title: Therapeutic efficacy of sulfadoxine-pyrimethamine and prevalence of resistance markers in Tanzania prior to revision of malaria treatment policy: Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase mutations in monitoring in vivo resistance.
abstract: Prior to the 2001 malarial treatment policy change in Tanzania, we conducted trials to assess the efficacy of sulfadoxine-pyrimethamine (SP) and the usefulness of molecular markers in monitoring resistance. A total of 383 uncomplicated Plasmodium falciparum malaria patients (between 6 and 59 months old) were treated with SP and their responses were assessed. Mutations in the P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes in admission day blood samples were analyzed. Results indicated that 85.6% of the patients showed an adequate clinical response, 9.7% an early treatment failure, and 4.7% a late treatment failure. The quintuple mutant genotype (pfdhfr 51 Ile, 59 Arg, and 108 Asn and pfdhps 437 Gly and 540 Glu) showed an association with treatment outcome (odds ratio = 2.1; 95% confidence interval = 0.94-4.48, P = 0.045). The prevalence of the triple pfdhfr mutant genotype (51 Ile, 59 Arg, and 108 Asn) at a site of high SP resistance (23.6%) was four times higher compared with that observed at sites of moderate SP resistance (6.8-14.4%) (P = 0.000001). The genotype failure index calculated by using this marker was invariable (1.96-2.1) at sites with moderate SP resistance, but varied (3.4) at a site of high SP resistance. In conclusion, our clinical and molecular findings suggest that SP may have a short useful therapeutic life in Tanzania; thus, its adoption as an interim first-line antimalarial drug. The findings also point to the potential of the triple pfdhfr mutant genotype as an early warning tool for increasing SP resistance. These data form the baseline SP efficacy and molecular markers profile in Tanzania prior to the policy change.
authors.affiliation: Ifakara Health Research and Development Centre, Ifakara, Tanzania. Kmugittu@ifakara.mimcom.net
authors.forename: Kefas
authors.initials: K
authors.lastname: Mugittu
authors.forename: Modesta
authors.initials: M
authors.lastname: Ndejembi
authors.forename: Allen
authors.initials: A
authors.lastname: Malisa
authors.forename: Martha
authors.initials: M
authors.lastname: Lemnge
authors.forename: Zulfikar
authors.initials: Z
authors.lastname: Premji
authors.forename: Alex
authors.initials: A
authors.lastname: Mwita
authors.forename: Watoky
authors.initials: W
authors.lastname: Nkya
authors.forename: Johannes
authors.initials: J
authors.lastname: Kataraihya
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.forename: Hassan
authors.initials: H
authors.lastname: Mshinda
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005819:Genetic Markers; D005838:Genotype; D006291:Health Policy; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013636:Tanzania; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D005819:Genetic Markers; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine