Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene

Zenglei Wang, Yingna Wang, Mynthia Cabrera Goss, Yanmei Zhang, Bhavna Gupta, Yanrui Wu, Karen Kemirembe, Yue Hu, Xiaoying Liang, Awtum Brashear, Sony Shrestha, Xiaolian Li, Jun Miao, Xiaodong Sun, Zhaoqing Yang, Liwang Cui

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Abstract

Artemisinin resistance in Plasmodium falciparum parasites in Southeast Asia is a major concern for malaria control. Its emergence at the China-Myanmar border, where there have been more than 3 decades of artemisinin use, has yet to be investigated. Here, we comprehensively evaluated the potential emergence of artemisinin resistance and antimalarial drug resistance status in P. falciparum using data and parasites from three previous efficacy studies in this region. These efficacy studies of dihydroartemisinin-piperaquine combination and artesunate monotherapy of uncomplicated falciparum malaria in 248 P. falciparum patients showed an overall 28-day adequate clinical and parasitological response of >95% and day 3 parasite-positive rates of 6.3 to 23.1%. Comparison of the 57 K13 sequences (24 and 33 from day 3 parasite-positive and - negative cases, respectively) identified nine point mutations in 38 (66.7%) samples, of which F446I (49.1%) and an N-terminal NN insertion (86.0%) were predominant. K13 propeller mutations collectively, the F446I mutation alone, and the NN insertion all were significantly associated with day 3 parasite positivity. Increased ring-stage survival determined using the ring-stage survival assay (RSA) was highly associated with the K13 mutant genotype. Day 3 parasite-positive isolates had ∼ 10 times higher ring survival rates than day 3 parasitenegative isolates. Divergent K13 mutations suggested independent evolution of artemisinin resistance. Taken together, this study confirmed multidrug resistance and emergence of artemisinin resistance in P. falciparum at the China-Myanmar border. RSA and K13 mutations are useful phenotypic and molecular markers for monitoring artemisinin resistance.

Original languageEnglish (US)
Pages (from-to)6952-6959
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number11
DOIs
StatePublished - Nov 1 2015

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Myanmar
China
Parasites
Plasmodium falciparum
Mutation
Genes
dihydroartemisinin
Survival
Southeastern Asia
Falciparum Malaria
Antimalarials
Multiple Drug Resistance
Point Mutation
Drug Resistance
Malaria
artemisinine
Survival Rate
Genotype

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Wang, Zenglei ; Wang, Yingna ; Cabrera Goss, Mynthia ; Zhang, Yanmei ; Gupta, Bhavna ; Wu, Yanrui ; Kemirembe, Karen ; Hu, Yue ; Liang, Xiaoying ; Brashear, Awtum ; Shrestha, Sony ; Li, Xiaolian ; Miao, Jun ; Sun, Xiaodong ; Yang, Zhaoqing ; Cui, Liwang. / Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene. In: Antimicrobial agents and chemotherapy. 2015 ; Vol. 59, No. 11. pp. 6952-6959.
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title = "Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene",
abstract = "Artemisinin resistance in Plasmodium falciparum parasites in Southeast Asia is a major concern for malaria control. Its emergence at the China-Myanmar border, where there have been more than 3 decades of artemisinin use, has yet to be investigated. Here, we comprehensively evaluated the potential emergence of artemisinin resistance and antimalarial drug resistance status in P. falciparum using data and parasites from three previous efficacy studies in this region. These efficacy studies of dihydroartemisinin-piperaquine combination and artesunate monotherapy of uncomplicated falciparum malaria in 248 P. falciparum patients showed an overall 28-day adequate clinical and parasitological response of >95{\%} and day 3 parasite-positive rates of 6.3 to 23.1{\%}. Comparison of the 57 K13 sequences (24 and 33 from day 3 parasite-positive and - negative cases, respectively) identified nine point mutations in 38 (66.7{\%}) samples, of which F446I (49.1{\%}) and an N-terminal NN insertion (86.0{\%}) were predominant. K13 propeller mutations collectively, the F446I mutation alone, and the NN insertion all were significantly associated with day 3 parasite positivity. Increased ring-stage survival determined using the ring-stage survival assay (RSA) was highly associated with the K13 mutant genotype. Day 3 parasite-positive isolates had ∼ 10 times higher ring survival rates than day 3 parasitenegative isolates. Divergent K13 mutations suggested independent evolution of artemisinin resistance. Taken together, this study confirmed multidrug resistance and emergence of artemisinin resistance in P. falciparum at the China-Myanmar border. RSA and K13 mutations are useful phenotypic and molecular markers for monitoring artemisinin resistance.",
author = "Zenglei Wang and Yingna Wang and {Cabrera Goss}, Mynthia and Yanmei Zhang and Bhavna Gupta and Yanrui Wu and Karen Kemirembe and Yue Hu and Xiaoying Liang and Awtum Brashear and Sony Shrestha and Xiaolian Li and Jun Miao and Xiaodong Sun and Zhaoqing Yang and Liwang Cui",
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Wang, Z, Wang, Y, Cabrera Goss, M, Zhang, Y, Gupta, B, Wu, Y, Kemirembe, K, Hu, Y, Liang, X, Brashear, A, Shrestha, S, Li, X, Miao, J, Sun, X, Yang, Z & Cui, L 2015, 'Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene', Antimicrobial agents and chemotherapy, vol. 59, no. 11, pp. 6952-6959. https://doi.org/10.1128/AAC.01255-15

Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene. / Wang, Zenglei; Wang, Yingna; Cabrera Goss, Mynthia; Zhang, Yanmei; Gupta, Bhavna; Wu, Yanrui; Kemirembe, Karen; Hu, Yue; Liang, Xiaoying; Brashear, Awtum; Shrestha, Sony; Li, Xiaolian; Miao, Jun; Sun, Xiaodong; Yang, Zhaoqing; Cui, Liwang.

In: Antimicrobial agents and chemotherapy, Vol. 59, No. 11, 01.11.2015, p. 6952-6959.

Research output: Contribution to journalArticle

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T1 - Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene

AU - Wang, Zenglei

AU - Wang, Yingna

AU - Cabrera Goss, Mynthia

AU - Zhang, Yanmei

AU - Gupta, Bhavna

AU - Wu, Yanrui

AU - Kemirembe, Karen

AU - Hu, Yue

AU - Liang, Xiaoying

AU - Brashear, Awtum

AU - Shrestha, Sony

AU - Li, Xiaolian

AU - Miao, Jun

AU - Sun, Xiaodong

AU - Yang, Zhaoqing

AU - Cui, Liwang

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Artemisinin resistance in Plasmodium falciparum parasites in Southeast Asia is a major concern for malaria control. Its emergence at the China-Myanmar border, where there have been more than 3 decades of artemisinin use, has yet to be investigated. Here, we comprehensively evaluated the potential emergence of artemisinin resistance and antimalarial drug resistance status in P. falciparum using data and parasites from three previous efficacy studies in this region. These efficacy studies of dihydroartemisinin-piperaquine combination and artesunate monotherapy of uncomplicated falciparum malaria in 248 P. falciparum patients showed an overall 28-day adequate clinical and parasitological response of >95% and day 3 parasite-positive rates of 6.3 to 23.1%. Comparison of the 57 K13 sequences (24 and 33 from day 3 parasite-positive and - negative cases, respectively) identified nine point mutations in 38 (66.7%) samples, of which F446I (49.1%) and an N-terminal NN insertion (86.0%) were predominant. K13 propeller mutations collectively, the F446I mutation alone, and the NN insertion all were significantly associated with day 3 parasite positivity. Increased ring-stage survival determined using the ring-stage survival assay (RSA) was highly associated with the K13 mutant genotype. Day 3 parasite-positive isolates had ∼ 10 times higher ring survival rates than day 3 parasitenegative isolates. Divergent K13 mutations suggested independent evolution of artemisinin resistance. Taken together, this study confirmed multidrug resistance and emergence of artemisinin resistance in P. falciparum at the China-Myanmar border. RSA and K13 mutations are useful phenotypic and molecular markers for monitoring artemisinin resistance.

AB - Artemisinin resistance in Plasmodium falciparum parasites in Southeast Asia is a major concern for malaria control. Its emergence at the China-Myanmar border, where there have been more than 3 decades of artemisinin use, has yet to be investigated. Here, we comprehensively evaluated the potential emergence of artemisinin resistance and antimalarial drug resistance status in P. falciparum using data and parasites from three previous efficacy studies in this region. These efficacy studies of dihydroartemisinin-piperaquine combination and artesunate monotherapy of uncomplicated falciparum malaria in 248 P. falciparum patients showed an overall 28-day adequate clinical and parasitological response of >95% and day 3 parasite-positive rates of 6.3 to 23.1%. Comparison of the 57 K13 sequences (24 and 33 from day 3 parasite-positive and - negative cases, respectively) identified nine point mutations in 38 (66.7%) samples, of which F446I (49.1%) and an N-terminal NN insertion (86.0%) were predominant. K13 propeller mutations collectively, the F446I mutation alone, and the NN insertion all were significantly associated with day 3 parasite positivity. Increased ring-stage survival determined using the ring-stage survival assay (RSA) was highly associated with the K13 mutant genotype. Day 3 parasite-positive isolates had ∼ 10 times higher ring survival rates than day 3 parasitenegative isolates. Divergent K13 mutations suggested independent evolution of artemisinin resistance. Taken together, this study confirmed multidrug resistance and emergence of artemisinin resistance in P. falciparum at the China-Myanmar border. RSA and K13 mutations are useful phenotypic and molecular markers for monitoring artemisinin resistance.

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