Transcript Human Immunodeficiency Virus and Antiretroviral Therapy

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
June 2008
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.
10 States or Dependent Areas Reporting Highest
Number of AIDS cases: 2005 (CDC, 2007)
State/Dependent Area
1. New York
2. Florida
3. California
4. Texas
5. Georgia
6. Illinois
7. Maryland
8. Pennsylvania
9. New Jersey
10. Puerto Rico
# AIDS Cases
6,299
4,960
4,088
3,113
2,333
1,922
1,595
1,510
1,278
1,033
Cumulative AIDS cases: 2005 (CDC, 2007)
Area
______________
1. New York
2. California
3. Florida
4. Texas
5. New Jersey
6. Illinois
7. Pennsylvania
8. Georgia
9. Maryland
10. Puerto Rico
Adults/
Adolescents
170,035
138,361
99,290
66,836
47,659
32,314
31,619
30,179
28,804
28,693
Children
<13 years
2,342
658
1,519
391
772
281
358
226
312
399
Total
____
172,377
139,019
100,809
67,227
48,431
32,595
31,977
30,405
29,116
29,092
HIV Virion
HIV Replication Cycle (1)
1. Binding and Fusion
– Virion’s gp120 and gp41 proteins bind to
cell surface receptors (CD4 and 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 cell’s 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
Sites of Action of ARVs
1.
NRTIs: Incorporate into DNA and block reverse transcriptase
2.
NNRTIs: Bind to reverse transcriptase
3.
PIs: Bind to protease to inhibit viral protein cleavage
4.
Fusion Inhibitors: Interact with virus to inhibit virus-cell fusion
5.
CCR5 antagonist: bind to CCR5 co-receptor
Feinberg & Maenza (2005).
Antiretroviral Therapy (ART)
 ART-
use of antiretroviral drugs to treat
HIV disease
 Highly
Active Antiretroviral Therapy
(HAART)-regimens combining several
antiretroviral drugs
Primary Goals of ART

Reduce HIV-related morbidity and prolong
survival

Improve quality of life

Restore and preserve immunologic function

Maximally and durably suppress viral load

Prevent 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 cell’s 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 cell’s 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
HIV’s 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)

Attachment and fusion inhibitors- block
CD4, CXCR4 receptors, preventing
attachment and fusion

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 potential

Results of genotypic drug resistance testing

Gender and pretreatment CD4 T-cell count if
considering nevirapine

HLA B*5701 testing if considering
abacavir
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/mm3
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-Hodgkin’s
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 non–AIDS-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
Enfuvirtide
CCR5 Antagonist

Maraviroc
Stavudine
Indinavir
Tenofovir
Lopinavir
Integrase Inhibitor
Zidovudine
Nelfinavir

Ritonavir
NNRTI
Saquinavir
Delavirdine
Tipranavir
Efavirenz
Etravirine
Nevirapine
Raltegravir
Initial ART: Preferred
NNRTI-based

NRTI Options¹
Efavirenz*
OR
PI-based (ritonavir-boosted)
Atazanavir
+ ritonavir
Fosamprenavir + ritonavir (BID)
Lopinavir/ritonavir (BID)
+
Abacavir +
lamivudine²
Tenofovir +
emtricitabine³
* Avoid Efavirenz in pregnant women and women with significant pregnancy
potential
¹ Emtricitabine can be used in place of lamivudine and vice versa
² For patients who have tested negative for HLA-B*5701
³ Tenofovir + emtricitabine or lamivudine is preferred in patients with
HIV/HBV co-infection
Initial ART: Alternative
NNRTI-based
 Nevirapine*
PI-based
+ Alternative Dual
Atazanavir¹
NRTIs (see
next slide)
Fosamprenavir
Fosamprenavir
+ ritonavir
(1x/day)
(1x/day)²
Saquinavir + ritonavir
Lopinavir/ritonavir
Nevirapine should not be initiated in women with CD4 counts >250 or men with
CD4 counts >400
¹ Atazanavir must be boosted with ritonavir if used with tenofovir
² May be insufficient if HIV RNA >100,000 copies/mL
Initial ART: Alternative Dual NRTIs
(in order of preference):

zidovudine/lamivudine* (coformulated)

didanosine + (lamivudine or emtricitabine*)
* 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 d4T, ddI, ZDV )
Adverse Effects: Fusion
Inhibitor

Enfuvirtide
– Injection-site reactions
– 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 Adult and
Adolescents.
Guidelines for the use of antiretroviral agents in HIV1-infected adults and adolescents. Department of
Health and Human Services. January 29, 2008; 1128.
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 - November 2, 2007.
Available at:
http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf

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/mm3

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

The percentage of total lymphocytes
comprised of CD4 cells

More stable than CD4 count

Normal range is 20% to 40%

CD4 percentage <14% is an indicator of
AIDS
Plasma Viral Load (PVL) (1)


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, every 2-8
weeks
– for initial assessment of ART efficacy
– to decide whether to change therapy

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 status should be recorded as an abacavir
allergy

If HLA-B*5701 testing is not available, abacavir
may be initiated, after counseling and with
appropriate monitoring for HSR
Labwork Do’s and Don’ts

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; ABC not used at this
time 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)