Weekly Dihydroartemisinin-Piperaquine Versus Monthly Sulphadoxine-Pyrimethamine for Malaria  Chemoprevention in Children with Sickle Cell Anaemia in Uganda and Malawi: A Randomised, Double-Blind, Placebo-Controlled Trial (Chemcha)

Abstract

BackgroundChildren with sickle cell anaemia (SCA) are recommended to receive malaria chemoprevention with monthly sulphadoxine-pyrimethamine or daily proguanil as the standard of care. However, the efficacy of these interventions is threatened by high-grade antifolate resistance and poor adherence. We determined whether malaria chemoprevention with weekly dihydroartemisinin-piperaquine is more effective at preventing clinical malaria in SCA than monthly sulphadoxine-pyrimethamine.MethodsWe conducted an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulphadoxine-pyrimethamine resistance in Uganda and Malawi. Children with SCA aged 6 months to 15 years, weighing ≥5kg were randomised (1:1) by computer-generated block randomisation, stratified by site, to receive either weekly courses of dihydroartemisinin-piperaquine (~2.5/20mg/kg/day) or monthly sulphadoxine-pyrimethamine (~25/1.25mg/kg for 1 day). The primary endpoint was the incidence of clinical malaria. Analysis was by modified intention to treat. Complete case analysis was conducted using negative-binomial regression for count outcomes. The trial is registered with ClinicalTrials.gov (NCT04844099).ResultsBetween April 17, 2021, and May 30, 2022, 725 participants were randomised; 724 contributed to the primary analysis (DP=367, SP=357). The incidence of clinical malaria was 8.8 and 43.7/100 person-years in the dihydroartemisinin-piperaquine and sulphadoxine-pyrimethamine groups, respectively (Incidence Rate Ratio [IRR]=0.20, 95%CI 0.14-0.30, p<0.0001). The number-needed-to-treat to avert one episode was 3. The incidence of hospitalisations with any malaria (10.4 vs 37.0/100 person-years, IRR=0.29 [0.20, 0.42], p<0.0001) and of blood transfusions (52.1 vs 72.5/per 100 person-years, IRR 0.70 [0.54, 0.90], p=0.006) was also lower with weekly dihydroartemisinin-piperaquine. However, children in the dihydroartemisinin-piperaquine group had more clinic visits unrelated to malaria (295 vs 268/100 person-years, IRR=1.12 [1.00, 1.24], p=0.042), and hospitalisations with pneumonia (13.1 vs 6.4/100 person-years, IRR=2.04 [1.23, 3.39], p=0.006), mainly in those 5 years or older (not receiving penicillin prophylaxis) (IRR 2.76 [1.32, 5.77], p=0.007), and less in children aged <5 years who routinely receive penicillin prophylaxis, (IRR=1.48, 0.74-2.96, p=0.2674). The incidence of serious adverse events was similar between the groups. No participant had a QTc value=>480 ms.InterpretationIn areas with high antifolate resistance, malaria chemoprophylaxis with weekly single-day dihydroartemisinin-piperaquine in children with SCA is safe and considerably more efficacious than monthly sulphadoxine-pyrimethamine and could be considered for children <5 years who receive concomitant penicillin. However, monthly sulphadoxine-pyrimethamine was associated with fewer episodes of non-malaria-related illnesses, especially in older children not receiving penicillin prophylaxis, which may reflect its malaria-independent effects. Trials that combine dihydroartemisinin-piperaquine and sulphadoxine-pyrimethamine and/or penicillin-V or other prophylactic antibiotics in older children should be considered.

Keywords: Sickle Cell Anaemia, chemoprevention, malaria, children, dihydroartemisinin-piperaquine, sulphadoxine-pyrimethamine