title: High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581.
abstract: BACKGROUND
  Sulphadoxine-pyrimethamine (SP) a widely used treatment for uncomplicated malaria and recommended for intermittent preventive treatment of malaria in pregnancy, is being investigated for intermittent preventive treatment of malaria in infants (IPTi). High levels of drug resistance to SP have been reported from north-eastern Tanzania associated with mutations in parasite genes. This study compared the in vivo efficacy of SP in symptomatic 6-59 month children with uncomplicated malaria and in asymptomatic 2-10 month old infants.
  
  
  RESULTS
  An open label single arm (SP) standard 28 day in vivo WHO antimalarial efficacy protocol was used in 6 to 59 months old symptomatic children and a modified protocol used in 2 to 10 months old asymptomatic infants. Enrolment was stopped early (87 in the symptomatic and 25 in the asymptomatic studies) due to the high failure rate. Molecular markers were examined for recrudescence, re-infection and markers of drug resistance and a review of literature of studies looking for the 581G dhps mutation was carried out. In symptomatic children PCR-corrected early treatment failure was 38.8% (95% CI 26.8-50.8) and total failures by day 28 were 82.2% (95% CI 72.5-92.0). There was no significant difference in treatment failures between asymptomatic and symptomatic children. 96% of samples carried parasites with mutations at codons 51, 59 and 108 in the dhfr gene and 63% carried a double mutation at codons 437 and 540. 55% carried a third mutation with the addition of a mutation at codon 581 in the dhps gene. This triple: triple haplotype maybe associated with earlier treatment failure.
  
  
  CONCLUSIONS
  In northern Tanzania SP is a failed drug for treatment and its utility for prophylaxis is doubtful. The study found a new combination of parasite mutations that maybe associated with increased and earlier failure.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00361114.
authors.affiliation: National Institute for Medical Research, Tanga Centre, Tanga, Tanzania.
authors.forename: Samwel
authors.initials: S
authors.lastname: Gesase
authors.forename: Roly D
authors.initials: RD
authors.lastname: Gosling
authors.forename: Ramadhan
authors.initials: R
authors.lastname: Hashim
authors.forename: Rosalynn
authors.initials: R
authors.lastname: Ord
authors.forename: Inbarani
authors.initials: I
authors.lastname: Naidoo
authors.forename: Rashid
authors.initials: R
authors.lastname: Madebe
authors.forename: Jacklin F
authors.initials: JF
authors.lastname: Mosha
authors.forename: Angel
authors.initials: A
authors.lastname: Joho
authors.forename: Victor
authors.initials: V
authors.lastname: Mandia
authors.forename: Hedwiga
authors.initials: H
authors.lastname: Mrema
authors.forename: Ephraim
authors.initials: E
authors.lastname: Mapunda
authors.forename: Zacharia
authors.initials: Z
authors.lastname: Savael
authors.forename: Martha
authors.initials: M
authors.lastname: Lemnge
authors.forename: Frank W
authors.initials: FW
authors.lastname: Mosha
authors.forename: Brian
authors.initials: B
authors.lastname: Greenwood
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
authors.forename: Daniel
authors.initials: D
authors.lastname: Chandramohan
mesh_terms: D000818:Animals; D002675:Child, Preschool; D003062:Codon; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D017125:Genes, Protozoan / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011739:Pyrimethamine / Q000008:administration & dosage* / Q000494:pharmacology; D013413:Sulfadoxine / Q000008:administration & dosage* / Q000494:pharmacology; D013636:Tanzania; D017211:Treatment Failure
chemical_list: D003062:Codon; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine