Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy
Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy
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DOI：
10.3389/fmicb.2019.01441
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发表时间：
2019-06-26
影响因子：
5.2
通讯作者：
Erasmus, Mzwandile
中科院分区：
文献类型：
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作者：
Darboe, Fatoumatta;Mbandi, Stanley Kimbung;Erasmus, Mzwandile
HIV 感染者患结核病的风险很高，而既往患有结核病的人疾病复发的风险甚至更高。识别结核病风险最高的个体的非痰生物标志物将允许有针对性的微生物检测和适当的治疗，并指导长期治疗的需要。我们确定了先前开发的全血转录组风险相关性 (COR) 特征在以下方面的效用：(1) 预测复发性结核病；(2) 结核病诊断；(3) 其在 HIV 感染者的结核病治疗监测中的潜在效用。我们从之前完成的三项临床研究中检索了冷冻保存的血液样本，并通过定量微流控实时 PCR 测量了 COR 特征。在接受抗逆转录病毒治疗 (ART) 的 HIV 感染者中，该特征可区分诊断后 3 个月内复发性结核病进展者与非进展者，受试者工作特征 (ROC) 曲线 (AUC) 下面积为 0.72（95% 置信区间 (CI)，0.58-0.85）。 43 名进展者中有 25 名（58%）在微生物学诊断时无症状，因此患有亚临床疾病。该特征显示未感染 HIV 的结核病病例和对照之间具有出色的诊断区分度（AUC 0.97；95% CI 0.94-1）。 HIV 感染者的表现较低（AUC 0.83；95% CI 0.81-0.96），并且签名评分与 HIV 病毒载量直接相关。还评估了新诊断出复发性结核病的 HIV 感染者接受 ART 时的结核病治疗反应。治疗期间特征评分显着下降。然而，治疗前评分无法区分2个月前和2个月后痰液转阴的患者。通过盲法验证，直接应用未经修饰的血液转录组 COR 特征在 HIV 感染者中检测出亚临床和活动性结核病。然而，复发性结核病的预后表现以及作为 HIV 感染者的诊断和治疗监测工具的表现不如 HIV 阴性队列的已发表结果。我们的结果表明，包含干扰素刺激基因的转录组特征的表现在HIV感染者中受到负面影响，特别是在那些病毒载量不完全抑制的个体中。
HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A nonsputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58-0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95% CI 0.94-1). Performance was lower in HIV-infected individuals (AUC 0.83; 95% CI 0.81-0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.