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Spread of artemisinin resistance in Plasmodium falciparum malaria.

ABSTRACT: 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.).

SUBMITTER: Ashley EA

PROVIDER: S-EPMC4143591 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Spread of artemisinin resistance in Plasmodium falciparum malaria.

Ashley Elizabeth A EA Dhorda Mehul M Fairhurst Rick M RM Amaratunga Chanaki C Lim Parath P Suon Seila S Sreng Sokunthea S Anderson Jennifer M JM Mao Sivanna S Sam Baramey B Sopha Chantha C Chuor Char Meng CM Nguon Chea C Sovannaroth Siv S Pukrittayakamee Sasithon S Jittamala Podjanee P Chotivanich Kesinee K Chutasmit Kitipumi K Suchatsoonthorn Chaiyaporn C Runcharoen Ratchadaporn R Hien Tran Tinh TT Thuy-Nhien Nguyen Thanh NT Thanh Ngo Viet NV Phu Nguyen Hoan NH Htut Ye Y Han Kay-Thwe KT Aye Kyin Hla KH Mokuolu Olugbenga A OA Olaosebikan Rasaq R RR Folaranmi Olaleke O OO Mayxay Mayfong M Khanthavong Maniphone M Hongvanthong Bouasy B Newton Paul N PN Onyamboko Marie A MA Fanello Caterina I CI Tshefu Antoinette K AK Mishra Neelima N Valecha Neena N Phyo Aung Pyae AP Nosten Francois F Yi Poravuth P Tripura Rupam R Borrmann Steffen S Bashraheil Mahfudh M Peshu Judy J Faiz M Abul MA Ghose Aniruddha A Hossain M Amir MA Samad Rasheda R Rahman M Ridwanur MR Hasan M Mahtabuddin MM Islam Akhterul A Miotto Olivo O Amato Roberto R MacInnis Bronwyn B Stalker Jim J Kwiatkowski Dominic P DP Bozdech Zbynek Z Jeeyapant Atthanee A Cheah Phaik Yeong PY Sakulthaew Tharisara T Chalk Jeremy J Intharabut Benjamas B Silamut Kamolrat K Lee Sue J SJ Vihokhern Benchawan B Kunasol Chanon C Imwong Mallika M Tarning Joel J Taylor Walter J WJ Yeung Shunmay S Woodrow Charles J CJ Flegg Jennifer A JA Das Debashish D Smith Jeffery J Venkatesan Meera M Plowe Christopher V CV Stepniewska Kasia K Guerin Philippe J PJ Dondorp Arjen M AM Day Nicholas P NP White Nicholas J NJ

The New England journal of medicine 20140701 5

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 25075834

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Project description:Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)

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Spread of artemisinin resistance in Plasmodium falciparum malaria.

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Spread of artemisinin resistance in Plasmodium falciparum malaria.

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