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

Abstract

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.

• Authors: Christin Sisowath, Ines Petersen, M Isabel Veiga, Andreas Mårtensson, Zul Premji, Anders Björkman, David A Fidock, José P Gil
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 199 Issue 5 Pg. 750-7 (Mar 01 2009) ISSN: 0022-1899 [Print] United States
• PMID: 19210165 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Artemether, Lumefantrine Drug Combination
• Artemisinins
• Drug Combinations
• Ethanolamines
• Fluorenes
• Membrane Transport Proteins
• PfCRT protein, Plasmodium falciparum
• Protozoan Proteins
• fanasil, pyrimethamine drug combination
• Sulfadoxine
• Chloroquine
• Pyrimethamine

Topics

• Alleles
• Animals
• Antimalarials (pharmacology, therapeutic use)
• Artemether, Lumefantrine Drug Combination
• Artemisinins (therapeutic use)
• Child
• Chloroquine (pharmacology)
• Drug Combinations
• Drug Resistance
• Ethanolamines (therapeutic use)
• Fluorenes (therapeutic use)
• Humans
• Malaria, Falciparum (drug therapy)
• Membrane Transport Proteins (genetics)
• Plasmodium falciparum (drug effects, genetics)
• Protozoan Proteins (genetics)
• Pyrimethamine (therapeutic use)
• Selection, Genetic
• Sulfadoxine (therapeutic use)