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

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.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.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.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.).