Evaluating Values-based Motivational Interviewing to Increase Treatment Completion With Fixed Dose Combination MK-5172/MK-8742 Among Veterans With Active Substance Use Disorders and Treatment-naïve Genotype 1 Chronic Hepatitis C
Phase: NA
Conditions: Patient Adherence, Chronic Hepatitis C, Alcohol-related Disorders
Sponsor: G.V. (Sonny) Montgomery VA Medical Center

 
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Title: Evaluating values-based motivational interviewing to increase treatment completion 
with fixed dose combination MK-5172/MK-8742 among Veterans with active substance 
use disorders and treatment-naïve genotype 1 chronic hepatitis C 
Investigators: Mary Jane Burton, M.D., Andrew C Voluse, PhD.,  
1. Objective and hypotheses. 
 
Primary Objective: Implement a values-based motivational interviewing (VBMI) 
intervention to promote treatment completion with fixed dose combination (FDC) MK-
5172/MK-8742 (elbasvir/grazoprevir, Zepatier™) x 12 weeks among treatment-naïve 
Veterans with substance use disorder (SUD) and genotype 1 chronic hepatitis C virus 
(HCV) infection.  
 
Primary Hypothesis: Veterans with SUD and genotype 1 chronic HCV infection who receive 
the VBMI intervention will complete the full course of treatment in 90% of cases.  
 
Secondary Objectives:  
 
1) Utilize VBMI to promote self-efficacy in taking FDC MK-5172/MK-8742 
(elbasvir/grazoprevir, Zepatier™)among Veterans with active SUD and chronic HCV 
infection.  
2) Demonstrate the feasibility of FDC MK-5172/MK-8742 (elbasvir/grazoprevir, 
Zepatier™) for obtaining sustained virologic response (SVR) in treatment-naïve genotype 1 
chronic HCV infection among Veterans with active SUD. 
 
3) Measure the prevalence of baseline NS5a resistance mutations in Veterans with active 
SUD and genotype 1a chronic HCV infection. NS5a is a nonstructural HCV protein. 
 
Secondary Hypotheses:  
1) Veterans with SUD enrolled in this study will demonstrate a trend towards clinically 
significant increases in HCV treatment adherence self-efficacy scores between 
baseline and week 4 of treatment.  
2) FDC MK-5172/MK-8742(elbasvir/grazoprevir, Zepatier™)  will be well-tolerated by 
Veterans with SUD.  
 
 
2. Study procedures 
2.1Background: The advent of direct acting antivirals (DAAs) for chronic HCV infection has 
increased the tolerability and effectiveness of curative HCV treatment. Disorders which can 
affect adherence to HCV treatment, including SUD, can reduce effectiveness of DAAs. During 
the pegylated interferon era, the VA HCV 001 study group demonstrated an association 

 
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between recent alcohol use and early treatment discontinuation, resulting in decreased 
treatment efficacy1. The authors concluded that patients with alcohol use should be provided 
additional support to assist with treatment completion.  
Motivational interviewing (MI) was initially developed to promote abstinence in those with 
alcohol use disorders2. In recent years, the core of MI techniques has been applied to other 
behavioral areas, including medication adherence3. Prior investigations have determined that 
MI can promote increased medication adherence among patients with HIV infection3-4, but less 
is known about the effect of MI on adherence to HCV medications. One prior study has 
associated self-efficacy, an idea conceptually linked to MI, with reduced risk of missed HCV 
medication doses5. 
Acceptance and Commitment Therapy (ACT) encourages the patient to use mindfulness to 
promote dedication to behavioral change6. The patients accept the difficulties inherent to 
making the change and develop techniques to manage these difficulties. One major component 
of ACT is identifying values that make a life worth living and then mindfully moving towards 
such values. This approach has shown promise with tobacco use disorders7 and has been used 
to promote psychotherapy attendance among substance use disorders8.  
We hypothesize an intervention which uses VBMI would increase rates of HCV treatment 
completion with FDC MK-5172/MK-8742 (elbasvir/grazoprevir, Zepatier™)among treatment 
naïve Veterans with HCV genotype 1 and SUD. MK-5172/MK-8742 (elbasvir/grazoprevir, 
Zepatier™) is a fixed dose combination once daily oral medication for chronic HCV. In clinical 
trials, treatment-naïve patients with genotype 1 HCV who received 12 weeks of MK-5172 and 
MK-8742 had sustained virologic response rates of 98%9. 
Approximately 1 in 4 Veterans with chronic HCV have an active SUD requiring hospitalization 
or residential treatment10. As patients with active SUD are often excluded from clinical trial 
participation, examining the feasibility of using emerging DAAs in this population is 
warranted.   
2.2We will conduct a prospective study of 20 Veterans with treatment-naive genotype 1 
chronic hepatitis C infection admitted to the Substance Abuse Residential Rehabilitation 
Treatment Program (SARRTP) and/or diagnosed with SUD with ICD-10 CM code for in past 6 
months. at the G.V. (Sonny) Montgomery VA Medical Center.  Institutional Review Board 
approval will be obtained prior to the conduction of the study. 
 
2.3.1 Study Population 
The G.V. (Sonny) Montgomery VAMC is an urban, academically-affiliated medical center in the 
Southeastern United States. . The center provides care to approximately 39,000 unique 
Veterans annually in rural and urban areas of Mississippi and surrounding states. The 
hepatitis clinics in the facility meet 3 ½ days weekly and, to date, have provided DAAs to over 
600 Veterans with chronic HCV.   As part of a pilot treatment program, 4 Veterans initiated 
HCV treatment while in residential treatment for SUD. Of these, 3 completed all 12 weeks of 
treatment while 1 relapsed into alcohol abuse and was lost to follow up. 
The HCV treatment clinics meet 3 ½ days weekly to provide DAA treatment for HCV. 
Veterans with co-existing MH conditions are frequently seen in clinic, including active SUD. 
Active SUD is not a contraindication for treatment provided the Veteran demonstrates he/she 
can adhere to medications and follow up visits.  Patients with active SUD who begin DAA 
treatment as an outpatient are followed every 2 weeks.  

 
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Inclusion criteria: 
  
1) Identified as having treatment-naïve genotype 1 chronic HCV infection; Veterans who 
are genotype 1a must have baseline NS5a resistance testing 
2) Current resident of the SARRTP program and/or ICD-10 CM code for SUD (F10-F19) 
within the past 6 months 
3)  Willing to initiate treatment with FDC MK-5172/MK-8742 (elbasvir/grazoprevir, 
Zepatier™)  
 
 
Exclusion criteria:   
1) Contraindications for therapy with FDC MK-5172/MK-8742 (elbasvir/grazoprevir, 
Zepatier™ 
2) Unable to provide written informed consent 
3) Hepatocellular carcinoma or other medical condition precluding HCV treatment 
4) Acute HCV infection 
5) Prior treatment for chronic HCV 
6) History of decompensated cirrhosis 
7) Platelet count < 75 K/cmm and/or albumin < 3 grams/dL 
8) Females and male sex partners of females who are pregnant, nursing and/or unwilling 
to use contraception 
9) Patients infected with genotype 1a who have not undergone baseline NS5a resistance 
testing 
See attached flow chart.      
2.5.1Participant Recruitment and Enrollment: Veterans with active SUD are regularly screened 
for chronic HCV infection. All patients with chronic HCV are subsequently referred to the HCV 
treatment clinic for treatment evaluation. When evaluating a patient for HCV treatment, 
current diagnoses including SUD (ICD10 CM F10-F19) are routinely noted. It is standard of 
care for patients who are infected with HCV genotype 1a to undergo baseline resistance 
testing before initiation with MK-5172/MK-8742 (elbasvir/grazoprevir, Zepatier™). Patients 
meeting inclusion criteria will be offered study participation at their clinic visit. Basic 
demographic data (age-if less than 89 years, race, gender) will be recorded on all patients who 
are asked to participate in the study to allow investigators to assess for enrollment bias. 
Patients who agree to participate will give their written informed consent. Patients will be 
assigned a unique study number that does not contain personal identifiers after signing 
informed consent. Each patient will have only one number for the duration of the study. Study 
records will be labeled with this unique study number and will not contain PHI.  Treatment 
will be prescribed in accordance with US labeling as described in the package insert. 
Genotype 1b: 12 weeks MK-5172/MK-8742(elbasvir/grazoprevir, Zepatier™) 
Genotype 1a without NS5a RAVs: 12 weeks MK-5172/MK-8742(elbasvir/grazoprevir, 
Zepatier™) 
Genotype 1a with NS5a RAVS: 16 weeks MK-5172-MK-8742 (elbasvir/grazoprevir, Zepatier™) 
with weight based ribavirin 
 

 
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2.5.2 Baseline visit: Patients will complete a survey of demographic (age, gender, 
race/ethnicity, income level, marital status, education level, distance from medical center) and 
medical information. Drug Abuse Screening Test(DAST) and AUDIT will be completed to 
assess severity of SUD. We will also assess health related quality of life (Rand-36 item Health 
Survey [Short Form-36]), social support (Medical Outcomes Study Social Support Survey 
[MOS-SSS]), depressive symptoms (Patient Health Questionnaire [PHQ-9]), and treatment 
adherence self-efficacy (HCV Treatment Self Efficacy-A [HCV TSE-A]). 
 
2.5.3. Description of the VBMI intervention  
Patients enrolled will receive 60-minute sessions at Weeks 0 and 2 and four 15-minute 
sessions at Weeks 4, 6, 8, and 10. The sessions at Weeks 0 and 2 will focus on identifying 
values and creating short-term goals within those values, consistent with an ACT framework6. 
Specifically, during these first two sessions values directly (e.g., “My health is important to 
me.”) and indirectly (e.g., “My family is important to me, and I need to be healthy to have time 
for my family.”) related to health behaviors and medication adherence will be elicited.  
Veterans will discuss how well they are living in accordance with their stated values and 
identify specific goals and objectives for increasing valued living through the use of goal-
setting exercises. The sessions in Weeks 4, 6, 8, and 10 will predominately be brief “check-in” 
meetings that will focus on helping the participant problem solve barriers to moving towards 
their values. For a more comprehensive description of the intervention, see Appendix F. The 
therapeutic approach of all sessions will be founded in MI techniques and specifically utilize 
the four core processes of engaging the Veteran to establish rapport, focusing the conversation 
on unhealthy behaviors and/or targets for change, evoking change-oriented talk and increased 
self-confidence, and planning specific practical steps for making change. All sessions will be 
conducted by a licensed psychologist who has extensive knowledge in ACT and MI or by a 
trained post-doctoral fellow under the supervision of a licensed psychologist. The sessions will 
be recorded (audio only) for the purposes of monitoring adherence of the psychologist to the 
VBMI protocol.  
 
2.5.4 Description of instruments:  
The Rand-36 item Health Survey (SF-36) is a validated instrument which evaluates physical 
and mental health.  The 36 questions cover 8 domains: physical function, role function as 
limited by physical health, bodily pain, social functioning, mental health, role function as 
limited by emotional health, vitality and general health perception. The survey was developed 
by Rand Corporation as part of the Medical Outcomes Study and has been previously used in 
Veterans with hepatitis C. 
 
The Medical Outcomes Study Social Support Survey (MOS-SSS) has also been widely used  
and validated among persons with chronic medical illness, including Veterans with chronic 
hepatitis C. This 19-item survey assesses the patients’ perceptions of their existing emotional 
support, tangible support, affectionate support, and social interactions.   
 
The Patient Health Questionnaire(PHQ-9) is a validated survey of depressive symptoms. 
Higher scores indicate a greater likelihood of clinical depression.  This survey is currently used 
to screen for depression annually in Veterans in care at VA Medical Centers.  

 
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The HCV-Treatment Self Efficacy (HCV-TSE) is a standardized survey which assesses self-
belief that a patient can complete his/her treatment regimen of pegylated interferon and 
ribavirin. The patient rates their confidence in their ability to take medications on a scale of 0 
to 10, where 0 indicates no confidence and 10 indicates full confidence. The answers to the 
four individual questions are averaged to a score of 0 to 10. We have adapted 4 questions from 
the original scale regarding medication adherence (HCV-TSE-A) to assess a patient’s 
perceptions of his/her ability to adhere to DAAs. 
 
2.5.5 Follow-up visits: 
The study will last 12 weeks, with follow up visits at Weeks 2, 4, 6, 8, 10 and 12, which will be 
coordinated to occur on the same date as Veterans’ substance abuse aftercare visits. Side 
effects of medications and tolerance of medications will be monitored at each visit using a 
single question about side effects experienced and response options including the most 
common side effects and a response of “other” and a description of that side effect. A single 
question will also be used to assess for any substance use since the last visit, with quantity and 
frequency being recorded if the response is positive.  
Adherence will be assessed at each follow up visit using the Visual Analog Scale and pill 
counts. Routine laboratory monitoring will include a CBC, CHEM 14, HCV RNA and a urine 
sample analyzed for cocaine, marijuana, opioid, and amphetamine use (all tests are standard 
of care). The HCV-TSE-A will be repeated at week 4. Assessments of depressive symptoms 
(PHQ-9) and health-related quality of life (SF-36) will be repeated at weeks 4 and 12. 
If a patient fails to complete the study, a lost to follow up form will be completed, 
As part of standard of care for HCV treatment, HCV RNA is measured 12 weeks after treatment 
completion to assess for sustained virologic response (SVR). Although there will not be a study 
visit 12 weeks post treatment, this data will be collected and listed in the informed consent. 
Although blood is only drawn as part of labs measured for standard of care and is not part of 
the study activities per se, the amount of blood drawn will not exceed 15 cc per visit.  
 
 
2.5.6 Measures of adherence: 
Visual Analog Scale (VAS): VAS is a self-report adherence measurement tool that is well-
validated in HIV populations1. The VAS is a 100 mm line which is anchored by word 
descriptions at either end. 
The patient will first name his medication and the prescribed dosing intervals. The 
interviewer will demonstrate the equivalence of 0%, 50% and 100% adherence on the scale. 
The patient will then mark their level of adherence with each medication over the two-week 
interval. The VAS is scored by measuring the distance in mm between 0 and the patient’s 
mark, which is recorded as % adherence. This % will be recorded at Weeks 2, 4, 6, 8, 10, and 
12 for FDC MK-5172/MK-8742(elbasvir/grazoprevir, Zepatier) .  
 
Pill Count: The number of each dispensed medications will be recorded at weeks 0, 2, 4, 6, 8, 
and 10. Patients will bring their pill bottles to each follow up visit where the remaining pills 
will be counted and recorded. Adherence will be calculated as: 
%  Adherence  = number dispensed-  number remaining          x 100 

 
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                                Number dispensed 
 
 
3. Data Management: 
Patients will be assigned a unique study number which does not contain PHI. This number will 
be used on all data collected for the purposes of this study. A master list of subjects which links 
the study number and patient identifiers will be maintained on an encrypted VA server. The 
data for this study will be entered into Microsoft Excel 2010. The investigator(s) and their 
research personnel are responsible for maintaining the study database, which will be kept on 
an encrypted VA server. No data will be stored on a hard drive of a PC. Only key personnel for 
this study will have access to the research data and access to this data will be terminated 
if/when the personnel are removed from the study. Research data will be maintained according 
the VA records schedule. Data containing PHI will not leave the VA premises A contract 
biostatistician will be used to analyze de-identified study data. 
 
Variables/Time Points of Interest 
The primary outcome of interest is the percentage of patients completing 12 weeks of 
treatment with FDC MK-5172/MK-8742 (elbasvir/grazoprevir, Zepatier™). Treatment 
completion will be defined as attendance at the last treatment visit (i.e.,Week 12).  
Adherence will be categorized into <90% adherence and > 90% adherence, based on an 
observed relationship between ribavirin adherence and early virologic response11. 
 
Statistical Methods 
Binary logistic regression analysis will be used to report adjusted odds ratios. Differences in the 
distribution of HSV-TSE-A scores across categorical visits (baseline vs. Week 4) will be accessed 
using Wilcoxon rank sum test. In addition, parametric models (linear regression) will be 
explored to estimate the differences. 
 
Power/Sample Size: 
In our pilot program of 4 Veterans, we found that 75%) completed 12 weeks of treatment.  
Estimating a 90% (18/20) completion rate in the VBMI arm, we anticipate that a sample size 
of 20 patients will demonstrate a trend towards higher completion rates with the VBMI 
intervention. We also anticipate the study will demonstrates a high rate of medication 
adherence. It is our intention to use data from this study to develop larger protocols with more 
robust sample sizes. 
Limitations: 
1) Enrollment bias may select for a different population of SUD patients than those who do not 
participate. We have requested approval to record demographic information from patients 
who do not enroll, to allow comparison for significant differences between groups in terms of 
age, race, gender.   
2)Patients with NS5a mutations conferring resistance to elbasvir will require the addition of 
weight-based ribavirin and treatment extension to 16 weeks.  Based on our current 
observations of patients with HCV infection and SUD, we anticipate that 47% are infected with 
genotype 1a . Estimating that 11% of patients with genotype 1a will have baseline NS5a 
resistance, we estimate that 2 patients will require 16 weeks of treatment.   We will not assess 

 
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adherence beyond 12 weeks of treatment and we will not assess adherence to ribavirin in this 
protocol.  
 
Adverse event reporting: 
Serious and unexpected adverse events to FDC MK-5172/MK-8742 (elbasvir/grazoprevir, 
Zepatier™) will be reported to the IRB and Research Compliance Officer, Merck at 1-877-888-
4231 immediately upon notification and/or the FDA (1-800-FDA-1088) or 
www.fda.gov/medwatch.  
For events regarding data loss/theft/unauthorized access, the ISO, IRB chair, PO and RCO will 
be notified immediately upon notification of event.  
 
Role of pharmacy: 
The research pharmacist will store and dispense MK-5172/MK-8742 . (elbasvir/grazoprevir, 
Zepatier™). 
 
If a patient fails to complete the study, a lost to follow up form will be completed.  
 
References 
1. 
Anand BS, Currie S, Dieperink E, et al. Alcohol use and treatment of hepatitis C virus: results 
of a national multicenter study. Gastroenterology 2006;130:1607-16. 
 2. 
 Miller WR, Rollnick S. Motivational interviewing: Preparing people to change addictive 
behavior. New York, NY: Guildford Press; 1991. 
3. 
DiIorio C, McCarty F, Resnicow K, et al. Using motivational interviewing to promote 
adherence to antiretroviral medications: a randomized controlled study. AIDS Care 2008;20:273-
83. 
4. 
Cooperman NA, Arnsten JH. Motivational interviewing for improving adherence to 
antiretroviral medications. Current HIV/AIDS reports 2005;2:159-64.  
 
5. 
Bonner JE, Esserman DA, Golin CE, Evon DM. Self-efficacy and adherence to antiviral 
treatment for chronic hepatitis C. J Clin Gastroenterol 2015;49:76-83. 
6. 
Hayes SC, Strosahl K, Wilson KG. Acceptance and Commitment Therapy: An experiential 
approach to behavior change. New York, N.Y.: Guilford Press; 1999. 
 
7. 
Bricker JB, Mull KE, Kientz JA, et al. Randomized, controlled pilot trial of a smartphone app 
for smoking cessation using acceptance and commitment therapy. Drug Alcohol Depend 2014. 
 
8. 
Luoma JB, Kohlenberg BS, Hayes SC, Fletcher L. Slow and steady wins the race: a 
randomized clinical trial of acceptance and commitment therapy targeting shame in substance use 
disorders. J Consult Clin Psychol 2012;80:43-53. 
 
9. 
el-Serag HB, Kunik M, Richardson P, Rabeneck L. Psychiatric disorders among veterans with 
hepatitis C infection. Gastroenterology 2002;123:476-82. 
 

 
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10. 
Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of 
treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in 
patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-
WORTHY): a randomised, open-label phase 2 trial. Lancet;385:1087-97. 
11.      Lo Re V, 3rd, Teal V, Localio AR, Amorosa VK, Kaplan DE, Gross R. Relationship between 
adherence to hepatitis C virus therapy and virologic outcomes: a cohort study. Ann Intern Med 
2011;155:353-60 
 
12.      Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and 
Sofosbuvir for Untreated HCV Genotype 1 Infection. New England Journal of Medicine. 
2014;370(20):1889-98. 
 
 
 

 
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Ammendment:  
 
Microbiome analysis 
Stool samples from patients with HCV who are on DAA therapy have been collected with their informed 
consent at baseline, week 4 and 12 of treatment.  Stool samples are stored in -80 degree freezer, 
identified only by study number with no patient PHI.   
16s ribosomal Bacterial DNA will be extracted from the stool samples using the QIAamp Fast DNA Stool 
Mini Kit (Qiagen) and placed into microcentrifuge tubes labeled with the study number. Bacterial DNA 
extraction will take place in R 403 and R 405.  
 
The stool samples will be returned to the -80 degree freezer and will not leave the VA premises, 
maintaining the chain of custody.  
 
The extracted bacterial DNA will be sent to the University of Mississippi Medical Center Molecular and 
Genomics Core for analysis. The bacterial DNA samples will be labeled with the study number (no PHI). 
The report the Core generates will also not contain PHI.  
 
We will analyze the changes in the gut microbiome during treatment for hepatitis C. We will be able to 
compare baseline alpha diversity of the microbiome at week 4 and week 12 of treatment in each 
patient.