Spread of artemisinin resistance in Plasmodium falciparum malaria.


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.).

DOI: 10.1056/NEJMoa1314981

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@article{Ashley2014SpreadOA, title={Spread of artemisinin resistance in Plasmodium falciparum malaria.}, author={Elizabeth A Ashley and Mehul Dhorda and Rick M Fairhurst and Chanaki Amaratunga and Parath Lim and Seila Suon and Sokunthea Sreng and Jennifer M Anderson and Sivanna Mao and Baramey Sam and Chantha Sopha and Char Meng Chuor and Chea Nguon and Siv Sovannaroth and Sasithon Pukrittayakamee and Podjanee Jittamala and Kesinee Chotivanich and Kitipumi Chutasmit and Chaiyaporn Suchatsoonthorn and Ratchadaporn Runcharoen and Tran Tinh Hien and Nguyen Thanh Thuy-Nhien and Ngo Viet Thanh and Nguyen Hoan Phu and Ye Htut and Kay-Thwe Han and Kyin Hla Aye and Olugbenga A Mokuolu and Rasaq R Olaosebikan and Olaleke O Folaranmi and Mayfong Mayxay and Maniphone Khanthavong and Bouasy Hongvanthong and Paul N Newton and Marie A Onyamboko and Caterina I Fanello and Antoinette K Tshefu and Neelima Mishra and Neena Valecha and Aung Pyae Phyo and Francois Nosten and Poravuth Yi and Rupam Tripura and Steffen Borrmann and Mahfudh Bashraheil and Judy Peshu and M Abul Faiz and Aniruddha Ghose and M Amir Hossain and Rasheda Samad and M Ridwanur Rahman and M Mahtabuddin Hasan and Akhterul Islam and Olivo Miotto and Roberto Amato and Bronwyn MacInnis and Jim Stalker and Dominic P Kwiatkowski and Zbynek Bozdech and Atthanee Jeeyapant and Phaik Yeong Cheah and Tharisara Sakulthaew and Jeremy Chalk and Benjamas Intharabut and Kamolrat Silamut and Sue J Lee and Benchawan Vihokhern and Chanon Kunasol and Mallika Imwong and Joel Tarning and Walter J Taylor and Shunmay Yeung and Charles J Woodrow and Jennifer A Flegg and Debashish Das and Jeffery Smith and Meera Venkatesan and Christopher V Plowe and Kasia Stepniewska and Philippe J Guerin and Arjen M Dondorp and Nicholas P Day and Nicholas J White}, journal={The New England journal of medicine}, year={2014}, volume={371 5}, pages={411-23} }