Human Immunodeficiency Virus and Human Immunodeficiency Virus and Antiretroviral TherapyAntiretroviral Therapy
Lucille Sanzero Eller, PhD, RNAssociate Professor
Rutgers, The State University of New Jersey College of Nursing
Local Performance Site of the NY/NJ AETCJune 2008
ObjectivesObjectives
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 10 States or Dependent Areas Reporting Highest Number of AIDS cases: 2005 (CDC, 2007)Number of AIDS cases: 2005 (CDC, 2007)
State/Dependent Area # AIDS Cases1. New York 6,2992. Florida 4,9603. California 4,0884. Texas 3,1135. Georgia 2,3336. Illinois 1,9227. Maryland 1,5958. Pennsylvania 1,5109. New Jersey 1,27810. Puerto Rico 1,033
Cumulative AIDS cases: 2005 Cumulative AIDS cases: 2005 (CDC, 2007)(CDC, 2007)
Area Adults/ Children Total
______________ Adolescents <13 years____
1. New York 170,035 2,342 172,377
2. California 138,361 658 139,019
3. Florida 99,290 1,519 100,809
4. Texas 66,836 391 67,227
5. New Jersey 47,659 772 48,431
6. Illinois 32,314 281 32,595
7. Pennsylvania 31,619 358 31,977
8. Georgia 30,179 226 30,405
9. Maryland 28,804 312 29,116
10. Puerto Rico 28,693 399 29,092
HIV VirionHIV Virion
HIV Replication Cycle (1)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)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)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)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 ARVsSites 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 Feinberg & Maenza (2005).
5. CCR5 antagonist: bind to CCR5 co-receptor
Antiretroviral Therapy (ART)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 ARTPrimary 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 ART Drug Classes and Mechanisms of Action: NRTIsof 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 ART Drug Classes and Mechanisms of Action: NNRTIsof 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 ART Drug Classes and Mechanisms of Action: PIsof 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 ART Drug Classes and Mechanisms of Action: FIs (Entry Inhibitors)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 ART Drug Classes and Mechanisms of Action: CCR5 Antagonistsof 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 ART Drug Classes and Mechanisms of Action: Integrase Inhibitorsof Action: Integrase Inhibitors
Integrase inhibitors
–Prevent integration of HIV DNA into the nucleus of infected cells
ART Drugs in Clinical Trials: Classes ART Drugs in Clinical Trials: Classes and Mechanisms of Action (1)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 ART Drugs in Clinical Trials: Classes and Mechanisms of Action (2)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 Factors to Consider in Selecting Initial ART Regimen (1)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 Factors to Consider in Selecting Initial ART Regimen (2)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 Indications for Initiation of ART (1)(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 Indications for Initiation of ART (2)(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 Indications for Initiation of ART (3)(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 Benefits of Early ART (1)(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, HPV-associated malignancies, and HIV-associated cognitive impairment)
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
Benefits of Early ART Benefits of Early ART (2)(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 Risks of Early ART (1)(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 Risks of Early ART (2)(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).
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)
DHHS Categories for Initial ARTDHHS Categories for Initial ART
Current Antiretroviral Medications
NRTIAbacavirDidanosine EmtricitabineLamivudineStavudineTenofovirZidovudine
NNRTIDelavirdineEfavirenzEtravirineNevirapine
PIAtazanavirDarunavirFosamprenavir
IndinavirLopinavirNelfinavirRitonavirSaquinavir Tipranavir
Fusion Inhibitor Enfuvirtide
CCR5 Antagonist Maraviroc
Integrase Inhibitor Raltegravir
Initial ART: Preferred
* * Avoid Efavirenz in pregnant women and women with significant pregnancy Avoid Efavirenz in pregnant women and women with significant pregnancy potentialpotential
¹ Emtricitabine can be used in place of lamivudine and vice versa¹ Emtricitabine can be used in place of lamivudine and vice versa² For patients who have tested negative for HLA-B*5701² For patients who have tested negative for HLA-B*5701³ Tenofovir + emtricitabine or lamivudine is preferred in patients with ³ Tenofovir + emtricitabine or lamivudine is preferred in patients with HIV/HBV co-infectionHIV/HBV co-infection
Efavirenz*
OR
Atazanavir + ritonavirFosamprenavir + ritonavir (BID)Lopinavir/ritonavir (BID)
PI-based (ritonavir-boosted)
Abacavir +
lamivudine²
Tenofovir +
emtricitabine³
+
NRTI Options¹NNRTI-based
Initial ART: AlternativeInitial ART: Alternative
Nevirapine should not be initiated in women with CD4 counts >250 or men with Nevirapine should not be initiated in women with CD4 counts >250 or men with CD4 counts >400 CD4 counts >400 ¹ Atazanavir must be boosted with ritonavir if used with tenofovir¹ Atazanavir must be boosted with ritonavir if used with tenofovir² May be insufficient if HIV RNA >100,000 copies/mL² May be insufficient if HIV RNA >100,000 copies/mL
Nevirapine*
Atazanavir¹ FosamprenavirFosamprenavir + ritonavir (1x/day)Lopinavir/ritonavir (1x/day)²Saquinavir + ritonavir
PI-based
NNRTI-based
+ Alternative Dual NRTIs (see
next slide)
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 AdvantagesNNRTI Class Advantages
Save PI options for future use Long half-lives Less metabolic toxicity
(hyperlipidemia, insulin resistance) than with some PIs
NNRTI Class DisadvantagesNNRTI 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 AdvantagesPI Class Advantages
Save NNRTI for future use Higher genetic barrier to resistance PI resistance uncommon with failure
(boosted PIs)
PI Class DisadvantagesPI 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 Dual NRTIs Advantages and DisadvantagesDisadvantages
Advantages– Established backbone of combination
therapy– Minimal drug interactions
Disadvantages– Lactic acidosis and hepatic steatosis
(especially with d4T, ddI, ZDV )
Adverse Effects: Fusion Adverse Effects: Fusion InhibitorInhibitor
Enfuvirtide – Injection-site reactions– Hypersensitivity reaction– Increased risk of bacterial pneumonia in
clinical trials
Adverse Effects: CCR5 AntagonistAdverse Effects: CCR5 Antagonist
Maraviroc – Abdominal pain– Upper respiratory tract infections– Cough– Hepatotoxicity– Musculoskeletal symptoms– Rash
Adverse Effects: Integrase InhibitorAdverse Effects: Integrase Inhibitor
Raltegravir – Nausea– Headache– Diarrhea– CPK elevation
Adult/ Adolescent RecommendationsAdult/ Adolescent Recommendations
Panel on Antiretroviral Guidelines for Adult and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1-128.
Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
Perinatal RecommendationsPerinatal 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 InitiationEvaluation 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 CD4 T Cell Count (1)(1)
T-4 cells, CD4+ lymphocytes, helper cells Lymphocytes with CD4 protein molecules
on cell surface Cells most often infected by HIVIndicator of degree of immune compromise
CD4 T Cell Count CD4 T Cell Count (2)(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 CountWhen 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 PercentageCD4 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) Plasma Viral Load (PVL) (1)(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) Plasma Viral Load (PVL) (2)(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 When to Evaluate PVL (1)(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 When to Evaluate PVL (2)(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 When to Evaluate PVL (3)(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 When to Evaluate PVL (4)(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 TestingResistance 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 AssayCo-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 ScreeningHLA-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’tsLabwork 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 PointsKey Points (1) (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 PointsKey Points (2) (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 Key Points (3)(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 Key Points (4)(4)
5. Considerations in Initiation of ART
– Comorbidity – Adherence potential– Convenience– Potential adverse drug effects/drug
interactions
Key Points Key Points (5)(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)