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.

Venkatesan M1, Gadalla NB1, Stepniewska K1, Dahal P1, Nsanzabana C1, Moriera C1, Price RN1, Mårtensson A1, Rosenthal PJ1, Dorsey G1, Sutherland CJ1,Guérin P1, Davis TM1, Ménard D1, Adam I1, Ademowo G1, Arze C1, Baliraine FN1, Berens-Riha N1, Björkman A1, Borrmann S1, Checchi F1, Dhorda MD1,Djimdé AA1, El-Sayed BB1, Eshetu T1, Eyase F1, Falade C1, Faucher JF1, Fröberg G1, Grivoyannis A1, Hamour S1, Houzé S1, Johnson J1, Kamugisha E1,Kariuki S1, Kiechel JR1, Kironde F1, LeBras PE1, Malmberg M1, Mwai L1, Ngasala B1, Nosten F1, Nsobya SL1, Oguike AN1, Otienoburu SD1, Ogutu B1,Ouédraogo JB1, Piola P1, Rombo L1, Schramm B1, Somé AF1, Thwing J1, Ursing J1, Wong RP1, Zeynudin A1, Zongo I1, Plowe CV1, Sibley CH2.

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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.