Unit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, Belgium.
Unit of Molecular Parasitology, Department of Biomedical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, Belgium; Adrem Data Lab, Department of Mathematics and Computer Science, University of Antwerp, Middelheim 1, 2020 Antwerp, Belgium.
EBioMedicine. 2020 May;55:102748. doi: 10.1016/j.ebiom.2020.102748. Epub 2020 Apr 28.
Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment.
Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine learning approach to establish a clinically-useful 4-gene set.
Distinct signatures of differentially expressed genes between D0 and D29 were identified for patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average area-under-the-ROC-curve of 0.95 (CI: 0.75-1.00).
A simple blood-based signature thus holds significant promise to facilitate treatment efficacy monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients.
Project funding was provided by the AfricoLeish project, supported by the European Union Seventh Framework Programme (EU FP7).
艾滋病毒感染者内脏利什曼病（VL）的治疗常常失败，并伴有高复发和病死率。因此，评估治疗效果至关重要，但需要通过侵入性器官抽吸来检测寄生虫。为了寻找一种非侵入性的替代方法，并且由于宿主免疫反应对免疫功能低下的 VL 患者的治疗结果至关重要，我们研究了 VL-HIV 患者在治疗过程中全血转录谱的变化。
在埃塞俄比亚西北部的一项临床试验中，对 28 例 VL-HIV 患者在完成 29 天的两性霉素 B 脂质体或两性霉素 B 脂质体/米替福新治疗方案前后的全血样本进行 RNA-Seq。将通路分析与机器学习方法相结合，建立了一个具有临床应用价值的 4 基因集。
对治疗失败和成功的患者，我们确定了 D0 和 D29 之间差异表达基因的特征。后者的通路分析强调了与宿主细胞活性和免疫相关的基因下调，以及吞噬溶酶体中抗菌肽活性的上调。在治疗失败的患者中，没有疾病缓解的迹象，也没有通路富集。接下来，我们确定了一个 4 基因治疗前后的特征（PRSS33、IL10、SLFN14、HRH4），可以在治疗结束时（D29）准确区分治疗效果，显示平均 AUC 为 0.95（CI：0.75-1.00）。
一个简单的基于血液的特征，因此有很大的希望来促进治疗效果监测，并提供一个替代的治愈测试来指导 VL-HIV 患者的管理。
项目资金由 AfricoLeish 项目提供，该项目由欧盟第七框架计划（EU FP7）支持。
