TY - JOUR
T1 - Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda
T2 - an open-label, single-arm, multicentre, therapeutic efficacy study
AU - Uwimana, Aline
AU - Umulisa, Noella
AU - Venkatesan, Meera
AU - Svigel, Samaly S.
AU - Zhou, Zhiyong
AU - Munyaneza, Tharcisse
AU - Habimana, Rafiki M.
AU - Rucogoza, Anicet
AU - Moriarty, Leah F.
AU - Sandford, Ryan
AU - Piercefield, Emily
AU - Goldman, Ira
AU - Ezema, Bryan
AU - Talundzic, Eldin
AU - Pacheco, M. Andreína
AU - Escalante, Ananias A.
AU - Ngamije, Daniel
AU - Mangala, Jean Louis N.
AU - Kabera, Michee
AU - Munguti, Kaendi
AU - Murindahabi, Monique
AU - Brieger, William
AU - Musanabaganwa, Clarisse
AU - Mutesa, Leon
AU - Udhayakumar, Venkatachalam
AU - Mbituyumuremyi, Aimable
AU - Halsey, Eric S.
AU - Lucchi, Naomi W.
N1 - Funding Information:
We thank the Malaria and Other Parasitic Diseases Division of the Rwanda Biomedical Center, the Maternal and Child Survival Program at Jhpiego, all the study team members, and the study participants. We thank the Division of Vector-borne Diseases, Thailand, for sharing the Plasmodium falciparum kelch 13 mutant isolates. This study was funded by the US President's Malaria Initiative (PMI). Molecular marker testing was funded as part of the PMI Antimalarial Resistance Monitoring in Africa network. The opinions expressed herein are those of the authors and do not necessarily reflect the views of the US Centers for Disease Control and Prevention or PMI.
Funding Information:
We thank the Malaria and Other Parasitic Diseases Division of the Rwanda Biomedical Center, the Maternal and Child Survival Program at Jhpiego, all the study team members, and the study participants. We thank the Division of Vector-borne Diseases, Thailand, for sharing the Plasmodium falciparum kelch 13 mutant isolates. This study was funded by the US President's Malaria Initiative (PMI). Molecular marker testing was funded as part of the PMI Antimalarial Resistance Monitoring in Africa network. The opinions expressed herein are those of the authors and do not necessarily reflect the views of the US Centers for Disease Control and Prevention or PMI.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
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U2 - 10.1016/S1473-3099(21)00142-0
DO - 10.1016/S1473-3099(21)00142-0
M3 - Article
C2 - 33864801
AN - SCOPUS:85104443082
SN - 1473-3099
VL - 21
SP - 1120
EP - 1128
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 8
ER -