Chemoprevention for malaria with monthly intermittent preventive treatment with dihydroartemisinin-piperaquine in pregnant women living with HIV on daily co-trimoxazole in Kenya and Malawi: a randomised, double-blind, placebo-controlled trial.

"Declaration of interests We declare no competing interests."

"AcknowledgmentsThis study received financial support from the European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) programme under Horizon 2020; the UK Joint Global Health Trials (JGHT), funded by the Medical Research Council, the UK Foreign, Commonwealth and Development Office, the National Institute for Health Research, and the Wellcome Trust (grant number TRIA-2015-1076b-IMPROVE-2) to the Liverpool School of Tropical Medicine; and the Swedish International Development Cooperation Agency. We are grateful to Montserrat Blázquez-Domingo from EDCTP2 for her support in managing the grant on behalf of EDCTP2 and JGHT. D'Artepp was provided free of charge by Fosun Pharma, Shanghai, China. We thank all the study participants and the research assistants who did the study. We are grateful to the members of the Trial Steering Committee (Laurence [Larry] Slutsker, Matthew Cairns, Miriam Laufer, Grant Dorsey, and Per Ashorn) and the Data Safety and Monitoring Board (DSMB; Andy Stergachis, Kathleen Wannemuehler, Steve Taylor, William [Billy] Ngasala, Ib Christian Bygbjerg, and Christian Funck-Brentano) for their expertise and guidance in conducting the trial and independent review of the safety data, study protocol, and statistical analysis plan. We are very thankful to Tracy Seddon, Helen Wong, and Katie Davies in Liverpool, UK, Benta Kamire, Sheila Nyarinda, and Josephine Owade in Kisumu, Kenya, and Zainab Longwe, Jones Chakholoma, and Palinji Mungoni in Malawi for their excellent managerial and administrative support. We want to thank the staff from the Global Health Trials Unit at the Liverpool School of Tropical Medicine for trial management and pharmacovigilance support. We are also grateful to the directors of Ahero sub-County Hospital, Rabuor sub-County Hospital, and Akala Health Centre in Siaya for accommodating the study in Kenya, and the directors and staff of Mpemba, Madziabango, and Zomba District Health Offices for accommodating the study in Malawi. We are grateful to Gerald Yonga in Kenya for supporting the cardiac monitoring component and to Fredrick Omiti, Michael Asembo, and Emily Adoyo for supporting site coordination and community engagement in Kenya. We thank Atusaye Ngwira in Malawi, and Henry Aura and Micah June in Kenya for technical support and internal monitoring, John Chabuka and John Lino for external monitoring, and Bernard Owino and Martina Oneko for safety monitoring. We would also like to thank Tao Chen for supporting the DSMB as the independent statistician with access to the study code and Tony Sang, the lead pharmacist, for support with the preparations of study drugs. This study is published with the permission of the Director, Kenya Medical Research Institute. The Liverpool School of Tropical Medicine was the sponsor. The findings and conclusions in this publication are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention or the US Department of Health and Human Services."

"The study was designed to achieve 80% power to detect a 50% reduction in the cumulative incidence of Plasmodium infection from 12% in the co-trimoxazole plus placebo group to 6% in the co-trimoxazole plus dihydroartemisinin–piperaquine group (risk ratio [RR] 0·50, two-sided α=0·05), which required 898 participants (449 per group), allowing for 20% loss to follow-up. Log-binomial regression was used for dichotomous endpoints to obtain RRs and corresponding 95% CIs and modified Poisson regression in case of non-convergence (). Linear regression was used for continuous outcomes, and results were expressed as mean difference and 95% CIs. Poisson regression with a log-link function and follow-up time as an offset was used for count variables to obtain incidence rate ratios (IRRs) and 95% CIs and incidence rate difference. The number needed to treat to avert one event was calculated as the inverse of the incidence rate difference per 15·5 weeks (the average duration of follow-up; ). The unadjusted (crude) analysis was the primary analysis and included the stratification factors of study site and HIV status (known positive and newly diagnosed) in all models. Secondary, covariate-adjusted analyses were done using several other prespecified baseline covariates in addition to HIV status and site, including gravidity, malaria status, socioeconomic status, season (average rainfall in the last 6 months before delivery), and malaria transmission intensity by study site (based on the prevalence of malaria at enrolment, continuous; ). Subgroup analyses included baseline covariates and gestational age at enrolment, country, and number of IPTp courses received (). Post-hoc analyses assessed mean haemoglobin concentration at delivery or in the third trimester (haemoglobin at delivery was used if assessed before the onset of birth, and otherwise the haemoglobin measurement from the third trimester was used). Missing covariates were imputed using simple imputation. A two-sided p value less than 0·05 was used to define statistical significance. P values and the widths of the CIs for the primary and secondary endpoints have not been adjusted for multiplicity, so the values should not be used to infer definitive treatment effects. The modified intention-to-treat (ITT) population (ie, all randomly assigned eligible participants with endpoint data) was used for primary or secondary analyses. A sensitivity analysis was done using non-responder imputation to assess the impact of attrition bias. The per-protocol population included participants who attended every scheduled visit, took all scheduled IPTp courses, did not use prohibited medication, and contributed to the endpoint. For the safety analysis, women were included if they received at least one dose of study drug. All analyses were prespecified (unless otherwise indicated as post hoc) in a statistical analysis plan approved by the data and safety monitoring board. Statistical analyses were done with Stata version 17. This trial is registered with ClinicalTrials.gov, NCT04158713. Methods: We did an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulfadoxine–pyrimethamine resistance in Kenya and Malawi. Pregnant women living with HIV on dolutegravir-based combination antiretroviral therapy (cART) who had singleton pregnancies between 16 weeks' and 28 weeks' gestation were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and HIV status (known positive vs newly diagnosed), to daily co-trimoxazole plus monthly dihydroartemisinin–piperaquine (three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine given daily for 3 days) or daily co-trimoxazole plus monthly placebo. Daily co-trimoxazole consisted of one tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim. The primary endpoint was the incidence of Plasmodium infection detected in the peripheral (maternal) or placental (maternal) blood or tissue by PCR, microscopy, rapid diagnostic test, or placental histology (active infection) from 2 weeks after the first dose of dihydroartemisinin–piperaquine or placebo to delivery. Log-binomial regression was used for binary outcomes, and Poisson regression for count outcomes. The primary analysis was by modified intention to treat, consisting of all randomised eligible participants with primary endpoint data. The safety analysis included all women who received at least one dose of study drug. All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, NCT04158713."