Spread of Artemisinin Resistance in Plasmodium falciparum Malaria
Open accessAbstract
BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).
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Treatment of malaria in pregnancy has been a major priority for preventing poor pregnancy outcomes worldwide, but the Thailand-Myanmar border region faces unique challenges due to high rates of P. falciparum multi drug resistance and the lack of a safe, radical cure that eliminates dormant P. vivax from the liver in pregnancy.
“Treatment of malaria in pregnancy has been a major priority for preventing poor pregnancy outcomes worldwide, but the Thailand-Myanmar border region faces unique challenges due to high rates of P. falciparum multi drug resistance [33] and the lack of a safe, radical cure that eliminates dormant P. vivax from the liver in pregnancy [34].”
From Distance matters: barriers to antenatal care and safe childbirth in a migrant population on the Thailand-Myanmar border from 2007 to 2015, a pregnancy cohort study (2021) · cites this paper as [33]
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Cites
Quantifying heterogeneity in a meta‐analysis
Higgins, J. P. T., & Thompson, S. G. (2002) · Statistics in Medicine · doi:10.1002/sim.1186 · Cited by 36,763 · see citing works
Artemisinin Resistance in <i>Plasmodium falciparum</i> Malaria
Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808859 · Cited by 3,424 · see citing works
Self-citationA molecular marker of artemisinin-resistant Plasmodium falciparum malaria
Ariey, F., Witkowski, B., Amaratunga, C., Beghain, J., Langlois, A.-C., Khim, N., Kim, S., Duru, V., Bouchier, C., Ma, L., et al. (2013) · Nature · doi:10.1038/nature12876 · Cited by 2,099 · see citing works
Self-citationEvidence of Artemisinin-Resistant Malaria in Western Cambodia
Noedl, H., Se, Y., Schaecher, K. E., Smith, B. L., Socheat, D., & Fukuda, M. M. (2008) · New England Journal of Medicine · doi:10.1056/nejmc0805011 · Cited by 1,789 · see citing works
Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study
Phyo, A. P., Nkhoma, S. C., Stepniewska, K., Ashley, E. A., Nair, S., McGready, R. M., Moo, C. L., Al‐Saai, S., Dondorp, A. M., Lwin, K. M., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60484-x · Cited by 927 · see citing works
Self-citationBhattarai, A., Ali, A. S., Kachur, S. P., Mårtensson, A., Abbas, A. K., Khatib, R., Al-mafazy, A.-W., Ramsan, M., Rotllant, G., Gerstenmaier, J. F., et al. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040309 · Cited by 647 · see citing works
Witkowski, B., Amaratunga, C., Khim, N., et al. (2013) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(13)70252-4 · Cited by 635 · see citing works
Self-citationMultiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia
Miotto, O., Garcia, J. A., Manske, M., MacInnis, B. L., Campino, S. G., Rockett, K. A., Amaratunga, C., Lim, P., Suon, S., Sreng, S., et al. (2013) · Nature Genetics · doi:10.1038/ng.2624 · Cited by 452 · see citing works
Self-citationA Major Genome Region Underlying Artemisinin Resistance in Malaria
Cheeseman, I. H., Miller, B. A., Nair, S., Nkhoma, S. C., Tan, A., Tan, J. C., Saai, S. A., Phyo, A. P., Moo, C. L., Lwin, K. M., et al. (2012) · Science · doi:10.1126/science.1215966 · Cited by 379 · see citing works
Self-citationAmaratunga, C., Sreng, S., Suon, S., et al. (2012) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(12)70181-0 · Cited by 347 · see citing works
Self-citationReduced Artemisinin Susceptibility of Plasmodium falciparum Ring Stages in Western Cambodia
Witkowski, B., Khim, N., Chim, P., Kim, S., Ke, S., Kloeung, N., Chy, S., Socheat, D., Leang, R., Ringwald, P., et al. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01868-12 · Cited by 309 · see citing works
Self-citationFlegg, J. A., Guerin, P. J., White, N. J., & Stepniewska, K. (2011) · Malaria Journal · doi:10.1186/1475-2875-10-339 · Cited by 285 · see citing works
Self-citationCarrara, V. I., Zwang, J., Ashley, E. A., Price, R. N., Stepniewska, K., Barends, M., Brockman, A., Anderson, T., McGready, R. M., Phaiphun, L., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004551 · Cited by 281 · see citing works
Self-citationThe past, present and future of childhood malaria mortality in Africa
Snow, R. W., Trape, J., & Marsh, K. (2001) · Trends in Parasitology · doi:10.1016/s1471-4922(01)02031-1 · Cited by 266 · see citing works
Takala‐Harrison, S., Clark, T. G., Jacob, C. G., Cummings, M. P., Miotto, O., Dondorp, A. M., Fukuda, M. M., Nosten, F. H., Noedl, H., Imwong, M., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211205110 · Cited by 266 · see citing works
Self-citationTeuscher, F., Gatton, M. L., Chen, N., Peters, J. M., Kyle, D. E., & Cheng, Q. (2010) · The Journal of Infectious Diseases · doi:10.1086/656476 · Cited by 249 · see citing works
Snounou, G., & Beck, H.-P. (1998) · Parasitology Today · doi:10.1016/s0169-4758(98)01340-4 · Cited by 215 · see citing works
White, N. J. (2011) · Malaria Journal · doi:10.1186/1475-2875-10-278 · Cited by 200 · see citing works
Self-citationReduced Susceptibility of Plasmodium falciparum to Artesunate in Southern Myanmar
Kyaw, M. P., Nyunt, M. H., Chit, K., Aye, M. M., Aye, K. H., Aye, M. M., Lindegårdh, N., Tärning, J., Imwong, M., Jacob, C. G., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057689 · Cited by 199 · see citing works
Self-citationLeang, R., Barrette, A., Bouth, D. M., Ménard, D., Abdur, R., Socheat, D., & Ringwald, P. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00686-12 · Cited by 185 · see citing works
Carrara, V. I., Lwin, K. M., Phyo, A. P., Ashley, E., Wiladphaingern, J., Sriprawat, K., Rijken, M., Boel, M., McGready, R., Proux, S., et al. (2013) · PLoS Medicine · doi:10.1371/journal.pmed.1001398 · Cited by 185 · see citing works
Self-citationMok, S., Imwong, M., Mackinnon, M. J., Sim, J. P. L., Ramadoss, R., Yi, P., Mayxay, M., Chotivanich, K., Liong, K., Russell, B., et al. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-391 · Cited by 173 · see citing works
Self-citationIntrahost modeling of artemisinin resistance in Plasmodium falciparum
Saralamba, S., Ngum, W. P., Maude, R. J., Lee, S. J., Tärning, J., Lindegårdh, N., Chotivanich, K., Nosten, F. H., Day, N. P. J., Socheat, D., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006113108 · Cited by 157 · see citing works
Self-citationIn Vivo Parasitological Measures of Artemisinin Susceptibility
Stepniewska, K., Ashley, E. A., Lee, S. J., Anstey, N. M., Barnes, K. I., Bình, T. Q., D’Alessandro, U., Day, N. P. J., de Vries, P. J., Dorsey, G., et al. (2010) · The Journal of Infectious Diseases · doi:10.1086/650301 · Cited by 155 · see citing works
Self-citationDenis, M. B., Tsuyuoka, R., Lim, P., Lindegårdh, N., Yi, P., Narann, T. S., Socheat, D., Fandeur, T., Annerberg, A., Christophel, E. M., et al. (2006) · Tropical Medicine & International Health · doi:10.1111/j.1365-3156.2006.01739.x · Cited by 149 · see citing works
Self-citationIn vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam
Hien, T. T., Nguyen, T.-N., Phu, N. H., et al. (2012) · Malaria Journal · doi:10.1186/1475-2875-11-355 · Cited by 138 · see citing works
Self-citationBarnes, K. I., Little, F., Mabuza, A. M., Mngomezulu, N., Govere, J. M., Dürrheim, D. N., Roper, C., Watkins, B., & White, N. J. (2008) · The Journal of Infectious Diseases · doi:10.1086/587645 · Cited by 114 · see citing works
Self-citationStepniewska, K., & White, N. J. (2006) · Malaria Journal · doi:10.1186/1475-2875-5-127 · Cited by 72 · see citing works
Self-citationLopera-Mesa, T. M., Doumbia, S., Chiang, S., Zeituni, A. E., Konate, D. S., Doumbouya, M., Keita, A. S., Stepniewska, K., Traoré, K., Diakité, S. A. S., et al. (2013) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit082 · Cited by 70 · see citing works
Self-citationLaboratory Detection of Artemisinin-Resistant Plasmodium falciparum
Chotivanich, K., Tripura, R., Das, D., Yi, P., Day, N., Pukrittayakamee, S., Chuor, C. M., Socheat, D., Dondorp, A. M., & White, N. J. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01924-13 · Cited by 48 · see citing works
Self-citationTwo patients with falciparum malaria and poor in vivo responses to artesunate
Luxemburger, C., Brockman, A., Silamut, K., Nosten, F. H., van Vugt, M., Gimenez, F., Chongsuphajaisiddhi, T., & White, N. J. (1998) · Transactions of the Royal Society of Tropical Medicine and Hygiene · doi:10.1016/s0035-9203(98)90807-0 · Cited by 39 · see citing works
Self-citationLeang, R., Ros, S., Socheat, D., et al. (2013) · Malaria Journal · doi:10.1186/1475-2875-12-343 · Cited by 14 · see citing works
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White, N. J. (2017) · Malaria Journal · doi:10.1186/s12936-017-1731-1 · Cited by 230 · see citing works
Self-citationEpidemiology, drug resistance, and pathophysiology of <i>Plasmodium vivax</i> malaria
Gowda, D., Dayananda, K., & Achur, R. (2018) · Journal of Vector Borne Diseases · doi:10.4103/0972-9062.234620 · Cited by 111 · see citing works
Molecular Farming in Artemisia annua, a Promising Approach to Improve Anti-malarial Drug Production
Pulice, G., Pelaz, S., & Matías-Hernández, L. (2016) · Frontiers in Plant Science · doi:10.3389/fpls.2016.00329 · Cited by 53 · see citing works
Steinbrook, E., Min, M. C., Kajeechiwa, L., Wiladphaingern, J., Paw, M. K., Pimanpanarak, M. P. J., Hiranloetthanyakit, W., Min, A. M., Tun, N. W., Gilder, M. E., et al. (2021) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-021-04276-5 · Cited by 47 · see citing works
Self-citationLi, G., Kim, C., Kim, J., Yoon, H., Zhou, H., & Kim, J. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150024 · Cited by 39 · see citing works
Parker, D. M., Landier, J., Thu, A. M., Lwin, K. M., Delmas, G., Nosten, F. H., & The Malaria Elimination Task Force Group (2017) · Wellcome Open Research · doi:10.12688/wellcomeopenres.12741.1 · Cited by 13 · see citing works
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- Authors
- Ashley, E. A., Dhorda, M., Fairhurst, R. M., Amaratunga, C., Lim, P., Suon, S., Sreng, S., Anderson, J. M., Mao, S., Sam, B., Sopha, C., Chuor, C. M., Nguon, C., Sovannaroth, S., Pukrittayakamee, S., Jittamala, P., Chotivanich, K., Chutasmit, K., Suchatsoonthorn, C., Runcharoen, R., Hien, T. T., Thuy-Nhien, N. T., Thanh, N. V., Phu, N. H., Htut, Y., Han, K.-T., Aye, K. H., Mokuolu, O. A., Olaosebikan, R. R., Folaranmi, O. O., Mayxay, M., Khanthavong, M., Hongvanthong, B., Newton, P. N., Onyamboko, M. A., Fanello, C. I., Tshefu, A. K., Mishra, N., Valecha, N., Phyo, A. P., Nosten, F., Yi, P., Tripura, R., Borrmann, S., Bashraheil, M., Peshu, J., Faiz, M. A., Ghose, A., Hossain, M. A., Samad, R., Rahman, M. R., Hasan, M. M., Islam, A., Miotto, O., Amato, R., MacInnis, B., Stalker, J., Kwiatkowski, D. P., Bozdech, Z., Jeeyapant, A., Cheah, P. Y., Sakulthaew, T., Chalk, J., Intharabut, B., Silamut, K., Lee, S. J., Vihokhern, B., Kunasol, C., Imwong, M., Tarning, J., Taylor, W. J., Yeung, S., Woodrow, C. J., Flegg, J. A., Das, D., Smith, J., Venkatesan, M., Plowe, C. V., Stepniewska, K., Guerin, P. J., Dondorp, A. M., Day, N. P., & White, N. J.
- Affiliations
- University of Oxford (GB)
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- Cambodia National Malaria Center (KH)
- Mahidol University (TH)
- Hospital for Tropical Diseases (GB)
- University of Ilorin Teaching Hospital (NG)
- University of Ilorin (NG)
- Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LA)
- Ecole de santé publique de Kinshasa (CD)
- Indian Council of Medical Research (IN)
- Kenya Medical Research Institute (KE)
- University of Tübingen (DE)
- Chittagong Medical College (BD)
- Wellcome Sanger Institute (GB)
- Centre for Human Genetics (GB)
- Nanyang Technological University (SG)
- London School of Hygiene & Tropical Medicine (GB)
- ORCID
- Ashley, Elizabeth A.
- Dhorda, Mehul
- Anderson, Jennifer M.
- Sovannaroth, Siv
- Pukrittayakamee, Sasithon
- Jittamala, Podjanee
- Chotivanich, Kesinee
- Hien, Tran Tinh
- Phu, Nguyen Hoan
- Mokuolu, Olugbenga A.
- Olaosebikan, Rasaq R.
- Folaranmi, Olaleke O.
- Mayxay, Mayfong
- Newton, Paul N.
- Onyamboko, Marie A.
- Tshefu, Antoinette K.
- Mishra, Neelima
- Phyo, Aung Pyae
- Tripura, Rupam
- Borrmann, Steffen
- Ghose, Aniruddha
- Hossain, M. Amir
- Miotto, Olivo
- Amato, Roberto
- MacInnis, Bronwyn
- Kwiatkowski, Dominic P.
- Bozdech, Zbynek
- Cheah, Phaik Yeong
- Chalk, Jeremy
- Lee, Sue J.
- Kunasol, Chanon
- Imwong, Mallika
- Yeung, Shunmay
- Woodrow, Charles J.
- Flegg, Jennifer A.
- Das, Debashish
- Plowe, Christopher V.
- Stepniewska, Kasia
- Guerin, Philippe J.
- Dondorp, Arjen M.
- Day, Nicholas P.
- White, Nicholas J.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-07-31
- Volume
- 371
- Issue
- 5
- Pages
- 411-423
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4143591
- OpenAlex
- W2171102256
- Cited by
- 2,205
- References
- 32
- Citations by year
- 2026: 97 · 2025: 115 · 2024: 140 · 2023: 134 · 2022: 170 · 2021: 224 · 2020: 219 · 2019: 191 · 2018: 212 · 2017: 222 · 2016: 248 · 2015: 185 · 2014: 42 · 2012: 1
- FWCI
- 230.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- Funders
- Bill and Melinda Gates Foundation
- Sigma-Tau Pharmaceuticals
- Wellcome Trust (077166, 090770, 090532, 093956, 093956/Z/10/Z)
- University of Oxford
- Department for International Development
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phytochemical compounds biological activities
- Life Sciences › Immunology and Microbiology › Parasitology › Bird parasitology and diseases
- Keywords
- artemisinin resistance, Plasmodium falciparum, falciparum malaria, kelch13, parasite clearance half-life, artesunate, artemisinin-based combination therapy, drug resistance spread, Southeast Asia, gametocytaemia, malaria elimination
- MeSH terms
- Adolescent, Adult, Antimalarials, Asia, Southeastern, Child, Child, Preschool, Drug Resistance, Humans, Infant, Middle Aged, Plasmodium falciparum, Protozoan Proteins, Multivariate Analysis, Malaria, Falciparum, Point Mutation, Africa South of the Sahara, Parasitemia, Artemisinins, Young Adult, Parasite Load
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