title: Validation of a simplified method for using molecular markers to predict sulfadoxine-pyrimethamine treatment failure in African children with falciparum malaria.
abstract: Surveillance of molecular markers for key mutations in Plasmodium falciparum 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.
authors: Department of Biochemistry, Makerere University Medical School, Kampala, Uganda.
authors: Daniel
authors: D
authors: Kyabayinze
authors: Adithya
authors: A
authors: Cattamanchi
authors: Moses R
authors: MR
authors: Kamya
authors: Philip J
authors: PJ
authors: Rosenthal
authors: Grant
authors: G
authors: Dorsey
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers; D002675:Child, Preschool; D017931:DNA Primers; D016054:DNA, Protozoan / Q000032:analysis; D004094:Dihydropteroate Synthase / Q000235:genetics; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology*; D008297:Male; D009154:Mutation; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000592:standards*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D011159:Population Surveillance / Q000379:methods; D015995:Prevalence; D011379:Prognosis; D011739:Pyrimethamine / Q000008:administration & dosage / Q000494:pharmacology*; D015203:Reproducibility of Results; D013413:Sulfadoxine / Q000008:administration & dosage / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D017211:Treatment Failure; D014454:Uganda / Q000453:epidemiology
chemical_list: D000962:Antimalarials; D015415:Biomarkers; D017931:DNA Primers; D016054:DNA, Protozoan; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine