CHAPAS-4 trial: second-line anchor drugs for children with HIV in Africa

Background Children living with HIV requiring second-line antiretroviral therapy (ART) have limited options, an unmet need considering children require life-long ART. Methods Children from Uganda, Zambia, Zimbabwe were randomised to one of four second-line anchor drugs: dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r), or lopinavir(LPV/r) in the factorial CHAPAS-4 trial([ISRCTN22964075][1])(second randomisation to tenofovir alafenamide fumarate(TAF) or standard-of-care(SOC) backbone, reported elsewhere). Dosing followed WHO weight-bands. The primary endpoint was viral load(VL) <400copies/mL at week-96, analysed using logistic regression, hypothesising that DTG and DRV/r would be superior (threshold p=0.03) to LPV/r and ATV/r arms combined and ATV/r would be non-inferior to LPV/r (12% margin). Secondary endpoints included immunology and safety. Analyses were intention-to-treat. Results 919 children, median(IQR) age 10(8-13) years, 54% male, baseline VL 17,573(5549,55700) copies/mL, CD4 669(413, 971) cells/mm3, weight-for-age Z-score -1.6(-2.4,-0.9), had spent median(IQR) 5.6(3.3,7.8) years on first-line ART. At week-96, DTG was superior (by 9.7%(95% CI 4.8%, 14.5%); p<0.0001) and DRV/r showed a trend to superiority (by 5.6%(0.3%, 11.0%); p=0.04) compared to LPV/r and ATV/r arms combined. ATV/r was non-inferior to LPV/r (+3.4%(-3.4%,+10.2%); p=0.33). CD4 counts increased with no differences between arms. Toxicity was lowest with DTG. All arms except LPV/r showed age-appropriate weight/height gains at week-96. DTG was not associated with excess absolute weight-gain (<1kg) vs. DRV/r or ATZ/r, irrespective of backbone randomisation. Conclusions DTG-based regimens are safe and cost-effective for second-line ART. DRV/r and ATV/r are also good options. Fixed-dose combinations of DTG, DRV/r or ATV/r with nucleoside/nucleotide-reverse-transcriptase-inhibitors (NRTIs) would increase access to robust, essential second-line options for children. ### 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