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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
Open accessAbstract
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.
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Partial residuals for the proportional hazards regression model
SCHOENFELD, D. (1982) · Biometrika · doi:10.1093/biomet/69.1.239 · Cited by 3,111
Cited by
Uwimana, A., Umulisa, N., Venkatesan, M., Svigel, S. S., Zhou, Z., Munyaneza, T., Habimana, R. M., Rucogoza, A., Moriarty, L. F., Sandford, R., et al. (2021) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(21)00142-0 · Cited by 435
Self-citationArtemisinin Action and Resistance in Plasmodium falciparum
Tilley, L., Straimer, J., Gnädig, N. F., Ralph, S. A., & Fidock, D. A. (2016) · Trends in Parasitology · doi:10.1016/j.pt.2016.05.010 · Cited by 359
Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria
Wicht, K. J., Mok, S., & Fidock, D. A. (2020) · Annual Review of Microbiology · doi:10.1146/annurev-micro-020518-115546 · Cited by 322
Metadata
- Authors
- Venkatesan, M., Gadalla, N. B., Stepniewska, K., Dahal, P., Nsanzabana, C., Moriera, C., Price, R. N., Mårtensson, A., Rosenthal, P. J., Dorsey, G., Sutherland, C. J., Guérin, P., Davis, T. M. E., Ménard, D., Adam, I., Ademowo, G., Arze, C., Baliraine, F. N., Berens-Riha, N., Björkman, A., Borrmann, S., Checchi, F., Desai, M., Dhorda, M., Djimdé, A. A., El-Sayed, B. B., 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, S. L., Nzila, A., Oguike, M., Otienoburu, S. D., Ogutu, B., Ouédraogo, J.-B., Piola, P., Rombo, L., Schramm, B., Somé, A. F., Thwing, J., Ursing, J., Wong, R. P. M., Zeynudin, A., Zongo, I., Plowe, C. V., Sibley, C. H., & _, _.
- Venue
- The American Society of Tropical Medicine and Hygiene
- Published
- 2014-10-01
- Volume
- 91
- Issue
- 4
- Pages
- 833-843
- ISSN
- 0002-9637 (ISSN-L)
- 1476-1645
- OpenAlex
- W2103439634
- Cited by
- 285
- References
- 1
- FWCI
- 18.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: 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. https://app.cochat.ai/papers/10.4269/ajtmh.14-0031
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- Venkatesan, M., Gadalla, N. B., Stepniewska, K., Dahal, P., Nsanzabana, C., Moriera, C., Price, R. N., Mårtensson, A., Rosenthal, P. J., Dorsey, G., Sutherland, C. J., Guérin, P., Davis, T. M. E., Ménard, D., Adam, I., Ademowo, G., Arze, C., Baliraine, F. N., Berens-Riha, N., . . . _, _. (2014). 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. The American Society of Tropical Medicine and Hygiene. https://doi.org/10.4269/ajtmh.14-0031
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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