SMART 2008.

Methods	The trial included 318 sites in 33 countries and enrollment commenced in January 2002 and was stopped early on 10 January 2006 by the Board. The trial compared a Viral Suppression (VS) strategy, with an experimental Drug Conservation (DC) strategy. The results for a sub‐set of those participants within the larger VS‐DC trial who were ARV treatment‐naive are included in this review. This analysis was reported as post‐hoc and included a group of participants who were either ART‐naive or who had received ART and ceased to take it 6 months prior to enrollment. For this review we report the results only for those ART‐naive participants. Routine visits occurred at 1 and 2 months, every 2 months thereafter for the first year, and every 4 months in subsequent years. Visits included clinical assessments, and samples were obtained for measurement of CD4 cell count and plasma HIV RNA level. At baseline and annually, a 12‐lead electrocardiogram was obtained, and data were electronically transmitted to a central reading facility for assessment of silent myocardial infarction. Median period of follow‐up was 18 months for entire RCT and for the sub‐set (including those participants who had recieved ART 6 months earlier). Follow‐up is not reported specifically for the ART‐naive participants only. Median follow‐up for the subset is reported as 15 months.
Participants	5.472 HIV‐infected participants with CD4 cell count > 350 cells/µL were randomly assigned to VS or DC. Of these, 477 participants were either treatment‐naive (n = 249) or had not received ART in the preceding 6 months (n = 228). Inclusion criteria: HIV‐infected, age ≥ 13 years of age, CD4 T cell count > 350 cells/µL, willing to initiate, modify, or stop antiretroviral therapy according to study guidelines. Exclusion criteria: pregnant or breast‐feeding. Additional criteria for post‐hoc sub‐set analysis were that participants were antiretroviral‐naive or not on treatment for greater than 6 months. We report the results for only those participants who were ART‐naive. Median age was 39 in the ART‐naive Viral Suppression group and 40 years in the ART‐naive Drug Conservation group. There were 27.5% females in the ART‐naive VS group and 20.3% in the ART‐naive DC group. Median log viral load at baseline was 4.3 copies/ml in the ART‐naive VS group and 4.6 in the ART‐naive DC group. Median CD4 count at baseline was 432 cells/ul in the ART‐naive VS group and 441 cells/ul ART‐naive DC group.
Interventions	Intervention: EARLY: In the Viral Suppression strategy available antiretroviral regimens were to be used in an uninterrupted manner with the goal of maximal and continuous suppression of HIV replication. Comparison: DEFERRED: The Drug Conservation strategy entailed the episodic use of antiretroviral therapy according to CD4+ count thresholds: the use of antiretroviral therapy was deferred until the CD4+ count decreased to less than 250 cells per cubic millimeter, at which time antiretroviral therapy was to be initiated (or reinitiated) and continued until the CD4+ count increased to more than 350 cells per cubic millimeter. The protocol also permitted antiretroviral therapy to be initiated (or reinitiated) if symptoms of disease from HIV infection (e.g., oral thrush) developed or the percentage of CD4+ lymphocytes (CD4+ percentage) was less than 15%. On confirmation that the CD4+ count was more than 350 cells per cubic millimeter, antiretroviral therapy was to be stopped and then resumed when the CD4+ count was less than 250 cells per cubic millimeter. The sub‐set of 477 participants were those participants who were treatment‐naive or not on ART for greater than 6 months. Of these 131 were ART‐naive in the Viral Suppressoin Group and 118 in the Drug Conservation Group. We report the results for this group.
Outcomes	Primary outcome: Death or Opportunistic Disease Secondary outcomes: Death from any cause Opportunistic Disease (fatal or non‐fatal) Serious non‐AIDS events (major cardiovascular, renal, or hepatic disease, and non‐AIDS cancers, and deaths from non‐OD causes) Composite outcome of b. and c. Adverse effects: Grade 4 adverse events (not including opportunistic disease) or death from any cause. Grade 4 adverse events were defined as potentially life‐threatening symptomatic events requiring medical intervention, according to the toxicity table of the Division of AIDS of the NIAID. Data on lower‐grade toxic effects were not collected.
Notes	The study was approved by the institutional review board at each site, and written informed consent was obtained from all participants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Stratified according to clinical site with the use of permeated blocks of random sizes. Assume computer‐generated
Allocation concealment?	Unclear risk	As for above
Blinding? All outcomes	High risk	Investigators and participants were aware of treatment assignments. For primary outcome, death or Opportunistic Disease, an end‐point review committee reviewed the events classification unaware of treatment assignments.
Incomplete outcome data addressed? All outcomes	Low risk	Eleven were lost to follow‐up of subset of 477 and median follow‐up was 15 months.
Free of selective reporting?	Unclear risk	Compares favourably with protocol on www.clinicaltrials.gov but outcomes not clearly reported in the online protocol (possibly due to trial registration on the registry prior to World Health Organization mandatory 20 item minimum dataset criteria for prospective trial registration). We will need to contact investigators to confirm reported outcomes conform to those in protocol.
Free of other bias?	High risk	Stopped early but acceptable statistical stopping rules applied to reduce effects of attrition bias. An O'Brien‐Fleming boundary and the Lan‐DeMets alpha spending function was used to determine whether to terminate the trial early. The results reported here are not free of bias as the analysis of the ART‐naive was post‐hoc and it is possible that other studies may not have conducted similar post‐hoc analysis so there is a threat of publication bias.