Estimating the Impact of DHPS Mutations on Sulfadoxine-Pyrimethamine Protective Efficacy: A Pooled Analysis of Individual Patient Data and Implications for Malaria Chemoprevention in Sub-Saharan Africa

Background: Sulfadoxine-pyrimethamine (SP) is the drug recommended for Perennial Malaria Chemoprevention to prevent malaria in young children in high burden areas. Pyrimethamine resistance associated with the dihydrofolate reductase (dhfr) gene is largely fixed across sub-Saharan Africa. Mutations in the dihydropteroate synthase (dhps) gene (437G/540E/581G) are associated with sulfadoxine resistance, but their effect on the protective efficacy of SP has not been quantified. Methods: We retrospectively analysed time to microscopy and PCR-confirmed re-infection in seven therapeutic efficacy trials from 1,639 participants in 12 malaria-endemic sites, to quantify the duration of SP protection against parasites with different SP resistance genotypes. We use a mathematical model that accounts for variation in transmission intensity and genotype frequencies to estimate the duration of SP protection using Weibull survival models in a Bayesian framework. Results from this model were applied to estimates of genotype frequencies to predict chemoprevention impact. Findings: Across sites, the longest duration of SP protection was >42 days against dhps sulfadoxine-susceptible parasites and 30·3 days (95%CrI:17·1-45·1) against the West-African genotype dhpsGKA (437G-K540-A581). A shorter duration of protection was estimated against parasites with additional mutations in the dhps gene, with 16·5 days (95%CrI:11·2-37·4) protection against parasites with the east-African genotype dhpsGEA (437G-540E-A581) and 11·7 days (95%CrI:8·0-21·9) against highly resistant parasites carrying the dhpsGEG (437G-540E-581G) genotype. Interpretation: The accumulation of dhps mutations is associated with reduced duration of SP protection against Plasmodium falciparum infection. These findings will inform decision-making on where to scale-up SP-based chemoprevention, and whether SP should be combined with other drugs in high-resistance areas.