In vivo selection of plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa

Sisowath, Christin; Petersen, Ines; Veiga, Maria Isabel; Martensson, Andreas; Premji, Zul; Bjorkman, Anders; Fidock, David A.; Gil, José Pedro

http://hdl.handle.net/10400.1/11666

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In Vivo Selection of Plasmodium falciparum Parasites Carrying the Chloroquine-Susceptible pfcrt K76 Allele after Treatment with Artemether-Lumefantrine in Africa.pdf		219.24 KB	Adobe PDF	Download

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Abstract(s)

Background. Artemether-lumefantrine (AL) is a major and highly effective artemisinin-based combination therapy that is becoming increasingly important as a new first-line therapy against Plasmodium falciparum malaria. However, recrudescences occurring after AL treatment have been reported. Identification of drug-specific parasite determinants that contribute to treatment failures will provide important tools for the detection and surveillance of AL resistance. Methods. The findings from a 42-day follow-up efficacy trial in Tanzania that compared AL with sulfadoxine-pyrimethamine (SP) were analyzed to identify candidate markers for lumefantrine tolerance/resistance in the chloroquine resistance transporter gene (pfcrt) and multidrug resistance gene 1 (pfmdr1). The findings were corroborated in vitro with genetically modified isogenic P. falciparum parasite lines. Results. Treatment with AL selected for the chloroquine-susceptible pfcrt K76 allele (P < .0001) and, to a lesser extent, the pfmdr1 N86 (P = .048) allele among recurrent infections. These genotypes were not selected during SP treatment. No pfmdr1 gene amplifications were observed. Isogenic pfcrt-modified parasite lines demonstrated a 2-fold increase in susceptibility to lumefantrine, which was directly attributable to the K76T mutation. Conclusions. Our findings suggest that the pfcrt K76T mutation is a drug-specific contributor to enhanced P. falciparum susceptibility to lumefantrine in vivo and in vitro, and they highlight the benefit of using AL in areas affected by chloroquine-resistant P. falciparum malaria.

Keywords

Antimalarial-Drug-Resistance Transmembrane Protein Pfcrt Pfmdr1 Gene Increased Sensitivity Malaria Mutations Mefloquine Malawi Amodiaquine Artemisinin