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1. 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

Author

Rosenthal, Philip, Venkatesan, M, Gadalla, NB, Stepniewska, K, Dahal, P, Nsanzabana, C, Moriera, C, Price, RN, Ma, A, Rosenthal, PJ, and Dorsey, G

Abstract

Copyright © 2014 by The American Society of Tropical Medicine and Hygiene.Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chl

Published
2014

2. 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.

Author

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 JF, Fröberg G, Grivoyannis A, Hamour S, Houzé S, Johnson J, Kamugisha E, Kariuki S, Kiechel JR, Kironde F, Kofoed PE, LeBras J, Malmberg M, Mwai L, Ngasala B, Nosten F, Nsobya SL, Nzila A, Oguike M, Otienoburu SD, Ogutu B, Ouédraogo JB, Piola P, Rombo L, Schramm B, Somé AF, Thwing J, Ursing J, Wong RPM, Zeynudin A, Zongo I, Plowe CV, Sibley CH, and Asaq Molecular Marker Study Group

Subjects
Amino Acid Substitution, Amodiaquine therapeutic use, Antimalarials pharmacology, Artemether, Artemisinins therapeutic use, Child, Child, Preschool, Chloroquine pharmacology, Datasets as Topic, Drug Combinations, Drug Resistance genetics, Drug Therapy, Combination, Ethanolamines therapeutic use, Fluorenes therapeutic use, Genetic Markers genetics, Genotype, Humans, Infant, Kaplan-Meier Estimate, Lumefantrine, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects, Risk Factors, Antimalarials therapeutic use, Malaria, Falciparum parasitology, Membrane Transport Proteins genetics, Multidrug Resistance-Associated Proteins genetics, Plasmodium falciparum genetics, Polymorphism, Genetic, Protozoan Proteins genetics
Abstract

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., (© The American Society of Tropical Medicine and Hygiene.)

Published
2014
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