日本顺天堂大学Toshihiro Mita团队研究了非洲青蒿素耐药疟疾的证据。这一研究成果于2021年9月22日发表在《新英格兰医学杂志》上。

在构成大湄公河次区域的六个东南亚国家中，恶性疟原虫对青蒿素衍生物产生了耐药性，而青蒿素是疟疾一线治疗的主要成分。包括非洲在内的其他全球地区对青蒿素单一疗法的临床耐药性将是一个威胁。

在乌干达北部进行的这项纵向研究中，研究组通过静脉注射青蒿琥酯（一种水溶性青蒿素衍生物）治疗恶性疟原虫感染患者，并估计寄生虫清除半衰期，使用环期生存试验和基因型耐药相关基因评估寄生虫的体外易感性。

从2017年到2019年，240名接受静脉注射青蒿琥酯的患者中，共有14名患者存在体内青蒿素耐药性（寄生虫清除半衰期>5小时）。在这14名患者中，13名感染了恶性疟原虫，kelch13基因中的A675V或C469Y等位基因发生突变。这种突变与延长寄生虫清除半衰期有关，其中A675V的几何平均数为3.95小时，C469Y为3.30小时，野生型等位基因为1.78小时，组间差异均显著。

环期存活试验表明，在具有A675V等位基因的生物体中，寄生虫存活的频率高于具有野生型等位基因的生物体。kelch13突变寄生虫的患病率显著增加，从2015年的3.9%增加到2019年的19.8%，主要原因是A675V和C469Y等位基因频率显著增加。乌干达A675V突变侧翼的单核苷酸多态性与东南亚的显著不同。

研究结果表明，非洲已发现临床上青蒿素耐药恶性疟原虫的独立出现和局部传播。这两种kelch13突变可能是检测这些耐药寄生虫的标志物。

附：英文原文

Title: Evidence of Artemisinin-Resistant Malaria in Africa

Author: Betty Balikagala, M.D., Ph.D.,, Naoyuki Fukuda, M.D., D.T.M.H., Ph.D.,, Mie Ikeda, Ph.D.,, Osbert T. Katuro, B.Sc.,, Shin-Ichiro Tachibana, Ph.D.,, Masato Yamauchi, M.P.H., Ph.D.,, Walter Opio, M.D.,, Sakurako Emoto, M.D.,, Denis A. Anywar, M.Sc.,, Eisaku Kimura, M.D., Ph.D.,, Nirianne M.Q. Palacpac, Ph.D.,, Emmanuel I. Odongo-Aginya, Ph.D.,, Martin Ogwang, M.D., M.M.E.D.,, Toshihiro Horii, Ph.D.,, and Toshihiro Mita, M.D., Ph.D.

Issue&Volume: 2021-09-22

Abstract:

BACKGROUND

In the six Southeast Asian countries that make up the Greater Mekong Subregion, Plasmodium falciparum has developed resistance to derivatives of artemisinin, the main component of first-line treatments for malaria. Clinical resistance to artemisinin monotherapy in other global regions, including Africa, would be problematic.

METHODS

In this longitudinal study conducted in Northern Uganda, we treated patients who had P. falciparum infection with intravenous artesunate (a water-soluble artemisinin derivative) and estimated the parasite clearance half-life. We evaluated ex vivo susceptibility of the parasite using a ring-stage survival assay and genotyped resistance-related genes.

RESULTS

From 2017 through 2019, a total of 14 of 240 patients who received intravenous artesunate had evidence of in vivo artemisinin resistance (parasite clearance half-life, >5 hours). Of these 14 patients, 13 were infected with P. falciparum parasites with mutations in the A675V or C469Y allele in the kelch13 gene. Such mutations were associated with prolonged parasite clearance half-lives (geometric mean, 3.95 hours for A675V and 3.30 hours for C469Y, vs. 1.78 hours for wild-type allele; P<0.001 and P=0.05, respectively). The ring-stage survival assay showed a higher frequency of parasite survival among organisms with the A675V allele than among those with the wild-type allele. The prevalence of parasites with kelch13 mutations increased significantly, from 3.9% in 2015 to 19.8% in 2019, due primarily to the increased frequency of the A675V and C469Y alleles (P<0.001 and P=0.004, respectively). Single-nucleotide polymorphisms flanking the A675V mutation in Uganda were substantially different from those in Southeast Asia.

CONCLUSIONS

The independent emergence and local spread of clinically artemisinin-resistant P. falciparum has been identified in Africa. The two kelch13 mutations may be markers for detection of these resistant parasites.

DOI: 10.1056/NEJMoa2101746

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2101746