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

HCV 和共病酒精使用障碍：抗病毒治疗结果对中枢神经系统功能的转化研究

• 批准号: 9564502
• 负责人: JENNIFER M LOFTIS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9564502
• 关键词: Address; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol or Other Drugs use; Antiviral Agents; Antiviral Therapy; Attention; Behavior; Biological Markers; Blood specimen; Brain; Brain Pathology; Brain imaging; C-reactive protein; Caring; Chronic; Chronic Hepatitis C; Clinical; Collection; Comorbidity; Control Groups; Data; Diffusion Magnetic Resonance Imaging; Disease; Evaluation; Extrahepatic; Fatigue; Flow Cytometry; Fogs; Functional Magnetic Resonance Imaging; Healthcare Systems; Hepatitis C; Hepatitis C Therapy; Hepatitis C virus; Immune response; Immunoassay; Immunologic Factors; Immunologics; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-1; Interleukin-10; Interleukin-8; Intervention; Investigation; Knowledge; Laboratories; Life; Linear Models; Liquid substance; Liver; Liver diseases; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Medical; Memory; Mental Depression; Mental Health; Metabolic Clearance Rate; Methods; Moods; Nervous System Physiology; Nervous System Trauma; Neuraxis; Neurons; Neuropsychology; Oral; Organ; Outcome; Participant; Patients; Pharmaceutical Preparations; Phenotype; Polymerase Chain Reaction; Prefrontal Cortex; Process; Publishing; Questionnaires; Recovery; Regimen; Research; Rest; Risk; Role; S100 Calcium Binding Protein; Signal Transduction; Substance abuse problem; T-Lymphocyte; Testing; Thinking; Time; TimeLine; Toxic effect; Translating; Treatment outcome; Urine; Veterans; Viral; Virus Diseases; Work; addiction; alcohol and other drug; alcohol effect; alcohol use disorder; base; brain dysfunction; chronic infection; clinical practice; cognitive ability; cognitive function; comparison group; cytokine; drug of abuse; executive function; follow-up; functional outcomes; healing; imaging modality; immune activation; immune function; improved; neuroimaging; neuropsychiatric symptom; neuropsychiatry; physical conditioning; prospective; protein B; relating to nervous system; repository; response; sample collection; side effect; standard of care; targeted treatment; therapy outcome; treatment guidelines; treatment strategy; white matter

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.

慢性丙型肝炎病毒（HCV）感染通常与外脑外表现有关，包括 中枢神经系统（CNS）损害和神经精神障碍可能会因 酗酒。超过一半的慢性HCV感染患者的“脑雾”（受损） 认知，疲劳）。引入直接作用抗病毒（DAA）疗法已彻底改变了HCV 治疗，持续病毒反应（SVR）速率约为90％。 VA现在正在为所有人提供DAA疗法 在VA医疗保健系统中接受HCV治疗的退伍军人，包括患有酒精饮酒障碍的退伍军人 （AUDS） - 与HCV的退伍军人之间的共同多人。尽管取得了进展和扩展 HCV治疗工作，没有关于脑功能结果的数据（例如，影响的结果 DAA治疗后的日常生活，例如认知能力，疲劳和药物滥用行为）。 关于病毒清除率对炎症因素的影响的数据也有限 影响神经精神病功能。这项优点审查项目计划进行纵向研究 成人（有或没有AUDS）接受抗病毒治疗以治疗HCV。人口统计学 - 没有HCV的退伍军人的匹配比较组（带有和没有AUD）也将评估为 确定HCV对受酗酒影响的结果的相对贡献。这是 假设患有HCV和合并AUD的成年人可能会增加持续大脑的风险 DAA治疗后功能障碍。通过比较神经精神功能，皮质活性，白色 物质完整性和具有和没有主动aud的退伍军人的免疫反应前后 DAA治疗，这项研究的结果有望确定大脑的改善程度 功能（例如神经连通性和认知能力）和炎症的减少 通过成功完成DAA治疗。提出了两个具体目标。 AIM 1将评估 DAA治疗对HCV退伍军人中CNS功能的影响，并将检验以下的假设 DAA疗法并获得SVR，参与者将显示：i）改善神经精神疗法的结果（例如， 与基线相比（DAA疗法），认知功能，疲劳，情绪），ii）恢复功能 在基线时检测到缺陷的白色物质轨道中的连通性和崩解性，iii） 免疫激活谱的归一化（例如，炎症细胞因子的表达降低和 与基线相比，恢复的T细胞表型）。 AIM 2将使用一般线性模型评估 后与DAA治疗之间的反应变化（例如，CNS功能结果）是否发生变化 这四个组之间的差异 - 由于AUD，HCV或这些因素的潜在相互作用， 确定活性AUD对神经精神病学，神经影像学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。评估将融入大脑 成像方法[即静息状态磁共振成像（MRI），功能性MRI和扩散 张量成像]以及临床和实验室方法，以确定酒精的互动效应 在大脑功能和炎症过程中使用并获得SVR。临床和实验室数据将 包括：i）人口统计学和医学信息，ii）注意力，记忆，记忆， 和执行功能，iii）神经精神症状问卷（例如抑郁，疲劳），iv）尿液 用于医疗实验室测试的口服流体收集，v）流式细胞仪的血液样本收集， QPCR和多重免疫测定值测量关键免疫因子，例如白介素（IL）-1，IL -8， IL-10，S100B和C反应蛋白以及对VA肝病存储库的贡献。 总的来说，该项目的结果试图识别大脑恢复的生物标志物并告知目标 将最大化HCV抗病毒疗法的长期临床益处的治疗策略。