Journal ArticleDOI
Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study.
Aline Uwimana,Noella Umulisa,Meera Venkatesan,Samaly S. Svigel,Zhiyong Zhou,Tharcisse Munyaneza,Rafiki M. Habimana,Anicet Rucogoza,Leah F. Moriarty,Ryan Sandford,Emily Piercefield,Ira F. Goldman,Bryan Ezema,Eldin Talundzic,M. Andreína Pacheco,Ananias A. Escalante,Daniel Ngamije,Jean Louis N. Mangala,Michee Kabera,Kaendi Munguti,Monique Murindahabi,William R. Brieger,Clarisse Musanabaganwa,Leon Mutesa,Venkatachalam Udhayakumar,Aimable Mbituyumuremyi,Eric S. Halsey,Naomi W. Lucchi +27 more
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TLDR
In this paper, the efficacy of artemether-lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes were investigated in three Rwandan sites: Masaka, Rukara, and Bugarama.Abstract:
Summary Background Partial artemisinin resistance is suspected if delayed parasite clearance (ie, persistence of parasitaemia on day 3 after treatment initiation) is observed. Validated markers of artemisinin partial resistance in southeast Asia, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L, have been reported in Rwanda but no association with parasite clearance has been observed. We aimed to establish the efficacy of artemether–lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes. Methods This open-label, single-arm, multicentre, therapeutic efficacy study was done in 2018 in three Rwandan sites: Masaka, Rukara, and Bugarama. Children aged 6–59 months with P falciparum monoinfection and fever were eligible and treated with a 3-day course of artemether–lumefantrine. Treatment response was monitored for 28 days using weekly microscopy screenings of blood samples for P falciparum. Mutations in Pfkelch13 and P falciparum multidrug resistance-1 (Pfmdr1) genes were characterised in parasites collected from enrolled participants. Analysis of flanking microsatellites surrounding Pfkelch13 was done to define the origins of the R561H mutations. The primary endpoint was PCR-corrected parasitological cure on day 28, as per WHO protocol. Findings 228 participants were enrolled and 224 (98·2%) reached the study endpoint. PCR-corrected efficacies were 97·0% (95% CI 88–100) in Masaka, 93·8% (85–98) in Rukara, and 97·2% (91–100) in Bugarama. Pfkelch13 R561H mutations were present in 28 (13%) of 218 pre-treatment samples and P574L mutations were present in two (1%) pre-treatment samples. 217 (90%) of the 240 Pfmdr1 haplotypes observed in the pretreatment samples, had either the NFD (N86Y, Y184F, D1246Y) or NYD haplotype. Eight (16%) of 51 participants in Masaka and 12 (15%) of 82 participants in Rukara were microscopically positive 3 days after treatment initiation, which was associated with pre-treatment presence of Pfkelch13 R561H in Masaka (p=0·0005). Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda. Interpretation We confirm evidence of emerging artemisinin partial resistance in Rwanda. Although artemether–lumefantrine remains efficacious, vigilance for decreasing efficacy, further characterisation of artemisinin partial resistance, and evaluation of additional antimalarials in Rwanda should be considered. Funding The US President's Malaria Initiative. Translation For the French translation of the abstract see Supplementary Materials section.read more
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A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa.
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References
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Analysis of Gene Diversity in Subdivided Populations
TL;DR: A method is presented by which the gene diversity (heterozygosity) of a subdivided population can be analyzed into its components, i.e., the gene diversities within and between subpopulations.
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Artemisinin Resistance in Plasmodium falciparum Malaria
Arjen M. Dondorp,François Nosten,Poravuth Yi,Debashish Das,Aung Phae Phyo,Joel Tarning,Khin Maung Lwin,Frédéric Ariey,Warunee Hanpithakpong,Sue J. Lee,Pascal Ringwald,Kamolrat Silamut,Mallika Imwong,Kesinee Chotivanich,Pharath Lim,Trent Herdman,Sen Sam An,Shunmay Yeung,Pratap Singhasivanon,Nicholas P. J. Day,Niklas Lindegardh,Duong Socheat,Nicholas J. White +22 more
TL;DR: The overall median clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours in Wang Pha (P<0.001) in each of the two locations as discussed by the authors.
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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.
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Evidence of Artemisinin-Resistant Malaria in Western Cambodia
TL;DR: Artemisinins are potent and rapidly acting antimalarial drugs, and their widespread use for treating patients with Plasmodium falciparum malaria raises the question of emerging drug resistance.
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Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study
Aung Pyae Phyo,Standwell Nkhoma,Kasia Stepniewska,Kasia Stepniewska,Elizabeth A. Ashley,Elizabeth A. Ashley,Shalini Nair,Rose McGready,Rose McGready,Carit Ler Moo,Salma Al-Saai,Arjen M. Dondorp,Arjen M. Dondorp,Khin Maung Lwin,Pratap Singhasivanon,Nicholas P. J. Day,Nicholas P. J. Day,Nicholas J. White,Nicholas J. White,Tim J. Anderson,François Nosten,François Nosten +21 more
TL;DR: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially, with experts predicting resistance will reach rates reported in western Cambodia in 2–6 years.
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