Eloff Lydia, Aranda-Díaz Andrés, Routledge Isobel, Wesolowski Amy, Chisenga Mukosha, Mangena Brighton, Chimumbwa John, Sikaala Chadwick, Uusiku Petrina, Katokele Stark, Raman Jaishree, Smith Jennifer, Mumbengegwi Davis R
Department of Biochemistry, Microbiology, and Biotechnology, School of Science, University of Namibia, Windhoek, Namibia.
Malaria Operational Research Program, Multidisciplinary Research Services, University of Namibia, Windhoek, Namibia.
Am J Trop Med Hyg. 2025 Jul 31. doi: 10.4269/ajtmh.24-0870.
Artemisinin-based combination therapies are a cornerstone of Namibia's efforts to eliminate malaria. Namibia has experienced a greater than 90% reduction in malaria cases since the introduction of these therapies in 2005. However, their efficacy has not been routinely monitored, with malaria outbreaks regularly reported since 2016. The recent emergence of artemisinin partial resistance in Africa has highlighted the role of malaria molecular surveillance in complementing efficacy studies. This cross-sectional genomic surveillance study was nested within Namibia's routine surveillance system and aimed to determine the prevalence of antimalarial drug resistance markers in northern Namibia. Dried blood spots (DBS) and epidemiological data were collected from patients with confirmed Plasmodium falciparum cases who presented at health facilities in the highest malaria-burden regions (Zambezi, Kavango East, Kavango West, Ohangwena, and Omusati) from April to September 2023. Twelve genes associated with resistance to seven antimalarial drugs were genotyped from 264 DBS using multiplexed targeted amplicon sequencing. Multiple kelch 13 mutations associated with artemisinin partial resistance were identified: the P441L candidate marker was the most abundant, at 33.2%, and the P574L and A675V validated markers were observed in 1.2% of samples. The chloroquine resistance transporter C72/V73/M74I/N75E/K76T haplotype was observed in 1% of samples, whereas the multidrug resistance protein 1 N86 genotype, which is associated with reduced susceptibility to lumefantrine, was found in all samples. Although sulfadoxine-pyrimethamine is not used in Namibia, a high proportion of sulfadoxine-pyrimethamine resistance-associated mutations in the dihydropteroate synthase and dihydrofolate reductase genes were observed. In this study, we underscore the need for routine genomic surveillance to monitor emerging drug resistance markers and call for further research to define their clinical implications.
以青蒿素为基础的联合疗法是纳米比亚消除疟疾努力的基石。自2005年引入这些疗法以来，纳米比亚的疟疾病例减少了90%以上。然而，其疗效并未得到常规监测，自2016年以来经常有疟疾疫情报告。非洲最近出现的青蒿素部分耐药性凸显了疟疾分子监测在补充疗效研究方面的作用。这项横断面基因组监测研究嵌套在纳米比亚的常规监测系统中，旨在确定纳米比亚北部抗疟药物耐药性标志物的流行情况。2023年4月至9月，从疟疾负担最重地区（赞比西河、卡万戈东、卡万戈西、奥汉圭纳和奥穆萨蒂）的医疗机构中确诊的恶性疟原虫病例患者那里收集了干血斑（DBS）和流行病学数据。使用多重靶向扩增子测序对来自264个干血斑的与七种抗疟药物耐药性相关的12个基因进行了基因分型。鉴定出了多个与青蒿素部分耐药性相关的kelch 13突变：P441L候选标志物最为常见，占33.2%，P574L和A675V验证标志物在1.2%的样本中被观察到。在1%的样本中观察到氯喹耐药转运蛋白C72/V73/M74I/N75E/K76T单倍型，而在所有样本中都发现了与对卤泛群敏感性降低相关的多药耐药蛋白1 N86基因型。尽管纳米比亚不使用磺胺多辛-乙胺嘧啶，但在二氢蝶酸合酶和二氢叶酸还原酶基因中观察到了高比例的与磺胺多辛-乙胺嘧啶耐药性相关的突变。在本研究中，我们强调了进行常规基因组监测以监测新出现的耐药性标志物的必要性，并呼吁进行进一步研究以确定其临床意义。
