Pfmdr1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border.
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.
Alker
Alisa P
AP
Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina 27599, USA.
Lim
Pharath
P
Sem
Rithy
R
Shah
Naman K
NK
Yi
Poravuth
P
Bouth
Denis Mey
DM
Tsuyuoka
Reiko
R
Maguire
Jason D
JD
Fandeur
Thierry
T
Ariey
Frederic
F
Wongsrichanalai
Chansuda
C
Meshnick
Steven R
SR
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
D037621:Artemisinins; D000077332:Artesunate; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012717:Sesquiterpenes; C513498:Mdr1 protein, Plasmodium falciparum