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: 10292432
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292432
• 关键词: Address; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; 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; Control Groups; Data; Diffusion Magnetic Resonance Imaging; Disease; Evaluation; Extrahepatic; Fatigue; Flow Cytometry; 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; United States Department of Veterans Affairs; Urine; Veterans; Veterans Health Administration; Viral; Virus Diseases; Work; addiction; alcohol and other drug; alcohol effect; alcohol use disorder; base; brain dysfunction; brain fog; chronic infection; clinical practice; cognitive ability; cognitive function; comorbidity; 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; substance use; 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）感染常伴有肝外表现，包括