title: Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine: mutations in pvdhfr and pvmdr1.
abstract: BACKGROUND
  Molecular markers for sulfadoxine-pyrimethamine (SP) resistance in Plasmodium vivax have been reported. However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce.
  
  
  METHODS
  We assessed pvdhfr (F57L/I, S58R, T61M, S117T/N, and I173F/L) and pvmdr1 (Y976F and F1076L) mutations in 94 patients who received amodiaquine (AQ) plus SP in Papua New Guinea (PNG). We then investigated the association between parasite genotype and treatment response.
  
  
  RESULTS
  The treatment failure (TF) rate reached 13%. Polymorphisms in pvdhfr F57L, S58R, T61M, and S117T/N and in pvmdr1 Y976F were detected in 60%, 67%, 20%, 40%, and 39% of the samples, respectively. The single mutant pvdhfr 57 showed the strongest association with TF (odds ratio [OR], 9.04; P= .01). The combined presence of the quadruple mutant pvdhfr 57L+58R+61M+117T and pvmdr1 mutation 976F was the best predictor of TF (OR, 8.56; P= .01). The difference in TF rates between sites was reflected in the genetic drug-resistance profile of the respective parasites.
  
  
  CONCLUSIONS
  The present study identified a new molecular marker in pvmdr1 that is associated with the in vivo response to AQ+SP. We suggest suitable marker sets with which to monitor P. vivax resistance against AQ+SP in countries where these drugs are used.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland.
authors.forename: Jutta
authors.initials: J
authors.lastname: Marfurt
authors.forename: Frédérique
authors.initials: F
authors.lastname: de Monbrison
authors.forename: Sara
authors.initials: S
authors.lastname: Brega
authors.forename: Laetitia
authors.initials: L
authors.lastname: Barbollat
authors.forename: Ivo
authors.initials: I
authors.lastname: Müller
authors.forename: Albert
authors.initials: A
authors.lastname: Sie
authors.forename: Mary
authors.initials: M
authors.lastname: Goroti
authors.forename: John C
authors.initials: JC
authors.lastname: Reeder
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.forename: Stéphane
authors.initials: S
authors.lastname: Picot
authors.forename: Blaise
authors.initials: B
authors.lastname: Genton
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000655:Amodiaquine / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002675:Child, Preschool; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D016780:Malaria, Vivax / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D020125:Mutation, Missense; D010219:Papua New Guinea; D010966:Plasmodium vivax / Q000187:drug effects* / Q000235:genetics; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D004338:Drug Combinations; D005819:Genetic Markers; D015800:Protozoan Proteins; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine