symptoms
Rash

Adverse Effects: Integrase Inhibitor

Raltegravir

Nausea
Headache
Diarrhea
CPK elevation

Adult/ Adolescent Recommendations

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. November 3, 2008; 1-139.
Available at
http://www.aidsinfo.nih.gov/ContentFiles/Adultand
AdolescentGL.pdf.

Perinatal Recommendations
Public

Health Service Task Force

Recommendations for Use of Antiretroviral
Drugs in Pregnant HIV-Infected Women for
Maternal Health and Interventions to Reduce
Perinatal HIV Transmission in the United
States - July 8, 2008.
Available at:
http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pd
f

Evaluation Prior to ART Initiation

The following should be assessed:
CD4 cell count

HIV RNA
Drug Resistance Testing
Co-receptor Tropism
HLA-B*5701 Screening (if ABC being
considered)

CD4 T Cell Count (1)

T-4

cells, CD4+ lymphocytes, helper cells

Lymphocytes

with CD4 protein molecules

on cell surface

Cells most often infected by HIV

Indicator

of degree of immune compromise

CD4 T Cell Count (2)

Normal

range 500-1600 cells/mm3

AIDS

case definition = CD4 <200 cells/mm 3

With

adequate viral suppression

Accelerated CD4 response first 3 months of

treatment
Average CD4 increase 100-150 cells/mm3 per
year

When to Evaluate CD4 T Cell Count

When

patient first tests HIV positive (check

CD4 count twice at baseline)

Every

3-6 months to

Determine when to initiate ART

Assess immune response to ART
Assess need to initiate chemoprophylaxis for

opportunistic infections

CD4 T Cell Percentage (1)

The

percentage of total lymphocytes

comprised of CD4 cells

More

stable than CD4 count

Normal
CD4

range is 20% to 40%

percentage <14% is an indicator of

AIDS

CD4 T Cell Percentage (2)

CD4 count may be influenced by factors

that may affect total WBC and lymphocyte
percentages. In the following cases, CD4
percentage may be a more appropriate
indicator of immune function:
Use of bone marrowsuppressive medications

or the presence of acute infections

Splenectomy or coinfection with HTLV-1 may
cause misleadingly elevated absolute CD4
counts.
Alpha-interferon may reduce CD4 count without
changing the CD4 percentage.

Plasma Viral Load (PVL) (1)

Most

important indicator of response to

therapy
PVL testing can detect HIV RNA a few days
after infection

3 types of FDA approved tests for PVL

Polymerase Chain Reaction (PCR)
Branched DNA (bDNA)
Nucleic acid sequence based amplification

(NASBA)

Plasma Viral Load (PVL) (2)

Significant

change in PVL is a 3-fold

increase or decrease
Changes are expressed as log changes;
change of 0.5 log10 copies/ml is meaningful
Undetectable PVL refers to PVL below
limits of assay detection
Undetectable PVL should be achieved
within 16-24 weeks of ART initiation or
change

When to Evaluate PVL (1)

In

presence of symptoms consistent with

acute HIV infection

To

establish diagnosis when HIV antibody

test is negative or indeterminate
Should be confirmed by ELISA and Western Blot

performed 2-4 months after initial negative or

indeterminate test

When to Evaluate PVL (2)

For

baseline evaluation of newly diagnosed

HIV infection, use in conjunction with CD4
count to determine whether to initiate or
defer therapy.

For

patients not on ART, every 3-4 months

to assess PVL changes, use in conjunction
with CD4 count to determine whether to
initiate ART.

When to Evaluate PVL (3)

After

initiation or change in ART, within 2-8

weeks for initial assessment of ART efficacy

Then

every 4-8 weeks until undetectable

During

stable therapy, every 3-4 months

to assess virologic effect of therapy

To decide whether to continue or change

therapy
Goal of ART- PVL undetectable

When to Evaluate PVL (4)

In

the case of a clinical event or a

significant decline in CD4 T cells
to determine association with a changing or

stable PVL
To decide whether to continue, initiate or
change therapy

Resistance Testing

Testing recommended for all at entry to care

whether ART is initiated or deferred

Assists in selecting active drugs in initial regimen

and when changing ART regimens in cases of
virologic failure

Recommended for all pregnant women prior to

initiating ART and for those entering pregnancy
with detectable viral load while on ART

Recommended when managing suboptimal

viral load reduction

Co-receptor Tropism Assay

Should

be performed when CCR5

antagonist is being considered

Consider

in patients with virologic failure on

a CCR5 antagonist

HLA-B*5701 Screening
Recommended

before starting abacavir, to reduce

risk of hypersensitivity reaction (HSR)

Positive

allergy

If

status should be recorded as an abacavir

HLA-B*5701 testing is not available, abacavir

may be initiated, after counseling and with
appropriate monitoring for HSR

Labwork Dos and Donts

To

minimize variability in results

Draw blood for CD4 counts at same time of day

(AM or PM)
Use same laboratory for testing
Over time, same type of test should be done
Defer testing 2-4 weeks after acute illness or
vaccination
Because of variability, base treatment decisions
to initiate or change ART on 2 or more similar
values on CD4 counts and viral load

Key Points (1)

1. HIV prevalence varies by race and region.
2. Goals of ART:
Reduce HIV-related morbidity and prolong

survival
Improve quality of life
Restore and/or preserve immune function
Maximally and durably suppress viral load
Prevent vertical HIV transmission

Key Points (2)

3. Current ARV mechanisms of action:
Block reverse transcriptase to disrupt copying
of HIV genetic code (NRTIs; NNRTIs)
Block protease enzyme, preventing maturation
of new virions (PIs)
Prevent fusion of HIV with cell membranes
(Fusion inhibitors)
Block CCR5 co-receptor (CCR5 antagonists)
Prevent integration of HIV DNA into the nucleus
of infected cells (integrase inhibitors)

Key Points (3)

4. The following should be assessed
prior to initiation of therapy

CD4 cell count

HIV RNA
Drug Resistance Testing
Coreceptor Tropism Assays
HLA-B*5701 Screening (if ABC being
considered; Abacavir is not a preferred
option for initial therapy

Key Points (4)

5. Considerations in Initiation of ART
Comorbidity
Adherence potential
Convenience
Potential adverse drug effects/drug

interactions

Key Points (5)

5. Considerations in Initiation of ART (cont.)
Pregnancy potential
Genotypic drug resistance
Gender and pretreatment CD4 T-cell count

(nevirapine)
HLA B*5701 testing (abacavir)