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

Completed

Conditions: Alcohol Use Disorder
Hepatitis C

Interventions: Diagnostic Test: Neuropsychological assessment
Behavioral: Neuroimaging

Registration Number: NCT03902366

Lead Sponsor: VA Office of Research and Development

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.

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 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

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)

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
AUD+/HCV-	Neuroimaging	-With Alcohol Use Disorder and without HCV
AUD-/HCV-	Neuropsychological assessment	-Without Alcohol Use Disorder and without HCV
AUD-/HCV+	Neuroimaging	* Without current Alcohol Use Disorder and with HCV * About to initiate DAA therapy for HCV
AUD+/HCV+	Neuropsychological assessment	* With current Alcohol Use Disorder and with HCV * About to initiate DAA therapy for HCV
AUD-/HCV+	Neuropsychological assessment	* Without current Alcohol Use Disorder and with HCV * About to initiate DAA therapy for HCV
AUD-/HCV-	Neuroimaging	-Without Alcohol Use Disorder and without HCV
AUD+/HCV+	Neuroimaging	* With current Alcohol Use Disorder and with HCV * About to initiate DAA therapy for HCV
AUD+/HCV-	Neuropsychological assessment	-With Alcohol Use Disorder and without HCV

Primary Outcome Measures

Name	Time	Method
Changes in Neuropsychological Assessment Battery (NAB) Attention Module Scores	Baseline and 6 months	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.
Changes in Neuropsychological Assessment Battery (NAB) Memory Module Scores	Baseline and 6 months	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.
Changes in Neuropsychological Assessment Battery (NAB) Executive Functions Module Scores	Baseline and 6 months	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.
Changes in Alcohol Use Measured Using the Timeline Follow Back (TLFB)	Baseline and 6 months	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.
Change in Behavior as Assessed by the Balloon Analogue Risk Task (BART)	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. 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.
Change in Behavior as Assessed by the Monetary Incentive Delay (MID) Task	Baseline and 6 months	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.
Change in Fatigue Severity Scale (FSS) Score	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 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.
Change in Beck Depression Inventory Second Edition (BDI-II) Score	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.
Change in Fractional Anisotropy (FA) in White Matter Tracts	Baseline and 6 months	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.
Change in Mean Diffusivity (MD) in White Matter Tracts	Baseline and 6 months	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.
Changes in Inflammatory Profile Markers: Neutrophil to Lymphocyte Ratio (NLR) and Monocyte to Lymphocyte Ratio (MLR)	Baseline and 6 months	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.