title: Plasmodium falciparum dhfr but not dhps mutations associated with sulphadoxine-pyrimethamine treatment failure and gametocyte carriage in northern Ghana.
abstract: Both use of sulphadoxine-pyrimethamine (SP) and SP-resistance of Plasmodium falciparum are increasing in sub-Saharan Africa. Mutations in the P. falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes can predict treatment failure of SP, however, the degree of this relationship varies regionally. In northern Ghana, pre-treatment dhfr/dhps genotypes were examined in 126 children and associations with PCR-corrected SP treatment outcome and gametocyte carriage were analysed. SP treatment failure within 4 weeks of follow-up occurred in 28%. Among all pre-treatment isolates, the dhfr triple mutation (Ile-51 + Arg-59 + Asn-108) was detected in 47%. Compared with dhfr wildtype parasites, the presence of the dhfr triple mutation increased the risk of treatment failure tenfold. Likewise, parasite clearance was delayed in the presence of dhfr variants. Dhfr mutants and dhps Gly-437 were selected in treatment failure isolates. Gametocytaemia 1 week following treatment was strongly associated with dhfr mutations. Remarkably, this was also true for the prevalence of gametocytes at recruitment. Dhps alleles did neither influence treatment outcome nor gametocyte carriage. In northern Ghana, the prevalence of the dhfr triple mutation can be used as a tool to screen for and to monitor SP resistance. The lack of association between dhps alleles and SP treatment outcome suggests a minor role of these molecular markers in this region at present.
authors.affiliation: Institute of Tropical Medicine, Charité-University Medicine Berlin, Berlin, Germany. frank.mockenhaupt@charite.de
authors.forename: Frank P
authors.initials: FP
authors.lastname: Mockenhaupt
authors.forename: J
authors.initials: J
authors.lastname: Teun Bousema
authors.forename: Teunis A
authors.initials: TA
authors.lastname: Eggelte
authors.forename: Jonas
authors.initials: J
authors.lastname: Schreiber
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehrhardt
authors.forename: Nasstasja
authors.initials: N
authors.lastname: Wassilew
authors.forename: Rowland N
authors.initials: RN
authors.lastname: Otchwemah
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bienzle
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D018512:Parasitemia / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D010963:Plasmodium falciparum / Q000235:genetics*; D015995:Prevalence; D011739:Pyrimethamine / Q000627:therapeutic use*; D018570:Risk Assessment / Q000379:methods; D013413:Sulfadoxine / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D017211:Treatment Failure
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine