Seasonal malaria chemoprevention and the spread of Plasmodium falciparum quintuple-mutant parasites resistant to sulfadoxine–pyrimethamine: a modelling study

Background: Seasonal malaria chemoprevention (SMC) with sulfadoxine–pyrimethamine plus amodiaquine prevents millions of clinical malaria cases in children younger than 5 years in Africa's Sahel region. However, Plasmodium falciparum parasites partially resistant to sulfadoxine–pyrimethamine (with quintuple mutations) potentially threaten the protective effectiveness of SMC. We evaluated the spread of quintuple-mutant parasites and the clinical consequences. Methods: We used an individual-based malaria transmission model with explicit parasite dynamics and drug pharmacological models to identify and quantify the influence of factors driving quintuple-mutant spread and predict the time needed for the mutant to spread from 1% to 50% of inoculations for several SMC deployment strategies. We estimated the impact of this spread on SMC effectiveness against clinical malaria. Findings: Higher transmission intensity, SMC coverage, and expanded age range of chemoprevention promoted mutant spread. When SMC was implemented in a high-transmission setting (40% parasite prevalence in children aged 2–10 years) with four monthly cycles to children aged 3 months to 5 years (with 95% initial coverage declining each cycle), the quintuple mutant required 53·1 years (95% CI 50·5–56·0) to spread from 1% to 50% of inoculations. This time increased in lower-transmission settings and reduced by half when SMC was extended to children aged 3 months to 10 years, or reduced by 10–13 years when an additional monthly cycle of SMC was deployed. For the same setting, the effective reduction in clinical cases in children receiving SMC was 79·0% (95% CI 77·8–80·8) and 60·4% (58·6–62·3) during the months of SMC implementation when the quintuple mutant was absent or fixed in the population, respectively. Interpretation: SMC with sulfadoxine–pyrimethamine plus amodiaquine leads to a relatively slow spread of sulfadoxine–pyrimethamine-resistant quintuple mutants and remains effective at preventing clinical malaria despite the mutant spread. SMC with sulfadoxine–pyrimethamine plus amodiaquine should be considered in seasonal settings where this mutant is already prevalent. Funding: Swiss National Science Foundation and Marie Curie Individual Fellowship.