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HIV Early Treatment Project Groups 1 and 2

HIV Early Treatment Project Groups 1 and 2.

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HIV Early Treatment Project Groups 1 and 2

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  1. HIV Early Treatment ProjectGroups 1 and 2 • Among HIV-infected participants in sub-Saharan Africa, does initiation of antiretroviral treatment (ART) at CD4+ counts above 500 cells/mm3 result in a reduction in all-cause mortality compared to deferral of initiation of ART until the CD4+ declines to < 350 cells/mm3?

  2. Reasons for Deferral • In high-income countries, absolute risk differences for AIDS or death are small compared with those at lower CD4+ counts (no good data for sub-Saharan Africa) • Concerns about complications of ART • Fear of waning adherence, resistance accumulation, and exhaustion of drug options • Unknown HIV status

  3. Serious Non-AIDS Outcomes in SMART Hazard Ratio (95% CI) No. of Patients with Events Rate Endpoints DC VS Major CVD, hepatic or renal disease 1041.81.1 1.7 CVD+ 79 1.30.8 1.6 Hepatic (Cirrhosis)17 0.30.2 1.4 Renal (ESRD) 11 0.20.1 4.5 NADM++ 47 0.80.5 1.4 Other non-AIDS death 51 0.90.5 1.8 Any of the above 1863.22.0 1.6 + MI (clinical or silent), stroke, surgery for CAD ++ Except non-melanoma skin Favors DC Favors VS

  4. Rate of AIDS and Non-AIDS Conditions by Current CD4 count AIDS defining illness Non-AIDS defining illness Steeper curve for AIDS than non-AIDS. Incidence per 1000 PYFU (95% CI) <50 51-100 101-200 201-350 351-500 501-700 >700 Current CD4 count (/mm3) Mocroft A et al, J Acquir Immune Defic Syndr 2010

  5. Evidence from Observational Studies for Initiating ART with CD4 > 350 • Comparison • CD4+ count strata HR for death • NA ACCORD <350 vs 350-500 1.7 (1.3 - 2.3) • 350-500 vs > 500 1.9 (1.4 – 2.8) • ART CC 251-350 vs 351-450 1.1 (0.8 - 1.6) • 351-450 vs 451-550 0.9 (0.6 - 1.4) • HIV-Causal 350 vs 500 1.0 (0.8-1.2) Kitahata MM et al, N Engl J Med 2009 When to Start Consortium, Lancet 2009. HIV Causal Collaboration, Annals Int Med, 2011

  6. Limitations of the Observational Studies • Conflicting results • Unmeasured confounders • Modeling assumptions required to adjust for measured confounders • Cohorts largely comprised of patients from resource-rich countries, none from sub Saharan Africa

  7. HPTN 052 Study • Primary endpoint (linked transmission) • 28 endpoints observed • 1 early therapy • 27 delayed therapy • HR=0.04; 0.01-0.27; p<.0001 Cohen MS, N Engl J Med 2011

  8. Strategic Timing of Antiretroviral Treatment (START) Design HIV-infected. 18 years or older, ART-naïve, and CD4+ count > 500 cells/mm3 Early ART Initiate ART immediately following randomization N=2,000 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm3 or AIDS develops N=2,000 Primary Composite Endpoint: Serious AIDS, serious non-AIDS or all-cause mortality. Event Target = 370 primary events.

  9. Questions To Consider • Target population (e.g., asymptomatic, PMCT) • Definition of deferred ART (e.g., reasons for initiation apart from CD4+ count) • Large, simple trial? • ART regimen to be used - flexible or fixed? • Secondary endpoints • Transmission risk behavior assessment?

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