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
• September 2009

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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.

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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
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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
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HIV VIRION
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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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ART Drug Classes and Mechanisms of Action
Integrase Inhibitors

• Integrase inhibitors
• Prevent integration of HIV DNA into the nucleus
  of infected cells

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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

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ART Drugs in Clinical Trials Classes and
Mechanisms of Action (2)

• Antisense drugs- mirror HIV genetic code, lock
  onto virus and block replication

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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

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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

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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).

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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).

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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.

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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).

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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).

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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).

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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).

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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).

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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).

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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).

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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)

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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

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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).

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Initial ART Preferred
NRTIs
NNRTI-based

Tenofovir emtricitabine1,2 (coformulated)
Efavirenz

OR
PI-based (ritonavir-boosted)
NRTIs
Atazanavir ritonavir qd Darunavir
ritonavir qd Fosamprenavir ritonavir bid
Lopinavir/ritonavir (coform) qd or bid
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
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Initial ART Alternative
NNRTI-based

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

• NRTIs
• abacavir/lamivudine (coformulated) (for patients
  who have tested negative for HLA-B5701
• didanosine (lamivudine or emtricitabine)
• zidovudine/lamivudine (coformulated)
• emtricitabine may be used in place of
  lamivudine or vice versa

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NNRTI Class Advantages

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

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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

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PI Class Advantages

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

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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

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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 )

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Adverse Effects Fusion Inhibitor

• Enfuvirtide
• Injection-site reactions (subcutaneous injection)
• Hypersensitivity reaction
• Increased risk of bacterial pneumonia in clinical
  trials

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Adverse Effects CCR5 Antagonist

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

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Adverse Effects Integrase Inhibitor

• Raltegravir
• Nausea
• Headache
• Diarrhea
• CPK elevation

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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/AdultandA
  dolescentGL.pdf.

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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.p
  df

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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)

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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

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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

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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

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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 lt14 is an indicator of AIDS

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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.

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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)

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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

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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

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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.

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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

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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

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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

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Co-receptor Tropism Assay

• Should be performed when CCR5 antagonist is being
  considered
• Consider in patients with virologic failure on a
  CCR5 antagonist

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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

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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

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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

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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)

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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 Abacavir is not a preferred option
  for initial therapy

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Key Points (4)

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

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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)