Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, NT, 0811, Darwin, Australia.
Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, NT, 0811, Darwin, Australia.
Int J Parasitol Drugs Drug Resist. 2021 Dec;17:46-56. doi: 10.1016/j.ijpddr.2021.06.002. Epub 2021 Jun 21.
Drug resistant Plasmodium parasites are a major threat to malaria control and elimination. After reports of high levels of multidrug resistant P. falciparum and P. vivax in Indonesia, in 2005, the national first-line treatment policy for uncomplicated malaria was changed in March 2006, to dihydroartemisinin-piperaquine against all species. This study assessed the temporal trends in ex vivo drug susceptibility to chloroquine (CQ) and piperaquine (PIP) for both P. falciparum and P. vivax clinical isolates collected between 2004 and 2018, by using schizont maturation assays, and genotyped a subset of isolates for known and putative molecular markers of CQ and PIP resistance by using Sanger and next generation whole genome sequencing. The median CQ IC values varied significantly between years in both Plasmodium species, but there was no significant trend over time. In contrast, there was a significant trend for increasing PIP ICs in both Plasmodium species from 2010 onwards. Whereas the South American CQ resistant 7G8 pfcrt SVMNT isoform has been fixed since 2005 in the study area, the pfmdr1 86Y allele frequencies decreased and became fixed at the wild-type allele in 2015. In P. vivax isolates, putative markers of CQ resistance (no pvcrt-o AAG (K10) insertion and pvmdr1 Y967F and F1076L) were fixed at the mutant alleles since 2005. None of the putative PIP resistance markers were detected in P. falciparum. The ex vivo drug susceptibility and molecular analysis of CQ and PIP efficacy for P. falciparum and P. vivax after 12 years of intense drug pressure with DHP suggests that whilst the degree of CQ resistance appears to have been sustained, there has been a slight decline in PIP susceptibility, although this does not appear to have reached clinically significant levels. The observed decreasing trend in ex vivo PIP susceptibility highlights the importance of ongoing surveillance.
耐药疟原虫是疟疾控制和消除的主要威胁。2005 年印度尼西亚报告高度耐多药恶性疟原虫和间日疟原虫后，2006 年 3 月国家将治疗无并发症疟疾的一线治疗方案改为青蒿琥酯-哌喹，用于所有疟原虫物种。本研究通过裂殖体成熟试验评估了 2004 年至 2018 年间收集的恶性疟原虫和间日疟原虫临床分离株对氯喹（CQ）和哌喹（PIP）的体外药敏趋势，并通过 Sanger 法和下一代全基因组测序对分离株进行了已知和推定的 CQ 和 PIP 耐药分子标记的亚组检测。两种疟原虫的 CQ IC 值中位数在不同年份之间差异显著，但随时间无明显趋势。相反，自 2010 年以来，两种疟原虫的 PIP IC 值呈显著上升趋势。自 2005 年以来，研究区域内的南美 CQ 耐药 7G8 pfcrt SVMNT 同种型已固定，而 pfmdr1 86Y 等位基因频率下降，并于 2015 年固定在野生型等位基因上。在间日疟原虫分离株中，CQ 耐药的假定标记（无 pvcrt-o AAG (K10) 插入和 pvmdr1 Y967F 和 F1076L）自 2005 年以来一直固定在突变等位基因上。在恶性疟原虫中未检测到任何假定的 PIP 耐药标记。在经过 12 年的 DHP 强烈药物压力后，对恶性疟原虫和间日疟原虫的 CQ 和 PIP 疗效进行了体外药敏和分子分析，结果表明，虽然 CQ 耐药程度似乎得到了维持，但 PIP 敏感性略有下降，尽管这似乎尚未达到临床显著水平。体外 PIP 敏感性观察到的下降趋势突出了持续监测的重要性。
