Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia

作者：Angana Mukherjee, Selina Bopp, Pamela Magistrado, Wesley Wong, Rachel F. Daniels, Allison Demas, S. F. Schaffner, Chanaki Amaratunga, Pharath Lim, Mehul Dhorda, Olivo Miotto, Charles J. Woodrow, Elizabeth A. Ashley, Arjen M. Dondorp, Nicholas J. White, Dyann F. Wirth, Rick M. Fairhurst, Sarah K. Volkman · 发表于：Malaria Journal · 年份：2017 · DOI：10.1186/s12936-017-1845-5 · 被引用次数：150 · 研究领域：Malaria Research and Control、Historical Medical Research and Treatments、Pharmaceutical Quality and Counterfeiting

Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin–piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA 0–3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. Among these 36 parasites one isolate demonstrated increased ring-stage survival for a Pf Kelch13 mutation (D584V, RSA 0–3h = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V Pf Kelch13 mutation with increased ring-stage survival and...