Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Young Ugandan Children and Risk of Malaria Following Cessation: A Randomised Controlled Trial

Abstract

Background. Intermittent preventive treatment of malaria (IPT) with dihydroartemisinin-piperaquine (DP) is a promising strategy for malaria prevention in young African children. However, the optimal dosing strategy is unclear and there are conflicting results regarding the risk of malaria following cessation of chemoprevention. Methods. We conducted a double-blind, randomised controlled trial of IPT with DP every 4 weeks versus every 12 weeks in a historically high transmission district of Uganda. Children received study drugs from 8 weeks to 24 months of age and followed to 36 months of age. The primary outcome was the incidence of malaria; secondary outcomes included parasite prevalence. All analyses were modified intention to treat and adjusted for potential confounders (maternal gravidity, maternal parasitemia status at enrollment, and placental malaria). Findings. Between October 2014 and May 2015, 191 children were born, and 183 children reached 8 weeks of age and assigned to receive DP every 4 (n=96) or 12 weeks (n=87) and included in the primary analysis. During the intervention, children receiving DP every 4 weeks had a significantly lower incidence of malaria (adjusted incident rate ratio (aIRR) 0*03, 95% CI 0*01-0*13, p<0*001) and parasite prevalence (0*6% vs 4*9%, p<0*001) compared to children receiving DP every 12 weeks. After stopping IPT, children who previously received DP every 4 weeks had a lower incidence of malaria (aIRR 0*61, 95% CI 0*40-0*93, p=0*02) and parasite prevalence (9*6% vs 14*9%, p=0*004) compared to children who previously received DP every 12 weeks. Both treatment arms were safe and well tolerated. Interpretation. IPT with DP given every 4 weeks was superior to DP given every 12 weeks for the prevention of malaria during childhood, and this protection was extended for up to one year after stopping IPT. This suggests that prevention of malaria with DP in children may enhance immunity against infection. Clinical Trial Number: This trial is registered at ClinicalTrials.gov (NCT02163447). Funding Statement: This study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD059454). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was approved by the ethics committees of Makerere University School of Biomedical Sciences, the Uganda National Council for Science and Technology, and the University of California San Francisco. Written informed consent was provided by all study participants.