Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene.
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 parasite-negative 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.
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Zenglei
Z
Wang
Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, China.
Yingna
Y
Wang
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Mynthia
M
Cabrera
Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, China.
Yanmei
Y
Zhang
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Bhavna
B
Gupta
Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, China.
Yanrui
Y
Wu
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Karen
K
Kemirembe
Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, China.
Yue
Y
Hu
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Xiaoying
X
Liang
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Awtum
A
Brashear
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Sony
S
Shrestha
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Xiaolian
X
Li
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Jun
J
Miao
Yunnan Institute of Parasitic Diseases, Puer, Yunnan Province, China.
Xiaodong
X
Sun
Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, China.
Zhaoqing
Z
Yang
Department of Entomology, The Pennsylvania State University, University Park, Pennsylvania, USA luc2@psu.edu.
Liwang
L
Cui
D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D002681:China; D018432:Drug Resistance, Multiple / Q000235:genetics; D005838:Genotype; D016778:Malaria, Falciparum / Q000188:drug therapy; D009154:Mutation; D002052:Myanmar; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000472:pathogenicity; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines
D037621:Artemisinins; D011804:Quinolines; C039060:artenimol; C031327:artemisinin; C034759:piperaquine; D010879:Piperazines