Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review

Kayiba, Nadine Kalenda; Yobi, Doudou Malekita; Tshibangu‐Kabamba, Evariste; Tuan, Vo Phuoc; Yamaoka, Yoshio; Devleesschauwer, Brecht; Mvumbi, Dieudonné Makaba; Wemakoy, Emile Okitolonda; Mol, Patrick De; Mvumbi, Georges Lelo; Hayette, Marie‐Pierre; Aguirre, Ángel Rosas; Speybroeck, Niko

doi:10.1016/s1473-3099(20)30493-x

Cited by 48 publications

(44 citation statements)

References 88 publications

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“…Furthermore, with a relatively small number of antimalarials in use ( WHO Report on antimalarial efficacy, 2020 ) and the importance of ACTs to malaria control efforts in Africa, Pfk13 mutants should be closely and systematically monitored in Africa. Numerous studies have been published examining Pfk13 mutations across the continent ( Kamau et al, 2015 ; Kayiba et al, 2020 ). A recent study conducted by Uwimana et al (2020) , between 2012 and 2015 in Rwanda, highlighted the local emergence of an ART resistance validated mutation, R561H.…”

Section: Molecular Epidemiologymentioning

confidence: 99%

“…Recently, a systematic review identified Pfk13 mutations across Africa that have been associated with ART resistance, though at low frequencies ( Kayiba et al, 2020 ). Here we present data of Pfk13 propeller domain mutations from >70 studies based on the PRISMA guidelines ( Fig.…”

Section: Summary Of the Pfk13 Mutations From The Extracted Literaturementioning

confidence: 99%

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A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa

Ndwiga

Kimenyi

Wamae

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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Artemisinin resistance (AR) emerged in South East Asia 13 years ago and the identification of the resistance conferring molecular marker, Plasmodium falciparum Kelch 13 ( Pfk13) , 7 years ago has provided an invaluable tool for monitoring AR in malaria endemic countries. Molecular Pfk13 surveillance revealed the resistance foci in the Greater Mekong Subregion, an independent emergence in Guyana, South America, and a low frequency of mutations in Africa. The recent identification of the R561H Pfk1 3 AR associated mutation in Tanzania, Uganda and in Rwanda, where it has been associated with delayed parasite clearance, should be a concern for the continent. In this review, we provide a summary of Pfk13 resistance associated propeller domain mutation frequencies across Africa from 2012 to 2020, to examine how many other countries have identified these mutations. Only four African countries reported a recent identification of the M476I, P553L, R561H, P574L, C580Y and A675V Pfk13 mutations at low frequencies and with no reports of clinical treatment failure, except for Rwanda. These mutations present a threat to malaria control across the continent, since the greatest burden of malaria remains in Africa. A rise in the frequency of these mutations and their spread would reverse the gains made in the reduction of malaria over the last 20 years, given the lack of new antimalarial treatments in the event artemisinin-based combination therapies fail. The review highlights the frequency of Pfk13 propeller domain mutations across Africa, providing an up-to-date perspective of Pfk13 mutations, and appeals for an urgent and concerted effort to monitoring antimalarial resistance markers in Africa and the efficacy of antimalarials by re-establishing sentinel surveillance systems.

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Section: Molecular Epidemiologymentioning

confidence: 99%

Section: Summary Of the Pfk13 Mutations From The Extracted Literaturementioning

confidence: 99%

A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa

Ndwiga

Kimenyi

Wamae

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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“…Since African pfk13-propeller mutations were shown to be different from those found in Southeast Asia, further molecular and biochemical studies should investigate whether other factors such as additional mutations could be associated with altered functions of the PFK13 protein, resulting in altered ART sensitivity. However, some of the validated and candidate mutations associated with ART resistance in Southeast Asia have been detected in the DRC [11,26] and in some neighbouring countries, such as Rwanda [8,9] and Uganda [10], providing evidence of de novo emergence of ART resistance in sub-Saharan Africa. Thus, surveillance must be strengthened to avoid the worst.…”

Section: Discussionmentioning

confidence: 99%

“…These mutations have spread within the Greater Mekong Subregion of Southeast Asia and have been classified as validated markers and candidate/associated markers of ART resistance [7]. Some of these mutations are increasingly being detected in sub-Saharan African countries, providing evidence for de novo emergence of resistance to artemisinin in Africa [8][9][10][11]. Mutations in the chloroquine resistance transporter gene (pfcrt) originally identified as a marker of CQ resistance, have also been associated with resistance to amodiaquine (AQ) [12].…”

Section: Introductionmentioning

confidence: 99%

Assessment of Plasmodium falciparum anti-malarial drug resistance markers in pfk13-propeller, pfcrt and pfmdr1 genes in isolates from treatment failure patients in Democratic Republic of Congo, 2018–2019

Yobi

Kayiba

Mvumbi

et al. 2021

Malar J

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Background The national policy for malaria treatment of the Democratic Republic of Congo recommends two first-line artemisinin-based combinations for the treatment of uncomplicated malaria: artesunate-amodiaquine and artemether-lumefantrine. This study investigated the presence of markers associated with resistance to the current first-line artemisinin-based combination therapy (ACT) in isolates of Plasmodium falciparum from treatment failure patients in the Democratic Republic of Congo. Methods From November 2018 to November 2019, dried blood spots were taken from patients returning to health centres for fever within 28 days after an initial malaria treatment in six sentinel sites of the National Malaria Control Programme across Democratic Republic of Congo. The new episode of malaria was first detected by a rapid diagnostic test and then confirmed by a real-time PCR assay to define treatment failure. Fragments of interest in pfk13 and pfcrt genes were amplified by conventional PCR before sequencing and the Pfmdr1 gene copy number was determined by a TaqMan real-time PCR assay. Results Out of 474 enrolled patients, 364 (76.8%) were confirmed positive by PCR for a new episode of P. falciparum malaria, thus considered as treatment failure. Of the 325 P. falciparum isolates obtained from 364 P. falciparum-positive patients and successfully sequenced in the pfk13-propeller gene, 7 (2.2%) isolates carried non-synonymous mutations, among which 3 have been previously reported (N498I, N554K and A557S) and 4 had not yet been reported (F506L, E507V, D516E and G538S). Of the 335 isolates successfully sequenced in the pfcrt gene, 139 (41.5%) harboured the K76T mutation known to be associated with chloroquine resistance. The SVMNT haplotype associated with resistance to amodiaquine was not found. None of the isolates carried an increased copy number of the pfmdr1 gene among the 322 P. falciparum isolates successfully analysed. Conclusion No molecular markers currently known to be associated with resistance to the first-line ACT in use were detected in isolates of P. falciparum from treatment failure patients. Regular monitoring through in vivo drug efficacy and molecular studies must continue to ensure the effectiveness of malaria treatment in Democratic Republic of Congo.

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“…In a recent study, F446I yielded no significant in vitro resistance in 3D7 parasites, although similar to our data this mutation was fitness-neutral (Siddiqui et al ., 2020). Of note, all four of these mutations, and others including C469Y, R622I and A675V, have now been detected in Africa and merit gene editing experiments in African strains (Warsame et al ., 2019; Asua et al ., 2020; Kayiba et al ., 2020).…”

Section: Discussionmentioning

confidence: 99%

P. falciparumK13 mutations present varying degrees of artemisinin resistance and reduced fitness in African parasites

Stokes

Rubiano

Dhingra

et al. 2021

Preprint

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The emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites, driven by K13 mutations, has led to widespread antimalarial treatment failure in Southeast Asia. In Africa, our genotyping of 3,299 isolates confirms the emergence of the K13 R561H variant in Rwanda and reveals the continuing dominance of wild-type K13 across 11 countries. We show that this mutation, along with M579I and C580Y, confers varying degrees of in vitro ART resistance in African parasites. C580Y and M579I cause substantial fitness costs, which may counter-select against their dissemination in high-transmission settings. We also define the impact of multiple K13 mutations on ART resistance and fitness in multiple Southeast Asian strains. ART susceptibility is unaltered upon editing point mutations in ferrodoxin or mdr2, earlier resistance markers. These data point to the lack of an evident biological barrier to mutant K13 mediating ART resistance in Africa, while identifying their detrimental impact on parasite growth.

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Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review

Cited by 48 publications

References 88 publications

A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa

A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa

Assessment of Plasmodium falciparum anti-malarial drug resistance markers in pfk13-propeller, pfcrt and pfmdr1 genes in isolates from treatment failure patients in Democratic Republic of Congo, 2018–2019

P. falciparumK13 mutations present varying degrees of artemisinin resistance and reduced fitness in African parasites

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