Journal article
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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Publisher copy:
- 10.4269/ajtmh.14-0031
Authors
- Publisher:
- American Society of Tropical Medicine and Hygiene
- Journal:
- American Journal of Tropical Medicine and Hygiene More from this journal
- Volume:
- 91
- Issue:
- 4
- Pages:
- 833-843
- Publication date:
- 2014-07-21
- Acceptance date:
- 2014-04-22
- DOI:
- EISSN:
-
1476-1645
- ISSN:
-
0002-9637
- Language:
-
English
- Keywords:
- Pubs id:
-
pubs:477447
- UUID:
-
uuid:0546a371-d2d6-42a0-a543-b583776c65d0
- Local pid:
-
pubs:477447
- Source identifiers:
-
477447
- Deposit date:
-
2014-08-06
- ARK identifier:
Terms of use
- Copyright holder:
- The American Society of Tropical Medicine and Hygiene
- Copyright date:
- 2014
- Notes:
- Copyright © 2014 by The American Society of Tropical Medicine and Hygiene. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Licence:
- CC Attribution (CC BY)
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