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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.


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.

SUBMITTER: Venkatesan M 

PROVIDER: S-EPMC4183414 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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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 Meera M   Gadalla Nahla B NB   Stepniewska Kasia K   Dahal Prabin P   Nsanzabana Christian C   Moriera Clarissa C   Price Ric N RN   Mårtensson Andreas A   Rosenthal Philip J PJ   Dorsey Grant G   Sutherland Colin J CJ   Guérin Philippe P   Davis Timothy M E TME   Ménard Didier D   Adam Ishag I   Ademowo George G   Arze Cesar C   Baliraine Frederick N FN   Berens-Riha Nicole N   Björkman Anders A   Borrmann Steffen S   Checchi Francesco F   Desai Meghna M   Dhorda Mehul M   Djimdé Abdoulaye A AA   El-Sayed Badria B BB   Eshetu Teferi T   Eyase Frederick F   Falade Catherine C   Faucher Jean-François JF   Fröberg Gabrielle G   Grivoyannis Anastasia A   Hamour Sally S   Houzé Sandrine S   Johnson Jacob J   Kamugisha Erasmus E   Kariuki Simon S   Kiechel Jean-René JR   Kironde Fred F   Kofoed Poul-Erik PE   LeBras Jacques J   Malmberg Maja M   Mwai Leah L   Ngasala Billy B   Nosten Francois F   Nsobya Samuel L SL   Nzila Alexis A   Oguike Mary M   Otienoburu Sabina Dahlström SD   Ogutu Bernhards B   Ouédraogo Jean-Bosco JB   Piola Patrice P   Rombo Lars L   Schramm Birgit B   Somé A Fabrice AF   Thwing Julie J   Ursing Johan J   Wong Rina P M RPM   Zeynudin Ahmed A   Zongo Issaka I   Plowe Christopher V CV   Sibley Carol Hopkins CH   Asaq Molecular Marker Study Group  

The American journal of tropical medicine and hygiene 20140721 4


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  ...[more]

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