K13 propeller mutations in Plasmodium falciparum populations in regions of malaria endemicity in Vietnam from 2009 to 2016

Nguyen Thuy-Nhien, Nguyen Kim Tuyen, Nguyen Thanh Tong, Nguyen Tuong Vy, Ngo Viet Thanh, Huynh Thuy Van, Pham Huong-Thu, Huynh Hong Quang, Maciej F. Boni, Christiane Dolecek, Jeremy Farrar, Guy E. Thwaites, Olivo Miotto, Nicholas J. White, Tran Tinh Hien

Research output: Contribution to journalArticle

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Abstract

The spread of artemisinin-resistant Plasmodium falciparum compromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT for P. falciparum infection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060 P. falciparum isolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29% (222/767), 6% (11/188), and 43% (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1% (34/43) of isolates in Binh Phuoc Province and 63% (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA) in vitro and prolonged parasite clearance in vivo. An analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.

Original languageEnglish (US)
Article numbere01578-16
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number4
DOIs
StatePublished - Apr 1 2017

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Vietnam
Plasmodium falciparum
dihydroartemisinin
Malaria
Mutation
Population
Haplotypes
Parasites
Therapeutics
Genotype
artemisinine
Genes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Thuy-Nhien, Nguyen ; Tuyen, Nguyen Kim ; Tong, Nguyen Thanh ; Vy, Nguyen Tuong ; Thanh, Ngo Viet ; Van, Huynh Thuy ; Huong-Thu, Pham ; Quang, Huynh Hong ; Boni, Maciej F. ; Dolecek, Christiane ; Farrar, Jeremy ; Thwaites, Guy E. ; Miotto, Olivo ; White, Nicholas J. ; Hien, Tran Tinh. / K13 propeller mutations in Plasmodium falciparum populations in regions of malaria endemicity in Vietnam from 2009 to 2016. In: Antimicrobial agents and chemotherapy. 2017 ; Vol. 61, No. 4.
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title = "K13 propeller mutations in Plasmodium falciparum populations in regions of malaria endemicity in Vietnam from 2009 to 2016",
abstract = "The spread of artemisinin-resistant Plasmodium falciparum compromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT for P. falciparum infection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060 P. falciparum isolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29{\%} (222/767), 6{\%} (11/188), and 43{\%} (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1{\%} (34/43) of isolates in Binh Phuoc Province and 63{\%} (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA) in vitro and prolonged parasite clearance in vivo. An analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.",
author = "Nguyen Thuy-Nhien and Tuyen, {Nguyen Kim} and Tong, {Nguyen Thanh} and Vy, {Nguyen Tuong} and Thanh, {Ngo Viet} and Van, {Huynh Thuy} and Pham Huong-Thu and Quang, {Huynh Hong} and Boni, {Maciej F.} and Christiane Dolecek and Jeremy Farrar and Thwaites, {Guy E.} and Olivo Miotto and White, {Nicholas J.} and Hien, {Tran Tinh}",
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Thuy-Nhien, N, Tuyen, NK, Tong, NT, Vy, NT, Thanh, NV, Van, HT, Huong-Thu, P, Quang, HH, Boni, MF, Dolecek, C, Farrar, J, Thwaites, GE, Miotto, O, White, NJ & Hien, TT 2017, 'K13 propeller mutations in Plasmodium falciparum populations in regions of malaria endemicity in Vietnam from 2009 to 2016', Antimicrobial agents and chemotherapy, vol. 61, no. 4, e01578-16. https://doi.org/10.1128/AAC.01578-16

K13 propeller mutations in Plasmodium falciparum populations in regions of malaria endemicity in Vietnam from 2009 to 2016. / Thuy-Nhien, Nguyen; Tuyen, Nguyen Kim; Tong, Nguyen Thanh; Vy, Nguyen Tuong; Thanh, Ngo Viet; Van, Huynh Thuy; Huong-Thu, Pham; Quang, Huynh Hong; Boni, Maciej F.; Dolecek, Christiane; Farrar, Jeremy; Thwaites, Guy E.; Miotto, Olivo; White, Nicholas J.; Hien, Tran Tinh.

In: Antimicrobial agents and chemotherapy, Vol. 61, No. 4, e01578-16, 01.04.2017.

Research output: Contribution to journalArticle

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T1 - K13 propeller mutations in Plasmodium falciparum populations in regions of malaria endemicity in Vietnam from 2009 to 2016

AU - Thuy-Nhien, Nguyen

AU - Tuyen, Nguyen Kim

AU - Tong, Nguyen Thanh

AU - Vy, Nguyen Tuong

AU - Thanh, Ngo Viet

AU - Van, Huynh Thuy

AU - Huong-Thu, Pham

AU - Quang, Huynh Hong

AU - Boni, Maciej F.

AU - Dolecek, Christiane

AU - Farrar, Jeremy

AU - Thwaites, Guy E.

AU - Miotto, Olivo

AU - White, Nicholas J.

AU - Hien, Tran Tinh

PY - 2017/4/1

Y1 - 2017/4/1

N2 - The spread of artemisinin-resistant Plasmodium falciparum compromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT for P. falciparum infection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060 P. falciparum isolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29% (222/767), 6% (11/188), and 43% (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1% (34/43) of isolates in Binh Phuoc Province and 63% (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA) in vitro and prolonged parasite clearance in vivo. An analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.

AB - The spread of artemisinin-resistant Plasmodium falciparum compromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT for P. falciparum infection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060 P. falciparum isolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29% (222/767), 6% (11/188), and 43% (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1% (34/43) of isolates in Binh Phuoc Province and 63% (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA) in vitro and prolonged parasite clearance in vivo. An analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.

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