title: Pfmdr1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border.
abstract: Artemisinin combination therapies (ACTs) have recently been adopted as first-line therapy for Plasmodium falciparum infections in most malaria-endemic countries. In this study, we estimated the association between artesunate-mefloquine therapy failure and genetic changes in the putative transporter, pfmdr1. Blood samples were acquired from 80 patients enrolled in an 2004 in vivo efficacy study in Pailin, Cambodia, and genotyped for pfmdr1 copy number and haplotype. Having parasites with three or more copies of pfmdr1 before treatment was strongly associated with recrudescence (hazard ratio [HR] = 8.30; 95% CI: 2.60-26.43). This relationship was maintained when controlling for initial parasite density and hematocrit (HR = 7.91; 95% CI: 2.38-26.29). Artesunate-mefloquine treatment selected for increased pfmdr1 copy number, because isolates from recurrent episodes had higher copy numbers than the paired enrollment samples (Wilcoxon rank test, P = 0.040). pfmdr1 copy number should be evaluated further as a surveillance tool for artesunate-mefloquine resistance in Cambodia.
authors.affiliation: Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina 27599, USA.
authors.forename: Alisa P
authors.initials: AP
authors.lastname: Alker
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.forename: Rithy
authors.initials: R
authors.lastname: Sem
authors.forename: Naman K
authors.initials: NK
authors.lastname: Shah
authors.forename: Poravuth
authors.initials: P
authors.lastname: Yi
authors.forename: Denis Mey
authors.initials: DM
authors.lastname: Bouth
authors.forename: Reiko
authors.initials: R
authors.lastname: Tsuyuoka
authors.forename: Jason D
authors.initials: JD
authors.lastname: Maguire
authors.forename: Thierry
authors.initials: T
authors.lastname: Fandeur
authors.forename: Frederic
authors.initials: F
authors.lastname: Ariey
authors.forename: Chansuda
authors.initials: C
authors.lastname: Wongsrichanalai
authors.forename: Steven R
authors.initials: SR
authors.lastname: Meshnick
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D002160:Cambodia / Q000453:epidemiology; D002648:Child; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology*; D008297:Male; D015767:Mefloquine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013785:Thailand / Q000453:epidemiology
chemical_list: D037621:Artemisinins; D000077332:Artesunate; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012717:Sesquiterpenes; C513498:Mdr1 protein, Plasmodium falciparum