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.

Public Health Relevance

Chronic hepatitis C virus (HCV) infection is associated with diseases or conditions that affect organs other than the liver, including the brain. The introduction of direct-acting antiviral (DAA) therapies has transformed the treatment of HCV, and the VA is now offering DAA therapy to all Veterans with HCV treated within VA health care systems. To accompany this effort, studies are needed to evaluate the impact of DAA therapy and obtaining a sustained viral response on brain function and the implications of having an alcohol use disorder, a co-occurring disorder that may hinder recovery. Results from this study are expected to determine the extent of improvement in brain function (e.g., nerve cell connectivity and thinking abilities) and reduction in inflammation that is achieved by successful completion of DAA therapy. This new information will: 1) address a gap in our knowledge concerning the effects of alcohol use on brain function following DAA therapy, 2) delineate the role of a network of immune factors in the brain healing process, and 3) enable targeted treatments.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX002061-05A2
Application #
9564502
Study Section
Neurobiology A (NURA)
Project Start
2013-10-01
Project End
2022-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
089461255
City
Portland
State
OR
Country
United States
Zip Code
97239
Wilhelm, Clare J; Fuller, Bret E; Huckans, Marilyn et al. (2017) Peripheral immune factors are elevated in women with current or recent alcohol dependence and associated with altered mood and memory. Drug Alcohol Depend 176:71-78
Loftis, Jennifer M; Lim, Miranda M (2016) Sleep disturbance in substance use disorders and comorbid chronic viral infections. Addiction 111:1093-4
Ellis, Carilyn; Hoffman, William; Jaehnert, Sarah et al. (2016) Everyday problems with executive dysfunction and impulsivity in adults recovering from methamphetamine addiction. Addict Disord Their Treat 15:1-5
Loftis, Jennifer M; Taylor, Jonathan; Raué, Hans-Peter et al. (2016) Alcohol intake alters immune responses and promotes CNS viral persistence in mice. Behav Brain Res 312:1-8
Loftis, Jennifer M (2015) Commentary: Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection. Front Microbiol 6:1473
Huckans, Marilyn; Fuller, Bret E; Chalker, Alison L N et al. (2015) Plasma Inflammatory Factors Are Associated with Anxiety, Depression, and Cognitive Problems in Adults with and without Methamphetamine Dependence: An Exploratory Protein Array Study. Front Psychiatry 6:178
Huckans, Marilyn; Fuller, Bret; Wheaton, Viva et al. (2015) A longitudinal study evaluating the effects of interferon-alpha therapy on cognitive and psychiatric function in adults with chronic hepatitis C. J Psychosom Res 78:184-92
Huckans, Marilyn; Fuller, Bret E; Olavarria, Hannah et al. (2014) Multi-analyte profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection. Brain Behav 4:123-42
Loftis, Jennifer M; Janowsky, Aaron (2014) Neuroimmune basis of methamphetamine toxicity. Int Rev Neurobiol 118:165-97
Anacker, Allison M J; Ahern, Todd H; Hostetler, Caroline M et al. (2014) Drinking alcohol has sex-dependent effects on pair bond formation in prairie voles. Proc Natl Acad Sci U S A 111:6052-7

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