Si Yu, Zeng Weilin, Li Na, Wang Chengqi, Siddiqui Faiza, Zhang Jie, Pi Liang, He Xi, Zhao Luyi, Wang Siqi, Zhao Hui, Li Xinxin, Yang Qi, Miao Jun, Yang Zhaoqing, Cui Liwang
Department of Pathogen Biology and Immunology, Kunming Medical University, Yunnan Province, China, Yunnan Province, China.
Department of Internal Medicine, Morsani College of Medicine, University of South Florida, 3720 Spectrum Boulevard, Suite 304, Tampa, FL, USA.
Antimicrob Agents Chemother. 2023 May 1;65(5). doi: 10.1128/AAC.02305-20. Epub 2021 Mar 8.
from the Greater Mekong subregion has evolved resistance to the artemisinin-based combination therapy dihydroartemisinin and the partner drug piperaquine. To monitor the potential westward spread or independent evolution of piperaquine resistance, we evaluated the susceptibility of 120 isolates collected at the China-Myanmar border during 2007-2016. The parasite isolates displayed a relatively wide range of piperaquine susceptibility estimates. While 56.7% of the parasites showed bimodal drug response curves, all but five generated area-under-the-curve (AUC) estimates consistent with a susceptible phenotype. Using the piperaquine survival assay (PSA), 5.6% parasites showed reduced susceptibility. Of note, parasites from 2014-2016 showed the highest AUC value and the highest proportion with a bimodal curve, suggesting falling effectiveness in these later years. Unsupervised K-mean analysis of the combined data assigned parasites into three clusters and identified significant correlations between IC, IC and AUC values. No parasites carried the E415G mutation in a putative exo-nuclease, new mutations in PfCRT, or amplification of the genes, suggesting mechanisms of reduced piperaquine susceptibility that differ from those described in other countries of the region. The association of increased AUC, IC, and IC values with major PfK13 mutations (F446I and G533S) suggests that piperaquine resistance may evolve in these PfK13 genetic backgrounds. Additionally, the Pfmdr1 F1226Y mutation was associated with significantly higher PSA values. Further elucidation of piperaquine resistance mechanisms and continuous surveillance are warranted.
来自大湄公河次区域的疟原虫已对基于青蒿素的联合疗法双氢青蒿素及辅助药物哌喹产生耐药性。为监测哌喹耐药性可能出现的向西传播或独立演变情况，我们评估了2007年至2016年在中国 - 缅甸边境收集的120株疟原虫分离株的敏感性。这些疟原虫分离株显示出哌喹敏感性估计值的范围相对较宽。虽然56.7%的疟原虫呈现双峰药物反应曲线，但除五株外，所有分离株产生的曲线下面积（AUC）估计值均与敏感表型一致。使用哌喹存活试验（PSA），5.6%的疟原虫显示敏感性降低。值得注意的是，2014年至2016年的疟原虫显示出最高的AUC值和双峰曲线的最高比例，表明在这些较晚年份疗效下降。对合并数据进行的无监督K均值分析将疟原虫分为三个簇，并确定了IC、IC和AUC值之间的显著相关性。没有疟原虫在假定的核酸外切酶中携带E415G突变、PfCRT中的新突变或基因扩增，这表明哌喹敏感性降低的机制与该区域其他国家所描述的不同。AUC、IC和IC值增加与主要的PfK13突变（F446I和G533S）之间的关联表明，哌喹耐药性可能在这些PfK13基因背景中演变。此外，Pfmdr1 F1226Y突变与显著更高的PSA值相关。有必要进一步阐明哌喹耐药机制并持续监测。
