Role of K13 Mutations in Artemisinin-Based Combination Therapy

Rasmussen, Charlotte; Ariey, Frédéric; Fairhurst, Rick M.; Ringwald, Pascal; Ménard, Didier

doi:10.1093/cid/ciw641

Cited by 4 publications

(5 citation statements)

References 8 publications

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“…Likewise, our limited surveillance of the Pfkelch13 limits our conclusions regarding artemisinin resistance in Senegal. Although we did not detect significant levels of either Pfkelch13 C580Y or Pfkelch13 A578S in Senegal, we did not examine the other mutations associated with delayed clearance in the Pfkelch13 propeller domain in our SNP-based molecular surveillance [46][47][48] or the Pfkelch13 C439Y and A675Y mutations observed in Uganda [49][50][51] . Expanding molecular surveillance to include amplicon-based 52 approaches to genotype the entire Pfkelch13 propeller domain would allow for better assessments of growing artemisinin resistance risk in Senegal.…”

Section: Haplotype Analyses Reveal Temporal Changes In Selection At P...mentioning

confidence: 71%

Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention

Ndiaye

Wong

Thwing

et al. 2023

Preprint

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Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. We analyzed data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasite strains in Senegal to determine how historical changes in drug administration policy may have affected parasite evolution. We profiled several known drug resistance markers and their surrounding haplotypes using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole-genome sequence (WGS) based population genomics. We observed rapid changes in drug resistance markers associated with the withdrawal of chloroquine and introduction of sulfadoxine-pyrimethamine in 2003. We also observed a rapid increase in Pfcrt K76T and decline in Pfdhps A437G starting in 2014, which we hypothesize may reflect changes in resistance or fitness caused by seasonal malaria chemoprevention (SMC). Parasite populations evolve rapidly in response to drug use, and SMC preventive efficacy should be closely monitored.

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Section: Haplotype Analyses Reveal Temporal Changes In Selection At P...mentioning

confidence: 71%

Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention

Ndiaye

Wong

Thwing

et al. 2023

Preprint

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“…When examining mutations associated with ART resistance, this study was limited to only those mutations in the Pfkelch13 propeller domain. With the exception of Pfkelch13 A578S, no other mutations in the Pfkelch13 propeller domain were observed [ 20 – 22 ]. A previous study using targeted deep amplicon sequencing performed on the Pfkelch13 gene in Senegalese parasites did not identify any additional mutations associated with ART resistance [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the multi-drug resistance Pfmdr1 gene that have been associated with resistance against many drugs, including amodiaquine (AQ), mefloquine, quinine, lumefantrine and other quinolines [ 17 – 19 ]. Mutations in the kelch propeller domain gene Pfkelch13 have been associated with ART resistance and delayed parasite clearance [ 3 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Based on the historical anti-malarial policy in Senegal, this study focused surveying WHO-validated and verified [ 4 ] SNPs in Pfcrt, Pfdhfr, Pfdhps, and Pfmdr1 associated with resistance to CQ, AQ, and SP [ 3 ]. Molecular surveillance of Pfkelch13 was started in 2015 in response to the emergence of Pfkelch13 C580Y as a marker associated with partial ART resistance markers in Southeast Asia [ 20 – 22 ] and to monitor the frequency of Pfkelch13 A578S, which is no longer considered to be associated with resistance but at the time was the most frequent mutation reported in Africa [ 23 ]. The goal of this study was to determine whether there were changes in parasite population genetics that could serve as an early warning sign for emerging drug resistance or changes in parasite fitness.…”

Section: Introductionmentioning

confidence: 99%

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Two decades of molecular surveillance in Senegal reveal rapid changes in known drug resistance mutations over time

Ndiaye,

Wong,

Thwing

et al. 2024

Malar J

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Background Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. Pathogen genomic surveillance could be invaluable for monitoring current and emerging parasite drug resistance. Methods Data from two decades (2000–2020) of continuous molecular surveillance of P. falciparum parasites from Senegal were retrospectively examined to assess historical changes in malaria drug resistance mutations. Several known drug resistance markers and their surrounding haplotypes were profiled using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole genome sequence based population genomics. Results This dataset was used to track temporal changes in drug resistance markers whose timing correspond to historically significant events such as the withdrawal of chloroquine (CQ) and the introduction of sulfadoxine-pyrimethamine (SP) in 2003. Changes in the mutation frequency at Pfcrt K76T and Pfdhps A437G coinciding with the 2014 introduction of seasonal malaria chemoprevention (SMC) in Senegal were observed. In 2014, the frequency of Pfcrt K76T increased while the frequency of Pfdhps A437G declined. Haplotype-based analyses of Pfcrt K76T showed that this rapid increase was due to a recent selective sweep that started after 2014. Discussion (Conclusion) The rapid increase in Pfcrt K76T is troubling and could be a sign of emerging amodiaquine (AQ) resistance in Senegal. Emerging AQ resistance may threaten the future clinical efficacy of artesunate-amodiaquine (ASAQ) and AQ-dependent SMC chemoprevention. These results highlight the potential of molecular surveillance for detecting rapid changes in parasite populations and stress the need to monitor the effectiveness of AQ as a partner drug for artemisinin-based combination therapy (ACT) and for chemoprevention.

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“…Mefloquine resistance is associated with increased copy number of the pfmdr1 gene, 57 while piperaquine resistance is associated with increased copy number of the plasmepsin II/III genes, 58 , 59 which tends to occur in the presence of a single copy pfmdr1 . 59 Consistent with this observation, geographic areas with highly prevalent piperaquine resistance have shown less prevalent mefloquine resistance, 60 , 61 although a recent study suggests possible emergence of triple mutant parasites containing both amplified plasmepsin II and pfmdr1 , as well as kelch13 C580Y. 62 The hypothesis of antagonistic resistance to these important partner drugs forms the rationale for triple combination therapy including an artemisinin derivative paired with both mefloquine and piperaquine.…”

Section: Which Drug Combinations Are Ideal For Mda In Regions With Mumentioning

confidence: 90%

Multidrug-resistant malaria and the impact of mass drug administration

Zuber

Takala-Harrison

2018

IDR

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Based on the emergence and spread throughout the Greater Mekong Subregion (GMS) of multiple artemisinin-resistant lineages, the prevalence of multidrug resistance leading to high rates of artemisinin-based combination treatment failure in parts of the GMS, and the declining malaria burden in the region, the World Health Organization has recommended complete elimination of falciparum malaria from the GMS. Mass drug administration (MDA) is being piloted as one elimination intervention to be employed as part of this effort. However, concerns remain as to whether MDA might exacerbate the already prevalent problem of multidrug resistance in the region. In this review, we briefly discuss challenges of MDA, the use of MDA in the context of multidrug-resistant malaria, and the potential of different drug combinations and drug-based elimination strategies for mitigating the emergence and spread of resistance.

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Role of K13 Mutations in Artemisinin-Based Combination Therapy

Cited by 4 publications

References 8 publications

Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention

Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention

Two decades of molecular surveillance in Senegal reveal rapid changes in known drug resistance mutations over time

Multidrug-resistant malaria and the impact of mass drug administration

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