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Human Immunodeficiency Virus and Antiretroviral Therapy

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Title: Human Immunodeficiency Virus and Antiretroviral Therapy


1
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

2
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.

3
(No Transcript)
4
10 States or Dependent Areas Reporting Highest
Number of AIDS cases 2005 (CDC, 2007)
  • State/Dependent Area AIDS Cases
  • 1. New York 6,299
  • 2. Florida 4,960
  • 3. California 4,088
  • 4. Texas 3,113
  • 5. Georgia 2,333
  • 6. Illinois 1,922
  • 7. Maryland 1,595
  • 8. Pennsylvania 1,510
  • 9. New Jersey 1,278
  • 10. Puerto Rico 1,033

5
Cumulative AIDS cases 2005 (CDC, 2007)
  • Area Adults/ Children Total
  • ______________ Adolescents lt13 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

6
HIV Virion
7
HIV Replication Cycle (1)
  • 1. Binding and Fusion
  • Virions 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

8
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

9
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

10
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

11
Sites of Action of ARVs
  • NRTIs Incorporate into DNA and block reverse
    transcriptase
  • NNRTIs Bind to reverse transcriptase
  • PIs Bind to protease to inhibit viral protein
    cleavage
  • Fusion Inhibitors Interact with virus to inhibit
    virus-cell fusion Feinberg Maenza (2005).
  • CCR5 antagonist bind to CCR5 co-receptor

12
Antiretroviral Therapy (ART)
  • ART- use of antiretroviral drugs to treat HIV
    disease
  • Highly Active Antiretroviral Therapy
    (HAART)-regimens combining several antiretroviral
    drugs

13
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

14
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

15
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

16
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

17
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

18
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

19
ART Drug Classes and Mechanisms of Action
Integrase Inhibitors
  • Integrase inhibitors
  • Prevent integration of HIV DNA into the nucleus
    of infected cells

20
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

21
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

22
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

23
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 B5701 testing if considering
  • abacavir

24
Indications for Initiation of ART (1)
  • All patients with a history of an AIDS-defining
    illness or with a CD4 count lt350 CD4 T cells/mm3
  • data supporting this recommendation are stronger
    for those with a CD4 T-cell count lt200 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).

25
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).

26
Indications for Initiation of ART (3)
  • In patients with CD4 count gt350 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).

27
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, HPV-associated malignancies, and
    HIV-associated cognitive impairment)
  • Panel on Clinical Practices for Treatment of HIV
    Infection. (2008).

28
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).

29
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).

30
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).

31

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)

32

Current Antiretroviral Medications

33

Initial ART Preferred
NNRTI-based

NRTI Options¹
  • Abacavir lamivudine²
  • Tenofovir emtricitabine³

OR

PI-based (ritonavir-boosted)
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-B5701 ³ Tenofovir
emtricitabine or lamivudine is preferred in
patients with HIV/HBV co-infection
34

Initial ART Alternative
NNRTI-based

PI-based
Alternative Dual NRTIs (see next slide)
  • Nevirapine should not be initiated in women with
    CD4 counts gt250 or men with
  • CD4 counts gt400
  • ¹ Atazanavir must be boosted with ritonavir if
    used with tenofovir
  • ² May be insufficient if HIV RNA gt100,000
    copies/mL

35

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

36
NNRTI Class Advantages
  • Save PI options for future use
  • Long half-lives
  • Less metabolic toxicity (hyperlipidemia, insulin
    resistance) than with some PIs

37
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

38
PI Class Advantages
  • Save NNRTI for future use
  • Higher genetic barrier to resistance
  • PI resistance uncommon with failure (boosted PIs)

39
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

40
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 )

41
Adverse Effects Fusion Inhibitor
  • Enfuvirtide
  • Injection-site reactions
  • Hypersensitivity reaction
  • Increased risk of bacterial pneumonia in clinical
    trials

42
Adverse Effects CCR5 Antagonist
  • Maraviroc
  • Abdominal pain
  • Upper respiratory tract infections
  • Cough
  • Hepatotoxicity
  • Musculoskeletal symptoms
  • Rash

43
Adverse Effects Integrase Inhibitor
  • Raltegravir
  • Nausea
  • Headache
  • Diarrhea
  • CPK elevation

44
Adult/ 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/ContentFi
    les/AdultandAdolescentGL.pdf

45
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.p
    df

46
Evaluation Prior to ART Initiation
  • The following should be assessed
  • CD4 cell count
  • HIV RNA
  • Drug Resistance Testing
  • Co-receptor Tropism
  • HLA-B5701 Screening (if ABC being considered)

47
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

48
CD4 T Cell Count (2)
  • Normal range 500-1600 cells/mm3
  • AIDS case definition CD4 lt200 cells/mm3
  • With adequate viral suppression
  • Accelerated CD4 response first 3 months of
    treatment
  • Average CD4 increase 100-150 cells/mm3 per year

49
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

50
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 lt14 is an indicator of AIDS

51
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)

52
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

53
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

54
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.

55
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

56
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

57
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

58
Co-receptor Tropism Assay
  • Should be performed when CCR5 antagonist is being
    considered
  • Consider in patients with virologic failure on a
    CCR5 antagonist

59
HLA-B5701 Screening
  • Recommended before starting abacavir, to reduce
    risk of hypersensitivity reaction (HSR)
  • Positive status should be recorded as an abacavir
    allergy
  • If HLA-B5701 testing is not available, abacavir
    may be initiated, after counseling and with
    appropriate monitoring for HSR

60
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

61
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

62
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)

63
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-B5701 Screening (if ABC being
    considered ABC not used at this time for
    initial therapy)

64
Key Points (4)
  • 5. Considerations in Initiation of ART
  • Comorbidity
  • Adherence potential
  • Convenience
  • Potential adverse drug effects/drug interactions

65
Key Points (5)
  • 5. Considerations in Initiation of ART (cont.)
  • Pregnancy potential
  • Genotypic drug resistance
  • Gender and pretreatment CD4 T-cell count
    (nevirapine)
  • HLA B5701 testing (abacavir)
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