In Vivo Selection of Plasmodium falciparum Parasites Carrying the Chloroquine-Susceptible pfcrt K76 Allele after Treatment with Artemether-Lumefantrine in Africa

作者：Sisowath Christin^*; Petersen Ines; Veiga M Isabel; Martensson Andreas; Premji Zul; Bjorkman Anders; Fidock David A; Gil Jose P

来源：Journal of Infectious Diseases, 2009, 199(5): 750-757.

DOI：10.1086/596738

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.

• 出版日期2009-3-1