Relapse after treatment with miltefosine for visceral leishmaniasis is associated with increased infectivity of the infecting Leishmania donovani strain.
Relapse after treatment with miltefosine for visceral leishmaniasis is associated with increased infectivity of the infecting Leishmania donovani strain.
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DOI：
10.1128/mbio.00611-13
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发表时间：
2013-10-08
期刊：
影响因子：
6.4
通讯作者：
Vanaerschot M
中科院分区：
文献类型：
--
作者：
Rai K;Cuypers B;Bhattarai NR;Uranw S;Berg M;Ostyn B;Dujardin JC;Rijal S;Vanaerschot M
杜氏利什曼原虫是一种导致利什曼病的细胞内原生动物寄生虫，根据感染物种的不同，利什曼病的范围从自我修复的皮肤病到致命的内脏疾病。米替福辛目前是过去几十年来最新也是唯一一种来自药物发现管道的口服抗利什曼药物，但最近的报告表明，它在印度次大陆对内脏利什曼病(也称为黑热病)的疗效显著下降。治疗后12个月内高达20%的复发率被证明与再感染、药物质量、药物暴露或抗药性寄生虫无关。因此，我们的目标是评估可能影响治疗结果的其他寄生虫表型，并发现在印度次大陆，后循环寄生虫的数量、寄生虫的传染性和患者治疗结果之间存在显著关联。结合之前关于利什曼原虫对五价锑耐药性的研究，这些数据表明，寄生虫的传染性或相关表型可能是内脏利什曼病治疗失败的更具决定性的因素，而不是药物敏感性，这需要重新评估我们目前对利什曼病及其他疾病治疗失败和耐药性的看法。米替福辛的高复发率对印度次大陆目前的卡拉-阿扎尔消除计划和世界各地的其他利什曼病控制计划构成了重大挑战。这种复发率与再感染、抗药性寄生虫或治疗质量下降无关。在这里，我们报告，寄生虫的传染性增加与内脏利什曼病(VL)患者的米替福辛复发有关。这些结果补充了用抗锑乳杆菌获得的结果，在那里也观察到了更高的传染性。这挑战了当前的观点，即利什曼原虫药物敏感性是导致利什曼病治疗失败的最大寄生因素。这些选定的更具传染性的寄生虫可能会给利什曼病控制项目带来额外的负担，突显出在印度次大陆和利什曼病流行的其他地区采取多方面控制措施以实现消除利什曼病的重要性。
Leishmania donovani is an intracellular protozoan parasite that causes leishmaniasis, which can range from a self-healing cutaneous disease to a fatal visceral disease depending on the infecting species. Miltefosine is currently the latest and only oral antileishmanial that came out of drug discovery pipelines in the past few decades, but recent reports indicate a significant decline in its efficacy against visceral leishmaniasis (also known as kala-azar) in the Indian subcontinent. This relapse rate of up to 20% within 12 months after treatment was shown not to be related to reinfection, drug quality, drug exposure, or drug-resistant parasites. We therefore aimed to assess other phenotypes of the parasite that may affect treatment outcome and found a significant association between the number of metacyclic parasites, parasite infectivity, and patient treatment outcome in the Indian subcontinent. Together with previous studies on resistance of L. donovani against pentavalent antimonials, these data suggest that the infectivity of the parasite, or related phenotypes, might be a more determinant factor for treatment failure in visceral leishmaniasis than drug susceptibility, warranting a reassessment of our current view on treatment failure and drug resistance in leishmaniasis and beyond. The high miltefosine relapse rate poses a major challenge for the current Kala-Azar Elimination Program in the Indian subcontinent and other leishmaniasis control programs worldwide. This relapse rate could not be related to reinfection, drug-resistant parasites, or reduced treatment quality. Here we report that an increased infectivity of the parasite is associated with miltefosine relapse of visceral leishmaniasis (VL) patients. These results supplement those obtained with antimonial-resistant L. donovani where an increased infectivity was also observed. This challenges the current view of Leishmania drug susceptibility being the biggest parasitic factor that contributes to treatment failure in leishmaniasis. These selected more infectious parasites may pose an additional burden to leishmaniasis control programs, highlighting the importance of multifaceted control measures to achieve leishmaniasis elimination in the Indian subcontinent and other regions where leishmaniasis is endemic.