title: High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children.
abstract: BACKGROUND
  Drug resistance contributes to the global malaria burden. Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP).
  
  
  METHODS
  The study assessed the frequency of SP resistance-conferring polymorphisms in Plasmodium falciparum-positive samples from two clinical studies in Lambaréné. Their role on treatment responses and transmission potential was studied in an efficacy open-label clinical trial with a 28-day follow-up in 29 children under five with uncomplicated malaria.
  
  
  RESULTS
  SP was well tolerated by all subjects in vivo. Three subjects were excluded from per-protocol analysis. PCR-corrected, 12/26 (46%) achieved an adequate clinical and parasitological response, 13/26 (50%) were late parasitological failures, while 1/26 (4%) had an early treatment failure, resulting in early trial discontinuation. Of 106 isolates, 98 (92%) carried the triple mutant dhfr haplotype. Three point mutations were found in dhps in a variety of haplotypic configurations. The 437G + 540E double mutant allele was found for the first time in Gabon.
  
  
  CONCLUSIONS
  There is a high prevalence of dhfr triple mutant with some dhps point mutations in Gabon, in line with treatment failures observed, and molecular markers of SP resistance should be closely monitored.
authors.affiliation: Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon.
authors.forename: Ghyslain
authors.initials: G
authors.lastname: Mombo-Ngoma
authors.forename: Sunny
authors.initials: S
authors.lastname: Oyakhirome
authors.forename: Rosalynn
authors.initials: R
authors.lastname: Ord
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Gabor
authors.forename: Katja C
authors.initials: KC
authors.lastname: Greutélaers
authors.forename: Katharina
authors.initials: K
authors.lastname: Profanter
authors.forename: Benedikt
authors.initials: B
authors.lastname: Greutélaers
authors.forename: Florian
authors.initials: F
authors.lastname: Kurth
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lell
authors.forename: Jürgen F J
authors.initials: JF
authors.lastname: Kun
authors.forename: Saadou
authors.initials: S
authors.lastname: Issifou
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Martin P
authors.initials: MP
authors.lastname: Grobusch
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000962:Antimalarials / Q000008:administration & dosage*; D002675:Child, Preschool; D004094:Dihydropteroate Synthase; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005681:Gabon; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D020125:Mutation, Missense; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D011110:Polymorphism, Genetic; D015995:Prevalence; D011739:Pyrimethamine / Q000008:administration & dosage*; D013413:Sulfadoxine / Q000008:administration & dosage*; 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