www.thelancet.com/hiv Published online January 15, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30003-1 1 Articles Which HIV-infected adults with high CD4 T-cell counts benefit most from immediate initiation of antiretroviral therapy? A post-hoc subgroup analysis of the START trial Jean-Michel Molina, Birgit Grund, Fred Gordin, Ian Williams, Mauro Schechter, Marcello Losso, Matthew Law, Ernest Ekong, Noluthando Mwelase, Athanasios Skoutelis, Martin J Wiselka, Linos Vandekerckhove, Thomas Benfield, David Munroe, Jens D Lundgren, James D Neaton, for the INSIGHT START study group Summary Background Immediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per µL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would beneft most from immediate treatment. Methods The START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per µL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per µL. The primary endpoint of the study was serious AIDS-defning illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecifed in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutof points, unless diferent cutofs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048. Findings Between April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across fve continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48–1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89–208). Signifcant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher. Interpretation Asymptomatic, ART-naive adults with CD4 counts higher than 500 cells per µL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load beneft most from immediate initiation of ART and should be prioritised for treatment. Funding US National Institute of Allergy and Infectious Diseases. Introduction The Strategic Timing of AntiRetroviral Treatment (START) trial was designed to establish the risks, benefts, and appropriate timing of initiation of antiretroviral therapy (ART) in asymptomatic, HIV-positive individuals with CD4 counts greater than 500 cells per µL. 1 This international trial showed that immediate initiation of treatment reduced the risk of serious AIDS, serious non- AIDS conditions, and death by 57% compared with deferral of therapy until CD4 counts were lower than 350 cells per µL or AIDS had developed. These fndings have led to rapid changes in international guidelines, which now recommend immediate ART for people with HIV regardless of CD4 cell count. 1–4 The clinical beneft of immediate ART was also confrmed in a randomised trial done in CÔte d’Ivoire. 5 In addition to reducing morbidity and mortality, ART substantially reduces infectivity, an important public health beneft. 6,7 In the START trial, 1 hazard ratios for the primary outcome were similar across subgroups formed by demographic and clinical baseline characteristics, with the same relative benefts seen with early treatment initiation. By contrast, event rates difered between subgroups. Given similar relative risk reductions, individuals at higher absolute risk would beneft more from immediate ART than individuals at lower absolute Lancet HIV 2018 Published Online January 15, 2018 http://dx.doi.org/10.1016/ S2352-3018(18)30003-1 See Online/Comment http://dx.doi.org/10.1016/ S2352-3018(18)30004-3 University of Paris Diderot, Sorbonne Paris Cité, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS), Paris, France (Prof J-M Molina MD); School of Statistics (B Grund PhD) and School of Public Health (Prof J D Neaton PhD), University of Minnesota, Minneapolis, MN, USA; Washington Veterans Affairs Medical Center, George Washington University, Washington, DC, USA (Prof F Gordin MD); University College London Medical School, London, UK (Prof I Williams MD); Projeto Praça Onze, Universidade Federal do Rio de Janeiro, Brazil (Prof M Schechter MD); Hospital General de Agudos JM Ramos, Buenos Aeres, Argentina (Prof M Losso MD); Kirby Institute, University of New South Wales, Sydney, NSW, Australia (M Law PhD); Institute of Human Virology, Abuja, Nigeria (E Ekong MD); Department of Medicine, University of Witwatersrand, Johannesburg, South Africa (Prof N Mwelase MD); Evanlegismos General Hospital, Athens, Greece (Prof A Skoutelis MD); Leicester Royal Infirmary, Leicester, UK (M J Wiselka MD); Universitaire Ziekenhuizen Gent, Ghent, Belgium (Prof L Vandekerckhove MD); Hvidovre Hospital (Prof T Benfield MD) and Rigshospitalet