Human Immunodeficiency Virus and Antiretroviral Therapy



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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
    • Virion’s 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 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

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 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)

  • 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

Regimen Simplification (1)

  • Regimen simplification is a change in established effective therapy to
    • Panel on Clinical Practices for Treatment of HIV Infection. (2008).

Regimen Simplification (2)

  • Rationales behind regimen simplification are
    • to improve the patient’s 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 drug-drug 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/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, HPV-associated malignancies, and HIV-associated 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).

  • 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
  • Abacavir
  • Didanosine
  • Emtricitabine
  • Lamivudine
  • Stavudine
  • Tenofovir
  • Zidovudine
  • NNRTI
  • Delavirdine
  • Efavirenz
  • Etravirine
  • Nevirapine
  • PI
  • Atazanavir
  • Darunavir
  • Fosamprenavir
  • Indinavir
  • Lopinavir
  • Nelfinavir
  • Ritonavir
  • Saquinavir
  • Tipranavir
  • Fusion Inhibitor
  • Enfuvirtide
  • CCR5 Antagonist
  • Maraviroc
  • Integrase Inhibitor
  • Raltegravir
  • 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-naïve patients generally consist of:
    • two NRTIs plus one NNRTI, or
    • two NRTIs plus a PI (with or without ritonavir boosting).

  • Initial ART: Preferred
  • **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
  • Efavirenz*
  • OR
  • PI-based (ritonavir-boosted)
  • Tenofovir + emtricitabine1,2 (coformulated)
  • +
  • NRTIs
  • NNRTI-based
  • Atazanavir + ritonavir qd Darunavir + ritonavir qd Fosamprenavir + ritonavir bid Lopinavir/ritonavir (coform) qd or bid
  • Tenofovir + emtricitabine1,2 (coformulated)
  • +
  • NRTIs

  • Initial ART: Alternative
  • 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
  • Nevirapine*
  • Atazanavir¹ (unboosted) qd
  • Fosamprenavir (unboosted) bid
  • Fosamprenavir + ritonavir qd
  • Saquinavir + ritonavir
  • PI-based
  • NNRTI-based
  • + Alternative Dual NRTIs (see next slide)
  • + Alternative Dual NRTIs (see next slide)

  • Initial ART: Alternative Dual NRTIs
  • NRTIs:
  • abacavir/lamivudine (coformulated) (for patients who have tested negative for HLA-B*5701
  • 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

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/AdultandAdolescentGL.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.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 (1)

  • 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

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 marrow–suppressive 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 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; 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)


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