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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa
Journal of Infectious Diseases, Volume 199, No. 5, Year 2009
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Description
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 sulfadoxinepyrimethamine (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. © 2009 by the Infectious Diseases Society of America. All rights reserved.
Authors & Co-Authors
Sisowath, Christin
Sweden, Stockholm
Karolinska Institutet
Sweden, Stockholm
Malaria Research
Petersen, Ines
United States, New York
Vagelos College of Physicians and Surgeons
Veiga, Maria Isabel
Sweden, Stockholm
Karolinska Institutet
Portugal, Faro
Universidade do Algarve
Mårtensson, Andreas A.
Sweden, Stockholm
Karolinska Institutet
Premji, Zulfiqarali G.
Tanzania, Dar es Salaam
Muhimbili University of Health and Allied Sciences
Bjǒrkman, Anders B.
Sweden, Stockholm
Karolinska Institutet
Fidock, David A.
United States, New York
Vagelos College of Physicians and Surgeons
Gil, Jose Pedro
Sweden, Stockholm
Karolinska Institutet
Portugal, Faro
Universidade do Algarve
Statistics
Citations: 221
Authors: 8
Affiliations: 5
Identifiers
Doi:
10.1086/596738
ISSN:
00221899
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases
Study Design
Cohort Study
Study Locations
Tanzania