HIV Early Treatment Project Groups 1 and 2 n Among HIV-infected participants in sub-Saharan Africa, does initiation of antiretroviral treatment (ART) at CD4+ counts above 500 cells/mm 3 result in a reduction in all-cause mortality compared to deferral of initiation of ART until the CD4+ declines to < 350 cells/mm 3 ?

Reasons for Deferral n 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) n Concerns about complications of ART n Fear of waning adherence, resistance accumulation, and exhaustion of drug options n Unknown HIV status

3 Serious Non-AIDS Outcomes in SMART No. of Patients with Events Endpoints Major CVD, hepatic or renal disease CVD Hazard Ratio (95% CI) Rate DCVS Renal (ESRD) Hepatic (Cirrhosis) NADM Favors DCFavors VS Other non-AIDS death Any of the above MI (clinical or silent), stroke, surgery for CAD ++ Except non-melanoma skin

4 Rate of AIDS and Non-AIDS Conditions by Current CD4 count AIDS defining illness Non-AIDS defining illness Incidence per 1000 PYFU (95% CI) 700 Mocroft A et al, J Acquir Immune Defic Syndr 2010 Steeper curve for AIDS than non-AIDS. Current CD4 count (/mm 3 )

5 Evidence from Observational Studies for Initiating ART with CD4 > 350 Kitahata MM et al, N Engl J Med 2009 When to Start Consortium, Lancet HIV Causal Collaboration, Annals Int Med, 2011 Comparison CD4+ count strata HR for death NA ACCORD <350 vs ( ) vs > (1.4 – 2.8) ART CC vs ( ) vs ( ) HIV-Causal 350 vs ( )

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; ; 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/mm 3 Early ART Initiate ART immediately following randomization N=2,300 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=2,300 Primary Composite Endpoint: Serious AIDS, serious non-AIDS or all-cause mortality. Event Target = 213 primary events.

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