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Issues and Controversies in Initiation of
Antiretroviral Therapy
Constance A. Benson, MD
CA Benson, MD, June 2001
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When To Start Antiretroviral Therapy

• Current Controversy Weighing benefit/risk for
  asymptomatic patients with CD4 T cell counts
  between 200 and 500 cells/µL
• Low to moderate risk of disease progression
• Moderate risk of complications of therapy,
  including
• - Poor adherence
• - Development of drug resistance
• - Short- and long-term toxicities

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Risk of Progression to AIDS (1987 Definition) in
3 years by Baseline CD4 Count and HIV RNA
Adapted from Mellors et al, Science 19962721167
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Benefits and Potential Risks of Early Therapy

• Benefits
• Control of viral replication easier to
  achieve/maintain
• Delay or prevention of immunodeficiency
• Lower risk of resistance
• Decreased risk of HIV transmission

• Risks
• Drug-related reduction in quality of life
• Greater cumulative drug-related adverse events
• Development of drug resistance in those with poor
  adherence
• Limitation of future treatment options

Adapted from DHHS Guidelines, February 2001
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Benefits and Potential Risks of Delayed Therapy

• Benefits
• Avoid negative effects on quality of life
• Avoid drug-related adverse events
• Delay in development of drug resistance
• Preserve maximum number of drug options when HIV
  disease risk is highest

• Risks
• Possible risk of immune system depletion
• Possible greater difficulty in suppressing viral
  replication
• Possible increased risk of HIV transmission

Adapted from DHHS Guidelines, February 2001
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CD4 Cell Rise is Greater the Earlier in Disease
ART is Initiated
Adapted from Swiss Cohort Study, Lancet, 1999
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Rationale for Earlier Initiation of Therapy

• Decreased risk of HIV transmission
• Viral load in genital secretions is greatly
  reduced in those receiving potent antiretroviral
  therapy
• Modeling studies suggest broad treatment with
  reductions in viral load of infected individuals
  will decrease the number of new infections
  (Science, 2000)
• Effect may be tempered by an increased risk of
  transmission of drug-resistant virus by treated
  patients who are incompletely suppressed

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CD4 Count is Better than Plasma HIV-1 RNA in
Determining When to Initiate HAART

• Retrospective review of the risk of a new OI or
  death based on CD4 count and viral load at
  initiation of HAART
• 1162 patients followed up at Johns Hopkins
• Median time of therapy - 533 days
• Viral load prior to initiation of therapy was not
  associated with risk of disease progression but
  CD4 count was
• CD4 at HAART Hazard Ratio (95 CI P
  value)
• CD4 lt 200 4.3 (2.6, 7.2 P lt 0.0001)
• CD4 201-350 1.6 (0.9, 2.9 P
  0.11)
• CD4 351-500 1.0
• 
  Adapted from T Sterling et al, 8th CROI

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Later Initiation of Antiretroviral Therapy is
Associated with Increased Risk of Death

• CDC Adult Spectrum of Disease Project record
  review of 5,110 persons starting 2- or 3-drug
  antiretroviral therapy
• CD4 at HAART 2-yr Survival Hazard Ratio
  (95 CI)
• 0 - 49 64.8 5.5 (3.0, 10.1)
  
• 50 - 99 78.1 3.6 (1.9, 6.8)
• 100 - 149 86.1 2.7 (1.4, 5.2)
• 150 - 199 89.9 2.3 (1.1, 4.7)
• 200 - 249 95.7 1.9 (0.9, 3.8)
• 250 - 299 93.7 1.9 (0.9, 3.9)
• 300 - 349 92.8 1.8 (0.9, 3.7)
• 350 - 399 96.3 1.1 (0.5, 2.4)

Adapted from J Kaplan et al, 8th CROI
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Clinical Benefit of Initiation of HAART in Pts
with Asymptomatic HIV infection and CD4 Count
gt350/?L

• Treatment-naïve patients with CD4 gt 350/µL
  starting HAART matched to untreated controls
  (Swiss HIV Cohort Study)
• Median follow-up of 2.1 years for 363 cases and
  1.3 years for 363 controls
• Hazard ratio for progression to a CDC Class B or
  C event was 0.15 for cases versus controls and
  mortality was 1.1 versus 3.3
• However, HAART treatment associated with
  treatment interruptions in 44.6, intolerance in
  17.9, and virologic failure in some patients

Adapted from Opravil et al, 8th CROI
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Rationale for Later Initiation of Therapy

• Treatment regimens are complex and difficult to
  tolerate gt incomplete adherence gt drug
  resistance, limiting future treatment options, ie
  burn through available drugs too quickly
• 90-95 adherence to nRTI/PI regimen required to
  achieve/maintain full suppression (Paterson DL,
  et al. Ann Intern Med, 2000)

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Correlation Between Adherence to ARV Therapy and
VL lt 400 (at 12 weeks)
Proportion with VL lt 400/mL
Adherence (MEMS Caps)
Adapted from Ann Intern Med 2000
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Impact of Adherence on Antiretroviral Regimen
Failure

• SAT GROUP study medication was self-administered
  following written and verbal instructions and
  adherence counseling
• DOT GROUP study medication was given under the
  supervision of a nurse who dispensed and observed
  subjects swallow the medication

Adapted from Fischl et al, 8th CROI, 2001
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Rationale for Later Initiation of Therapy

• Emerging complications of ART may have short- and
  long-term effects on future health
• Pancreatitis
• Peripheral neuropathy
• Hyperlipidemia
• Body fat distribution abnormalities
• Hyperglycemia
• Lactic acidosis
• Osteopenia/osteoporosis

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Indications for Initiation of Antiretroviral
Therapy

• Clinical Category CD4 Cells/µL HIV RNA
  Recommendation
• Copies/mL
• Symptomatic Any Any Treat
• Asymptomatic
• (AIDS) lt 200 Any Treat
• Asymptomatic 200-350 Any Generally Treat
• Asymptomatic gt 350 gt 55,000 Generally
  Treat
• Asymptomatic gt 350 lt 55,000 Generally
  Observe

Adapted from DHHS Guidelines, February 2001
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What The New Guidelines Do Not Tell Us

• Those who started ART with a CD4 T cell count gt
  350 cells/?L or a VL lt 55,000 copies/mL started
  too early.
• Those who started ART with a CD4 T cell count gt
  350 cells/?L or a VL lt 55,000 copies/mL should
  stop therapy.
• Those who wish to start ART earlier should not do
  so.
• Patients should wait until they are symptomatic
  to start ART.
• The risk of developing serious complications of
  therapy outweighs the risk of disease progression.

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When Should Therapy Be Started?

• No single answer is valid for every patient
• Factors to consider
• Biological factors
• CD4 T cell count
• Plasma HIV-1 RNA level
• Toxicities and risk factors for their development
• Commitment to therapy
• Social and demographic factors
• Flexibility and individualization

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Recommended ARV Therapy for Treatment of
Established HIV Infection

• Recommended One each from column A and column B
• Column A Column B
• Indinavir Zidovudine/Lamivudine
• Nelfinavir Stavudine/Lamivudine
• Ritonavir/Saquinavir Zidovudine/Didanosine
• Ritonavir/Indinavir Stavudine/Didanosine
• Lopinavir/Ritonavir
• Efavirenz
• Alternative Nevirapine, Delavirdine, Didanosine/
  Lamivudine
• Abacavir, Amprenavir,
  Zidovudine/Zalcitabine
• Nelfinavir/Saquinavir

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What to Start Options

• Regimen Advantages Disadvantages
• PI2 nRTI Clinical endpoint data,
  Complexity, pill burden,
• longest experience long-term toxicity,
  effect
• on future Rx
• NNRTI2 nRTI Defers PI, low pill burden Limited
  long-term data,
• effect on future Rx
• 2 PI2 nRTI High potency, convenient Pill
  burden, long-term
• dosing toxicity
• 3 nRTI Defers PI and NNRTI, Lower potency at
  higher
• low pill burden VL, limited long-term
• data, effect on future Rx
• PINNRTInRTI High potency Complexity,
  long-term
• toxicity, effect on future Rx