HCV and co-morbid alcohol use disorders: a translational investigation of antiviral therapy outcomes on CNS function

慢性丙型肝炎病毒(丙型肝炎病毒)感染通常与肝外表现有关，包括 中枢神经系统(CNS)损伤和神经精神障碍，可通过以下方式加剧 酗酒。超过一半的慢性丙型肝炎患者抱怨“脑雾”(受损 认知、疲劳)。直接作用抗病毒(DAA)疗法的引入彻底改变了丙型肝炎病毒 治疗，持续病毒应答(SVR)率约90%。退伍军人管理局现在向所有人提供DAA疗法 患有丙型肝炎的退伍军人在退伍军人保健系统内接受治疗，包括那些有酒精使用障碍的人 (AUDS)--在患有丙型肝炎的退伍军人中常见的共同发病率。尽管在这方面取得了进展和扩大 关于丙型肝炎病毒治疗的努力，关于脑功能结果的数据不足(例如，影响 DAA治疗后的日常生活(如认知能力、疲劳和药物滥用行为)。 关于病毒清除对炎症因子的影响的数据也有限，据推测 影响神经精神功能。这个功绩评估项目计划对以下项目进行纵向研究 接受丙型肝炎病毒抗病毒治疗的成人(有无AUDS)。从人口统计上看- 没有丙型肝炎的退伍军人(有和没有AUD)的匹配对照组也将被评估为 确定丙型肝炎病毒对酒精滥用影响的结果的相对贡献。它是 假设患有丙型肝炎病毒和共病AUDS的成年人可能有更高的持久性脑风险 DAA治疗后的功能障碍。通过比较神经精神功能，皮质活动，白色 退伍军人AUD活动前后物质完整性和免疫反应 DAA治疗，这项研究的结果有望确定大脑的改善程度 功能(例如，神经连接和认知能力)和实现的炎症减少 通过成功完成DAA治疗。提出了两个具体目标。目标1将评估 DAA治疗对患有丙型肝炎的退伍军人中枢神经系统功能的影响 DAA治疗和获得SVR，参与者将显示：i)改善神经精神结果(例如， 认知功能、疲劳、情绪)与基线(DAA治疗前)相比，II)恢复功能 在基线时具有可检测到缺陷的白质轨迹内的连通性和不完整性，以及iii) 免疫激活特征的正常化(例如，炎性细胞因子和 恢复T细胞表型)，与基线相比。目标2将使用一般线性模型来评估 DAA治疗前后的反应(如中枢神经系统功能结果)是否发生变化 这四个组之间的差异--无论是由于澳大利亚、丙型肝炎或这些因素的潜在相互作用--到 确定活跃的AUD对神经精神、神经影像和免疫学结果的影响。 参与者将在基线和治疗后12周进行评估。评估将纳入大脑 成像方法[即静息状态磁共振成像(MRI)、功能MRI和弥散成像 张量成像]以及临床和实验室方法来确定酒精的交互作用 使用并获得关于脑功能和炎症过程的SVR。临床和实验室数据将 包括：一)人口统计和医学信息，二)注意力、记忆力、 和执行功能，iii)神经精神症状问卷(例如，抑郁、疲劳)，iv)尿液 和用于医学实验室测试的口服液采集，以及v)用于流式细胞仪的血样采集， 定量聚合酶链式反应和多重免疫分析检测关键免疫因子，如白细胞介素1、白细胞介素8、 IL-10、S100B和C-反应蛋白，并向退伍军人事务部肝病储存库捐款。 总而言之，该项目的结果试图识别大脑恢复的生物标记物，并向目标 将使丙型肝炎病毒抗病毒治疗的长期临床益处最大化的治疗策略。

Chronic hepatitis C virus (HCV) infection is often associated with extrahepatic manifestations, including central nervous system (CNS) damage and neuropsychiatric impairments that can be exacerbated by alcohol abuse. More than half of patients with chronic HCV infection complain of “brain fog” (impaired cognition, fatigue). The introduction of direct-acting antiviral (DAA) therapies has revolutionized HCV treatment, with sustained viral response (SVR) rates of ~90%. The VA is now offering DAA therapy to all Veterans with HCV treated within VA health care systems, including those with alcohol use disorders (AUDs)—a common co-morbidity among Veterans with HCV. Despite this progress and expansion in HCV treatment efforts, there are insufficient data on brain function outcomes (e.g., outcomes that affect daily life such as cognitive abilities, fatigue, and substance abuse behavior) following DAA therapy. There are also limited data on the effects of viral clearance on inflammatory factors that putatively influence neuropsychiatric function. This Merit Review project plans to conduct a longitudinal study of adults (with and without AUDs) undergoing antiviral therapy for the treatment of HCV. Demographically- matched comparison groups of Veterans without HCV (with and without AUD) will also be evaluated to determine the relative contribution of HCV to outcomes that are affected by alcohol abuse. It is hypothesized that adults with HCV and co-morbid AUDs may be at increased risk of persistent brain dysfunction following DAA therapy. By comparing neuropsychiatric functioning, cortical activity, white matter integrity, and immune response among Veterans with and without active AUD before and after DAA therapy, results from this study are expected to determine the extent of improvement in brain function (e.g., neural connectivity and cognitive abilities) and reduction in inflammation that is achieved by successful completion of DAA therapy. Two specific aims are proposed. Aim 1 will evaluate the impact of DAA therapy on CNS function in Veterans with HCV and will test the hypotheses that following DAA therapy and obtaining an SVR, participants will show: i) improved neuropsychiatric outcomes (e.g., cognitive function, fatigue, mood), as compared to baseline (pre-DAA therapy), ii) restored functional connectivity and disintegrity within white matter tracks that had detectable deficits at baseline, and iii) normalization of immune activation profiles (e.g., decreased expression of inflammatory cytokines and restored T cell phenotypes), as compared to baseline. Aim 2 will use general linear models to assess whether change in the response (e.g., CNS functional outcomes) between post- and pre-DAA therapy differs among the four groups—either due to AUD, HCV, or the potential interaction of these factors—to determine the impact of an active AUD on neuropsychiatric, neuroimaging, and immunological outcomes. Participants will be assessed at baseline and 12 weeks post-therapy. Evaluations will incorporate brain imaging methods [i.e., resting state magnetic resonance imaging (MRI), functional MRI, and diffusion tensor imaging] along with clinical and laboratory methods to determine the interactive effects of alcohol use and obtaining an SVR on brain function and inflammatory processes. Clinical and laboratory data will include: i) demographic and medical information, ii) neuropsychological measures of attention, memory, and executive function, iii) neuropsychiatric symptom questionnaires (e.g., depression, fatigue), iv) urine and oral fluid collection for medical laboratory tests, and v) blood sample collection for flow cytometry, qPCR, and multiplex immunoassays to measure key immune factors, such as interleukin (IL) -1, IL-8, IL-10, S100B, and C-reactive protein and for contribution to the VA Liver Disease Repository. Collectively, the results from this project seek to identify biomarkers of brain recovery and inform targeted treatment strategies that will maximize the long-term clinical benefits of HCV antiviral therapy.