Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study

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 rep...

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Published in:	The Lancet infectious diseases Vol. 21; no. 8; pp. 1120 - 1128
Main Authors:	Uwimana, Aline, Umulisa, Noella, Venkatesan, Meera, Svigel, Samaly S, Zhou, Zhiyong, Munyaneza, Tharcisse, Habimana, Rafiki M, Rucogoza, Anicet, Moriarty, Leah F, Sandford, Ryan, Piercefield, Emily, Goldman, Ira, Ezema, Bryan, Talundzic, Eldin, Pacheco, M Andreína, Escalante, Ananias A, Ngamije, Daniel, Mangala, Jean-Louis N, Kabera, Michee, Munguti, Kaendi, Murindahabi, Monique, Brieger, William, Musanabaganwa, Clarisse, Mutesa, Leon, Udhayakumar, Venkatachalam, Mbituyumuremyi, Aimable, Halsey, Eric S, Lucchi, Naomi W
Format:	Journal Article
Language:	English
Published:	United States Elsevier Ltd 01-08-2021 Elsevier B.V Elsevier Limited
Subjects:	Analysis Animals Antimalarials - therapeutic use Artemether Artemether, Lumefantrine Drug Combination - therapeutic use Artemisinin Artemisinins - therapeutic use Child, Preschool Drug dosages Drug Resistance - genetics Female Fever Genetic analysis Genotype Genotypes Haplotypes Health aspects Humans Infant Infectious diseases Malaria Malaria, Falciparum - drug therapy Malaria, Falciparum - epidemiology Malaria, Falciparum - parasitology Male Microsatellites Microscopy Multidrug resistance Mutation Mutation, Missense Parasites Parasitic diseases Parasitic Sensitivity Tests Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - genetics Polymorphism, Genetic Pretreatment Protozoan Proteins - genetics Public health Rwanda - epidemiology Translation Vector-borne diseases Vigilance Rwanda Cambodia Africa
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Summary:	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. 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. 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. 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. The US President's Malaria Initiative. For the French translation of the abstract see Supplementary Materials section.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AU, NU, EF, KM, WB, MM, MV, and EH designed and planned the study. AU, NU, AM, DN, AR, JLM, CM, and LM coordinated and supported all the field operations of the study. RMH, TM, SS, BE, IG, prepared the sample inventories, performed the molecular assays and data processing. ET, NWL, ZZ, and VU supervised the molecular assays and data processing and interpretations. MAP and AE did the microsatellite data analysis. LFM, MK, RS, NWL, and MV provided statistical analysis support. AU, NWL, EH, VU, and AM supervised the study including analysis, interpretation, and writing of the Article. All authors read and revised the manuscript and agreed to the final version. AU, LFM, VU, EH and NWL had access to and verified the data. Contributors
ISSN:	1473-3099 1474-4457
DOI:	10.1016/S1473-3099(21)00142-0