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

NCT03902366 | Completed Results DMC

• 2 other identifiers: NURA-007-17F03967
• Study Type: observational
• Target: 63
• Locations: 1 country
• Sites: 1

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.

Conditions

Hepatitis C; Alcohol Use Disorder

Keywords

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

Outcome Measures

Primary Outcomes (11)

• Changes in Neuropsychological Assessment Battery (NAB) Attention Module Scores

  The Attention Module is a marker of attentional capacity, working memory, and processing speed. T-scores are derived by converting raw scores using normative tables that account for age and education. T-scores range from 20 to 80 with a mean of 50 and standard deviation of 10. Lower T-scores (below 40) indicate below average performance and higher T-scores (above 60) indicate above-average performance. NAB Attention Module subtests include: Dots, Numbers and Letters, Driving Scenes, Digits Forward, and Digits Backward. Subtest scores were averaged to compute a total score. Change was calculated as the value at 6 months minus the value at baseline. Larger numbers represent greater improvement in attention performance, a score of 0 indicates no change in performance and negative numbers indicate a worsening of attention performance over time.

  Baseline and 6 months

• Changes in Neuropsychological Assessment Battery (NAB) Memory Module Scores

  The Memory Module is a marker of learning, recall, and recognition memory. T-scores are derived by converting raw scores using normative tables that account for age and education. T-scores range from 20 to 80 with a mean of 50 and standard deviation of 10. Lower T-scores (below 40) indicate below average performance and higher T-scores (above 60) indicate above-average performance. NAB Memory Module subtests include: List Learning, Shape Learning, Story Learning, and Daily Living Memory. Subtest scores were averaged to compute a total score. Change was calculated as the value at 6 months minus the value at baseline. Larger numbers represent greater improvement in memory performance, a score of 0 indicates no change in performance and negative numbers indicate a worsening of memory performance over time.

  Baseline and 6 months

• Changes in Neuropsychological Assessment Battery (NAB) Executive Functions Module Scores

  The Executive Functions Module of the NAB is a marker of executive function, including problem-solving and mental flexibility. T-scores are derived by converting raw scores using normative tables that account for age and education. T-scores range from 20 to 80 with a mean of 50 and standard deviation of 10. Lower T-scores (below 40) indicate below average performance and higher T-scores (above 60) indicate above-average performance. NAB Executive Function Module subtests include: Mazes, Judgement, Categories, and Word Generation. Subtest scores were averaged to compute a total score. Change was calculated as the value at 6 months minus the value at baseline. Larger numbers represent greater improvement in executive function performance, a score of 0 indicates no change in performance and negative numbers indicate a worsening of executive functioning performance over time.

  Baseline and 6 months

• Changes in Alcohol Use Measured Using the Timeline Follow Back (TLFB)

  This outcome measure evaluates the change in the number of days of alcohol use from baseline to a 6-month follow-up, using the 30-Day Timeline Followback (TLFB) method. The TLFB is a structured, retrospective interview technique that allows participants to accurately recall their alcohol consumption patterns over the previous 30 days. For this outcome, the number of days on which alcohol was consumed will be assessed at baseline (the start of the study) and again at the 6-month follow-up assessment. A positive change would indicate an increase in the number of days of alcohol use, while a negative change would indicate a reduction in the number of days of alcohol use over the 6-month period.

  Baseline and 6 months

• Change in Behavior as Assessed by the Balloon Analogue Risk Task (BART)

  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. The ratio of balloon pumps made to maximum pumps allowed is a measure of risk-taking behavior. A ratio of 1 indicates that a participant inflated the balloon to its maximum allowed pumps, while a ratio closer to 0 suggests that the participant was much more conservative in their approach. Change was calculated as the value at 6 months minus the value at baseline and ranges from -1 to 1. A positive change indicates an increase in risk-taking behavior and a negative change indicates a decrease in risk-taking behavior over time.

  Baseline and 6 months

• Change in Behavior as Assessed by the Monetary Incentive Delay (MID) Task

  The MID is a validated task to examine anticipatory brain responses to reward during fMRI scanning. This outcome measure evaluates the change in reaction time (RT) of participants in response to monetary reward cues during the MID. Reaction time is defined as the duration (in milliseconds) from the presentation of the cue to the participant's response (e.g., button press). The MID involves various reward conditions, including different monetary values and probabilities, allowing for an evaluation of participants' anticipatory responses to potential rewards. A positive difference indicates an increase in RT at 6-months compared to baseline, suggesting potential decreases in motivation, cognitive load, or changes in reward sensitivity. Conversely, a negative difference indicates a decrease in reaction time, which may reflect improved motivation, enhanced cognitive processing speed, or increased responsiveness to monetary incentives over time.

  Baseline and 6 months

• Change in Fatigue Severity Scale (FSS) Score

  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 score for all 9 items is summed to constitute the FSS score. The minimum FSS score is 7 and the maximum score possible is 63. A higher score represents greater fatigue severity. Change was calculated as the value at 6 months minus the value at baseline and reported here. A higher positive score indicates an increase in fatigue symptoms at 6 months compared to baseline, a lower negative score would indicate a decrease in fatigue symptoms over 6 months and a score of 0 would indicate no change in fatigue symptoms over 6 months.

  Baseline and 6 months

• Change in Beck Depression Inventory Second Edition (BDI-II) Score

  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.

  Baseline and 6 months

• Change in Fractional Anisotropy (FA) in White Matter Tracts

  MRI-based diffusion tensor imaging (DTI) tractography is used to measure fractional anisotropy (FA), an indicator of CNS microstructural integrity. Increases in FA may reflect enhanced fiber organization or myelination, while decreases often indicate demyelination, axonal loss, or reduced coherence of white matter tracts. The JHU white-matter tractography atlas was used to extract FA values from 20 structures. Percent change was calculated. A positive number indicates an increase in FA after 6 months and a negative number indicates a decrease in FA from baseline to 6 months.

  Baseline and 6 months

• Change in Mean Diffusivity (MD) in White Matter Tracts

  MRI-based diffusion tensor imaging (DTI) tractography is used to measure mean diffusivity (MD), which is the average rate of water diffusion in all directions within brain tissue. An increase in MD often indicates microstructural disruption, such as axonal loss, demyelination, or increased extracellular space due to edema or atrophy and decreases in MD can reflect cellular proliferation or restricted diffusion, as seen in certain types of gliosis or inflammatory conditions. The JHU white-matter tractography atlas was used to extract MD values from 20 structures. Percent change was calculated. A positive number indicates an increase in MD after 6 months and a negative number indicates a decrease in MD from baseline to 6 months.

  Baseline and 6 months

• Changes in Inflammatory Profile Markers: Neutrophil to Lymphocyte Ratio (NLR) and Monocyte to Lymphocyte Ratio (MLR)

  Change was calculated as the value at 6 months minus the value and baseline. A positive number indicates an increase in inflammatory markers in plasma samples and a negative value indicates a decrease in inflammatory markers at 6 months.

  Baseline and 6 months

Study Arms (4)

AUD+/HCV+

* With current Alcohol Use Disorder and with HCV * About to initiate DAA therapy for HCV

Diagnostic Test: Neuropsychological assessment; Behavioral: Neuroimaging

AUD-/HCV+

* Without current Alcohol Use Disorder and with HCV * About to initiate DAA therapy for HCV

Diagnostic Test: Neuropsychological assessment; Behavioral: Neuroimaging

AUD+/HCV-

-With Alcohol Use Disorder and without HCV

Diagnostic Test: Neuropsychological assessment; Behavioral: Neuroimaging

AUD-/HCV-

-Without Alcohol Use Disorder and without HCV

Diagnostic Test: Neuropsychological assessment; Behavioral: Neuroimaging

Interventions

Neuropsychological assessment DIAGNOSTIC_TEST

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).

AUD+/HCV+; AUD+/HCV-; AUD-/HCV+; AUD-/HCV-

Neuroimaging BEHAVIORAL

Subjects, well characterized with respect to their substance use, will be evaluated with functional magnetic resonance imaging (fMRI) tasks, resting state MRI (rsMRI), high resolution anatomical MRI, standard diffusion weighted imaging (DWI) and high angular resolution diffusion imaging (HARDI) at baseline and 6 months later.

AUD+/HCV+; AUD+/HCV-; AUD-/HCV+; AUD-/HCV-

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

• 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)

Sponsors & Collaborators

• VA Office of Research and Development: lead
• Oregon Health and Science University: collaborator
• Portland VA Medical Center: collaborator

Study Sites (1)

VA Portland Health Care System, Portland, OR

Portland, Oregon, 97207-2964, United States

Location

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).

MeSH Terms

Conditions

Hepatitis C; Alcoholism

Interventions

Neuroimaging

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Neurological; Investigative Techniques

Results Point of Contact

• Title: Jennifer Loftis, PhD
• Organization: VA Portland Health Care System

jennifer.loftis@va.gov

503-220-8262

Study Officials

• Jennifer M Loftis, MA PhD

  VA Portland Health Care System, Portland, OR

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 18, 2019
• First Posted: April 4, 2019
• Study Start: May 16, 2019
• Primary Completion: October 31, 2023
• Study Completion: December 29, 2023
• Last Updated: March 27, 2025
• Results First Posted: March 27, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)