HCV and Co-morbid Alcohol Use Disorders: A Translational Investigation of Antiviral Therapy Outcomes on CNS Function

The primary objective of this research project is to compare neuropsychiatric functioning, cortical activity, white matter integrity, and immune response among Veterans with and without alcohol use disorder (AUD), before and after direct-acting antiviral (DAA) therapy \[a new treatment for chronic infection with the hepatitis C virus (HCV)\]. Demographically-matched comparison groups of Veterans without HCV (HCV-, with and without AUD) will similarly be evaluated to determine the relative contribution of HCV and an HCV "cure" to outcomes putatively affected by alcohol abuse.

Two specific aims are proposed.

Aim 1: Determine the impact of DAA therapy and a sustained viral response on central nervous system (CNS) function.

Aim 2: Evaluate the effects of AUD and unhealthy alcohol drinking on DAA therapy outcomes and CNS function.

The information learned will address a critical gap in knowledge concerning the effects of alcohol use on DAA therapy outcomes and will help inform treatment guidelines that could be translated to clinical practice, such as targeted interventions to treat AUD in conjunction with HCV infection and follow-up strategies for patients who successfully complete DAA therapy but then need care for other potential CNS-related outcomes.

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 a sustained viral response (SVR) \[i.e., when the virus continues to be undetectable in blood 12 weeks (or more) after completing therapy\], 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 structural integrity within white matter tracks that had been observed at baseline, and iii) reduced immune activation profiles (e.g., decreased expression of inflammatory biomarkers and restored T cell balance), as compared to baseline. Aim 2 will determine the impact of an active AUD on the neuropsychiatric, neuroimaging, and immunological outcomes observed in aim 1. Participants will be evaluated at two time points \[i.e., baseline and 12 weeks post-therapy (week 24)\]. 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 assess the interactive effects of alcohol use and HCV on brain function. 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 and anxiety), iv) urine and oral fluid collection for medical laboratory tests, and v) blood sample collection for planned experiments (e.g., flow cytometry, quantitative polymerase chain reaction (qPCR), and multiplex immunoassays) and for contribution to the VA Liver Disease Repository.

Evidence-based guidelines for the new DAA therapies are needed (e.g., How much alcohol is too much?). The VA is at the forefront of treating HCV and is now offering DAA therapy to all Veterans with HCV treated within VA health care systems. The proposed studies will address a critical gap in our knowledge concerning the effects of co-morbid HCV and AUD on antiviral therapy outcomes, particularly CNS function and neuropsychiatric symptoms that contribute to addiction and relapse.

Eligibility Criteria:
Inclusion Criteria:

* Adult Veteran (\>21 years)
* Able to provide informed consent.

Exclusion Criteria:

* Current substance use disorder other than alcohol (except nicotine or caffeine)
* Medical conditions likely to impact immunological function or central nervous system function (such as HIV, cancer, lupus, stroke, neurodegenerative disease, hepatic encephalopathy, multiple sclerosis, or a traumatic brain injury)
* Visible intoxication or impaired capacity to understand study risks and benefits or otherwise provide informed consent
* Past or present schizophrenia, schizoaffective disorder, or current psychosis or mania
* Visual or auditory impairments that would prevent valid neuropsychiatric testing
* Contraindications to MRI (such as surgical aneurysm clips, pacemaker, prosthetic heart valve, neuro-stimulator, implanted pumps, cochlear implants, metal rods, plates or screws, previous surgery, hearing aids, history of welding, metal shrapnel)