Validation of a simplified method for using molecular markers to predict sulfadoxine-pyrimethamine treatment failure in African children with falciparum malaria

Surveillance of molecular markers for key mutations in Plasmodhon falciparton dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) has been proposed as a means of predicting sulfadoxine/pyrimethamine (SP) treatment outcomes in Africa. This study assessed the association between DHFR and DHPS mutations and standardized clinical outcomes in children treated with SP for uncomplicated malaria in Kampala, Uganda. Two mutations (DHFR Asn-108 and Ile-51) were too common to be useful predictors. Three other mutations (DHFR Arg-59, DHPS Gly-437, and DHPS Glu-540) were associated with clinical treatment failure after 14 days, although associations were not significant. When follow-up was extended to 28 days and genotyping was used to distinguish recrudescence from new infections, associations were significantly strengthened. The presence of both the DHFR Arg-59 and DHPS Glu-540 mutations had the strongest association with clinical treatment failure (odds ratio 10.7, P = 0.009). These results support a previously proposed method of predicting clinical outcomes based on the prevalence of these two mutations.