title: Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria.
abstract: Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.
authors.affiliation: Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA. jkublin@medicine.umaryland.edu
authors.forename: James G
authors.initials: JG
authors.lastname: Kublin
authors.forename: Fraction K
authors.initials: FK
authors.lastname: Dzinjalamala
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Kamwendo
authors.forename: Elissa M
authors.initials: EM
authors.lastname: Malkin
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Martino
authors.forename: Rabia A G
authors.initials: RA
authors.lastname: Mukadam
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rogerson
authors.forename: Andres G
authors.initials: AG
authors.lastname: Lescano
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Peter A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: Phillips
authors.initials: P
authors.lastname: Chimpeni
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D003622:Dapsone / Q000008:administration & dosage*; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004311:Double-Blind Method; D004338:Drug Combinations; D024881:Drug Resistance, Bacterial; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D009154:Mutation; D002727:Proguanil / Q000008:administration & dosage* / Q000031:analogs & derivatives; D011446:Prospective Studies; D011739:Pyrimethamine / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D013413:Sulfadoxine / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D017211:Treatment Failure
chemical_list: D000962:Antimalarials; D015415:Biomarkers; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; C007030:chlorproguanil; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D002727:Proguanil; D011739:Pyrimethamine