HCV and Co-morbid Alcohol Use Disorders: A Translational Investigation of Antiviral Therapy Outcomes on CNS Function
Conditions: Hepatitis C, Alcohol Use Disorder
Sponsor: VA Office of Research and Development

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Summary results for ClinicalTrials.gov  
 
Title: NURA-007-17F, HCV and co-morbid alcohol use disorder: a translational investigation of antiviral therapy 
outcomes on CNS function 
 
NCT number: NCT03902366  
 
Document date: October 30, 2024 
 
Thank you for the opportunity to conduct this research study. 
 
Please contact me with any questions. 
 
 
Sincerely, 
 
 
 
 
Jennifer M. Loftis, Ph.D. 
Principal investigator 
 
 
 
 
 
 
 
 
 
 
 
Research & Development Service 
3710 SW US Veterans Hospital Rd.  
Mail code: R&D 16 
Portland, OR 97239 
 
tel  503 220-8262, ext. 57155 
fax  503 273-5152 
 
Jennifer.loftis2@va.gov 
loftisj@ohsu.edu 
www.ohsu.edu/pniresearch 

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Research Protocol 
Title 
HCV and Co-morbid Alcohol Use Disorders: A Translational Investigation of Antiviral Therapy Outcomes 
on CNS Function 
 
Investigators  
Principal Investigator: Jennifer Loftis, Ph.D.  
Responsible Clinician: Michael Chang, M.D. 
 
Specific Aims/Purpose 
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 our 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. 
 
Central hypothesis: It is hypothesized that adults with HCV and co-morbid AUDs may be at 
increased risk of persistent brain dysfunction following DAA therapy.  
 
Specific hypotheses: Hypotheses 1.1 and 2.1 (neuropsychiatric outcomes). Following DAA therapy 
and obtaining a sustained viral response (SVR), 1.1: participants will show improved neuropsychiatric 
outcomes (e.g., cognitive function, fatigue, mood), as compared to baseline (pre-DAA therapy). 2.1: 
participants without AUDs will show greater improvement in neuropsychiatric outcomes than 
participants with AUDs. Hypothesis 1.2 and 2.2 (neuroimaging outcomes). Reduced fractional 
anisotropy (FA) will be observed in the tracts that connect regions between which there is decreased 
functional connectivity. 1.2 and 2.2: Disintegrity within white matter tracks [as measured by FA and 
mean diffusivity (MD)] observed at baseline visits will be improved following DAA therapy, with 
greater improvement observed in participants without AUDs. On the fMRI Balloon analogue risk task 
(BART) and Monetary incentive delay task (MID), adults with HCV will be significantly more likely to 
display more impulsivity during the baseline visit, as compared to the post-DAA therapy visit. It is 
hypothesized that AUD may attenuate the positive antiviral therapy effects on impulsivity. Hypothesis 
1.3 and 2.3 (immune activation profile). Inflammatory profiles will be associated with neuropsychiatric 
impairments and alterations in white matter integrity and cortical activity. Following DAA therapy and 
obtaining an SVR, 1.3: participants will show reduced immune activation profiles (i.e., restored T cell 
phenotypes and a reduced inflammatory profile), as compared to baseline, and 2.3: participants 
without AUDs will show greater a reduction in inflammatory factors than participants with AUDs.  

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Scientific Rationale and Significance  
Direct-acting antiviral (DAA) therapies are being widely used to treat patients with chronic HCV 
infection. The Department of Veterans Affairs (VA) is at the forefront of these transformative 
treatment efforts and is now offering DAA therapy to all Veterans with HCV who are treated within the 
VA health care system (Graham, 2016), with estimated viral clearance rates of ~90% (Fitz, 2016). 
Despite this progress, there are limited data on long term physical health outcomes following DAA 
therapy, and there are no published studies on alcohol addiction and mental health outcomes—
outcomes that affect daily life such as cognitive function and substance abuse behavior. Given that 
alcohol use disorders (AUDs) are almost three times more prevalent in Veterans with HCV compared 
to those without HCV infection (Butt et al., 2007), and similarly, that adults with HCV report greater 
alcohol intake than other adults (Taylor et al., 2016), longitudinal studies are needed. Chronic HCV 
infection is often accompanied by impairments in cognitive function and mood, but whether these 
adverse effects are caused by HCV or by the co-morbid substance abuse has been challenging to 
disentangle. Unlike interferon-alpha (IFN-) based therapies (previously the standard of care for HCV 
treatment within VA health care systems), DAA therapies are not associated with neuropsychiatric 
side effects or the induction of inflammatory signaling cascades—making it possible for the first time 
to investigate interactions between alcohol use and viral clearance on CNS function and immune 
response. It was recently reported that; “…we do not have enough data on mental health after HCV 
eradication with the newer antiviral agents…the currently available data call for a more intense study 
of the neuroimmunological and neuroinflammatory consequences of HCV” [(Weissenborn and 
Tillmann, 2016); see also (Solinas et al., 2015)]. 
 
Relevance to Veterans’ health: The introduction of DAA therapies are expected to significantly 
improve viral clearance rates and treatment outcomes. The goal for the VA is “to eradicate as much 
of the disease as we can,” said Chester Good, M.D., Chair of the VA’s medical advisory panel for 
pharmacy benefits management (JAMA, Aug. 10th, 2016). Yet, there are very few data on DAA 
therapy outcomes. The titer of HCV is not always predictive of the clinical course. It has been argued 
that SVRs may not be adequate to assess HCV treatment outcomes (Gurusamy et al., 2013), and 
unlike the HIV titer, little effort has been made to validate the SVR. This research study will generate 
CNS-focused outcome data following DAA therapy that can be used not only to help guide treatment 
strategies for HCV and co-morbid AUD, but also may contribute towards validating the SVR as a 
surrogate marker of HCV cure. A recent retrospective study among adults treated at VA health care 
systems found that the majority of patients with HCV who drink unhealthy amounts of alcohol can 
obtain an SVR following DAA therapy (Tsui et al., 2016); however, it is important to recognize that 
continued alcohol use, even after HCV eradication, may hinder improvements in mental health and 
cognitive function and put patients at risk for progression of liver disease. Despite high likelihood of 
cure for most patients with HCV in the DAA era, rates of HCV are increasing over time (CDC, 2017), 
and unhealthy alcohol use influences treatment completion and outcomes (Anand et al., 2006, 
Grodensky et al., 2012). Thus, studies to inform evidence-based decision-making for patients with co-
morbid AUD and HCV are needed [e.g., (Boyd et al., 2012)]. Among VA patients being treated for 
HCV, 44% have a documented alcohol use disorder (Tsui et al., 2016), and unhealthy alcohol use is 
expected to be disproportionately represented among those who are awaiting treatment, given 
previous contraindications to HCV treatment in this population. 
 
 
 

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Preliminary Studies 
To investigate how HCV and co-
morbid AUD contribute to 
neuropsychiatric impairments, altered 
immune responses, and CNS 
abnormalities, the following work has 
been accomplished.  
STUDY 1. This study of 55 male 
Veterans with HCV was conducted at 
VA Portland and Long Beach Health 
Care Systems and results were 
presented at the Digestive Diseases 
Week conference (McCready et al., 
2017) and recently accepted for 
publication in Alcohol Clinical & 
Experimental Research (Loftis et al., 
in press). Adults with HCV (not 
undergoing treatment for HCV) and 
co-morbid AUD [n = 42; mean age (SD) = 59 (5.55)] who were 
participating in a brief psychosocial treatment intervention to 
change alcohol use behavior were compared to adults without 
AUD [n = 13; mean age (SD) = 60 (4.62)]. Participants were 
evaluated at three time points to assess changes in alcohol 
use and inflammatory factors over a 12-week period. The 
Beck Depression Inventory, 2nd Edition (BDI-II), Posttraumatic 
Stress Disorder Checklist (PCL-C) (Karstoft et al., 2014), AUD 
Identification Test-Consumption (AUDIT-C), and Timeline 
Followback (TLFB) were used to assess psychiatric function 
and alcohol use. Indices of immune activation, blood brain 

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barrier damage (S100B), liver function, and viral load were measured in blood using immunoassays 
and PCR assays.  
Neuropsychiatric function. Co-morbid AUD was associated with increased symptoms of depression 
and PTSD (Fig. 1). Among participants in the AUD group, there was a significant reduction from 
baseline to 12 weeks in number of alcohol drinks per two-week segment (p < 0.0001), and nine 
participants in the AUD reported obtaining abstinence from alcohol by week 4. Alcohol use (as 
measured by the TLFB) was positively correlated with the severity of depressive and PTSD 
symptoms (Fig. 2).  
Immune activation biomarkers. Blood samples from the same study of participants with HCV (with or 
without co-morbid AUD) were analyzed for the expression of immune factors and a subset of results 
are shown in Figures 3 and 4. For the data presented in Figure 3, plasma samples were analyzed 
with a multiplex bead-based immunoassay conducted to measure peripheral immune biomarkers 
associated with inflammation, mood disorders, and infection control [i.e., C-reactive protein (CRP), IL-
1, IL-1 receptor antagonist (IL-1RA), IL-6, IL-8, IL-10, monocyte chemoattractant protein-1, tumor 
necrosis factor- (TNF-)]. Results from three of the factors are shown (CRP, IL-10, and IL-1RA). 
Figure 4 summarizes data on S100 calcium-binding protein B (S100B) levels—a common marker for 
BBB permeation, which is expressed primarily by astrocytes that cover blood vessels. To investigate 
the effects of AUD on BBB integrity in Veterans with HCV, we measured S100B in plasma samples 
using enzyme-linked immunosorbent assays using previously published methods (Loftis et al., 2013). 
Taken together, results from STUDY 1 indicate that HCV and co-morbid AUD is associated with 
increased symptoms of depression and anxiety and altered levels of immune factors [e.g., IL-10, 
S100B—biomarkers that accompany neuropsychiatric impairments and brain pathology (Chen et al., 
2017, Huckans et al., 2014)].  
STUDY 2. Our group previously reported that adults with HCV (with and without a history of 
substance abuse) show greater discounting of delayed rewards (a measure of impulsivity that 
correlates with executive function) than adults without HCV (Huckans et al., 2011). In a follow-up 
study, we hypothesized that levels of impulsivity would be associated with differences in brain 
activation when choosing between easy and difficult reward choices.  
Functional MRI and delay discounting. Age-matched adults with (n = 22) and without (n = 24) HCV 
completed three runs of delay discounting (DD) task while undergoing functional T2-weighted 
echoplanar imaging on a 3T Siemens Magnetom Trio. In preliminary analyses, across participants, 
the hard vs. easy decision contrast was associated with activation in the medial prefrontal cortex 
(mPFC). There were no statistically significant group differences in any of the contrasts. However, 

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examination of the relationship between area above the curve (AAC) (as a measure of impulsivity) 
and brain activation in the hard vs. easy contrast revealed a significant group by AAC interaction on 
activation in bilateral dorsolateral PFC, inferior frontal gyrus, insula, and superior parietal lobule. Post 
hoc analyses detected a positive relationship in controls but a negative relationship in the HCV group. 
In the HCV group, AAC was negatively correlated with left insula activation. Given the insula’s roles in 
the processing of reward or anxiety and in regulating impulsive behavior, the negative correlation 
observed suggests that impulsive behavior in patients with HCV may be associated with altered 
insula function (Fig. 5). In addition, for the HCV group, duration of HCV infection was positively 
correlated with activation in the mPFC (r= 0.458 and p= 0.021). These and related preliminary 
findings from this study were presented at the Organization for Human Brain Mapping conference 
(McCready et al., 2017) and a full manuscript is under review for publication in the Journal of 
Neurovirology.  
Summary of work accomplished. Taken together, the work accomplished is beginning to suggest 
immunological mechanisms and identify key brain circuits where co-morbid HCV infection and AUD 
exert adverse effects on brain and neuropsychiatric function. What remains to be determined is how 
DAA therapy-induced HCV clearance impacts these CNS functions.  
In published work, we reported post-hoc exploratory analyses that were conducted to 
determine whether SVR contributed to cognitive and psychiatric outcomes in adults with HCV who 
had undergone IFN-based therapy. Patients with SVR following IFN therapy (n = 19) had significantly 
less fatigue and reported fewer symptoms of depression, as compared to patients without SVR (n = 
6). No significant relationship between SVR and cognitive function was found; however, IFN therapy 
was not associated with significant changes in cognitive performance in our sample of patients 
[(Huckans et al., 2015), Table 5 in Huckans et al., 2015 provides a summary of selected published 
studies prospectively following the neuropsychological performance of adults with HCV across IFN 
therapy]. DAA therapies, unlike IFN-based therapies, are not associated with neuropsychiatric side 
effects or the induction of inflammatory signaling cascades. Further, active AUDs are not considered 
contraindications to DAA therapy, as they were with IFN- therapies. Thus, it possible for the first 
time to investigate interactions between alcohol use and viral clearance on CNS function and immune 
response—outcomes that will be critical to assess following DAA therapy and HCV clearance. 
 
 
 

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Research Design and Methods  
Overview. We plan to conduct a longitudinal cohort study and evaluate participants with (n = 30) and 
without (n = 30) active AUD at two time points [baseline (prior to DAA therapy initiation) and 12 weeks 
post-therapy (SVR assessment time point; SVR = negative for HCV RNA 12 weeks after the end of 
DAA therapy)]. Table 1 provides a timeline for participant enrollment and study completion. 
Comparison groups of adults with: i) active AUD and no HCV (n = 30) and ii) no AUD or HCV (n = 30) 
will also be studied. Thus, we will enroll 120 participants into the following four study groups: 1) 
AUD+/HCV+, 2) AUD-/HCV+, 3) AUD+/HCV- and 4) AUD-/HCV-. Evaluations will incorporate 
neuropsychiatric assessments, brain imaging [resting state (rs) magnetic rsMRI, functional (f) MRI 
(fMRI), and diffusion tensor imaging], and laboratory methods [e.g., multicolor flow cytometry, 
quantitative polymerase chain reaction (PCR), and multiplex immunoassays] to assess the interactive 
effects of alcohol use on brain and immune function [e.g. changes in T cell response and 
inflammatory cytokines, such as TNF-] that contribute to viral persistence and neuropsychiatric 
impairments. We will use general linear models to assess whether average change in the response 
(e.g., neuropsychiatric and immunologic outcomes) over six months between post- and pre-DAA 
therapy for each subject differs among the four groups—either due to AUD, HCV, or the potential 
interaction of these factors—after controlling for other subject-level covariates that remain constant 
(or nearly so) over the 6 months (e.g., age, sex). Variables that could meaningfully vary over time 
(e.g., TLFB score) will be summarized in terms of a difference and then included as a covariate. 
Table 1. Overview of human subjects procedures, including research visits and HCV treatment schedulea (as per standard of care) 
Weeks 
-2 
 
 
0 
12 
 
 
    18 
 
 
24 
 
                                            26 
Baseline visits (wks -2-0)c 
 
DAA therapy completion (wk 12)   - Check-in w/participantsb 
SVR assessment (wk 24; 12-wk post DAA therapy) 
     - Clinical interview  
 
ETR assessment (wk 12)  
 
 
 
6-month follow-up visits (wks 24-26)c 
     - Neuropsychiatric assessment  
- Check-in w/participantsb 
 
 
 
- Neuropsychiatric assessment 
    - Specimen collection  
 
 
 
 
 
 
 
 - Specimen collection 
 
 
  
    - Neuroimaging evaluation 
DAA therapy initiation (wk 0) 
 
 
 
 
 - Neuroimaging evaluation 
 
 
 
aIn addition to the visits outlined in this table, Veterans receiving DAA therapy participate in two standard, follow-up clinic appointments at weeks 4 and 8 (typically 
15-20 min appointments). Note: The follow-up clinic is a large multidisciplinary clinic comprised of doctors, fellows, nurse practitioners, liver clinic pharmacist and 
pharmacy students. Patients do not usually see the same clinician at the follow-up appointments that they saw at the start appointment. In addition, approximately 
50% of individuals started on DAA therapy are followed in the pharmacist phone clinic, and the week 4 and 8 appointments are by phone (~10 min calls). The 
potential impact of these additional interactions on study outcomes is discussed in Expected outcomes and alterative considerations. bClinical research staff will 
check-in with participants (phone contact) to assess general well-being, complete the TLFB (Sobell et al., 1996), and confirm schedules for follow-up visits. 
cParticipants will be paid $125 for the baseline visits ($75 for visit 1 [clinical interview, neuropsychiatric assessment, specimen collection] and $50 for visit 2 
[specimen collection, neuroimaging evaluation]). Subjects who participate in the 6-month follow-up visits will receive an additional $125 ($75 for visit 3 
[neuropsychiatric assessment, specimen collection] and $50 for visit 4 [specimen collection, neuroimaging evaluation]). In sum, subjects can earn $250 total if they 
complete all of the scheduled visits. 
Enrollment procedures. Prior to enrollment, a phone screening will be conducted by study staff to 
ensure that Veterans are interested in participating and meet eligibility criteria. Following screening, 
interested Veterans will be scheduled for a first study visit to review consent materials either in person 
at the VAPORHCS, by telephone, or VA approved teleconferencing software (i.e., VA Video Connect 
[VVC] or non-public facing technologies [i.e., Cisco WebEx, Skype for Business, Zoom for 
Healthcare, Doxy.me]).  
If the Veteran chooses to complete the first study visit by telephone or video, Veterans will be mailed 
informed consent materials (VA Informed Consent form, OHSU Informed Consent form, and VA 
HIPAA Authorization) and first visit materials (questionnaires). After the Veteran receives the study 
materials, a trained study team member will call the Veteran to go through the informed consent 
procedures and answer any questions. If the Veteran chooses to participate, he or she will sign the 
VA Informed Consent form, OHSU Informed Consent form, and VA HIPAA Authorization, and mail 
them back to Dr. Loftis using a pre-addressed and stamped envelope. Immediately after signing the 
consent forms, participants will have the option to complete portions of the neuropsychiatric study 

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visit measures, which includes the clinical interview, neuropsychiatric interview, neuropsychological 
assessment, and questionnaire battery via telephone or videoconference. Twelve of the fourteen 
neuropsychological assessments can be administered by phone or video. The remaining 
neuropsychological assessments will be administered at the time of the participant’s next in-person 
visit. This research data will be collected from the participant prior to the study team receiving the 
signed informed consent forms and HIPAA authorization. Remaining research data and specimen 
collection will occur at the time of their next in-person research study visit once the signed informed 
consent forms and HIPAA authorization have been received. 
Neuropsychiatric study visits. 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 12 weeks after DAA therapy completion).  
The protocol includes the following sources of material: 1) Breathalyzer and/or saliva alcohol test (if 
subject presents at study visit in an apparent intoxicated state and/or study staff have any concerns 
about recent alcohol use) to provide estimates of blood alcohol levels and CIWA-Ar test results to 
provide estimates of alcohol withdrawal symptom severity, 2) Clinical interview to collect demographic 
data and medical [including liver health status (e.g., fibrosis) and virological information (e.g., HCV 
genotype)], medication (including prior exposure to IFN-based or other antiviral therapies), and 
substance use history, 3) SCID-5-RV to confirm past and present substance use disorders and 
psychiatric diagnoses, 4) medical record review to cross-validate the psychiatric, substance use, and 
medical history gained through clinical interview, 5) a neuropsychological battery to measure 
attention, memory, and executive function, 6) a questionnaire battery to measure neuropsychiatric 
symptoms (e.g., depression, anxiety, fatigue and pain), 7) blood, urine, and oral fluid collection for 
completion of medical laboratory tests [i.e., Blood is used for complete blood count (CBC), liver 
function panel, and HCV viral counts (obtained as part of standard care for HCV treatment). Oral fluid 
is used toward HIV antibody screening and alcohol testing. Urine is used for urine alcohol [i.e., ethyl 
glucuronide (EtG) levels] and drug analysis and pregnancy tests.], 8) blood sample collection for 
planned experiments and for contribution to the VA Liver Disease Repository (Director: Dr. Lissi 
Hansen), and 9) neuroimaging data [diffusion tensor imaging (DTI) and resting state and functional 
MRI scans are obtained at the Advanced Imaging Research Center (AIRC) at Oregon Health & 
Science University (OHSU) and the data are downloaded to a computer located at the VA Portland 
Health Care System (VAPORHCS)].  
Veterans will have the option to complete portions of the neuropsychiatric study visit measures, 
including the clinical interview, neuropsychiatric interview, neuropsychological assessment, and 
questionnaire battery via telephone, videoconferencing, and/or mail. If a Veteran chooses to complete 
activities via telephone, video, and/or mail, a study team member will mail the Veteran the required 
visit materials (along with a pre-addressed and stamped envelope) and Dr. Loftis or another trained, 
IRB-approved study team member will conduct the activities via telephone or video.  
If a Veteran chooses to complete the neuropsychological assessments via telephone or video, a 
study team member will administer the cognitive tests suitable for phone or video administration by 
reading the instructions and questions to the Veteran and recording their response. This will include 
twelve of the fourteen neuropsychological assessments. The remaining neuropsychological 
assessments will be administered at the time of the participant’s next in-person visit.  
Breathalyzer and saliva alcohol testing. A breathalyzer and/or saliva alcohol test is administered to 
participants that present at study visits in an apparent intoxicated state and/or study staff have any 
concerns about recent alcohol use in order to assure that participants are not impaired and to provide 
estimates of blood alcohol concentration (BAC) levels. The following test guidelines are used for our 
current and previous clinical studies in patients with AUDs. Test result = 0.00-0.05: Continue with 

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appointment; Test result > 0.05 but ≤ 0.08: We are not allowed to consent a person for participation in 
a research study if there is any indication that their thinking may be impaired. If reasonable, given 
time of day and BAC level, reschedule for later in the day. If a patient is allowed to return to retest 
later in the day, the original BAC should be recorded on the Screen Result form. Otherwise, 
reschedule for a future date; Test result > 0.08 (or patient is visibly impaired): visits are discontinued 
and follow-up procedures are conducted, including notifying the responsible clinician (Dr. Chang, Co-
I). Participants that are over the legal limit will be rescheduled, and asked how they plan to get home. 
If taking public transportation, they will be allowed to leave unless clearly unable to take care of 
themselves based on clinical assessment of the responsible clinician. If driving in an automobile or 
motorcycle, or other personally controlled vehicle, they will be informed that they must remain at the 
hospital until they are no longer too inebriated to drive, will be retested using the breathalyzer or 
saliva alcohol test and recommended to stay in the clinic until the test is below the legal limit. If the 
participant threatens to leave and drive home while intoxicated, the VA Police will be called.  
Alcohol withdrawal status. The Clinical Institute Withdrawal Assessment for Alcohol, revised version 
(CIWA-Ar) will be administered and scored at every visit. Using this scale mild alcohol withdrawal is 
defined with a score less than or equal to 15. For participants who score in the mild range, we will 
record the score and continue with the visit. For participants in the moderate (scores of 16 to 20) or 
severe (scores > 20) ranges, visits are discontinued and follow-up procedures are conducted, 
including notifying the responsible clinician (Dr. Chang, Co-I). Visits that are discontinued do to 
moderate or severe CIWA-Ar scores will be rescheduled. 
Description of neuropsychiatric study visit measures. The neuropsychiatric study visit battery was 
designed to assess a full range of neuropsychiatric symptoms (e.g., AUD severity, cravings, 
depression, anxiety, fatigue, pain) and cognitive skills (e.g., attention, memory, executive function). 
The cognitive domains were selected for assessment because previous research by our group and 
others has demonstrated that HCV is associated with impairments in these domains (Huckans et al., 
2009, Huckans et al., 2011). The present study follows up on these findings by evaluating whether 
individuals who receive DAA therapy for HCV evidence improved psychiatric and cognitive function, 
and the extent to which AUDs impact outcomes. Measures were selected because of their sound 
psychometric properties (e.g., reliability, validity, large normative sample that can be corrected for 
demographics), and because they are widely used by clinicians and have established clinical utility. 
The neuropsychological measures that will be repeated have equivalent versions that will be 
alternated across study visits to minimize practice effects. Measures will be administered according to 
published standard administration procedures. 
Psychiatric and substance use disorder diagnoses 
• SCID-5-RV. The SCID is a copyrighted and commercially available structured clinical interview. 
The SCID is administered via computer or in paper-pencil form and is also available in an 
abbreviated format [Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 2006)]. 
The interviewer asks participants about whether or not they have experienced specific psychiatric 
symptoms across their lifetime or recently in order to determine whether they have met DSM5 
criteria for psychiatric and substance use disorders. Total administration time ranges from 15-60 
minutes depending on the number of symptoms an individual endorses. 
Neuropsychological battery 
• Wide Range Achievement Test, Fifth Edition (WRAT5™) (Wilkinson and Robertson, 2017) 
This copyrighted and commercially available assessment to measure reading, spelling, and 
math skills is used to estimate baseline intellectual functioning. This measure will be 
administered at baseline only. 

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• Reynolds Intellectual Screening Test (RIST) (Reynolds and Kamphaus, 2003). This copyrighted 
and commercially available measure is used to estimate baseline intellectual functioning. This 
measure will be administered at baseline only. 
• Neuropsychological Assessment Battery (NAB) (Stern and White, 2003). This copyrighted and 
commercially available battery of subtests assesses a variety of cognitive domains. We will 
administer the modules on attention, memory, and executive functioning at both study visits (i.e., 
baseline and 6-month follow-up).  
o The Attention Module includes the following subtests:   
▪ Digit Span – measure of auditory attention capacity and working memory 
▪ Dots – measure of visual attention capacity and working memory   
▪ Numbers & Letters – measures of sustained visual attention, speeded information 
processing, and inhibition/switching    
▪ Driving Scenes – measure of visual attention/working memory 
o The Memory Module includes the following subtests:  
▪ List Learning – verbal learning and memory task    
▪ Shape Learning – visual learning and memory task 
▪ Story Learning – verbal learning and memory task, involving immediate and delayed recall 
of verbally presented stories  
▪ Daily Living Memory – verbal learning and memory task, involving recall of medication 
instructions, and a name, address, and phone number.   
o The Executive Functions Module consists of the following subtests:  
▪ Mazes – measure of problem-solving and planning 
▪ NAB Judgment - measure of everyday problem-solving/executive function  
▪ Categories – measure of mental flexibility and categorization 
▪ Word Generation – measure of initiation and mental flexibility.  
Questionnaire battery. AUD Identification Test-C [AUDIT-C; 3-item screening tool to be administered 
at baseline only (Bush et al., 1998)]; Severity of Dependence Scale (SDS) (Gossop et al., 1997, 
Gossop et al., 1995); Alcohol Timeline Followback (TLFB) (to be administered in-person at pre- and 
post-DAA therapy study visits, as well as over the phone at weeks 12 and 18). In addition to in-person 
interviews, the TLFB has demonstrated reliability and validity over the phone (Sobell, 1992, Sobell et 
al., 1996); Clinical Institute Withdrawal Assessment for Alcohol scale, revised (CIWA-Ar) (Sullivan et 
al., 1989); Visual Analogue Scale (rates level of craving for alcohol over the past 24 hours on a scale 
of 0 to 100); Beck Depression Inventory, Second Edition (BDI) (Beck, 1996); Generalized Anxiety 
Disorder Inventory (GADI) (Argyropoulos et al., 2007) and PCL-C (Weathers et al., 1994); Fatigue 
Severity Scale (FSS) (Krupp et al., 1989); Brief Pain Inventory, Short Form (BPI) (Cleeland and Ryan, 
1994), and Sickness Impact Profile (Bergner et al., 1981).   
Specimen collection and laboratory measures. At study visits, oral fluid is collected and used 
toward HIV antibody screening by OraQuick (OraSure Technologies Inc.) or similar "in-home" oral 
swab test and alcohol testing by Alco-Screen (Chematics, Inc.) or similar alcohol saliva test. Urine is 
collected and used for urine alcohol [i.e., ethyl glucuronide (EtG) levels] and drug analysis and 
pregnancy tests. EtG assessments are done with EtG Alcohol Test Dip Cards (Rapid Exams Inc.). 
Drug analysis and pregnancy tests are conducted using 5 panel Drug Screen Cups (Rapid Exams 
Inc.) and human chorionic gonadotropin (hCG) urine dip card tests (Rapid Exams Inc.), respectively. 
Blood is collected by a trained phlebotomist or trained VA research personnel in four, 8 mL capacity 
Cell Preparation Tubes (CPTs, BD Biosciences) for planned experiments (≤ 32 mL of blood is 
collected at both the initial and 6-month study visits). If not already obtained per standard care for 
HCV, blood samples (≤ 23.5 mL) may also be collected to obtain HCV viral load, liver enzyme levels, 

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and complete blood counts by the VAPORHCS laboratory, per SOP. For participants without HCV 
and who do not require HCV viral load clinical laboratory test per standard of care, absence of HCV 
will be confirmed using Oraquick HCV rapid antibody test (OraSure Technologies Inc.). Following the 
neuropsychiatric study visit, research staff immediately transports the human blood samples to Dr. 
Loftis’ laboratory for processing and storage. Dr. Loftis’ research staff centrifuges the blood samples 
per SOPs so that components [e.g., plasma, peripheral blood mononuclear cells (PBMCs)] can be 
collected, frozen, and cryopreserved.  
Immune factor detection. Plasma samples and cell culture supernatants will be analyzed for the 
expression of specific immune activation markers using multiplex immunoassays and Luminex 
technology and PCR [e.g., (Wilhelm et al., 2013, Wilhelm et al., 2012)]. The immune activation profile 
[i.e., CRP, interferon-gamma (IFN-γ)-inducible protein-10 (CXCL10), IL-1, IL-6, IL-8, IL-10, IL-18, 
MCP-1, MMP-3, S100B, TIMP-1, TNF-] was selected based on published (Huckans et al., 2014, 
Loftis et al., 2008, Mascia et al., 2017) and preliminary findings (Figs. 3 and 4) regarding the role of 
these cytokines and chemokines in infection control and neuropsychiatric impairments.  
Immune cell phenotype and function. PBMCs collected before and after DAA therapy will be used to 
evaluate phenotypic and functional changes in memory T cells (central, effector, and transitional) and 
macrophages that regulate viral suppression and persistence. Cell phenotype will be determined 
using flow cytometry, as previously described [e.g., (Loftis et al., 2016, Wilhelm et al., 2013)]. Briefly, 
single-cell suspensions of human PBMCs will be stained to identify and analyze viable cell 
phenotypes, including subsets of CD4+ and CD8+ T cells (e.g., effector and regulatory cell 
subpopulations), programmed cell death 1+ (PD-1+) cells, and activated macrophages 
(CD45hiCD11b+ cells). Immune cell function will be assessed by measuring cell proliferation and 
inflammatory factors secreted from cells stimulated in vitro, as described in methods reviewed by the 
VA Subcommittee on Research Safety (SRS). Given that chronic viral infections and AUD are 
associated with phenotypic and functional impairments in CD4 and CD8 T cell subsets and the PD-1 
inhibitory receptor [measure of an “exhausted” phenotype; e.g., (Utzschneider et al., 2016)], we will 
focus on these immune cells and signaling pathways. Our analyses will additionally be guided by a 
recent cross-sectional study of patients with AUD which found significant alterations in CD8+ and 
CD4+ T subpopulations in patients with AUD, as compared to healthy controls (Zuluaga et al., 2016). 
Neuroimaging.* Following the neuropsychiatric study visit, all eligible participants are scheduled for a 
separate neuroimaging study visit. Neuroimaging may be omitted for medical reasons or if 
determined by study team to not be in the subject’s best interest. Subjects, well characterized with 
respect to their substance use, will then be evaluated with fMRI tasks (BART and MID), rsMRI, high 
resolution anatomical MRI, standard DWI and high angular resolution diffusion imaging (HARDI). 
Breathalyer tests, alcohol withdrawal symptom scales, urine alcohol and drug screens, and 
pregnancy tests will be administered at the neuropsychiatric study visits and the imaging evaluations. 
The neuroimaging protocol will take approximately one hour and will include the Balloon Analogue 
Risk Task (BART) and Monetary Incentive Delay Task (MID).  
Balloon Analogue Risk Task (BART): A version of the BART (Lejuez et al., 2002), adapted for event-
related fMRI, will be used. Balloons are either red or blue (active trials) or white (control trials). When 
presented with an active balloon, participants will select between pumping the balloon for a potential 
increase in earnings ($0.25/pump) or cashing out to retain earnings accumulated during that trial. 
Continued pumping will ultimately result in a balloon explosion and the forfeiture of unrealized 
earnings accumulated during the trial. Prior to scanning, participants will be informed that red and 
blue balloons are associated with monetary reward but that they will not receive the monetary reward 
at the end of the trial. Participants will not be informed that the number of pumps to produce an 
explosion is pre-determined for each balloon from a uniform probability distribution (maximum 8 or 12 

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pumps for red and blue balloons, respectively). Participants will be informed that the white balloons 
do not explode and are not associated with potential reward, and they will be instructed to pump the 
white balloon until the end of the trial (maximum 12 pumps according to a uniform probability 
distribution). The task will be administered in two 10-min runs; typically 50-60 active trials and 10-14 
control trials.  Participants will not receive the earnings at the end of the scanning session. The 
variables to assess adaptive decision-making and risk-taking behavior include: the total and average 
number of pumps across all trials and in trials that end in a choice to cash-out (“adjusted pumps”), as 
balloon explosions may restrict the range of risk-taking behavior; the total and average number of 
cash-out trials, total earnings, and the average reaction time (RT) for all pumps, cash-outs, and of the 
first and last pump from each trial. 
Monetary Incentive Delay Task (MID): The MID is a validated task to examine incentive-reward 
reactivity of the ventral striatum. The task requires little cognitive demand and participants simply 
respond to a brief presentation of a visual target to win or lose money. Participants will not receive the 
winnings from this task. The MID task session consists of 180 6-second trials. During each trial, 
participants are shown a cue (cue phase, 1 second), indicating that they have the potential to win or 
lose money ($0.20, $1 or $5) or that no money is at stake for that trial (Control). A fixation cross is 
present during a variable interval (anticipatory delay phase, 2000–2500 ms), and when a target 
appears, participants press a button (target phase, 160–260 ms). For WIN trials, participants will be 
told that if they successfully press the button while the target is onscreen (a “hit”) they will win the 
amount of money indicated by the cue. For LOSE trials, participants will be told that no money will be 
won or lost for hits, but misses will lead to a loss of the amount indicated by the cue for that trial. By 
contrasting brain activations in the anticipatory delay phase in WIN trials vs. Control trials it is 
possible to examine the extent to which the anticipation of potential reward modulates ventral striatal 
activity during this preparatory period. A Feedback phase (1650 ms) follows the target's 
disappearance. Feedback will display amount won or lost for each trial and total cumulative winnings. 
*Methodological details for imaging acquisition, processing, and analysis were provided by the 
Hoffman lab and are summarized on pages 10-11. 
MRI Imaging Acquisition: We will use the Human Connectome Project (HCP) Lifespan Protocol 
using a 3T Siemens Magnetom Prisma scanner and a 32-channel phased array head coil. fMRI (T2*-
weighted): Three (2 PDD and 1 DSNBACK) T2*- weighted echo-planar imaging (EPI) functional runs 
will be acquired (60 slices, 2 mm thick, TR/TE/α=2000 ms/38 ms/55°, matrix=128 × 128, FOV=220 
mm2, PAT mode/Accel factor = GRAPPA/2, 310 volumes per run) with an in-plane pixel size of 2.0 
mm2 while subjects perform the PDD or the DSNBACK. Each run will be 10.3 minutes long. rsfMRI: 
Identical to fMRI settings with 200 volumes. High-resolution anatomical (T1-weighted [T1w]): One 
magnetically prepared rapid acquisition gradient echo (MPRAGE) (208 0.8 mm isovoxels, TR/TE/TI/α 
= 2400 ms/2.24 ms/1060 ms/8°, FOV=256x240 mm, 2x Parallel Imaging, duration 6.38 min), will be 
acquired for co-registration with functional images and statistical overlay. High-resolution 
anatomical (T2-weighted [T2w]): 208 slices, 0.8 mm isovoxels, TR/TE: 3200 ms/564 ms; variable flip 
angle; FOV 256x263 mm, 2x Parallel imaging; Futsyion 5.57 min. HARDI: Two HARDI scans will be 
acquired (66 axial slices, 2.2 mm thick, TR/TE/α = 4300 ms/96 ms/90°, FOV= 25.6 cm2, PAT mode 
/Accel factor = GRAPPA/2) consisting of six non-diffusion weighted (B0) images followed by 32 non-
collinear directions at B0 = 1000 s mm-2 and at B0 = 2000 s mm-2. Each HARDI scan lasts 4.73 min.  
fMRI Standard Preprocessing: Task-related and resting-state fMRI data will be preprocessed 
identically. We include only scans with minimal movement (< 3 mm) and free of artifacts (Murphy et 
al., 2013). Functional images will be realigned for motion corrections, unwarped then co-registered to 
structural images for each subject and then transformed to Talairach coordinates and then resampled 
into atlas space with 3 mm isovoxels. Motion correction is applied with the standard 6 parameters and 
then frame-by frame spatial deviations are assessed with the temporal derivative of the time course. 

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The anatomical volume is then segmented into gray matter, white matter, and cerebrospinal fluid. 
Next, we apply a temporal bandpass filter (0.009 Hz <  < 0.08Hz), spatial smoothing (6 mm full width 
at half maximum (FWHM) Gaussian kernel), regression with the 6 rigid body motion parameters, 
regression of the whole brain signal and regression of the signal for ventricles and white matter. 
Opposite phase-encode polarity spin echo images will be used to estimate the B0 distortion field, 
which will be applied to each gradient echo frame after accounting for estimated head motion. 
Gradient nonlinearity distortions will be corrected using scanner-specific field maps. Both corrections 
are vital for proper registration to structural images. Images will be preprocessed using AFNI_16.1.26. 
To enable cortical surface-based analyses, fMRI time courses will be sampled to the cortical surface 
mesh, using the extent of overlap with the cortical ribbon as a weighting factor to account for partial 
voluming. Voxels with high variability relative to their local neighborhood will be excluded. The 
functional EPI images will be despiked (3dDespike), slice time corrected (3dTshift), motion corrected 
(3dvolreg), aligned to warped MPRAGE (align_epi_anat.py) and corrected for oblique slice 
acquisition. A 4 mm FWHM three-dimensional Gaussian blur will be applied to the functional images 
(3dmerge) and each voxel time series will be scaled to have a mean of 100 (3dTstat, 3dcalc). 
Anatomical (T1w and T2w). MPRAGE and T2w structural images will be corrected for gradient 
nonlinearity distortions using scanner specific, nonlinear transformations, provided by MRI scanner 
manufacturers, and verified using phantom scans. Spatial distortion in the readout direction due to B0 
variation will be corrected based on the distortion maps generated from our fast field mapping. T2w 
images will be registered to T1w images using mutual information after coarse pre-alignment via 
within-modality registration to atlas brains. Intensity non-uniformity correction will be performed by 
dividing image intensities by a smooth bias field estimated from the geometric mean of the T1w and 
T2w images. Anatomical scans will be corrected for oblique acquisition, skull stripped (3dSkullStrip), 
and warped into MNI-152 space with @auto_tlrc.  
Diffusion-Weighted Imaging: DTI preprocessing will be performed using the DTI preprocess script 
(Takuya Hayashi, Center for Life Science Technologies, RIKEN, Kobe, JP) for FSL [(Smith et al., 
2004) FMRIB, Oxford]. Scans will be corrected for eddy current distortion and motion. B0 
inhomogeneity distortion will be corrected using a B0 field map (magnitude and phase) in FSL's 
fugue. DTI estimates (FA 1-3, V1-3, MD) will be calculated using DTIFIT. Voxelwise statistical analysis 
will be performed with TBSS (Smith et al., 2006) and nonlinear registration to the FMRIB58_FA 
common space will be conducted. Each subject's aligned FA data will be projected onto a mean 
skeleton. Voxelwise cross-subject statistics will be performed with FSL's Randomise with threshold-
free cluster enhancement (TFCE). 
Voxel-Based Morphometry: Structural images will be analyzed with FSL-VBM (Douaud et al., 2007) 
an optimized VBM protocol (Good et al., 2001) carried out with FSL (Smith et al., 2004). Images will 
be brain-extracted and tissue segmented, registered to the MNI-152 standard space using non-linear 
registration (Andersson et al., 2007), and flipped along the x-axis to create a left-right symmetric, 
study-specific gray matter template and modulated with a voxel-wise division by the Jacobian 
determinant of the non-linear transformation matrix to correct for local expansion or contraction. The 
modulated gray matter images will be smoothed with an isotropic Gaussian kernel with a sigma of 3 
mm (FWHM = 7 mm). Group contrasts will be tested with FSL's Randomise, a permutation-based 
non-parametric procedure. 
Statistical analyses and power. Statistical analyses for the project will be performed by the 
research team and the Biostatistics and Design Program at OHSU. All data sent to OHSU for 
statistical analysis will be coded.   
Neuropsychiatric and laboratory measures. We plan to calculate the change in the response over six 
months between post- and pre-DAA therapy for each subject and use general linear models (GLMs) 
to assess whether average change differs among the four groups—either due to AUD, HCV, or the 

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potential interaction of these factors—after possibly controlling for other subject-level covariates that 
remain constant (or nearly so) over the six months (e.g., age, sex, HCV genotype). Variables that 
could meaningfully vary over time (e.g., TFLB score, CIWA-Ar score) will be summarized in terms of a 
difference and then included as a covariate. Number of DAA therapy provider contacts will be 
included as an extra covariate that counts total contacts. All models will use “robust” (sandwich 
estimators) of variance to guard against potential misspecification of the underlying distribution of 
change scores or due to non-constant variance among the groups (Long and Ervin, 2000). The AUD 
× HCV interaction will be assessed first in all models fit, and will be removed from the model only if 
evidence suggests (p > 0.10) these two factors don’t modify one another; otherwise, subsequent 
comparisons of each separate effect will be made within each level of the other (e.g., effect of HCV 
separately characterized for those with and then without AUD).  
A supervised and directed approach will be taken in the exploratory analysis of inflammatory 
biomarkers. Principal component analysis (PCA) will be used to reduce the collection of ~12 
correlated immune factors to a smaller number of uncorrelated linear combinations (the principal 
components) of biomarkers [e.g., (Bowman et al., 2012)]. Each component of this reduced set of 
uncorrelated patterns of inflammatory expression will be subjected to the same general linear models 
described earlier to determine whether AUD, HCV or AUD x HCV are associated with it, even after 
adjustment for other covariates. If the overall test of association in the linear model shows significant 
(p < 0.10, for initial screen) variation among the groups, then separate models will be conducted on 
those biomarkers that most heavily contribute/dominate the principal component being screened. In 
this way, we may identify combinations of markers that are sensitive to AUD and HCV treatment 
outcomes, particularly CNS function. 
Neuroimaging measures. We will use the methods of the Fair Laboratory (Miranda-Dominguez et al., 
2014) to analyze the rsMRI scans. We will use an ROI-to-ROI approach to calculate connectivity in 
the pre-processed data, based on the a priori regions previously associated with alcohol effects. 
Bivariate correlations between the average (BOLD) signal from these regions provide connectivity 
estimates. Several sources of spurious variance along with their temporal derivatives are then 
removed from the data through linear regression (e.g., signal from ventricular regions and signal from 
the white matter). The magnitude of connectivity changes between groups will be compared utilizing 
two-tailed t-tests. The raw p-values will be corrected for multiple comparisons and thresholded at a 
false discovery rate (FDR) correction of PFDR < 0.05. Data from discounting tasks will be fit to 
equations using a softmax procedure (Miedl et al., 2012). We calculate the fractional areas under the 
discounting curves as impulsivity measures.  

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Power. We estimated group size using fmripower (Mumford and Nichols, 2008). The MATLAB-based 
program calculates a power estimate given the between-group and within-subject error terms 
associated with a two tailed t-test of regression coefficients. The results suggested that 30 subjects 
(male and female) per group would yield a power of 0.8 for the test comparison. This sample size 
yields an 80% chance for us to identify AUD × HCV interaction effects of 0.91 standard deviation (SD) 
or larger at the 0.10 level of significance. Use of the higher alpha-level is done to lessen the chance 
of making a type II (overlook) error and mistakenly omitting this term from the model. We also have 
80% power for a 0.05-level test to detect any main effect, for either AUD or for HCV, of at least 0.51 
SD in size. Table 2 shows the smallest average change (between post- and pre-DAA therapy) among 
groups that would be of practical interest and the subsequent main effects (AUD+ vs AUD-; HCV+ vs 
HCV-) and interactions that derive from these minimally relevant average changes. The anticipated 
SD for the change scores was derived from reported SDs of each outcome supported by literature, 
and then converted to a SD for the difference assuming a modest correlation of 0.60 between pre- 
and post-DAA responses within the same subject. The principal comparisons proposed in this work 
parallel those in our preliminary work, and we were able to readily demonstrate differences in planned 
comparisons between the groups. Therefore, the proposed 30 subjects per group should provide us 
with sufficient power to test the predictions, anticipating that a small number of participants with HCV 
may not achieve SVR (n = ~3-6).  
 
 
Table 2. Statistical power to evaluate antiviral therapy outcomes of significant clinical impact 
 
 
Treatment groupa 
Effects and Powerb  
Response/outcome  
SD(diff) 
AUD-/HCV- 
AUD-/HCV+ 
AUD+/HC
V- 
AUD+/HCV+ 
AUD main 
HCV main 
Interact. 
Cognitive performancec 
Attention 
Memory 
Executive function 
 
2.25 
2.50 
1.80 
 
3.5 
3.0 
2.0 
 
3.7 
3.4 
2.1 
 
1.2 
0.4 
0.3 
 
3.5 
3.0 
2.0 
 
-1.25 (0.85) 
-1.50 (0.91) 
-0.90 (0.78) 
 
 1.25 (0.85) 
 1.50 (0.91) 
 0.90 (0.78) 
 
2.1 (0.81) 
2.2 (0.78) 
1.6 (0.78) 
Behavioral response 
Impulsivity 
(BART/MID)d 
Alcohol use (TLFB) 
 
1.35 
 
18.9 
 
0 
 
0 
 
-0.2 
 
-1.0 
 
-0.1 
 
-18 
 
-1.5 
 
-36 
 
-0.70 (0.80) 
 
-26.5 (0.99) 
 
-0.80 (0.90) 
 
-9.50 (0.78) 
 
-1.20 (0.78) 
 
-17.0 (0.79) 
Mental health 
Depression (BDI) 
Fatigue (FSS) 
 
4.0 
0.63 
 
0 
0 
 
-3.5 
-1.1 
 
-2.7 
-0.8 
 
-11.0 
-1.3 
 
-5.1 (0.99) 
-0.5 (0.99) 
 
-5.9 (0.99) 
-0.8 (0.99) 
 
-4.8 (0.94) 
 0.6 (0.83) 
CNS microstructuree 
FA 
MD (x105) 
 
0.02 
8.9 
 
0 
0 
 
-0.001 
-6.0 
 
-0.003 
7.5 
 
-0.02 
15.0 
 
-0.01 (0.91) 
 14.5 (0.99) 
 
-0.01 (0.78) 
 0.75 (0.07) 
 
-0.016 (0.78) 
 13.5 (0.99) 
Inflammatory profile 
Immune factor 
concentrationf 
T cell 
subpopulationsg 
 
4.05 
 
22.5 DP 
27.0 DN 
 
0 
 
0 
0 
 
-10 
 
-18 DP 
 38 DN 
 
2.5 
 
0 
0 
 
-3 
 
-9 DP 
19 DN 
 
4.75 (0.99) 
 
 4.5 (0.19) 
-9.5 (0.48) 
 
-7.75 (0.99) 
 
-13.5 (0.90) 
 28.5 (0.99) 
 
4.5 (0.92) 
 
   9 (0.29) 
-19 (0.61) 
aNumbers shown are minimally meaningful mean change scores, post- minus pre-DAA therapy, for the primary outcome variables. Conjectured standard deviation for a given 
outcome was based on published studies conducted by the PI and others, as referenced and converted to a standard deviation (SD) for the difference by conservatively assuming a 
correlation of 0.60 between post- and pre-DAA therapy values. bPower for main effects use 0.05 as level of significance while interaction uses 0.10. Based on n = 30 per group (N = 
120 total). cNAB module scores are reported as demographically corrected standard index change scores. dHigher (i.e., less negative) values represent a stronger tendency to 
discount larger delayed rewards in favor of smaller immediate rewards. eNeuroimaging outcome projections are for brain regions and tracks most significantly affected by a history of 
HCV infection and alcohol abuse (e.g., insula, superior fronto-occipital fasciculus). fImmune factors included in the inflammatory profile: CRP, CXCL10, IL-1, IL-6, IL-8, IL-10, IL-18, 
MCP-1, MMP-3, S100B, TIMP-1, TNF-. gT-cells will initially be evaluated for changes in the frequencies of double negative (DN; CD4-CD8-) and double positive (DP; CD4+CD8+) 
CD3+ cells; further investigation of subpopulations (e.g., effector, regulatory) will be conducted as described under Laboratory measures and in the Specific methods section. 
Abbreviations: BDI = Beck Depression Inventory, 2nd Edition; CNS = central nervous system; DAA = direct acting antiviral therapy; BART/MID = Balloon analogue risk task/Monetary 
incentive delay task; FSS = Fatigue Severity Scale; FA = fractional anisotropy; MD = mean diffusivity; NAB = Neuropsychological Assessment Battery 

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Expected outcomes and alterative considerations. Results are expected to determine the extent 
of improvement in CNS function (including neuropsychiatric outcomes) that is gained by successful 
completion of DAA therapy and whether or not co-morbid AUDs affect HCV treatment outcomes. Our 
hypotheses would be supported by finding improved CNS function following successful completion of 
DAA therapy (i.e., obtaining an SVR), including: i) increased FA in the tracts that previously 
connected regions between which there was decreased functional connectivity, ii) improved functional 
connectivity, iii) reduced impulsivity, and iv) improved cognitive abilities. Following DAA therapy, 
these changes in CNS function will be associated with reduced peripheral immune activation. 
Individuals with active AUDs and HCV may show attenuated benefits in CNS function and immune 
response, post-DAA therapy. In participants with HCV and co-morbid AUDs, cumulative disruptions in 
cerebral connectivity that result from anatomical disruptions may contribute to persistent cognitive 
deficits and elevated inflammatory profiles. Alternatively, it is possible that floor effects for some of the 
variables (e.g., BDI-II scores) may limit our ability to detect significant improvements. However, 
cognitive performance benefits have been reported following IFN-based therapy for HCV (Kraus et 
al., 2013, Kuhn et al., 2017), and we have observed improvements in depression and fatigue in 
patients who obtained SVR (Huckans et al., 2015). It is also possible that differences in the number of 
DAA therapy provider visits between participants in the HCV+ and HCV- groups may affect 
neuropsychiatric outcome variables (e.g., alcohol use behavior). To assess the impact of this 
potential confound, we plan to include that characteristic as an extra covariate. Because CNS 
recovery may continue beyond the SVR assessment timepoint, patients who agree to participate in 
the study will be asked to allow our research team permission (via the informed consent process) to 
contact them for future follow-up investigation, which is beyond the scope of this current protocol. We 
also considered the potential concern that there may be a lack of research participants with HCV 
(given the pace at which the VA is treating HCV); however, estimates indicate that by 2020, there will 
still be ~560,000 adults with HCV in the US (Chhatwal et al., 2016). 
Table 3. Project timeline 
Year 1 
Year 2 
Year 3 
Year 4 
To test hypotheses for aims 1 and 2, 120 Veterans will be recruited to participate in a prospective study that will evaluate patients with HCV before and after DAA 
therapy. Participants will be enrolled in the study for a total of six months 
Months 1-3: Obtain IRB and other 
regulatory approvals; Apply for 
Certificate of Confidentiality; Train 
staff in protocol and data analysis.  
Months 13-15: Enroll and conduct 
baseline study visits; Complete 6-
month follow-up visits for ~10 
participants  
Months 25-28: Complete 6-month 
follow-up visits for ~10 participants. 
Months 37–40: Complete 6-month 
follow-up visits for remaining 
participants (goal: n = 120 completed 
by month 40); Conduct flow cytometry 
analysis of cryopreserved PBMCs. 
Month 4: Begin recruitment of 
subjects using existing relationships 
with clinics at the VAPORHCS; Enroll 
and conduct baseline study visits for 4 
participants.  
Months 16-19; Enroll and conduct 
baseline study visits; Begin analyzing 
behavioral data and continue to 
conduct analysis of individual 
neuroimaging data; Complete 6-month 
follow-up visits for ~14 participants. 
Months 29-35: Complete 6-month 
follow-up visits for ~30 participants; 
Assess drop-out rates and intensify 
follow-up efforts, if needed.  
Month 41-42: Perform multiplex 
plasma sample testing for immune 
activation biomarkers; Submit abstract 
for conference presentation. 
Months 5-9: Enroll and conduct 
baseline study visits for 30 
participants at a rate of ~1-2 
participants per week. 
Month 10: First 4 participants 
complete study procedures; Begin 
preliminary analysis of individual 
neuroimaging data; Enroll and 
conduct baseline study visits. 
Months 20-24: Enroll and conduct 
baseline study visits; Complete 6-
month follow-up visits for ~16 
participants; Assess recruitment and 
drop-out rates and intensify follow-up 
efforts, if needed (goal: n = 60 
completed by end of year 2); Submit 
abstract for conference presentation. 
Month 36: Complete 6-month follow-
up visits (goal n = 100 completed by 
end of year 3/beginning of year 4); 
Continue to analyze behavioral and 
neuroimaging data; Submit abstract 
for conference presentation; 
Compile results for future 
publications (see months 43-48), 
and if sample sizes permit, publish 
behavioral findings (outcomes 
critical for patients with HCV 
seeking DAA therapy). 
Months 43-48: Complete human 
subjects data analysis; Prepare and 
submit final manuscripts. Disseminate 
evidence-based information regarding 
the effects of AUD on DAA therapy 
outcomes, as appropriate 
Months 11-12: Enroll and conduct 
baseline study visits for 10 
participants; Complete 6-month 
follow-up visits for ~10 participants; 
Assess recruitment and drop-out 
rates and intensify follow-up efforts, if 

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Study Population  
Up to 150 participants will be consented for this study (including screen failures), and 120 participants 
will be enrolled (n = 30 per group). Table 3 summarizes a time table for the overall study. 
Standardized inclusion and exclusion criteria. 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+), confirmed with the Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5), Research Version (SCID-5-RV), and 2) adults 
without current AUDs (AUD-/HCV+), confirmed with the SCID-5-RV. 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.  
Exclusion criteria for the AUD+/HCV+ and AUD+/HCV- groups include: 1) medical conditions (other 
than HCV for the AUD+/HCV+ group) 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), 2) visible intoxication or impaired 
capacity to understand study risks and benefits or otherwise provide informed consent (note: subjects 
will be administered alcohol withdrawal tests and, if deemed necessary due to possible recent alcohol 
use, breathalyzer and/or saliva alcohol tests prior to each study visit), 3) schizophrenia, 
schizoaffective disorder, or current psychosis or mania, 4) visual or auditory impairments that would 
prevent valid neuropsychiatric testing, and 5) contraindications to magnetic resonance imaging (MRI) 
(e.g., 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, or potentially pregnant).  
Exclusion criteria for the AUD-/HCV- and AUD-/HCV+ groups include: 1) medical conditions (other 
than HCV for the AUD-/HCV+ group only) 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), 2) visible intoxication or impaired 
capacity to understand study risks and benefits or otherwise provide informed consent (note: subjects 
will be administered alcohol withdrawal tests and, if deemed necessary due to possible recent alcohol 
use, breathalyzer and/or saliva alcohol tests prior to each study visit), 3) schizophrenia, 
schizoaffective disorder, or current psychosis or mania, 4) heavy alcohol use (Women: average 
alcohol use > 7 drinks per week for > one year. Men: average alcohol use > 14 drinks per week for > 
one year.), 5) visual or auditory impairments that would prevent valid neuropsychiatric testing, and 6) 
contraindications to MRI (e.g., 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, or potentially pregnant). 
Subject Identification/Recruitment 
Recruitment, eligibility screening, consenting, and neuropsychiatric study visits will be conducted by 
approved clinical research staff at the VA Portland Health Care System. A Waiver of Authorization 
and Informed Consent Process for Screening/Recruitment Purposes will be obtained to facilitate 
subject identification and recruitment.  
1. Potential participants who meet the study criteria will be recruited into this study through word 
of mouth referrals from clinicians at VAPORHCS. Research staff may contact patients who 
needed (goal: n = 20 completed by 
end of year 1).  

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indicate to their clinicians that they are interested in participating. Potential participants may 
also contact the study personnel after learning of the study (e.g., from advertisements). Initial 
phone screening will be done for each subject when they contact the lab and are interested in 
participating. The potential participant will be screened by study personnel using a screening 
form. Potential participants will be recruited from the Substance Abuse Treatment Program 
(SATP) and Liver Clinic. A study member will give regular presentations of the study at SATP 
access meetings. Attendance at these recruitment meetings by potential subjects is entirely 
voluntary. Potential subjects will be given the IRB-approved advertisement with contact 
information and asked to call the contact number if they are interested in participation.  
2. IRB-approved flyers will be posted in designated research advertisement space at 
VAPORHCS, which includes elevators and lobby spaces, as well as common spaces at OHSU 
and in the community.  
3. Other recruitment strategies include the use of social media. Study advertisements will be 
posted on VAPORHCS sponsored social media accounts including internal 
publication/promotion (Weekly E-news employee newsletter and Employee SharePoint E-Post) 
and external publication/promotion (VA Social Media Sites including VAPORHCS Facebook 
and Twitter pages, Public VAPORHCS Web Page, Quarterly Veteran Connection Newsletter, 
and Email Updates through GovDelivery). All recruitment advertisements will ask prospective 
participants to telephone the study coordinator if they are interested in participating. Email or 
social media messaging will not be utilized. Craigslist will also be utilized for recruitment. The 
study coordinator will create Craigslist postings that include a text version of the IRB approved 
study advertisement. Email responses to the Craigslist posting will be disabled so subjects will 
only be able to respond via telephone. All potential participants will be screened using the 
screening form when they contact research staff.   
4. We will conduct a CPRS search of patients who have been previously seen in the 
Gastroenterology and Hepatology and/or Mental Health & Clinical Neurosciences Division at 
the VA Portland Health Care System to identify patients >21 years old who have been 
diagnosed with HCV and/or an alcohol-use disorder. We will then conduct a Pre-Screening 
(i.e., via a medical record review) of individuals who meet the diagnostic criteria to identify 
individuals who meet study criteria. We will then send individuals who meet the study criteria 
an individualized letter (i.e., addressed to the patient) from the Clinical Director of the Mental 
Health & Clinical Neurosciences Division and/or the Section Chief of Gastroenterology and 
Hepatology about the study; the Director’s letter will be accompanied by our study flyer and a 
form letter (not individualized) from the study PI. The letter will provide the Research 
Assurance Officer’s telephone number so the potential participant can verify that the study 
constitutes VA research. The letter will state that the individual may opt out by calling the 
research team or returning an enclosed document indicating that they do not wish to be 
contacted (using a pre-stamped/addressed return envelope that we will provide), or they may 
indicate they are interested in learning more about the study by calling the study team or 
returning the enclosed document saying they want to be contacted. The letter will state that if 
the individual has not returned a response to the letter within two weeks, research personnel 
will contact them by phone. Study Personnel will call all those who are interested in the study 
to answer any questions they might have about the study and to schedule an Initial Study Visit 
if they remain interested. If no response to the letter is received within two weeks, the research 
team will contact the individual by phone but with limited interaction and using a phone script. 
The researcher will identify themselves, explain why they are calling, and ask if the individual 
received the letter. If they did, the researcher will ask if they have reviewed the letter and 
whether or not they are interested in hearing more about the study. If the individual has 

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received but not reviewed the letter, the researcher may ask if they are interested in hearing 
more about the study or receiving more information. After answering their questions, the 
researcher will schedule an Initial Study Visit for those who state they are interested in 
participating. If the Veteran has not received the letter, the researcher will only ask permission 
to send a second letter and confirm the individual’s address; no other information will be 
requested at that time. 
 
An appointment confirmation letter will be mailed to a participant after they have scheduled their initial 
visit. An appointment confirmation letter will also be sent prior to the week 24 visit. If a participant is 
enrolled in the study and not returning phone calls to schedule additional research visits, a no-show 
letter will be sent in the mail asking the participant to contact the research coordinator to discuss their 
interest in their continued involvement in the research study. If the research coordinator does not hear 
back from the participant within two weeks of sending the letter, the participant will be disenrolled 
from the research study.  
Reminder phone calls will be made the day prior to scheduled on-site appointments. During reminder 
calls, study team will ask participants if they have recently had any recent exposure and/or symptoms 
of COVID-19. If a participant suggests that they might be experiencing symptoms or have had a 
known exposure to COVID-19, we will offer information on COVID-19 testing and self-isolation and 
postpone the study visit for at least two weeks following exposure or until symptoms are completely 
resolved. When the participant arrives for their appointment, their temperature will be taken using a 
digital thermometer and the same screening questions will be asked again before beginning the 
appointment. The participant will be sent home with the same information on testing and self-isolation 
upon indication or disclosure of any symptoms or exposure to someone with confirmed or suspected 
COVID-19. Also during confirmation calls, participants will be informed that masks are required to be 
worn during their entire visit. If a subject does not have access to a mask, the study team will provide 
one. Subjects will be instructed on how to properly care for their masks if they need to remove them 
during the study visit. 
Inclusion of women and minorities. Inclusion of women and minorities in this prospective cohort 
study is appropriate and is encouraged. Subject selection is based only on the criteria described in 
the subject eligibility section. Women and minorities are not excluded from the study solely based on 
either of those demographic characteristics. Population characteristics, racial characteristics, and 
prior experience with recruitment at VA health care systems reveal that it is a good place to conduct 
such a study since the prevalence of HCV infection and co-morbid AUDs are disproportionately high 
among the Veteran population. Because sex effects may be observed, we will make every effort to 
enroll equal numbers of men and women—a charge that is less challenging than it previously was, as 
the number of female service members has been rapidly increasing over the last few years. It was 
recently reported that; “In 2013, female service members accounted for 14.9% of the Department of 
Defense active duty force and 18.5% of the selected reserve forces” (Department of Defense. 2013 
Demographics: Profile of the military community; summarized in (Brickell et al., 2017)). Given that all 
research participants will be Veterans treated within the VAPORHCS, children will not be included in 
this study. 
Informed Consent & HIPAA Authorization 
Interested Veterans will be given the opportunity to meet in person at VAPORHCS or by telephone or 
video to complete informed consent procedures. If the Veteran chooses to complete the informed 
consent process by phone or video, study staff will mail materials to the Veteran along with a pre-
addressed and stamped envelope. Study materials include: the VA Informed Consent form, OHSU 
Informed Consent form, and VA HIPAA Authorization. At the initial meeting, approved study 

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personnel will describe the study, apprise the participant of the risks, determine if the participant 
meets inclusion criteria and, if the participant wishes to participate, obtain written informed consent 
and HIPAA authorization. The participant will be given the opportunity to ask questions and discuss 
the protocol with their family. If the Veteran chooses to participate, he or she will sign the VA Informed 
Consent form, OHSU Informed Consent form, and VA HIPAA Authorization. If completed by phone or 
video, the participant will mail the documents back to Dr. Loftis using the pre-addressed and stamped 
envelope.  
If consenting is completed remotely, study staff will offer the participant the opportunity to complete 
portions of the neuropsychiatric study visit measures, including the clinical interview, neuropsychiatric 
interview, 12 out of 14 neuropsychological assessment measures, and questionnaire battery via 
telephone or video. Thus, research data be collected prior to the signed informed consent form and 
authorization having been received by the study team. Remaining research data and specimen 
collection will occur at the time of the participant’s next in-person research study visit once the signed 
informed consent forms and HIPAA authorization have been received. 
Risks, Side Effects, and Protections  
This human subjects prospective cohort study does not involve treatment or invasive procedures. The 
DAA therapy that patients will be receiving is part of standard care for HCV (and not administered for 
research purposes).  
• Patients may become upset while answering personal questions during the clinical interview. 
There are also risks to confidentiality, particularly of sensitive information about drug use and 
abuse and HIV/HCV infection status.  
• Subjects who experience claustrophobia may become anxious in the MRI instrument. Subjects 
with metal fragments, wire sutures, staples, implanted pacemakers or defibrillators or metal 
fragments from welding are at risk from damage due to movement of metal fragments in the 3T 
magnetic field. Participants will be systematically assessed for metallic foreign bodies and 
excluded if there are any uncertainties. The research team will obtain orbital x-rays if subjects have 
any history of welding, grinding or other exposure to metallic particles that could lodge in the orbit. 
Pregnant women (negative urine pregnancy test required before the scan), because of the 
unknown risk to the fetus, will also be excluded. Rarely, subjects experience vertigo, a metallic 
taste, or muscle stimulation. If a subject becomes anxious during the procedure, the procedure 
can be terminated immediately. 
• Blood drawing may cause pain or bruising at the site and carries a small risk of infection. 
Additional protections from risk. In order to provide additional protections against risk, during the 
consent process, subjects will be asked to sign an optional release of information to have laboratory 
test results released to their primary care provider, hepatologist, or other appropriate health care 
provider. In the event of abnormal results, clinical research staff will report the results to the 
participant and instruct the participant to consult with their health care provider to determine whether 
follow-up is required. Clinical research staff will also release results to the healthcare provider if the 
subject opted to sign a release during the study visit. Clinical research staff will have clinical 
experience and training (e.g., clinical psychology, clinical research) and will be trained to provide pre- 
and post-test counseling specific to HIV testing and HCV testing. Clinical research staff will be 
available to subjects for a post-test counseling visit in the event of a positive screen.  
A mental health provider (e.g., Drs. Hoffman) will be available to consult with any participants 
who experience discomfort for any reason during the study visit. Subjects will be asked to remain at 
the study visit either until the problem has been resolved or referral to appropriate treatment is 
accomplished. Subjects not in need of emergent treatment will be offered referral to counseling or 

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other support resources, as appropriate (e.g., should they be interested in additional addiction 
treatment, healthcare, or other services).  
For study activities that involve contact with participants via telephone or video, study team 
members will only contact Veterans from a private area so no one outside of the study team can 
overhear the conversation or have access to research information or protected health information. 
The study team member that conducts a study activity via telephone or video will obtain the address 
of the Veteran's location where they will participate and the contact information of a person at or near 
the Veteran's location who can be called in the case of emergency. If there is not a person at or near 
the Veteran’s location available in case of emergency, the study team member will notify the Veteran 
that they will call 911 if there is an emergency and provide the 911 dispatch with the Veteran’s 
address.  Veterans will participate via phone or video only if they have a safe, private location from 
which to participate. No phone or video contact will be recorded in any way.  
Benefits 
Subjects may benefit from HIV screens as well as medical laboratory tests. Those findings may be 
helpful in their clinical care if the patients wish the data to be shared with their clinicians. The study is not 
intended to directly benefit the subjects. As an indirect benefit to the subjects and others, the study may 
enhance collaboration between hepatology, substance use treatment, and mental health providers to 
bring about a higher level of coordinated patient care and substance use treatment. Collectively, these 
potential benefits outweigh the relatively small risks associated with filling out study questionnaires, 
submitting blood, saliva, and urine samples, and participating in neuroimaging assessments. 
Protected Health Information 
The date that biological specimens are collected, processed, and/or stored will be listed on the 
storage containers (e.g., cryovials) utilized for this study. This identifier is used for quality control 
purposes in order to track specimens and monitor sample integrity/viability. The PHI to be collected is 
the minimum necessary needed to conduct the research and can’t be further reduced.  
 
The purpose of the data collected regarding drug abuse, alcoholism, alcohol abuse, and 
infection with HIV is to conduct scientific research, and no personnel involved in the study will identify, 
directly or indirectly, any individual patient or subject in any report of such research (e.g. manuscript 
or publication). 
Multi-Site Study Concerns  
Determining VA from Non-VA Research 
This study will take place both at the Portland VA and at OHSU. VA Research will include consent, 
screening, breathalyzer and/or saliva alcohol testing, interviews, questionnaires, blood draws, oral 
fluid collection, urinalyses, and x-rays. Non-VA Research will include the MRI scans acquired at 
OHSU’s Advanced Imaging Research Center (AIRC) Address: 3181 SW Sam Jackson Park Rd, 
L452, Portland, OR  97239; Phone: (503) 418-1505. In addition, some statistical analyses for this 
project will be performed by the Biostatistics and Design Program at OHSU. All data sent to OHSU for 
statistical analysis will be coded.   
Costs To Subjects 
None of the participants will pay for any of the procedures or visits in this study because they are only 
for research study purposes. 
Subject Compensation  
Subjects will be reimbursed $125 for the initial visits ($75 for visit 1 and $50 for visit 2). Subjects who 
participate in the 6-month follow up visits will receive an additional $125 ($75 for visit 3 and $50 for visit 
4). In sum, subjects can earn $250 total if they complete all of the scheduled visits. Payment will be 

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provided in the form of electronic fund transfer (EFT) into the Veteran’s bank account. This 
compensation is reasonable and commensurate with the expected contributions of the participant. 
The amount of payment and terms of the payment are described in the informed consent form. 
Payments are fair and appropriate and do not constitute (or appear to constitute) undue pressure or 
influence on, or coercion of, the prospective research subjects to volunteer for or continue 
participation in the research study. 
Privacy and Confidentiality 
All study data derived from subject procedures will be obtained specifically for research purposes. 
Research records will be maintained according to the VA research records retention schedule. Data 
will be stored in a manner intended to preserve patient confidentiality. Hard-copy protected health 
information (PHI) (e.g., collected from clinical interviews and neuropsychiatric study visit procedures) 
will be stored in locked cabinets in the PIs VA office and laboratory space. Electronic PHI will be 
stored on servers behind the VA firewall accessed by password-protected VA computers. Each 
subject is assigned a unique identifier (study ID) based on a study identifier and number (i.e., DAA-
xxx). Only coded or de-identified data, not PHI, are used for analysis. The file linking the study ID to 
the patient’s name will be stored in a separate password-protected file on a secure server behind the 
VA firewall. Coded data will be stored on OHSU's REDCap application, a highly secure and robust 
web-based research data collection and management system.  No identifiable information will be 
entered into this application at any time. The statisticians will not have access to the code or PHI at 
any time. The spreadsheet linking the code to the subject will remain behind the VA firewall at 
VAPORHCS. Once the study has ended, the link will be stored by the VAPORHCS Research & 
Development Service.  
DTI and MRI images will be collected at the AIRC at OHSU. No PHI is used to identify subjects 
and only the subject’s coded ID is entered at the time of the scan. The raw data for each scan are 
downloaded to the Hoffman Lab (Co-I) Linux workstations in Building 100, room 5C-107 or Building 
103, room E-141 at the VAPORHCS. Image analysis will take place on these workstations in VA 
space. The primary storage location for the coded neuroimages will be on a password-protected 
network drive at the OHSU Advanced Computing Center (ACC), to which only the research team has 
access. Study personnel will also analyze coded neuroimages using the ACC Exacloud System, a 
shared server which executes specific analysis scripts without removing data from its secure network 
drive.  
Additionally, to complete image analysis remotely, study personnel will utilize an OHSU 
computer that is connected to the virtual private network (VPN) per OHSU ITG. This allows 
computers connected remotely to access the OHSU network and utilize network resources, including 
remote access of other network computers, while still having the same security level as being on 
campus. Using remote access software (TeamViewer, putty, etc.) for Linux workstations or 
MobaXterm software for accessing the ACC Exacloud System, study personnel will conduct image 
analyses remotely. 
 
As participants are seen within clinical spaces for research visits, and to ensure that participants are in 
the right area for study visits, participants will check-in with front desk staff/MSAs of the appropriate 
clinic. Study staff will send appropriate MSAs an encrypted e-mail with participant name, date, and time 
of study visit to allow MSAs to perform normal clinical duties and assist participants in being routed to 
study staff. 
 
 
 

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Certificate of Confidentiality 
To further protect subject’s privacy and confidentiality, the investigators will obtain a Certificate of 
Confidentiality from the National Institute of Health. With this Certificate, the investigators cannot be 
forced (for example by court subpoena) to disclose information that may identify subject’s in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings. 
Information and/or Specimen Management 
Blood specimens are collected from human subjects by study personnel or the VA phlebotomy lab 
specifically for research purposes. Specimens are coded with the subjects’ unique identifiers and the 
date that the samples are processed or stored. The unique identifier matches the subjects’ coded 
neuropsychiatric and demographic data. To track frozen sample storage, a hand-written log is 
maintained and secured in Dr. Loftis’ laboratory. An electronic record is additionally created. Together 
with research staff, Dr. Loftis maintains viable samples by monitoring freezer temperatures and 
ventilation, tracking specimen identification and location, and training staff involved in any aspect of 
the process. 
 
Clinical and laboratory data collected from consenting participants will be contributed into an 
existing IRB-approved VA Liver Disease repository (Lissi Hansen, PI, IRB #3891). Contribution to the 
repository is required, as stated in the informed consent form and the HIPAA authorization. 
Transfer of Data Ownership 
N/A 
Data and Safety Monitoring Plan (DSMP)  
Monitoring human participant recruitment, biological specimen collection, neuropsychiatric data 
collection, neuroimaging assessments, and data entry will be performed by the PI and study staff that 
performs the study visits and procedures. Any adverse events will be reported immediately to the PI 
and Dr. Chang (Co-I; Responsible Clinician) who will evaluate the patient and determine if any 
additional evaluation or treatment is needed. Dr. Loftis will ensure that adverse events are properly 
reported to the IRB. The study staff will examine all cumulative adverse events quarterly to determine 
if there are any systematic problems. 
Study staff is trained on the protocols to ensure that procedures are being conducted within the scope 
of the approved protocols. Dr. Maya O’Neil, a licensed psychologist and neuropsychologist, trains and 
supervises the clinical research staff in the administration and scoring of neuropsychological tests 
and psychological measures. Dr. Hoffman, a psychiatrist and expert in neuroimaging, trains and 
supervises the research staff in neuroimaging procedures and data analysis. Recruitment and 
enrollment for clinical projects are reviewed regularly at Dr. Loftis’ weekly laboratory meetings with 
research staff and at monthly meetings with Dr. Hoffman (Co-I). At these meetings, research staff 
provides enrollment updates, and the research team problem solves recruitment issues to ensure that 
projected enrollment numbers are obtained. The PI checks procedures (at least monthly) to verify that 
they are being conducted per the approved protocol, including the responsibilities and roles for 
gathering and monitoring data. The data are recorded by research staff as it is collected, and data 
accuracy is verified by double scoring, data entry and visual verification.  
 
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Appendix – Supporting Documents List 
 
 
 
 
 
Questionnaires and surveys 
Alcohol Timeline Followback (TLFB) (Sobell, 1992, Sobell et al., 1996) 
AUD Identification Test-C (AUDIT-C) (Bush et al., 1998)  
Beck Depression Inventory, Second Edition (BDI) (Beck, 1996) 
Brief Pain Inventory, Short Form (BPI) (Cleeland and Ryan, 1994) 
Clinical Institute Withdrawal Assessment for Alcohol scale, revised (CIWA-Ar) (Sullivan et al., 1989) 
Visual Analogue Scale (rates level of craving for alcohol)  
Fatigue Severity Scale (FSS) (Krupp et al., 1989) 
Generalized Anxiety Disorder Inventory (GADI) (Argyropoulos et al., 2007) 
Neuropsychological Assessment Battery (NAB) (Stern and White, 2003)--attention, memory, and 
executive functioning modules  
PCL-C (Weathers et al., 1994) 
Reynolds Intellectual Screening Test (RIST) (Reynolds and Kamphaus, 2003).  
Severity of Dependence Scale (SDS) (Gossop et al., 1997, Gossop et al., 1995) 
Sickness Impact Profile (Bergner et al., 1981) 
Structured Clinical Interview for DSM-5, research version (SCID-5-RV)  
Wide Range Achievement Test, Fifth Edition (WRAT5™) (Wilkinson and Robertson, 2017)