Sequence Variations in the Genes Encoding Dihydropteroate Synthase and Dihydrofolate Reductase and Clinical Response to Sulfadoxine‐Pyrimethamine in Patients with Acute Uncomplicated Falciparum Malaria

Leonardo K. Basco, Rachida Tahar, Annick Keundjian, Pascal Ringwald
2000 Journal of Infectious Diseases  
Mutations in dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) are associated with in vitro resistance to sulfadoxine and pyrimethamine, respectively. The response of 75 patients to sulfadoxine-pyrimethamine was determined, and the genes of the corresponding Plasmodium falciparum isolates were sequenced. Of 12 different unmixed allelic combinations, the triple dhfr mutation Asn-108/Arg-59/Ile-51 was observed in all patients responding with early treatment failure. Some, but not
more » ... all, patients with an adequate clinical response also harbored isolates with the triple dhfr mutation. Higher initial parasitemia and fever distinguished these 2 patient groups. The dhps genotype apparently had no influence on the clinical outcome. The other dhfr alleles with 1 or 2 mutations and the wild-type allele were found in patients with an adequate clinical response. The triple dhfr mutation is one of the genetic determinants associated with in vivo resistance to sulfadoxine-pyrimethamine. Since the rapid spread of chloroquine resistance in Asia and South America in the 1960s and 1970s, sulfadoxine-pyrimethamine has been one of the most important second-line drugs for the treatment of chloroquine-resistant Plasmodium falciparum infections [1]. The extensive use of sulfadoxine-pyrimethamine has led to the selection of resistant strains and declining efficacy to the point that this drug is no longer recommended in some areas endemic for the disease. In Africa, chloroquine resistance emerged much later than in other endemic areas. Chloroquine is still the first-line drug in central and West Africa, and sulfadoxine-pyrimethamine usually is re-
doi:10.1086/315731 pmid:10915101 fatcat:be2nslewhnbg7azi5aiwehyy5q