Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Published

Journal Article

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Full Text

Duke Authors

Cited Authors

  • Venkatesan, M; Gadalla, NB; Stepniewska, K; Dahal, P; Nsanzabana, C; Moriera, C; Price, RN; Mårtensson, A; Rosenthal, PJ; Dorsey, G; Sutherland, CJ; Guérin, P; Davis, TME; Ménard, D; Adam, I; Ademowo, G; Arze, C; Baliraine, FN; Berens-Riha, N; Björkman, A; Borrmann, S; Checchi, F; Desai, M; Dhorda, M; Djimdé, AA; El-Sayed, BB; Eshetu, T; Eyase, F; Falade, C; Faucher, J-F; Fröberg, G; Grivoyannis, A; Hamour, S; Houzé, S; Johnson, J; Kamugisha, E; Kariuki, S; Kiechel, J-R; Kironde, F; Kofoed, P-E; LeBras, J; Malmberg, M; Mwai, L; Ngasala, B; Nosten, F; Nsobya, SL; Nzila, A; Oguike, M; Otienoburu, SD; Ogutu, B; Ouédraogo, J-B; Piola, P; Rombo, L; Schramm, B; Somé, AF; Thwing, J; Ursing, J; Wong, RPM; Zeynudin, A; Zongo, I; Plowe, CV; Sibley, CH; Asaq Molecular Marker Study Group,

Published Date

  • October 2014

Published In

Volume / Issue

  • 91 / 4

Start / End Page

  • 833 - 843

PubMed ID

  • 25048375

Pubmed Central ID

  • 25048375

Electronic International Standard Serial Number (EISSN)

  • 1476-1645

Digital Object Identifier (DOI)

  • 10.4269/ajtmh.14-0031

Language

  • eng

Conference Location

  • United States