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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

2009-03Journal article Open access
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dc.contributor.authorSisowath, Christin
dc.contributor.authorPetersen, Ines
dc.contributor.authorVeiga, Maria Isabel
dc.contributor.authorMartensson, Andreas
dc.contributor.authorPremji, Zul
dc.contributor.authorBjorkman, Anders
dc.contributor.authorFidock, David A.
dc.contributor.authorGil, José Pedro
dc.date.accessioned2018-12-07T14:53:44Z
dc.date.available2018-12-07T14:53:44Z
dc.date.issued2009-03
dc.description.abstractBackground. 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.
dc.description.sponsorshipNIAID NIH HHS [R01 AI50234, R01 AI050234-08, R01 AI050234]
dc.identifier.doi10.1086/596738
dc.identifier.issn0022-1899
dc.identifier.issn1537-6613
dc.identifier.urihttp://hdl.handle.net/10400.1/11666
dc.language.isoeng
dc.peerreviewedyes
dc.publisherOxford Univ Press Inc
dc.subjectAntimalarial-Drug-Resistance
dc.subjectTransmembrane Protein Pfcrt
dc.subjectPfmdr1 Gene
dc.subjectIncreased Sensitivity
dc.subjectMalaria
dc.subjectMutations
dc.subjectMefloquine
dc.subjectMalawi
dc.subjectAmodiaquine
dc.subjectArtemisinin
dc.titleIn vivo selection of plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceLorne, Australia
oaire.citation.endPage757
oaire.citation.issue5
oaire.citation.startPage750
oaire.citation.titleJournal of Infectious Diseases
oaire.citation.title3Rd Meeting On Molecular Approaches To Malaria (Mam 2008)
oaire.citation.volume199
person.familyNameVeiga
person.familyNameGil
person.givenNameMaria Isabel
person.givenNameJosé Pedro
person.identifier.ciencia-id271C-6028-9C6B
person.identifier.ciencia-idD01A-B30E-BCD5
person.identifier.orcid0000-0002-2205-8102
person.identifier.orcid0000-0002-6107-9379
person.identifier.ridH-9922-2018
person.identifier.scopus-author-id12767840900
person.identifier.scopus-author-id7201625436
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication76e56d6c-a7cb-4b41-8ad7-0e480b31ed41
relation.isAuthorOfPublicationcb728715-0e4c-4ae5-9e21-b6a8f35a8313
relation.isAuthorOfPublication.latestForDiscovery76e56d6c-a7cb-4b41-8ad7-0e480b31ed41

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