Lack of K13 mutations in Plasmodium falciparum persisting after artemisinin combination therapy treatment of Kenyan children

Muwanguzi, Julian; Henriques, Gisela; Sawa, Patrick; Bousema, Teun; Sutherland, Colin J.; Beshir, Khalid B.

doi:10.1186/s12936-016-1095-y

Cited by 63 publications

(53 citation statements)

References 17 publications

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“…Firstly, parasite persistence and slow clearance in African studies are not associated with the pfk13 polymorphism [10,21]. Secondly, K13 variants do not determine parasite recurrence after treatment with the ACT DHA-piperaquine (DP), as recently reported for three sites in Vietnam [17].…”

Section: The Perceived Threat To Artemisinin-based Malaria Therapeuticsmentioning

confidence: 58%

“…Further studies of these candidate molecular markers for artemisinin susceptibility, including any yet to be identified, are keenly awaited. Certainly, there is no doubt that K13-independent artemisinin susceptibility phenotypes have arisen [10,36], and may continue to arise in the future, under universal selection pressure from ACT deployment worldwide. This threat makes it imperative that strategies to preserve the efficacy of our current regimens are vigorously pursued in the short term, as we await the next generation of antimalarial drugs [25].…”

Section: K13-independent Artemisinin Susceptibility Phenotypes In Plamentioning

confidence: 99%

“…• studies of the distribution of polymorphisms in the field, particularly in Africa [9][10][11][12][13];…”

Section: A New Artemisinin Susceptibility Phenotype Arises In Asiamentioning

confidence: 99%

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Genetic markers of artemisinin resistance in Plasmodium spp. parasites

Sutherland

2017

Emerging Topics in Life Sciences

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The vast majority of malaria patients worldwide are currently treated with combination therapy comprising one of the artemisinin family of drugs, characterised by rapid action and short plasma half-life, co-formulated with a longer-lasting drug from the amino arylalcohol or quinoline families. There is now a widely perceived threat to treatment efficacy, as reduced susceptibility to rapid artemisinin clearance in vivo has become prevalent among populations of Plasmodium falciparum in the Greater Mekong subregion since 2008. In vitro and in vivo drug selection studies, heterologous cell expression experiments and genetic epidemiology have identified many candidate markers of reduced ring-stage susceptibility to artemisinin. Certain variants of the P. falciparum pfk13 gene, which encodes a kelch domain protein implicated in the unfolded protein response, are strongly associated with slow parasite clearance by artemisinin in the Mekong subregion. However, anomalies in the epidemiological association of pfk13 variants with true treatment failure in vivo and the curious cell-cycle stage specificity of this phenotype in vitro warrant exploration in some depth. Taken together, available data suggest that the emergence of P. falciparum expressing K13 variants has not yet precipitated a public health emergency. Alternative candidate markers of artemisinin susceptibility are also described, as K13-independent treatment failure has been observed in African P. falciparum and in the rodent malaria parasite Plasmodium chabaudi.

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Section: The Perceived Threat To Artemisinin-based Malaria Therapeuticsmentioning

confidence: 58%

Section: K13-independent Artemisinin Susceptibility Phenotypes In Plamentioning

confidence: 99%

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Genetic markers of artemisinin resistance in Plasmodium spp. parasites

Sutherland

2017

Emerging Topics in Life Sciences

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“…8 But accumulation of data over time suggests that mutations in this gene vary geographically and mostly in accordance with the employed antimalarial regimens. [14][15][16][17][18][19][20][21] In a recent study, non-reference K13 mutations viz., 584V, 580Y, 574L, 568G, 553L, 543T, 539T, 493H, 481V, 449A, 255K, and 189T have been found involved in prolonged parasite clearance, and it was also stated that artemisinin resistance in SEA has emerged independently without sweeping from Cambodia. 22 In 2016, most of them became either validated or candidate K13 mutation for artemisinin resistance.…”

Section: Introductionmentioning

confidence: 99%

K13 Kelch Propeller Domain and mdr1 Sequence Polymorphism in Field Isolates From Northeast Region, India

Dutta¹,

Chetry²,

Kalita³

et al. 2017

HPD

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Emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia has made an intense warning to global malaria control programme since Southeast Asia is playing a key role in the evolution of drug resistant malaria parasites. Several polymorphisms in K13 gene have been designated with developing resistance either in vitro or in vivo. In this study, polymorphisms within K13 kelch propeller domain and Pf mdr1 gene were investigated in a total of 134 P. falciparum field isolates circulating in 3 states of Northeast region of India, namely, Assam, Arunachal Pradesh, and Tripura because information regarding this is limited from this region. Six polymorphisms were detected, out of which 2 were new. A481V mutation was found in 4.5% of the total field isolates. A675V and D702N new mutations were present in 3.7% and 1.5% isolates, respectively. Synonymous polymorphism at codon 703 was highly observed (6.7%) than other polymorphisms. N86Y allele in Pf mdr1 gene was also noticed in isolates that contained mutation in K13 propeller domain, but N86 wild-type allele was found comparatively higher in frequency within overall isolates. Moreover, both nucleotide and haplotype diversities in K13 gene were high in Arunachal Pradesh isolates than other 2 states. This is the first report from Northeast region of India with evidence of A675V candidate mutation along with 2 other new mutations which pays attention for further molecular surveillance in this region to document detailed scenario of K13 polymorphism pattern corresponding to artemisinin resistance.

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“…There is ample in vitro and in vivo evidence collected over the last 2 decades demonstrating that the susceptibility of P. falciparum to artemisinin is impacted by variants at a number of loci, including pfmdr1, pfcrt, pfap2mu, and pfubp1 (3-6). As a result, it can be readily argued that pfk13-indpendent mechanisms of reduced susceptibility to artemisinins may be developing in African settings (7).…”

mentioning

confidence: 99%