LAUSR

Background Children with sickle cell anemia in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. The comparative efficacy of prevention regimens is largely unknown. Methods and Findings We enrolled Kenyan children aged 1-10 years with HbSS in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SPAQ), or monthly dihydroartemisinin/piperaquine (DP). The primary outcome was the cumulative incidence of clinical malaria at 12 months and the main secondary outcome was the cumulative incidence of painful events. Negative-binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated Population. 246 children were randomized to daily Proguanil (n=81), monthly SP-AQ (n=83), or monthly DP (n=82). Overall, 53.3% (n=131) were boys and the mean age was 4.6 +/- 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36-26.14; p=0.39) and DP (IRR: 1.36, 95% CI: 0.21-8.85; p=0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP reduced the rate of dactylitis (IRR: 0.47; 95% CI: 0.23-0.96; p=0.038). The incidence of P. falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17-1.20; p=0.13) but reduced with monthly DP (IRR 0.21; 9 5% CI: 0.08-0.56; p=0.002). Serious adverse events were common and distributed between groups, though more children died receiving monthly SP-AQ (n=7) than Proguanil (2) or DP (1). Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle-cell care is more limited. Conclusions Despite limited malaria transmission, monthly malaria chemoprevention with dihydroartemisinin-piperaquine reduced dactylitis and P. falciparum parasitization in Kenyan children with sickle cell anemia. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted.