Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study
Chanaki Amaratunga,Sokunthea Sreng,Seila Suon,Erika S. Phelps,Kasia Stepniewska,Pharath Lim,Chongjun Zhou,Sivanna Mao,Jennifer M. Anderson,Niklas Lindegardh,Hongying Jiang,Jianping Song,Xin-zhuan Su,Nicholas J. White,Arjen M. Dondorp,Tim J. Anderson,Michael P. Fay,Jianbing Mu,Socheat Duong,Rick M. Fairhurst +19 more
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TLDR
Heritable artemisinin resistance is established in a second Cambodian province and future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation.Abstract:
Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD , which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum : age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54–6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean parasite heritability of half-life was 0·40 (SD 0·17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.read more
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Journal ArticleDOI
Spread of Artemisinin Resistance in Plasmodium falciparum Malaria
Elizabeth A. Ashley,Mehul Dhorda,Rick M. Fairhurst,Chanaki Amaratunga,Pharath Lim,Seila Suon,Sokunthea Sreng,Jennifer M. Anderson,Mao S,Sam B,Chantha Sopha,Char Meng Chuor,Chea Nguon,Siv Sovannaroth,Sasithon Pukrittayakamee,Podjanee Jittamala,Kesinee Chotivanich,K Chutasmit,C Suchatsoonthorn,R Runcharoen,Tran Tinh Hien,Nguyen Thuy-Nhien,Thanh Nv,Nguyen Hoan Phu,Ye Htut,Han Kt,Kyin Hla Aye,Olugbenga A. Mokuolu,Rasaq Olaosebikan,Olaleke Oluwasegun Folaranmi,Mayfong Mayxay,Maniphone Khanthavong,Bouasy Hongvanthong,Paul N. Newton,M A Onyamboko,Caterina I. Fanello,Antoinette Tshefu,Neelima Mishra,Neena Valecha,Aung Pyae Phyo,François Nosten,Yi P,Rupam Tripura,Steffen Borrmann,Mahfudh Bashraheil,Judy Peshu,M A Faiz,Aniruddha Ghose,M A Hossain,Rasheda Samad,M. R. Rahman,Manal Hasan,Ashraful 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,Lee Sj,Benchawan Vihokhern,Chanon Kunasol,Mallika Imwong,Joel Tarning,Taylor Wj,Shunmay Yeung,Charles J. Woodrow,Jennifer A. Flegg,Debashish Das,Jennifer L. Smith,Meera Venkatesan,Christopher V. Plowe,Kasia Stepniewska,Philippe J Guerin,Arjen M. Dondorp,Nicholas P. J. Day,Nicholas J. White +82 more
TL;DR: Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing, and the incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission.
Journal ArticleDOI
A molecular marker of artemisinin-resistant Plasmodium falciparum malaria
Frédéric Ariey,Benoit Witkowski,Chanaki Amaratunga,Johann Beghain,Anne-Claire Langlois,Nimol Khim,Saorin Kim,Valentine Duru,Christiane Bouchier,Laurence Ma,Pharath Lim,Rithea Leang,Socheat Duong,Sokunthea Sreng,Seila Suon,Char Meng Chuor,Denis Mey Bout,Sandie Menard,William O. Rogers,Blaise Genton,Thierry Fandeur,Olivo Miotto,Pascal Ringwald,Jacques Le Bras,Antoine Berry,Jean Christophe Barale,Rick M. Fairhurst,Françoise Benoit-Vical,Odile Mercereau-Puijalon,Didier Menard +29 more
TL;DR: Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance.
Journal ArticleDOI
K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates
Judith Straimer,Nina F. Gnädig,Benoit Witkowski,Chanaki Amaratunga,Valentine Duru,Arba Pramundita Ramadani,Arba Pramundita Ramadani,Mélanie Dacheux,Nimol Khim,Lei Zhang,Stephen Lam,Philip D. Gregory,Fyodor D. Urnov,Odile Mercereau-Puijalon,Françoise Benoit-Vical,Françoise Benoit-Vical,Rick M. Fairhurst,Didier Menard,David A. Fidock +18 more
TL;DR: The data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites and imperils efforts to reduce the global malaria burden.
Journal ArticleDOI
Genetic architecture of artemisinin-resistant Plasmodium falciparum.
Olivo Miotto,Roberto Amato,Elizabeth A. Ashley,Bronwyn MacInnis,Jacob Almagro-Garcia,Chanaki Amaratunga,Pharath Lim,Daniel Mead,Samuel O. Oyola,Mehul Dhorda,Mallika Imwong,Charles J. Woodrow,Magnus Manske,Jim Stalker,Eleanor Drury,Susana Campino,Lucas Amenga-Etego,Thanh T-Nn.,Hien Tinh Tran,Pascal Ringwald,Delia Bethell,François Nosten,Aung Pyae Phyo,S Pukrittayakamee,Kesinee Chotivanich,Char Meng Chuor,Chea Nguon,Seila Suon,Sokunthea Sreng,Paul N. Newton,Mayfong Mayxay,Maniphone Khanthavong,Bouasy Hongvanthong,Ye Htut,K T Han,Myat Phone Kyaw,MA Faiz,Caterina I. Fanello,M A Onyamboko,Olugbenga A. Mokuolu,Christopher G Jacob,Shannon Takala-Harrison,Christopher V. Plowe,Nicholas P. J. Day,Arjen M. Dondorp,Spencer Cca.,Gil McVean,Rick M. Fairhurst,Nicholas J. White,Dominic P. Kwiatkowski +49 more
TL;DR: Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance.
Journal ArticleDOI
Novel phenotypic assays for the detection of artemisinin- resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies
Benoit Witkowski,Chanaki Amaratunga,Nimol Khim,Sokunthea Sreng,Pheaktra Chim,Saorin Kim,Pharath Lim,Pharath Lim,Sivanna Mao,Chantha Sopha,Baramey Sam,Jennifer M. Anderson,Socheat Duong,Char Meng Chuor,Walter R. J. Taylor,Seila Suon,Odile Mercereau-Puijalon,Rick M. Fairhurst,Didier Menard +18 more
TL;DR: The in-vitro RSA of 0-3 h ring-stage parasites provides a platform for the molecular characterisation of artemisinin resistance and the ex-vivo RSA can be easily implemented where surveillance for artemis inin resistance is needed.
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Artemisinin Resistance in Plasmodium falciparum Malaria
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