PMID- 29150377 OWN - NLM STAT- MEDLINE DCOM- 20180919 LR - 20230812 IS - 2352-3018 (Electronic) IS - 2405-4704 (Print) IS - 2352-3018 (Linking) VI - 5 IP - 1 DP - 2018 Jan TI - Urgent versus post-stabilisation antiretroviral treatment in hospitalised HIV-infected children in Kenya (PUSH): a randomised controlled trial. PG - e12-e22 LID - S2352-3018(17)30167-4 [pii] LID - 10.1016/S2352-3018(17)30167-4 [doi] AB - 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. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Njuguna, Irene N AU - Njuguna IN AD - Kenyatta National Hospital, Nairobi, Kenya; Department of Epidemiology, University of Washington, Seattle, WA, USA. Electronic address: irenen@uw.edu. FAU - Cranmer, Lisa M AU - Cranmer LM AD - Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA. FAU - Otieno, Vincent O AU - Otieno VO AD - Kenya Medical Research Institute, Kisumu, Kenya. FAU - Mugo, Cyrus AU - Mugo C AD - Department of Pediatrics and Child Health, University of Nairobi, Nairobi, Kenya. FAU - Okinyi, Hellen M AU - Okinyi HM AD - Department of Pediatrics and Child Health, University of Nairobi, Nairobi, Kenya. FAU - Benki-Nugent, Sarah AU - Benki-Nugent S AD - Department of Global Health, University of Washington, Seattle, WA, USA. FAU - Richardson, Barbra AU - Richardson B AD - Department of Global Health, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA. FAU - Stern, Joshua AU - Stern J AD - Department of Biostatistics, University of Washington, Seattle, WA, USA. FAU - Maleche-Obimbo, Elizabeth AU - Maleche-Obimbo E AD - Department of Pediatrics and Child Health, University of Nairobi, Nairobi, Kenya. FAU - Wamalwa, Dalton C AU - Wamalwa DC AD - Department of Pediatrics and Child Health, University of Nairobi, Nairobi, Kenya. FAU - John-Stewart, Grace C AU - John-Stewart GC AD - Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA. LA - eng SI - ClinicalTrials.gov/NCT02063880 GR - K12 HD000850/HD/NICHD NIH HHS/United States GR - K24 HD054314/HD/NICHD NIH HHS/United States GR - R01 HD023412/HD/NICHD NIH HHS/United States GR - UL1 TR002319/TR/NCATS NIH HHS/United States GR - P30 AI027757/AI/NIAID NIH HHS/United States GR - D43 TW009783/TW/FIC NIH HHS/United States GR - UL1 TR000423/TR/NCATS NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural DEP - 20171114 PL - Netherlands TA - Lancet HIV JT - The lancet. HIV JID - 101645355 RN - 0 (Anti-Retroviral Agents) SB - IM CIN - Lancet HIV. 2018 Jan;5(1):e2-e3. PMID: 29150376 MH - Anti-Retroviral Agents/adverse effects/*therapeutic use MH - Child MH - Child, Preschool MH - Female MH - HIV Infections/*drug therapy/*mortality MH - Hospitalization MH - Humans MH - Infant MH - Infant, Newborn MH - Intention to Treat Analysis MH - Male MH - Survival Analysis MH - Treatment Outcome PMC - PMC5777310 MID - NIHMS922380 COIS- Declaration of interests Dr. Richardson reports grants from NIH, during the conduct of the study; personal fees from Tobira Therapeutics, Inc, personal fees from Theratechnologies, Inc., outside the submitted work. Joshua Stern reports grants from CFAR, during the conduct of the study; personal fees from University of Washington, outside the submitted work. Dr. John-Stewart reports grants from NIH, non-financial support from UW, during the conduct of the study; grants from NIH, grants from CDC, grants from Thrasher Foundation, other from UpToDate, personal fees from IMPAACT, other from NIH, outside the submitted work. Other authors have no conflicts of interest to disclose. LMC reports grants from NIH, American Academy of Pediatrics, and American Pediatric Society during the conduct of the study; grants from Firland foundation, Seattle Children's Center for Clinical and Translational Research and Emory Univerity pediatric Research Center, outside the submitted work. EDAT- 2017/11/19 06:00 MHDA- 2018/09/20 06:00 PMCR- 2019/01/01 CRDT- 2017/11/19 06:00 PHST- 2017/05/17 00:00 [received] PHST- 2017/08/30 00:00 [revised] PHST- 2017/09/04 00:00 [accepted] PHST- 2017/11/19 06:00 [pubmed] PHST- 2018/09/20 06:00 [medline] PHST- 2017/11/19 06:00 [entrez] PHST- 2019/01/01 00:00 [pmc-release] AID - S2352-3018(17)30167-4 [pii] AID - 10.1016/S2352-3018(17)30167-4 [doi] PST - ppublish SO - Lancet HIV. 2018 Jan;5(1):e12-e22. doi: 10.1016/S2352-3018(17)30167-4. Epub 2017 Nov 14.