Parasitological efficacy of sulfadoxine-pyrimethamine and amodiaquine for seasonal malaria chemoprevention in Africa

Abstract Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) protects millions of African children, yet the contribution of each drug to preventive efficacy remains unclear. We pooled individual-level data on drug concentrations and malaria infection in 934 children from Uganda (NCT05323721), Mozambique (NCT05186363), and Burkina Faso (NCT05478954). The primary outcome was malaria infection by day 28, and the secondary outcome was the day 28 qPCR cycle threshold value. From natural variation in drug exposure, desethylamodiaquine, the active amodiaquine metabolite, was the primary determinant of malaria infection (OR 0.55, 95% CI 0.44–0.68 per standard deviation increase in log concentration). Children with low day 28 desethylamodiaquine exposure (<24 ng/mL) had nearly twice the risk of malaria infection (RR 1.9, 95% CI 1.5–2.4). Sulfadoxine and pyrimethamine showed only weak associations, consistent across countries despite varying resistance haplotypes. SPAQ efficacy appears primarily amodiaquine-driven and the role of single-dose sulfadoxine–pyrimethamine merits further evaluation.