In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa.
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.
Sisowath
Christin
C
Infectious Diseases Unit, Department of Medicine and Karolinska Institutet, Stockholm, Sweden.
Petersen
Ines
I
Veiga
M Isabel
MI
Mårtensson
Andreas
A
Premji
Zul
Z
Björkman
Anders
A
Fidock
David A
DA
Gil
José P
JP
D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D002738:Chloroquine / Q000494:pharmacology*; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000627:therapeutic use*; D005449:Fluorenes / Q000627:therapeutic use*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D026901:Membrane Transport Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000627:therapeutic use; D012641:Selection, Genetic; D013413:Sulfadoxine / Q000627:therapeutic use
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D002738:Chloroquine; D011739:Pyrimethamine