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

Uwimana, Aline; Umulisa, Noella; Venkatesan, Meera; Svigel, Samaly S.; Zhou, Zhansong; Munyaneza, Tharcisse; Habimana, Rafiki M.; Rucogoza, Anicet; Moriarty, Leah F.; Sandford, Ryan; Piercefield, Emily; Goldman, Ira F.; Ezema, Bryan; Talundzic, Eldin; Pacheco, M. Andreína; Escalante, Ananías A.; Ngamije, Daniel; Mangala, Jean Louis N.; Kabera, Michee; Munguti, Kaendi; Murindahabi, Monique; Brieger, William R.; Musanabaganwa, Clarisse; Mutesa, Léon; Udhayakumar, Venkatachalam; Mbituyumuremyi, Aimable; Halsey, Eric S.; Lucchi, Naomi W.

doi:10.1016/s1473-3099(21)00142-0

Cited by 282 publications

(246 citation statements)

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“…It has recently been shown through haplotype analysis of well-characterized clinical isolates of Plasmodium falciparum that genetic resistance to the artemisinins is mediated by polymorphisms in the gene encoding the Kelch propeller domain 13, and these mutations arise independently in several locations [32]. Studies conducted in Tanzania and Rwanda have also associated the nonsynonymous P. falciparum Kelch 13 mutations (P574L and R561H) with delayed parasite clearance [6][7][8][9]. The implication of these observations in close monitoring of resistant parasites cannot be overestimated especially in endemic areas where case management relies principally on the use of ACTs.…”

Section: Discussionmentioning

confidence: 99%

“…The P. falciparum Kelch 13 (K13) propeller variants are the main markers responsible for resistance to artemisinins [5]. In Africa, even though resistance to the artemisinins is not yet a threat to malaria treatment, recent studies have reported the presence of R561H and P574L polymorphisms conferring partial resistance to ACTs [6][7][8][9]. The human host factors responsible for delayed parasite clearance after the administration of ACTs have not been fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Discrete Survival Model Analysis of Plasmodium falciparum Response to Artemisinin-Based Combination Therapies among Children in Regions of Varying Malaria Transmission in Cameroon

et al. 2021

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The need to monitor changes in parasite clearance following treatment with artemisinin-based combination therapies (ACTs) is important in the containment of drug resistance. This study aimed to model Plasmodium falciparum response to ACTs among children in two different transmission settings (Mutengene and Garoua) in Cameroon. Using the step function, a discrete-time survival model was fitted with all the covariates included that might play a role in parasite clearance. The probability of clearing parasites within 24 h following treatment was 21.6% and 70.3% for younger children aged 6 to 59 months and 29.3% and 59.8% for older children aged 60 to 120 months in Mutengene and Garoua, respectively. After two days of treatment, the conditional probability of clearing parasites given that they were not cleared on day 1 was 76.7% and 96.6% for children aged 6–59 months and 83.1% and 93.5% for children aged 60–120 months in Mutengene and Garoua, respectively. The model demonstrated that the ecological setting, age group and pretreatment serum levels of creatinine and alanine aminotransferase were the main factors that significantly influenced parasite clearance in vivo after administration of ACTs (p < 0.05). The findings highlight the need for further investigations on host differential response to ACTs in current practice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discrete Survival Model Analysis of Plasmodium falciparum Response to Artemisinin-Based Combination Therapies among Children in Regions of Varying Malaria Transmission in Cameroon

et al. 2021

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“…In artemisinin-based combinations, the artemisinin component is short-acting and kills the majority of parasites within the first 2 days of treatment; the remaining parasites are cleared by the longer-acting partner drug [ 9 ], thus helping to abate the acquisition of parasite resistance to the treatment. However, resistance to artemisinin derivatives, defined as delayed parasite clearance (presence of > 10% parasitaemia on day 3 after the start of treatment), has been reported in Southeast Asia [ 10 – 12 ] and Rwanda [ 13 ]. Resistance to specific anti-malarials is associated with polymorphisms, such as a single nucleotide polymorphisms (SNPs), a combination of SNPs, or gene copy number variation in drug target genes.…”

Section: Introductionmentioning

confidence: 99%

“…Artemisinin partial resistance is associated with polymorphisms in the P. falciparum kelch 13 ( pfk13 ) gene [ 10 ] and ten SNPs in pfk13 gene are currently validated molecular markers for artemisinin partial resistance: F446 I , N458 Y , M476 I , Y493 H , R539 T , I543 T , P553 L , R561 H , P574 L and C580 Y [ 14 ]. One of these mutations, R561 H , has been reported to be present in multiple samples from different sites in Rwanda [ 13 , 15 , 16 ], highlighting the importance of conducting molecular surveillance to identify emerging artemisinin and partner drug resistance genotypes. To date, there have been no reports of pfk13 polymorphisms associated with artemisinin partial resistance in Mozambique [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular surveillance for polymorphisms associated with artemisinin-based combination therapy resistance in Plasmodium falciparum isolates collected in Mozambique, 2018

Chidimatembue

Svigel

Mayor

et al. 2021

Malar J

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Background Due to the threat of emerging anti-malarial resistance, the World Health Organization recommends incorporating surveillance for molecular markers of anti-malarial resistance into routine therapeutic efficacy studies (TESs). In 2018, a TES of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) was conducted in Mozambique, and the prevalence of polymorphisms in the pfk13, pfcrt, and pfmdr1 genes associated with drug resistance was investigated. Methods Children aged 6–59 months were enrolled in four study sites. Blood was collected and dried on filter paper from participants who developed fever within 28 days of initial malaria treatment. All samples were first screened for Plasmodium falciparum using a multiplex real-time PCR assay, and polymorphisms in the pfk13, pfcrt, and pfmdr1 genes were investigated by Sanger sequencing. Results No pfk13 mutations, associated with artemisinin partial resistance, were observed. The only pfcrt haplotype observed was the wild type CVMNK (codons 72–76), associated with chloroquine sensitivity. Polymorphisms in pfmdr1 were only observed at codon 184, with the mutant 184F in 43/109 (39.4%) of the samples, wild type Y184 in 42/109 (38.5%), and mixed 184F/Y in 24/109 (22.0%). All samples possessed N86 and D1246 at these two codons. Conclusion In 2018, no markers of artemisinin resistance were documented. Molecular surveillance should continue to monitor the prevalence of these markers to inform decisions on malaria treatment in Mozambique.

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“…This resistance is caused by mutations of the kelch13 protein [2] and is characterized clinically by delayed parasitic clearance potentially leading to treatment failure of ACTs [3]. Initially discovered in South-East Asia, where they have become widespread [3], kelch13 mutations are now found in Africa, where they have recently been linked to in vitro resistances against artemisinin derivatives [4,5]. Thus, discovery of new antimalarial compounds with novel mechanisms of action is a priority in the battle against malaria.…”

Section: Introductionmentioning

confidence: 99%

2-Cyclopropyl-6-phenyl-2,3-dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one

Mustière

Vanelle

Primas

2021

Molbank

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As part of our ongoing scaffold hopping work on antimalarial 2-aminothieno[3,2-d]pyrimidin-4-one scaffold, we explored the dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one as a potential new antimalarial series. Using conditions found in the literature, we obtained 2-cyclopropyl-6-phenyl-2,3-dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one with 93% yield through a simple treatment. It was then characterized by NMR (1H and 13C) and HRMS. Given the structure of this molecule, its aqueous stability was assessed to determine its suitability for biological tests. To our knowledge, this is the first dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one described.

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

Cited by 282 publications

References 27 publications

Discrete Survival Model Analysis of Plasmodium falciparum Response to Artemisinin-Based Combination Therapies among Children in Regions of Varying Malaria Transmission in Cameroon

Discrete Survival Model Analysis of Plasmodium falciparum Response to Artemisinin-Based Combination Therapies among Children in Regions of Varying Malaria Transmission in Cameroon

Molecular surveillance for polymorphisms associated with artemisinin-based combination therapy resistance in Plasmodium falciparum isolates collected in Mozambique, 2018

2-Cyclopropyl-6-phenyl-2,3-dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one

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