Background Urgent antiretroviral therapy (ART) among hospitalised HIV-infected children might accelerate recovery or worsen outcomes associated with immune reconstitution. We aimed to compare urgent versus post-stabilisation ART among hospitalised HIV-infected children in Kenya. Methods In this unmasked randomised controlled trial, we randomly assigned (1:1) HIV-infected, ART-naive children aged 0–12 years who were eligible for treatment to receive ART within 48 h (urgent group) or in 7–14 days (post-stabilisation group) at four hospitals in Kenya (two in Nairobi and two in western Kenya). We excluded children with suspected or confirmed CNS infection. A statistician not involved in study procedures did block randomisation with variable block sizes generated using STATA version 12. We followed children for 6 months for primary outcomes: mortality, drug toxicity, and immune reconstitution inflammatory syndrome (IRIS). We did all analyses in a modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02063880. Findings We began enrolment on April 24, 2013, and completed follow-up on Nov 17, 2015. We enrolled 191 (76%) of 250 hospitalised HIV-infected children. Of these, 183 children were randomly assigned: 90 to urgent ART and 93 to post-stabilisation ART. 181 (99%) of 183 children were included in the modified intention-to-treat analysis. Median age was 1·9 years (IQR 0·8–4·8). Baseline sociodemographic, clinical, and virological characteristics did not differ between groups except median CD4 cell percentage, which was lower in the urgent group (13% [IQR 9–18] vs 17% [IQR 9–24]; p=0·052). Of 181 admission diagnoses, 118 (65%) were pneumonia, 58 (32%) malnutrition, and 27 (15%) suspected tuberculosis. Median time to ART was 1 day (IQR 1–1) in the urgent group and 8 days (IQR 7–11) in the post-stabilisation group. Overall, mortality risk at 6 months was 61 per 100 person-years. Mortality risk did not differ by group (70 per 100 person-years in the urgent group vs 54 per 100 person-years in the post-stabilisation group; hazard ratio [HR] 1·26, 95% CI 0·67–2·37) p=0.47, even after adjusting for baseline CD4 cell percentage (adjusted HR 1·30, 95% CI 0·69–2·45; p=0·41). The incidence of IRIS, and drug toxicity was not significantly different between trial arms. There were no differences between treatment groups in the proportion of grade 3 or 4 adverse events (34 [38%] of 90 children in the urgent group vs 40 [44%] of 91 children in the post-stabilisation group; p=0·40) or the proportion of any change in ART regimen (five [7%] vs six [8%]; p=0·79). We discontinued randomisation at interim review when the futility boundary was crossed. Interpretation Early mortality risk was extremely high among hospitalised HIV-infected children. Urgent ART did not improve survival. Funding National Institute of Child Health and Human Development, National Institutes of Health, USA.
