Sequence variations in the genes encoding dihydropteroate synthase and dihydrofolate reductase and clinical response to sulfadosine-pyrimethamine in patients with acute uncomplicated falciparum malaria

Mutations in dihydropteroate synthase (DHPS) and dihydrofolate reductase (D HFR) are associated with in vitro resistance to sulfadoxine and pyrimethami ne, respectively. The response of 75 patients to sulfadoxine-pyrimethamine was determined, and the genes of the corresponding Plasmodium falciparum is olates were sequenced. Of 12 different unmixed allelic combinations, the tr iple dhfr mutation Asn-108/Arg-59/Ile-51 was observed in all patients respo nding with early treatment failure. Some, but not all, patients with an ade quate clinical response also harbored isolates with the triple dhfr mutatio n. Higher initial parasitemia and fever distinguished these 2 patient group s. The dhps genotype apparently had no influence on the clinical outcome. T he other dhfr alleles with 1 or 2 mutations and the wild-type allele were f ound in patients with an adequate clinical response. The triple dhfr mutati on is one of the gene tic determinants associated with in vivo resistance t o sulfadoxine-pyrimethamine.