Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria.
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.
Kublin
James G
JG
Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA. jkublin@medicine.umaryland.edu
Dzinjalamala
Fraction K
FK
Kamwendo
Deborah D
DD
Malkin
Elissa M
EM
Cortese
Joseph F
JF
Martino
Lisa M
LM
Mukadam
Rabia A G
RA
Rogerson
Stephen J
SJ
Lescano
Andres G
AG
Molyneux
Malcolm E
ME
Winstanley
Peter A
PA
Chimpeni
Phillips
P
Taylor
Terrie E
TE
Plowe
Christopher V
CV
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
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