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

• ClinicalTrials.gov Identifier: NCT03902366
• Recruitment Status: Recruiting
• First Posted: April 4, 2019
• Last Update Posted: August 25, 2021
• Sponsor: VA Office of Research and Development
• Collaborators: Oregon Health and Science University; Portland VA Medical Center
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Hepatitis C; Alcohol Use Disorder	Diagnostic Test: Neuropsychological assessment; Behavioral: Neuroimaging

Detailed Description:

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 disintegrity 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, 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.

Study Design

• Study Type: Observational
• Estimated Enrollment: 120 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: HCV and Co-morbid Alcohol Use Disorders: A Translational Investigation of Antiviral Therapy Outcomes on CNS Function
• Actual Study Start Date: May 16, 2019
• Estimated Primary Completion Date: October 31, 2023
• Estimated Study Completion Date: October 31, 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
AUD+/HCV+; With current Alcohol Use Disorder and with HCV; About to initiate DAA therapy for HCV	Diagnostic Test: Neuropsychological assessment; Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).; Behavioral: Neuroimaging; Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.
AUD-/HCV+; Without current Alcohol Use Disorder and with HCV; About to initiate DAA therapy for HCV	Diagnostic Test: Neuropsychological assessment; Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).; Behavioral: Neuroimaging; Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.
AUD+/HCV-; -With Alcohol Use Disorder and without HCV	Diagnostic Test: Neuropsychological assessment; Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).; Behavioral: Neuroimaging; Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.
AUD-/HCV-; -Without Alcohol Use Disorder and without HCV	Diagnostic Test: Neuropsychological assessment; Clinical research staff will complete a standardized neuropsychiatric study visit protocol with eligible participants who provide informed consent. The protocol will be conducted twice for each participant (baseline and 6 months later).; Behavioral: Neuroimaging; Subjects, well characterized with respect to their substance use, will be evaluated with fMRI tasks, rsMRI, high resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.

Outcome Measures

Primary Outcome Measures :

1. Changes in Neuropsychological Assessment Battery (NAB) Attention Module Scores [ Time Frame: Baseline and 6 months ]
   The neuropsychological test battery measures an individual's attentional capacity, working memory, psychomotor speed, selective attention, divided attention, and information processing speed. Raw scores will be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test.
2. Changes in Neuropsychological Assessment Battery (NAB) Memory Module Scores [ Time Frame: Baseline and 6 months ]
   The neuropsychological test assesses an individual's verbal explicit learning, visual explicit learning, verbal delayed free recall, visual delayed recognition memory, and verbal explicit learning and recognition of information likely to be encountered in daily living. Raw scores will be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test.
3. Changes in Neuropsychological Assessment Battery (NAB) Executive Functions Module Scores [ Time Frame: Baseline and 6 months ]
   The neuropsychological test assesses executive function, such as problem-solving, planning, and mental flexibility. Raw scores will be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test.
4. Changes in alcohol use measured using the Timeline Follow Back (TLFB) [ Time Frame: Baseline and 6 months ]
   The TLFB will be used to measure change across several dimensions of alcohol drinking behavior: (a) variability (i.e., scatter); (b) pattern (i.e., shape); and (c) extent of drinking (i.e., elevation/reduction; how much).
5. Change in behavior as assessed by the Balloon Analogue Risk Task (BART) [ Time Frame: Baseline and 6 months ]
   The BART is a computerized measure of risk-taking behavior that concurrently measures several domains (i.e., risky decision-making, reward/negative outcome processing) during fMRI scanning.
6. Change in behavior as assessed by the Monetary Incentive Delay (MID) task [ Time Frame: Baseline and 6 months ]
   The MID is a validated task to examine anticipatory brain responses to reward during fMRI scanning.
7. Change in Fatigue Severity Scale (FSS) score [ Time Frame: Baseline and 6 months ]
   The Fatigue Severity Scale (FSS) is a 9-item self-report questionnaire designed to measure level of fatigue. The FSS is graded on a 7-point Likert-like scale ranging from 1 ("strongly disagree") to 7 ("strongly agree"). The minimum score is 9 and the maximum score possible is 63. A higher score represents a greater fatigue severity. The average score for all 9 items constitute the FSS score.
8. Change in Beck Depression Inventory Second Edition (BDI-II) score [ Time Frame: Baseline and 6 months ]
   The Beck Depression Inventory Second Edition (BDI-II) is a 21-question multiple-choice self-report inventory that measures depression. There is a four-point scale for each item ranging from 0-3. The total score can range from 0 to 63 points. Higher scores reflect a great level of depression severity.
9. Change in fractional anisotropy (FA) in white matter tracts [ Time Frame: Baseline and 6 months ]
   MRI-based diffusion tensor imaging (DTI) tractography is used to measure fractional anisotropy (an indicator of CNS microstructural integrity).
10. Change in mean diffusivity in white matter tracks [ Time Frame: Baseline and 6 months ]
    MRI-based DTI tractography is used to measured mean diffusivity (an indicator of CNS microstructural integrity).
11. Changes in inflammatory profile marker concentration [ Time Frame: Baseline and 6 months ]
    Immune factors in the inflammatory profile include: C-reactive protein (CRP), C-X-C motif chemokine (CXCL10), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-18 (IL-18), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-3 (MMP-3), S100 calcium binding protein B (S100B), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor alpha (TNF-alpha).
12. Changes in T cell subpopulation frequency [ Time Frame: Baseline and 6 months ]
    T-cells will be evaluated for changes in the frequencies of double negative (DN; CD4-CD8-) and double positive (DP; CD4+CD8+) CD3+ cells.

Biospecimen Retention:   Samples With DNA

Blood specimens are collected from human subjects by study personnel or the VA phlebotomy lab specifically for research purposes. Research staff centrifuges the blood samples so that components [e.g., plasma, peripheral blood mononuclear cells (PBMCs)] can be collected, frozen, cryopreserved, and contributed to the VA Liver Disease Repository (Director: Dr. Lissi Hansen).

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Adult Veterans (> 21 years old) who are about to initiate DAA therapy for HCV are recruited into two demographically matched (i.e., similar in terms of age, gender, race, and years of education) groups (n = 30/group): 1) adults with current alcohol use disorder (AUD+/HCV+) and 2) adults without current AUDs (AUD-/HCV+). Two additional groups of demographically-matched adults: 1) without AUD or HCV (AUD-/HCV-) (n = 30), and 2) with AUD and no HCV (AUD+/HCV-) will be recruited as a comparison groups to determine the relative contribution of a history of HCV infection to alcohol-induced brain pathology.

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)

Contacts and Locations

Contacts

Contact: Kate M Shirley, MA BA; (503) 220-8262 ext 52470; kate.shirley@va.gov

Contact: Jennifer M Loftis, MA PhD; Jennifer.Loftis2@va.gov

Locations

United States, Oregon

VA Portland Health Care System, Portland, OR; Recruiting

Portland, Oregon, United States, 97239

Contact: Kate M Shirley, MA BA 503-220-8262 ext 52470 kate.shirley@va.gov

Principal Investigator: Jennifer M Loftis, MA PhD

Sponsors and Collaborators

VA Office of Research and Development

Oregon Health and Science University

Portland VA Medical Center

Investigators

• Principal Investigator: Jennifer M Loftis, MA PhD; VA Portland Health Care System, Portland, OR

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT03902366
• Other Study ID Numbers: NURA-007-17F; 03967 ( Other Grant/Funding Number: Portland VA Medical Center )
• First Posted: April 4, 2019
• Last Update Posted: August 25, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:

Hepatitis C; Direct-acting antiviral therapies; DAA; Chronic HCV infection; Alcohol Use Disorder

Additional relevant MeSH terms:

Hepatitis C; Hepatitis; Disease; Alcoholism; Alcohol Drinking; Pathologic Processes; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders