Plasmodium falciparum Founder Populations in Western Cambodia Have Reduced Artemisinin Sensitivity
            <i>In Vitro</i>

Amaratunga, Chanaki; Witkowski, Benoît; Dek, Dalin; Try, Vorleak; Khim, Nimol; Miotto, Olivo; Ménard, Didier; Fairhurst, Rick M.

doi:10.1128/aac.03055-14

Cited by 47 publications

(41 citation statements)

References 17 publications

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“…45 In the KARMA study, 8 nonsynonymous mutations that were observed in Southeast Asia and China — F446I, N458Y, N537D, R539T, I543T, P553L, P574L, and C580Y — were associated with positive results on day 3, findings that were consistent with data from previous studies that used parasite-clearance half-lives to identify artemisinin resistance 12,14,24,26–28 and that provide further evidence of the positivity rate on day 3 as a sensitive indicator of clinical resistance to artemisinins.…”

Section: Discussionsupporting

confidence: 86%

“…The recent discovery of mutations in portions of a P. falciparum gene encoding kelch (K13)–propeller domains as the primary determinant of artemisinin resistance provided unprecedented opportunities for improving resistance monitoring. 24,25 To date, 13 independent K13 mutations have been shown to be associated with clinical resistance, 3,12,14,26–28 with evidence of independent emergence of the same mutation in different geographic areas. 28,29 Four Asian mutations (C580Y, R539T, I543T, and Y493H) have been validated in vitro.…”

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confidence: 99%

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A Worldwide Map ofPlasmodium falciparumK13-Propeller Polymorphisms

Ménard¹,

Khim²,

Beghain³

et al. 2016

N Engl J Med

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493

596

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BACKGROUND Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)–propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale. METHODS We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci. RESULTS We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas — one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China — with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay. CONCLUSIONS No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral.

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

A Worldwide Map ofPlasmodium falciparumK13-Propeller Polymorphisms

Ménard¹,

Khim²,

Beghain³

et al. 2016

N Engl J Med

Self Cite

493

596

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“…33 Survival rates in the RSA were also strongly correlated with clinical phenotype (half-life for parasite clearance). 31,34 A molecular marker. The molecular signatures associated with resistance to artemisinins were then investigated by sequencing the exome of an African strain (F32-Tanzania) that became resistant to artemisinin after repeated exposure to increasing concentrations of the drug over a period of 5 years (F32-ART).…”

Section: Resistance To Artemisinin Derivatives: Past and Present Resementioning

confidence: 99%

Plasmodium falciparum Resistance to Artemisinin Derivatives and Piperaquine: A Major Challenge for Malaria Elimination in Cambodia

Duru

Witkowski

Ménard

2016

The American Society of Tropical Medicine and Hygiene

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Abstract. Artemisinin-based combination therapies (ACTs) are the cornerstone of current strategies for fighting malaria. Over the last decade, ACTs have played a major role in decreasing malaria burden. However, this progress is being jeopardized by the emergence of artemisinin-resistant Plasmodium falciparum parasites. Artemisinin resistance was first detected in western Cambodia in 2008 and has since been observed in neighboring countries in southeast Asia. The problem of antimalarial drug resistance has recently worsened in Cambodia, with reports of parasites resistant to piperaquine, the latest generation of partner drug used in combination with dihydroartemisinin, leading to worrying rates of clinical treatment failure. The monitoring and the comprehension of both types of resistance are crucial to prevent the spread of multidrug-resistant parasites outside southeast Asia, and particularly to Africa, where the public health consequences would be catastrophic. To this end, new tools are required for studying the biological and molecular mechanisms underlying resistance to antimalarial drugs and for monitoring the geographic distribution of the resistant parasites. In this review, we detail the major advances in our understanding of resistance to artemisinin and piperaquine and define the challenges that the malaria community will have to face in the coming years. BACKGROUND

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“…These groups of highly-differentiated, clonal subpopulations are as different from each other as each of them is to African parasites, suggesting they have undergone extreme recent bottlenecking and subsequent expansion. Second, seven of the 11 founders were found to be artemisinin-resistant in patients [44, 45], and three of them were additionally confirmed to be artemisinin-resistant in the RSA 0–3h [23], suggesting that most of them were naturally selected by artemisinin. Third, each founder was tagged by a single K13-propeller mutation, with the C580Y mutation independently emerging on three different founders in Cambodia.…”

Section: What Are the Genetic Determinants Of Artemisinin Resistance?mentioning

confidence: 99%

Understanding artemisinin-resistant malaria

Fairhurst

2015

Current Opinion in Infectious Diseases

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Purpose of review The emergence of artemisinin resistance in Southeast Asia, where artemisinin combination therapies (ACTs) are beginning to fail, threatens global endeavors to control and eliminate Plasmodium falciparum malaria. Future efforts to prevent the spread of this calamity to Africa will benefit from last year’s tremendous progress in understanding artemisinin resistance. Recent findings Multiple international collaborations have established that artemisinin resistance is associated with slow parasite clearance in patients; increased survival of early ring-stage parasites in vitro; single-nucleotide polymorphisms (SNPs) in the parasite’s ‘K13’ gene; parasite ‘founder’ populations sharing a genetic background of four additional SNPs; parasite transcriptional profiles reflecting an “unfolded protein response” and decelerated parasite development; and elevated parasite phosphatidylinositol-3-kinase activity. In Western Cambodia, where the K13 C580Y mutation is approaching fixation, the frontline ACT is failing to cure nearly half of patients, likely due to partner drug resistance. In Africa, where dozens of K13 mutations have been detected at low frequency, there is no evidence yet of artemisinin resistance. Summary In Southeast Asia, clinical and epidemiological investigations are urgently needed to stop the further spread of artemisinin resistance; monitor ACT efficacy where K13 mutations are prevalent; identify currently-available drug regimens that cure ACT failures; and rapidly advance new antimalarial compounds through clinical trials.

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Plasmodium falciparum Founder Populations in Western Cambodia Have Reduced Artemisinin Sensitivity In Vitro

Cited by 47 publications

References 17 publications

A Worldwide Map ofPlasmodium falciparumK13-Propeller Polymorphisms

A Worldwide Map ofPlasmodium falciparumK13-Propeller Polymorphisms

Plasmodium falciparum Resistance to Artemisinin Derivatives and Piperaquine: A Major Challenge for Malaria Elimination in Cambodia

Understanding artemisinin-resistant malaria

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