Second-line tenofovir alafenamide for children with HIV in Africa

Background Children living with HIV have few second-line antiretroviral therapy(ART) options, especially fixed-dose-combinations(FDC). Methods Children from Uganda, Zambia, Zimbabwe were randomised to second-line tenofovir alafenamide(TAF)/emtricitabine(FTC) or standard-of-care(SOC) backbone (abacavir(ABC) or zidovudine(ZDV) with lamivudine(3TC)) in the factorial CHAPAS-4 trial([ISRCTN22964075][1]). The second randomisation (reported elsewhere) was to dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r) or lopinavir(LPV/r) as anchor drug. All drugs were dosed using WHO weight-bands and children <25kg received a new paediatric TAF/FTC(15/120mg) FDC tablet. The primary endpoint was viral load(VL)<400copies/ml at week-96, analysed using logistic regression, hypothesising that TAF/FTC would be non-inferior to SOC (10% margin). Secondary endpoints included safety and immunological outcomes. Analyses were intention-to-treat. Results 919 children 3-15years, 497(54%) male, median[IQR] baseline viral load(VL) 17,573copies/ml [5549-55,700] and CD4 count 669cells/mm3[413-971], spent 99% of time on allocated NRTI backbone. At week-96, 406/454(89.4%) receiving TAF/FTC vs. 378/454(83.3%) receiving SOC had VL<400copies/mL (adjusted difference[95%CI]: 6.3%[2.0%,10.6%], p=0.004), with no evidence that this varied by ABC/3TC or ZDV/3TC SOC. CD4 count improved similarly in both arms. Growth was better with TAF/FTC vs. SOC, without evidence of excess weight-gain with any backbone/anchor drug combination (including DTG +/- TAF/FTC, interaction p=0.51). Bone health parameters were similar between arms, irrespective of anchor drug. One child died (treatment-unrelated); 29(3%) had serious adverse events without differences between arms. Conclusions TAF/FTC was virologically superior to SOC ZDV/3TC or ABC/3TC with a favourable safety profile, irrespective of anchor drug. Development of child-friendly TAF/FTC FDCs (+/- anchor drug) would increase cost-effective ART options for children and reduce drug access gaps between children and adults. ### Competing Interest Statement V Musiime declares membership of DSMB/advisory board: ViiV Health Care. The institution of ASW received funding to support a course on Critical Appraisal. ### Clinical Trial ISRCTN22964075 ### Clinical Protocols ### Funding Statement The CHAPAS-4 Trial is sponsored by University College London (UCL), with central management by the Medical Research Council (MRC) Clinical Trials Unit at UCL supported by MRC core funding (MC\_UU\_00004/03). The main funding for this study is provided by the European and Developing Countries Clinical Trials Partnership. This project is part of the EDCTP programme supported by the European Union (EDCTP; TRIA2015-1078). This publication was produced by CHAPAS-4 which is part of the EDCTP programme supported by the European Union. The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP. Additional funding for the CHAPAS-4 extended follow up was provided by UNIVERSAL project. This project, grant number RIA2019PD- 2882, is part of the EDCTP2 programme supported by the European Union. Additional funding and drug donations were received from Janssen Pharmaceuticals, and Gilead Sciences Inc. Drug donations were also received from Viiv Healthcare and Cipla. Drugs were also purchased from Emcure Pharmaceuticals. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by ethics committees in Uganda (Joint Research Ethics Committee (JREC)), Zambia (University of Zambia Biomedical Research Ethics Committee (UNZABREC)), Zimbabwe (Joint Research Ethics Committee University of Zimbabwe College of Health Sciences (JREC), Research Council Zimbabwe (RCZ)), South Africa (University of Cape Town Human Research Ethics Committee) and United Kingdom (University College London (UCL) Research Ethics Committee). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes MRC CTU at UCL supports a controlled access approach based on completion of a data request proforma available from the corresponding author (mrcctu.ucl.ac.uk/our-research/other-research-policy/data-sharing). [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN22964075