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RESEARCH REPORT
doi:10.1111/add.12679
Efficacy of motivational enhancement therapy on alcohol use disorders in patients with chronic hepatitis C: a randomized controlled trial Eric Dieperink1,5, Bret Fuller2,7, Carl Isenhart1,5, Kelly McMaken1, Rebecca Lenox4, Christine Pocha6, Paul Thuras1,5 & Peter Hauser3,8 Veterans Affairs Healthcare Systems, Minneapolis, MN, USA,1 Veterans Affairs Healthcare Systems, Portland, OR, USA,2 Veterans Affairs Healthcare Systems, Long Beach, CA, USA,3 Veterans Affairs Healthcare Systems, Palo Alto, CA, USA,4 Departments of Psychiatry, University of Minnesota-Medical School, Minneapolis, MN, USA,5 Departments of Medicine, University of Minnesota-Medical School, Minneapolis, MN, USA,6 Oregon Health and Science University, Portland, OR, USA7 and VISN 22 Desert Pacific Healthcare Network Office, Long Beach, CA, USA8
ABSTRACT Aims To determine the efficacy of motivational enhancement therapy (MET) on alcohol use in patients with the hepatitis C virus (HCV) and an alcohol use disorder (AUD). Design Randomized, single-blind, controlled trial comparing MET to a control education condition with 6-month follow-up. Setting Patients were recruited from hepatitis clinics at the Minneapolis, Minnesota and Portland, Oregon Veterans Affairs Health Care Systems, USA. Participants and Intervention Patients with HCV, an AUD and continued alcohol use (n = 139) were randomized to receive either MET (n = 70) or a control education condition (n = 69) over 3 months. Measurements Data were self-reported percentage of days abstinent from alcohol and number of standard alcohol drinks per week 6 months after randomization. Findings At baseline, subjects in MET had 34.98% days abstinent, which increased to 73.15% at 6 months compared to 34.63 and 59.49% for the control condition. Multi-level models examined changes in alcohol consumption between MET and control groups. Results showed a significant increase in percentage of days abstinent overall (F(1120.4) = 28.04, P < 0.001) and a significant group × time effect (F(1119.9) = 5.23, P = 0.024) with the MET group showing a greater increase in percentage of days abstinent at 6 months compared with the education control condition. There were no significant differences between groups for drinks per week. The effect size of the MET intervention was moderate (0.45) for percentage of days abstinent. Conclusion Motivational enhancement therapy (MET) appears to increase the percentage of days abstinent in patients with chronic hepatitis C, alcohol use disorders and ongoing alcohol use. Keywords
Alcohol, alcohol use disorder, hepatitis C, liver disease, motivational enhancement therapy, motivation.
Correspondence to: Eric Dieperink, VAHCS, Department of Psychiatry (116A), One Veterans Drive, Minneapolis, MN 55417, USA. E-mail: [email protected] Submitted 19 November 2013; initial review completed 24 February 2014; final version accepted 1 July 2014
INTRODUCTION The hepatitis C virus (HCV) is the most common bloodborne viral infection, affecting approximately 170 million people world-wide and 3.2 million Americans [1,2]. Alcohol use disorders and alcohol use are common among patients with HCV. A national seroprevalence study found that 48% of participants with HCV consumed five or more drinks in a single day during the previous year, and 33% had done so on at least 50 days [1]. In a large sample of Veterans, approximately 75% had a history of an alcohol
use disorder (AUD) [3]. A study of privately insured patients with HCV found that more than 93% reported drinking prior to obtaining an HCV diagnosis and 67.9% had a heavy drinking pattern [4]. Alcohol use is of particular concern in patients with HCV, as it accelerates liver fibrosis, often leading to cirrhosis with subsequent increased risk of liver decompensation, hepatocellular carcinoma and death [5–12]. As of 2007, deaths due to HCV in the United States exceeded those due to the human immunodeficiency virus, and over the next two decades HCV mortality is expected to increase [13].
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Alcohol use is also a significant barrier to receipt of antiviral therapy [14]. Studies show that patients with HCV and AUDs are generally not referred for HCV treatment evaluation, or when evaluated are excluded from antiviral therapy [14–16]. A major reason for exclusion is the concern for non-adherence to antiviral therapy. In a large study of HCV patients, alcohol use was associated with reduced treatment candidacy and significantly higher antiviral treatment discontinuation [17]. Given that the newer and more effective [18–20] antiviral therapies require strict medication adherence, patients using alcohol may face increased barriers to antiviral therapy, thus reducing the potential of these life-saving treatments [21]. Treatments to address alcohol use are needed, as reducing or eliminating alcohol use may increase access to new antiviral treatments. A variety of effective interventions exist to address AUDs but most are lengthy and not adapted easily outside specialty alcohol treatment settings. Alcohol treatment based on motivational psychology has been well studied. Motivational enhancement therapy (MET) in particular is an effective treatment for AUDs. MET is brief, has been manualized and can be exported easily to a variety of clinical settings [22]. To date, only one observational study has been published showing that a brief motivational intervention provided in a hepatitis clinic reduces alcohol use in patients with HCV [23]. However, no controlled studies of MET in individuals with HCV have been published. The objective of this study was to determine the efficacy of MET in reducing alcohol use in a population of HCV-infected patients who are currently drinking alcohol and have AUDs. The primary hypothesis of this study was that patients with HCV, an AUD and continued excessive alcohol use who receive MET will have a greater reduction in the number of standard alcohol drinks per week and a greater percentage of days abstinent than patients who receive health education.
AUD and current alcohol use were enrolled into the study. One subject in the control condition was randomized but did not meet inclusion criteria and had no alcohol use data, and was excluded from the analysis, leaving 138 subjects with analyzable data. Participants were recruited from hepatitis clinics at the Minneapolis, Minnesota (n = 93) and Portland, Oregon (n = 46) Veteran Affairs Health Care Systems (VAHCSs) between 18 November 2008 and 15 December 2011. Eligibility criteria included (1) chronic HCV diagnosed via positive HCV antibody and polymerase chain reaction confirmation of viremia; (2) alcohol dependence or abuse according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) [24], using the Structured Clinical Interview for the DSM-IV-TR (SCID) [25]; and (3) Veterans aged 18 years and older, current alcohol use, drinking seven or more standard drinks per week for each of the preceding 2 weeks or at least one heavy drinking (four or more standard drinks in 1 day) day per week for 2 weeks. A standard drink was 14 g of pure alcohol, equivalent to 12 oz of beer, 5 oz of wine and 1.5 oz of 80-proof alcohol. Exclusion criteria included (1) meeting DSM-IV (SCID) diagnostic criteria for opiate, cocaine or methamphetamine dependence in the past 6 months and (2) pre-existing medical conditions that could interfere with participation in the protocol, such as: brain trauma, cognitive impairment, dementia, hepatic encephalopathy or acute psychiatric instability (significant psychosis, mania or elevated risk for suicide). Cannabis abuse or dependence was not exclusionary. Medications to deter alcohol use were not reason for exclusion. However, no subjects were taking these medications prior to randomization and only one subject in the education arm had two 30-day prescription fills for naltrexone during the trial. The study was approved by the Minneapolis, Minnesota and Portland, Oregon Veterans Affairs Health Care System (VAHCS) institutional review boards and participants provided written informed consent.
METHODS Participants
Assessment
Patients were referred to the study by hepatitis providers if they scored >3 on the Alcohol Use Disorder Identification Test—consumption [24] or, based on clinical evaluation, were considered to be drinking excessive amounts of alcohol. The Portland, Oregon site also had flyers in the hepatology clinic and a minority of patients was recruited from the flyer. Patients were screened for study eligibility by research assistants; final eligibility was determined using chart data and review by site investigator. Data were collected to 31 July 2012. One hundred and thirty-nine men and women Veterans with HCV, an
All participants were assessed for study eligibility and to collect demographic information. Participants were assessed at baseline and at 3 and 6 months after baseline with the following measures: • Time-line follow-back (TLFB)-measured alcohol use over the prior 30 days [26]. • Beck Depression Inventory, 2nd edition (BDI-II)measured depressive symptoms over the past 7 days [27]. • Brief Symptom Inventory (BSI)-measured anxiety and other symptoms over the past 7 days [28].
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• Post-Traumatic Stress Disorder (PTSD) Checklist— civilian (PCL-C)-measured PTSD symptoms over the prior 30 days [29]. • Urine drug screen. • The TLFB was used to gather past 30-day use of cannabis, cocaine, methamphetamines and nonprescribed opioids. Quantity of use was not obtained. • Breath alcohol concentration as measured by breathalyzer. • Biomarkers of alcohol use including percentage of carbohydrate-deficient transferrin (%CDT), ethyl glucuronide (EtG) and ethyl sulfate (EtS). All measures were administered by a research assistant who was blinded to the randomized condition.
Treatment conditions Motivational enhancement therapy MET was developed in conjunction with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for Project MATCH (Matching Alcoholism Traatment to Client Homogeneity) [22]. MET was delivered by a licensed health-care professional (one physician, five psychologists). MET consists of four sessions, each lasting approximately 30–45 minutes. At each session, participants were given feedback regarding their liver function tests (LFT) [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamic transpeptidase (GGT), bilirubin] if available from the chart. HCV-specific feedback was incorporated into each session in order to maximize the participant’s motivation to reduce alcohol use. Key elements included: (i) discussion of the synergistic effects of alcohol and HCV on liver fibrosis; (ii) discussion of the impact of alcohol on antiviral therapy (i.e. reduces efficacy); and (iii) alcohol as a barrier to receiving antiviral therapy. Control health education sessions The education control sessions were administered by the same six licensed mental health clinicians who administered MET. The control condition consisted of four sessions of general health education; each session lasted 30–45 minutes. Topics covered included sleep hygiene, nutrition and diet, relaxation training and exercise. Health education was used to control for the effect of therapist contact (time) and provided individual clinician contact without engaging the participants in discussion of alcohol or motivational themes. At each session, liver function tests (ALT, AST, GGT and bilirubin) were given to subjects if available from the chart. Data were given in written form and if subjects had questions about the data they were asked to contact hepatitis clinicians for answers.
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Treatment fidelity monitoring All clinicians were trained in administering both MET and the health education conditions. Providers attended a 1-day motivational interviewing workshop that included didactics, video and live presentations and role plays. This was followed by approximately every other week group consultation with one of us (C.I.), who is part of the Motivational Interviewing Network of Trainers. Providers received training in the education condition that included a didactic review of the material and role plays. Providers received feedback regarding taped sessions both for adherence to motivational interviewing (MI) principles using the Motivational Interviewing Treatment Integrity code (MITI) for MET sessions and adherence to the control condition, although no specific metrics were used for the control condition. Before treating participants with MET, the clinicians submitted at least two tape-recorded cases that met thresholds based on the MITI [30]. Therapy sessions were audiotaped and 15 minutes of each tape was scored using a version of the MITI modified for this project [31]. Corrective action was taken to ensure adherence to MET and the education sessions. The MITI consists of six measures of adherence to MI principles. A total of 197 MET sessions and 198 education sessions were audiotaped and evaluated using the modified MITI. A total of 72.1% (142 of 197) MET and only 1.5% (three of 198) of education sessions met either five or six thresholds on the MITI, indicating significant fidelity to MI principles in the MET group. Procedures Eligible participants were assigned randomly to one of two groups (MET or education control) using Pocock & Simon’s minimization method [32]. Randomization was stratified by site (Portland, Minneapolis) and BDI-II score (BDI-II ≤ 19 versus BDI-II > 19). Within each strata participants were randomized in blocks of four using Random Allocation Software (version 1.0) by the study statistician (P.T.). Patients were randomized at the time of the first therapy session, which occurred on average 7 days after consent but could not occur more than 28 days after consent. In order to maximize flexibility and enhance the possibility of subjects completing all therapy sessions, the length between sessions was negotiated between the clinicians and the subject. All four sessions were completed prior to the 3-month research evaluation. Statistical methods Sample size determination The power analysis was performed for drinking days per week using Nquery Advisor 4 (Statistical Solutions, Boston, MA, USA) under the following assumptions:
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(1) repeated-measures analysis of variance (ANOVA) with the main effects of treatment (control versus MET) and time (0, 3, 6 months) and the treatment × time interaction; (2) compound symmetrical covariance matrix; and (3) type I error level = 0.05. The estimates for the mean, standard deviation and intrasubject correlation were obtained from a similar study conducted among 47 HCV-infected patients with heavy alcohol consumption [23]. The treatment effect is captured by the treatment × time interaction, i.e. differential patterns of alcohol consumption over time. We calculated that a sample size of 136 patients (68 in each group) would provide 87% power to detect an effect size of 0.30. Based on the Dieperink et al. study and other publications [33–35], we expected the effect size of the interaction to range from 0.25 to 0.35, depending on the amount of intrasubject correlation. Hence, this study was calculated to have sufficient power to detect the expected effect size of the primary objective. Calculating alcohol consumption The primary end-point for measuring alcohol consumption was the number of standard drinks per week and percentage of days abstinent. These measures are well validated, used frequently in alcohol treatment studies and were included in the large NIAAA-funded Project MATCH. Analysis of outcome Each subject was assessed for the outcome variables at baseline, 3 months and 6 months. For the primary objective (i.e. the analysis of the efficacy of MET in reducing alcohol use), we used mixed-effects models to examine change over time in our analysis with both intercept and slope as random effects [36,37]. Mixed-effects models allow incomplete repeated-measures data as well as continuous and categorical covariates, fixed and timedependent covariates, and unstructured as well as structured covariance matrices. SPSS (version 0.19) was used for all analyses. For other secondary analyses we used χ2 procedures to test for differences in antiviral treatment initiation and regression analyses to examine relationships between reduction in alcohol use, %CDT and EtG/EtS. The Wilcoxon signed-rank test was used to evaluate changes in abstinence from baseline to 6 months.
RESULTS Seventy participants received MET and 68 participants received the health education control condition. Participants attended approximately the same number of ses-
Table 1 Baseline characteristics. MET (n = 70) Age, mean (SD) Sex Male Female Race/ethnicity Caucasian African American Native American Other Self-reported alcohol drinking Percentage of days abstinent (%, SD) Mean drinks per week (SD) Baseline symptom measures BDI-II BSI PCL-C Urine drug screen Cannabis Cocaine Methamphetamine Opioids Self-reported use past 30 days Cannabis Cocaine Methamphetamine Opioids
Education (n = 68)
55.8 (6.8)
55.2 (6.3)
97.1% (68) 2.9% (2)
94.1% (64) 5.9% (4)
68.6% (48) 28.6% (20) 0% 2.9% (2)
66.2% (45) 30.9% (21) 2.9% (2) 0%
34.98% (26.7)
34.63% (27.0)
35.45 (25.42)
38.86 (46.19)
17.40 (11.58) 51.23 (41.23) 38.01 (15.21)
17.31 (10.79) 56.91 (44.18) 40.61 (16.04)
32.8% (20/61) 8.2% (5/61) 3.3% (2/61) 9.8% (6/61)
18.3% (11/60) 3.3% (2/60) 0% (0/60) 6.7% (4/60)
35.7% (25/70) 7.1% (5/70) 4.3% (3/70) 0% (0/70)
39.7% (27/68) 7.4% (5/68) 1.5% (1/68) 1.5% (1/68)
MET = motivational enhancement therapy; BDI-II = Beck Depression Inventory—second edition; BSI = Brief Symptom Inventory; PCLC = Post-Traumatic Stress Disorder Checklist—civilian; SD = standard deviation.
sions in each group, with 40 subjects in MET and 38 subjects in the control condition attending all four sessions. Two subjects did not receive the allocated treatment, as they did not return for the intervention, but 84.3% (59 of 70) of MET subjects and 89.7% (61 of 68) in the control condition attended the 6-month research follow-up visit. Participants in both groups had similar baseline characteristics (Table 1). All participants with baseline alcohol use data and who were randomized were included in the analysis (Fig. 1). A total of 18 subjects did not complete the 6-month follow-up. We examined those who completed the 6-month follow-up versus those who did not on baseline characteristics and found no significant differences on primary outcome measures. We also compared those without any follow-up information to those who had some follow-up information (3 or 6 months), and found no significant differences on primary outcomes.
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Enrollment Assessed for eligibility (n = 513)
Excluded (n = 374) Not meeƟng inclusion criteria (n = 296) Declined to parƟcipate (n = 78)
Randomized (n = 139)
AllocaƟon Allocated to MET (n = 70)
Allocated to Health EducaƟon (n = 69)
Received MET (n = 68)
Received Health EducaƟon (n = 68)
• 1 Session (n = 7) • 2 Sessions (n = 7) • 3 Sessions (n = 11) • 4 Sessions (n = 43) Did not receive allocated intervenƟon (n = 2) (Did not return for intervenƟon, n = 2)
• 1 Session (n = 6) • 2 Sessions (n = 10) • 3 Sessions (n = 7) • 4 Sessions (n = 45) Did not receive allocated intervenƟon (n = 1) (Did not meet inclusion criteria, n = 1)
Follow-Up AƩended 6 month follow up (n = 59) Lost to follow-up (n = 11) • • • • •
AƩended 6 month follow up (n = 61) Lost to follow-up (n = 8)
Dropped out of study (n = 6) Died (n = 1) Withdrew consent (n = 1) Incarcerated (n = 2) Removed for psychiatric instability (n = 1)
• Dropped out of study (n = 5) • Died (n = 2) • Did not meet inclusion criteria (n = 1)
Analysis Analysed (n = 70) Excluded from analysis (n = 0)
Analysed (n = 68) Excluded from analysis (n = 1), no data available
Figure 1 Flow of participants through the trial
For the primary analysis of change in percentage of days abstinent, the MET group showed a significant increase in percentage of days abstinent from baseline to 6 months compared to the control condition. At baseline, subjects in MET had 34.98% days abstinent, which increased to 69.91 and 73.15% at 3 and 6 months. Subjects in the education condition had 34.63% days abstinent at baseline and this increased to 58.23 and 59.49% at 3 and 6 months. We observed a significant increase in
percentage of days abstinent overall (F(1120.4) = 28.04, P < 0.001) and a significant group × time effect (F(1119.9) = 5.23, P = 0.024) (Fig. 2). For the primary analysis of change in drinks per week we did not find significant results. Mean drinks per week in the MET group dropped from 35.45 at baseline to 14.6 and 15.5 at 3 and 6 months and from 38.9 in the education group at baseline to 18.9 and 22.1 at 3 and 6 months. While there was a significant drop overall in drinks per week
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Figure 2 Change in percentage of days abstinent
(F(1134.5) = 6.38, P = 0.013), there was no group × time difference (F(1133.4) = 0.30, P = 0.57) (Table 2). There were no significant differences between groups on any secondary outcome measures (Table 2). Overall 30-day abstinence at 6 months was significantly higher (Z = −5.20, P < 0.001) and heavy drinking days were significantly lower at 6 months (F(1,245) = 16.55, P < 0.001) across both groups. Both groups showed a reduction in the biological measures of alcohol use. EtG, EtS and %CDT decreased over the 6-month period, but no significant difference between groups was found. Other measures, including the BDI, BSI and PCL-C, decreased from baseline to 6 months, but no significant difference was found between groups (Table 2). Significant adverse events were more common in the control condition. A total of seven adverse events occurred in the MET condition (two deaths, three nonalcohol- and two alcohol-related hospitalizations) and 14 in the control (three deaths, seven non-alcohol- and four alcohol-related hospitalizations). Overall, we found that 7.2% of the MET subjects versus 2.9% of education subjects initiated antiviral treatment (χ2(1) = 1.31, P = 0.253). However, none of the subjects at the Portland site initiated antiviral treatment. When we restricted the analysis to Minneapolis, we found that 10.9% of those in the MET group initiated antiviral treatment versus 4.3% in the control group (χ2(1) = 4.18, P = 0.041).
DISCUSSION MET was significantly more efficacious than a control education condition for increasing percentage of days abstinent in a sample of patients with HCV and comorbid AUDs. Other measures of alcohol use, including drinks per week, heavy drinking days and abstinence, were not statistically different between groups. The effect size of the MET intervention was moderate (0.45) for percentage of days abstinent. The effect size is similar to most studies of treatment for AUDs [38]. However, most prior studies do not include individuals who are not seeking treatment for their alcohol use, and typically do not include patients with significant psychiatric and substance use symptoms, such as those in this study. These data are consistent with a prior nonrandomized clinical trial and show that a relatively brief intervention can help to reduce alcohol use in patients with HCV [23]. Reducing alcohol use in this population is important, as alcohol significantly hastens fibrosis [5,39] and has been shown to be responsible for more than onethird of the cases of cirrhosis in HCV patients presenting to a hepatitis clinic [11]. MET offers an evidence-based approach to the treatment of alcohol use in HCV patients and may help to reduce the overall burden from advanced liver disease. The subjects in this study had significant psychiatric symptoms and non-alcohol substance use. The mean BDI
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SD = standard deviation; %CDT = percentage carbohydrate-deficient transferrin; EtG = ethyl glucuronide; EtS = ethyl sulfate; BDI-II = Beck Depression Inventory—second edition; BSI = Brief Symptom Inventory; PCL-C = PostTraumatic Stress Disorder Checklist—civilian; MET = motivational enhancement therapy; EDU = education control condition; CI = confidence interval. Effect size = Cohen’s d.
0.26 0.14 0.01 0.08 0.02 0.20 0.01 0.16 0.45 0.97 0.70 0.92 0.28 0.95 −2.28 (−5.48 to 0.93) 5.7% (−9.5 to 21.0%) 0.4% (−19.7 to 20.4%) 3.9% (−24.5 to 16.6%) −0.21 (−4.2 to 3.8) −8.21 (−25.2 to 7.36) 0.19 (−5.47 to 5.85) 15.04 (9.53) 0 19/49 (38.8%) 49/62 (79%) 17.31 (10.79) 56.91 (44.18) 40.61 (16.04) 14.03 (8.74) 0 20/53 (37.7%) 46/63 (73%) 17.40 (11.58) 51.23 (41.23) 38.01 (15.21)
6.24 (9.31) 14/58 (24.1%) 11/36 (30.6%) 25/47 (53.2%) 13.11 (11.36) 41.52 (41.88) 33.58 (15.26)
8.27 (8.98) 8/60 (13.3%) 15/41 (36.6%) 34/48 (70.8%) 13.64 (10.38) 47.70 (42.31) 36.95 (16.02)
5.10 (8.10) 15/59 (25.4%) 9/34 (26.5%) 22/40 (55%) 13.37 (11.66) 40.25 (43.23) 33.89 (16.03)
7.38 (9.53) 12/61 (19.7%) 12/46 (26.1%) 33/56 (58.9%) 13.57 (10.19) 49.17 (44.35) 33.70 (14.59)
0.024 0.57 59.49 (35.30) 21.41 (29.39) 73.15 (32.18) 14.88 (27.94) 58.23 (34.05) 19.94 (25.50) 34.63 (27.05) 38.86 (46.19) 34.98 (26.7) 35.45 (25.42)
% days abstinent (SD) Drinks/week (SD) Secondary outcomes Heavy drinking days (≥4 drinks) (SD) 30-day abstinence %CDT >2.1 EtG/EtS %positive BDI-II BSI (SD) PCL-C (SD)
69.91 (31.99) 13.35 (18.86)
MET MET EDU MET Primary outcomes
Baseline
Table 2 Drinking outcomes and effect size estimates at 6 months.
3 months
EDU
6 months
EDU
P
Mean difference between groups at 6 months (95% CI) 13.66 (1.4 to 25.9) −6.52 (−16.9 to 3.85)
Effect size d 0.45 0.23
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score was more than 17, indicating moderate depressive symptoms. Similarly, elevated BSI and PCL-C scores indicate significant anxiety and other psychiatric symptoms. The most common non-alcohol substance used was cannabis, but cocaine, methamphetamines and opioids were also used. Despite these significant symptoms, MET was helpful in increasing percentage of days abstinent. This suggests that MET will be helpful in the broader population of people with HCV and comorbid AUDs. The therapeutic effect of MET was most pronounced at 3 months, but drinking continued to decline at 6 months. Alcohol use in the control condition also decreased significantly at 3 months but plateaued at 6 months. This suggests that, unlike the health education intervention, MET is durable. In clinical practice, clinicians could consider adding more sessions to further enhance the effectiveness of MET in this population. However, further research is needed to determine whether adding more sessions would further reduce alcohol use. Overall initiation of antiviral treatment was low. This was not unexpected, as not all patients want antiviral therapy, and during the study new antiviral treatments with greater efficacy were in the process of becoming approved by the US Food and Drug Administration. Practitioners may have been waiting to initiate these new therapies with the expectation that they would be more efficacious. Although there was no overall difference in antiviral treatment initiation between groups, we found that MET was associated with greater initiation of antiviral therapy at the Minneapolis site. Prior data indicate that patients with significant alcohol problems can initiate and benefit successfully from antiviral therapy, but typically require multi-disciplinary support [40,41]. Our data are consistent with prior research indicating that initiation of antiviral therapy is influenced by patient, provider and system factors [42,43]. Future studies should determine whether efforts to reduce alcohol use increase initiation of antiviral therapy and outcomes such as a sustained virological response. There are several limitations to the current study. All subjects were Veterans and most were male, thus results may not apply to all people with HCV. However, many other characteristics of this group, including significant psychiatric and substance use symptoms, are typical of many people with HCV and thus the results have broader applicability. The only significant effect of MET was an increase in the percentage of days abstinent. It is possible that although we designed the control condition to be a neutral intervention with respect to alcohol use, it probably provided more support than a treatment-as-usual approach, thus diluting the effect of MET. Other factors, such as giving control subjects their liver function tests and rigorous assessment of alcohol use, may also have
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contributed to the reduction in alcohol use in the control condition. Although the biological measures of alcohol use (%CDT and EtG/EtS) were consistent with selfreported reductions in alcohol use, there were no significant differences between groups. The power to detect a difference between groups may have been hampered by our inability to collect samples from all subjects. Another limitation of the study is that it was not possible for participants to be blinded to the intervention condition. However, research assistants who completed the research follow-up visits were blinded to the intervention condition assignment, thus mitigating this concern. Although more than 84% of both groups had follow-up data at 6 months and analyses included all participants, attrition is a limitation of this study. Finally, findings are limited by the 6-month follow-up period. However, 6 months is a typical follow-up period used by hepatologists to monitor alcohol use, so results at 6 months have clinical relevance and help to determine antiviral treatment readiness. Future studies that examine long-term follow-up are needed, not only to examine the relationship between alcohol use reduction and antiviral treatment initiation, but also to examine the impact of MET and alcohol use reduction on morbidity and mortality. In summary, MET was more efficacious in increasing self-reported percentage of days abstinent than a control education condition in patients with HCV, comorbid AUDs and continued drinking. MET is a brief treatment that could be implemented widely. Systems that have ‘integrated’ care hepatology clinics (those who have access to mental health clinicians) or patient-aligned care teams would be ideal settings for such an intervention. Finally, MET interventions have the potential to increase access to antiviral therapy, reduce fibrosis progression and thereby reduce the significant morbidity and mortality associated with HCV. Trial registration Clinicaltrials.gov Identifier: NCT00596960. Declaration of interests E.D. has received research funding from the Department of Veterans Affairs and holds stock in Terras Irradiant and Genii. B.F. and P.H. have received research funding from the Department of Veterans Affairs. K.McM., R.L., P.T., C.I. and C.P. have no conflicts of interest. The authors have no affiliation with tobacco, alcohol, pharmaceutical or gaming industries or any body substantially funded by one of these organizations. Acknowledgements This study was supported by a grant from the Research Service of the Department of Veterans Affairs (Principle
Investigator: Eric Dieperink MD). The Department of Veteran Affairs had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this paper are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.
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RESEARCH REPORT
doi:10.1111/add.12679
Efficacy of motivational enhancement therapy on alcohol use disorders in patients with chronic hepatitis C: a randomized controlled trial Eric Dieperink1,5, Bret Fuller2,7, Carl Isenhart1,5, Kelly McMaken1, Rebecca Lenox4, Christine Pocha6, Paul Thuras1,5 & Peter Hauser3,8 Veterans Affairs Healthcare Systems, Minneapolis, MN, USA,1 Veterans Affairs Healthcare Systems, Portland, OR, USA,2 Veterans Affairs Healthcare Systems, Long Beach, CA, USA,3 Veterans Affairs Healthcare Systems, Palo Alto, CA, USA,4 Departments of Psychiatry, University of Minnesota-Medical School, Minneapolis, MN, USA,5 Departments of Medicine, University of Minnesota-Medical School, Minneapolis, MN, USA,6 Oregon Health and Science University, Portland, OR, USA7 and VISN 22 Desert Pacific Healthcare Network Office, Long Beach, CA, USA8
ABSTRACT Aims To determine the efficacy of motivational enhancement therapy (MET) on alcohol use in patients with the hepatitis C virus (HCV) and an alcohol use disorder (AUD). Design Randomized, single-blind, controlled trial comparing MET to a control education condition with 6-month follow-up. Setting Patients were recruited from hepatitis clinics at the Minneapolis, Minnesota and Portland, Oregon Veterans Affairs Health Care Systems, USA. Participants and Intervention Patients with HCV, an AUD and continued alcohol use (n = 139) were randomized to receive either MET (n = 70) or a control education condition (n = 69) over 3 months. Measurements Data were self-reported percentage of days abstinent from alcohol and number of standard alcohol drinks per week 6 months after randomization. Findings At baseline, subjects in MET had 34.98% days abstinent, which increased to 73.15% at 6 months compared to 34.63 and 59.49% for the control condition. Multi-level models examined changes in alcohol consumption between MET and control groups. Results showed a significant increase in percentage of days abstinent overall (F(1120.4) = 28.04, P < 0.001) and a significant group × time effect (F(1119.9) = 5.23, P = 0.024) with the MET group showing a greater increase in percentage of days abstinent at 6 months compared with the education control condition. There were no significant differences between groups for drinks per week. The effect size of the MET intervention was moderate (0.45) for percentage of days abstinent. Conclusion Motivational enhancement therapy (MET) appears to increase the percentage of days abstinent in patients with chronic hepatitis C, alcohol use disorders and ongoing alcohol use. Keywords
Alcohol, alcohol use disorder, hepatitis C, liver disease, motivational enhancement therapy, motivation.
Correspondence to: Eric Dieperink, VAHCS, Department of Psychiatry (116A), One Veterans Drive, Minneapolis, MN 55417, USA. E-mail: [email protected] Submitted 19 November 2013; initial review completed 24 February 2014; final version accepted 1 July 2014
INTRODUCTION The hepatitis C virus (HCV) is the most common bloodborne viral infection, affecting approximately 170 million people world-wide and 3.2 million Americans [1,2]. Alcohol use disorders and alcohol use are common among patients with HCV. A national seroprevalence study found that 48% of participants with HCV consumed five or more drinks in a single day during the previous year, and 33% had done so on at least 50 days [1]. In a large sample of Veterans, approximately 75% had a history of an alcohol
use disorder (AUD) [3]. A study of privately insured patients with HCV found that more than 93% reported drinking prior to obtaining an HCV diagnosis and 67.9% had a heavy drinking pattern [4]. Alcohol use is of particular concern in patients with HCV, as it accelerates liver fibrosis, often leading to cirrhosis with subsequent increased risk of liver decompensation, hepatocellular carcinoma and death [5–12]. As of 2007, deaths due to HCV in the United States exceeded those due to the human immunodeficiency virus, and over the next two decades HCV mortality is expected to increase [13].
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Alcohol use is also a significant barrier to receipt of antiviral therapy [14]. Studies show that patients with HCV and AUDs are generally not referred for HCV treatment evaluation, or when evaluated are excluded from antiviral therapy [14–16]. A major reason for exclusion is the concern for non-adherence to antiviral therapy. In a large study of HCV patients, alcohol use was associated with reduced treatment candidacy and significantly higher antiviral treatment discontinuation [17]. Given that the newer and more effective [18–20] antiviral therapies require strict medication adherence, patients using alcohol may face increased barriers to antiviral therapy, thus reducing the potential of these life-saving treatments [21]. Treatments to address alcohol use are needed, as reducing or eliminating alcohol use may increase access to new antiviral treatments. A variety of effective interventions exist to address AUDs but most are lengthy and not adapted easily outside specialty alcohol treatment settings. Alcohol treatment based on motivational psychology has been well studied. Motivational enhancement therapy (MET) in particular is an effective treatment for AUDs. MET is brief, has been manualized and can be exported easily to a variety of clinical settings [22]. To date, only one observational study has been published showing that a brief motivational intervention provided in a hepatitis clinic reduces alcohol use in patients with HCV [23]. However, no controlled studies of MET in individuals with HCV have been published. The objective of this study was to determine the efficacy of MET in reducing alcohol use in a population of HCV-infected patients who are currently drinking alcohol and have AUDs. The primary hypothesis of this study was that patients with HCV, an AUD and continued excessive alcohol use who receive MET will have a greater reduction in the number of standard alcohol drinks per week and a greater percentage of days abstinent than patients who receive health education.
AUD and current alcohol use were enrolled into the study. One subject in the control condition was randomized but did not meet inclusion criteria and had no alcohol use data, and was excluded from the analysis, leaving 138 subjects with analyzable data. Participants were recruited from hepatitis clinics at the Minneapolis, Minnesota (n = 93) and Portland, Oregon (n = 46) Veteran Affairs Health Care Systems (VAHCSs) between 18 November 2008 and 15 December 2011. Eligibility criteria included (1) chronic HCV diagnosed via positive HCV antibody and polymerase chain reaction confirmation of viremia; (2) alcohol dependence or abuse according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) [24], using the Structured Clinical Interview for the DSM-IV-TR (SCID) [25]; and (3) Veterans aged 18 years and older, current alcohol use, drinking seven or more standard drinks per week for each of the preceding 2 weeks or at least one heavy drinking (four or more standard drinks in 1 day) day per week for 2 weeks. A standard drink was 14 g of pure alcohol, equivalent to 12 oz of beer, 5 oz of wine and 1.5 oz of 80-proof alcohol. Exclusion criteria included (1) meeting DSM-IV (SCID) diagnostic criteria for opiate, cocaine or methamphetamine dependence in the past 6 months and (2) pre-existing medical conditions that could interfere with participation in the protocol, such as: brain trauma, cognitive impairment, dementia, hepatic encephalopathy or acute psychiatric instability (significant psychosis, mania or elevated risk for suicide). Cannabis abuse or dependence was not exclusionary. Medications to deter alcohol use were not reason for exclusion. However, no subjects were taking these medications prior to randomization and only one subject in the education arm had two 30-day prescription fills for naltrexone during the trial. The study was approved by the Minneapolis, Minnesota and Portland, Oregon Veterans Affairs Health Care System (VAHCS) institutional review boards and participants provided written informed consent.
METHODS Participants
Assessment
Patients were referred to the study by hepatitis providers if they scored >3 on the Alcohol Use Disorder Identification Test—consumption [24] or, based on clinical evaluation, were considered to be drinking excessive amounts of alcohol. The Portland, Oregon site also had flyers in the hepatology clinic and a minority of patients was recruited from the flyer. Patients were screened for study eligibility by research assistants; final eligibility was determined using chart data and review by site investigator. Data were collected to 31 July 2012. One hundred and thirty-nine men and women Veterans with HCV, an
All participants were assessed for study eligibility and to collect demographic information. Participants were assessed at baseline and at 3 and 6 months after baseline with the following measures: • Time-line follow-back (TLFB)-measured alcohol use over the prior 30 days [26]. • Beck Depression Inventory, 2nd edition (BDI-II)measured depressive symptoms over the past 7 days [27]. • Brief Symptom Inventory (BSI)-measured anxiety and other symptoms over the past 7 days [28].
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• Post-Traumatic Stress Disorder (PTSD) Checklist— civilian (PCL-C)-measured PTSD symptoms over the prior 30 days [29]. • Urine drug screen. • The TLFB was used to gather past 30-day use of cannabis, cocaine, methamphetamines and nonprescribed opioids. Quantity of use was not obtained. • Breath alcohol concentration as measured by breathalyzer. • Biomarkers of alcohol use including percentage of carbohydrate-deficient transferrin (%CDT), ethyl glucuronide (EtG) and ethyl sulfate (EtS). All measures were administered by a research assistant who was blinded to the randomized condition.
Treatment conditions Motivational enhancement therapy MET was developed in conjunction with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for Project MATCH (Matching Alcoholism Traatment to Client Homogeneity) [22]. MET was delivered by a licensed health-care professional (one physician, five psychologists). MET consists of four sessions, each lasting approximately 30–45 minutes. At each session, participants were given feedback regarding their liver function tests (LFT) [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamic transpeptidase (GGT), bilirubin] if available from the chart. HCV-specific feedback was incorporated into each session in order to maximize the participant’s motivation to reduce alcohol use. Key elements included: (i) discussion of the synergistic effects of alcohol and HCV on liver fibrosis; (ii) discussion of the impact of alcohol on antiviral therapy (i.e. reduces efficacy); and (iii) alcohol as a barrier to receiving antiviral therapy. Control health education sessions The education control sessions were administered by the same six licensed mental health clinicians who administered MET. The control condition consisted of four sessions of general health education; each session lasted 30–45 minutes. Topics covered included sleep hygiene, nutrition and diet, relaxation training and exercise. Health education was used to control for the effect of therapist contact (time) and provided individual clinician contact without engaging the participants in discussion of alcohol or motivational themes. At each session, liver function tests (ALT, AST, GGT and bilirubin) were given to subjects if available from the chart. Data were given in written form and if subjects had questions about the data they were asked to contact hepatitis clinicians for answers.
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Treatment fidelity monitoring All clinicians were trained in administering both MET and the health education conditions. Providers attended a 1-day motivational interviewing workshop that included didactics, video and live presentations and role plays. This was followed by approximately every other week group consultation with one of us (C.I.), who is part of the Motivational Interviewing Network of Trainers. Providers received training in the education condition that included a didactic review of the material and role plays. Providers received feedback regarding taped sessions both for adherence to motivational interviewing (MI) principles using the Motivational Interviewing Treatment Integrity code (MITI) for MET sessions and adherence to the control condition, although no specific metrics were used for the control condition. Before treating participants with MET, the clinicians submitted at least two tape-recorded cases that met thresholds based on the MITI [30]. Therapy sessions were audiotaped and 15 minutes of each tape was scored using a version of the MITI modified for this project [31]. Corrective action was taken to ensure adherence to MET and the education sessions. The MITI consists of six measures of adherence to MI principles. A total of 197 MET sessions and 198 education sessions were audiotaped and evaluated using the modified MITI. A total of 72.1% (142 of 197) MET and only 1.5% (three of 198) of education sessions met either five or six thresholds on the MITI, indicating significant fidelity to MI principles in the MET group. Procedures Eligible participants were assigned randomly to one of two groups (MET or education control) using Pocock & Simon’s minimization method [32]. Randomization was stratified by site (Portland, Minneapolis) and BDI-II score (BDI-II ≤ 19 versus BDI-II > 19). Within each strata participants were randomized in blocks of four using Random Allocation Software (version 1.0) by the study statistician (P.T.). Patients were randomized at the time of the first therapy session, which occurred on average 7 days after consent but could not occur more than 28 days after consent. In order to maximize flexibility and enhance the possibility of subjects completing all therapy sessions, the length between sessions was negotiated between the clinicians and the subject. All four sessions were completed prior to the 3-month research evaluation. Statistical methods Sample size determination The power analysis was performed for drinking days per week using Nquery Advisor 4 (Statistical Solutions, Boston, MA, USA) under the following assumptions:
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(1) repeated-measures analysis of variance (ANOVA) with the main effects of treatment (control versus MET) and time (0, 3, 6 months) and the treatment × time interaction; (2) compound symmetrical covariance matrix; and (3) type I error level = 0.05. The estimates for the mean, standard deviation and intrasubject correlation were obtained from a similar study conducted among 47 HCV-infected patients with heavy alcohol consumption [23]. The treatment effect is captured by the treatment × time interaction, i.e. differential patterns of alcohol consumption over time. We calculated that a sample size of 136 patients (68 in each group) would provide 87% power to detect an effect size of 0.30. Based on the Dieperink et al. study and other publications [33–35], we expected the effect size of the interaction to range from 0.25 to 0.35, depending on the amount of intrasubject correlation. Hence, this study was calculated to have sufficient power to detect the expected effect size of the primary objective. Calculating alcohol consumption The primary end-point for measuring alcohol consumption was the number of standard drinks per week and percentage of days abstinent. These measures are well validated, used frequently in alcohol treatment studies and were included in the large NIAAA-funded Project MATCH. Analysis of outcome Each subject was assessed for the outcome variables at baseline, 3 months and 6 months. For the primary objective (i.e. the analysis of the efficacy of MET in reducing alcohol use), we used mixed-effects models to examine change over time in our analysis with both intercept and slope as random effects [36,37]. Mixed-effects models allow incomplete repeated-measures data as well as continuous and categorical covariates, fixed and timedependent covariates, and unstructured as well as structured covariance matrices. SPSS (version 0.19) was used for all analyses. For other secondary analyses we used χ2 procedures to test for differences in antiviral treatment initiation and regression analyses to examine relationships between reduction in alcohol use, %CDT and EtG/EtS. The Wilcoxon signed-rank test was used to evaluate changes in abstinence from baseline to 6 months.
RESULTS Seventy participants received MET and 68 participants received the health education control condition. Participants attended approximately the same number of ses-
Table 1 Baseline characteristics. MET (n = 70) Age, mean (SD) Sex Male Female Race/ethnicity Caucasian African American Native American Other Self-reported alcohol drinking Percentage of days abstinent (%, SD) Mean drinks per week (SD) Baseline symptom measures BDI-II BSI PCL-C Urine drug screen Cannabis Cocaine Methamphetamine Opioids Self-reported use past 30 days Cannabis Cocaine Methamphetamine Opioids
Education (n = 68)
55.8 (6.8)
55.2 (6.3)
97.1% (68) 2.9% (2)
94.1% (64) 5.9% (4)
68.6% (48) 28.6% (20) 0% 2.9% (2)
66.2% (45) 30.9% (21) 2.9% (2) 0%
34.98% (26.7)
34.63% (27.0)
35.45 (25.42)
38.86 (46.19)
17.40 (11.58) 51.23 (41.23) 38.01 (15.21)
17.31 (10.79) 56.91 (44.18) 40.61 (16.04)
32.8% (20/61) 8.2% (5/61) 3.3% (2/61) 9.8% (6/61)
18.3% (11/60) 3.3% (2/60) 0% (0/60) 6.7% (4/60)
35.7% (25/70) 7.1% (5/70) 4.3% (3/70) 0% (0/70)
39.7% (27/68) 7.4% (5/68) 1.5% (1/68) 1.5% (1/68)
MET = motivational enhancement therapy; BDI-II = Beck Depression Inventory—second edition; BSI = Brief Symptom Inventory; PCLC = Post-Traumatic Stress Disorder Checklist—civilian; SD = standard deviation.
sions in each group, with 40 subjects in MET and 38 subjects in the control condition attending all four sessions. Two subjects did not receive the allocated treatment, as they did not return for the intervention, but 84.3% (59 of 70) of MET subjects and 89.7% (61 of 68) in the control condition attended the 6-month research follow-up visit. Participants in both groups had similar baseline characteristics (Table 1). All participants with baseline alcohol use data and who were randomized were included in the analysis (Fig. 1). A total of 18 subjects did not complete the 6-month follow-up. We examined those who completed the 6-month follow-up versus those who did not on baseline characteristics and found no significant differences on primary outcome measures. We also compared those without any follow-up information to those who had some follow-up information (3 or 6 months), and found no significant differences on primary outcomes.
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Enrollment Assessed for eligibility (n = 513)
Excluded (n = 374) Not meeƟng inclusion criteria (n = 296) Declined to parƟcipate (n = 78)
Randomized (n = 139)
AllocaƟon Allocated to MET (n = 70)
Allocated to Health EducaƟon (n = 69)
Received MET (n = 68)
Received Health EducaƟon (n = 68)
• 1 Session (n = 7) • 2 Sessions (n = 7) • 3 Sessions (n = 11) • 4 Sessions (n = 43) Did not receive allocated intervenƟon (n = 2) (Did not return for intervenƟon, n = 2)
• 1 Session (n = 6) • 2 Sessions (n = 10) • 3 Sessions (n = 7) • 4 Sessions (n = 45) Did not receive allocated intervenƟon (n = 1) (Did not meet inclusion criteria, n = 1)
Follow-Up AƩended 6 month follow up (n = 59) Lost to follow-up (n = 11) • • • • •
AƩended 6 month follow up (n = 61) Lost to follow-up (n = 8)
Dropped out of study (n = 6) Died (n = 1) Withdrew consent (n = 1) Incarcerated (n = 2) Removed for psychiatric instability (n = 1)
• Dropped out of study (n = 5) • Died (n = 2) • Did not meet inclusion criteria (n = 1)
Analysis Analysed (n = 70) Excluded from analysis (n = 0)
Analysed (n = 68) Excluded from analysis (n = 1), no data available
Figure 1 Flow of participants through the trial
For the primary analysis of change in percentage of days abstinent, the MET group showed a significant increase in percentage of days abstinent from baseline to 6 months compared to the control condition. At baseline, subjects in MET had 34.98% days abstinent, which increased to 69.91 and 73.15% at 3 and 6 months. Subjects in the education condition had 34.63% days abstinent at baseline and this increased to 58.23 and 59.49% at 3 and 6 months. We observed a significant increase in
percentage of days abstinent overall (F(1120.4) = 28.04, P < 0.001) and a significant group × time effect (F(1119.9) = 5.23, P = 0.024) (Fig. 2). For the primary analysis of change in drinks per week we did not find significant results. Mean drinks per week in the MET group dropped from 35.45 at baseline to 14.6 and 15.5 at 3 and 6 months and from 38.9 in the education group at baseline to 18.9 and 22.1 at 3 and 6 months. While there was a significant drop overall in drinks per week
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Figure 2 Change in percentage of days abstinent
(F(1134.5) = 6.38, P = 0.013), there was no group × time difference (F(1133.4) = 0.30, P = 0.57) (Table 2). There were no significant differences between groups on any secondary outcome measures (Table 2). Overall 30-day abstinence at 6 months was significantly higher (Z = −5.20, P < 0.001) and heavy drinking days were significantly lower at 6 months (F(1,245) = 16.55, P < 0.001) across both groups. Both groups showed a reduction in the biological measures of alcohol use. EtG, EtS and %CDT decreased over the 6-month period, but no significant difference between groups was found. Other measures, including the BDI, BSI and PCL-C, decreased from baseline to 6 months, but no significant difference was found between groups (Table 2). Significant adverse events were more common in the control condition. A total of seven adverse events occurred in the MET condition (two deaths, three nonalcohol- and two alcohol-related hospitalizations) and 14 in the control (three deaths, seven non-alcohol- and four alcohol-related hospitalizations). Overall, we found that 7.2% of the MET subjects versus 2.9% of education subjects initiated antiviral treatment (χ2(1) = 1.31, P = 0.253). However, none of the subjects at the Portland site initiated antiviral treatment. When we restricted the analysis to Minneapolis, we found that 10.9% of those in the MET group initiated antiviral treatment versus 4.3% in the control group (χ2(1) = 4.18, P = 0.041).
DISCUSSION MET was significantly more efficacious than a control education condition for increasing percentage of days abstinent in a sample of patients with HCV and comorbid AUDs. Other measures of alcohol use, including drinks per week, heavy drinking days and abstinence, were not statistically different between groups. The effect size of the MET intervention was moderate (0.45) for percentage of days abstinent. The effect size is similar to most studies of treatment for AUDs [38]. However, most prior studies do not include individuals who are not seeking treatment for their alcohol use, and typically do not include patients with significant psychiatric and substance use symptoms, such as those in this study. These data are consistent with a prior nonrandomized clinical trial and show that a relatively brief intervention can help to reduce alcohol use in patients with HCV [23]. Reducing alcohol use in this population is important, as alcohol significantly hastens fibrosis [5,39] and has been shown to be responsible for more than onethird of the cases of cirrhosis in HCV patients presenting to a hepatitis clinic [11]. MET offers an evidence-based approach to the treatment of alcohol use in HCV patients and may help to reduce the overall burden from advanced liver disease. The subjects in this study had significant psychiatric symptoms and non-alcohol substance use. The mean BDI
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SD = standard deviation; %CDT = percentage carbohydrate-deficient transferrin; EtG = ethyl glucuronide; EtS = ethyl sulfate; BDI-II = Beck Depression Inventory—second edition; BSI = Brief Symptom Inventory; PCL-C = PostTraumatic Stress Disorder Checklist—civilian; MET = motivational enhancement therapy; EDU = education control condition; CI = confidence interval. Effect size = Cohen’s d.
0.26 0.14 0.01 0.08 0.02 0.20 0.01 0.16 0.45 0.97 0.70 0.92 0.28 0.95 −2.28 (−5.48 to 0.93) 5.7% (−9.5 to 21.0%) 0.4% (−19.7 to 20.4%) 3.9% (−24.5 to 16.6%) −0.21 (−4.2 to 3.8) −8.21 (−25.2 to 7.36) 0.19 (−5.47 to 5.85) 15.04 (9.53) 0 19/49 (38.8%) 49/62 (79%) 17.31 (10.79) 56.91 (44.18) 40.61 (16.04) 14.03 (8.74) 0 20/53 (37.7%) 46/63 (73%) 17.40 (11.58) 51.23 (41.23) 38.01 (15.21)
6.24 (9.31) 14/58 (24.1%) 11/36 (30.6%) 25/47 (53.2%) 13.11 (11.36) 41.52 (41.88) 33.58 (15.26)
8.27 (8.98) 8/60 (13.3%) 15/41 (36.6%) 34/48 (70.8%) 13.64 (10.38) 47.70 (42.31) 36.95 (16.02)
5.10 (8.10) 15/59 (25.4%) 9/34 (26.5%) 22/40 (55%) 13.37 (11.66) 40.25 (43.23) 33.89 (16.03)
7.38 (9.53) 12/61 (19.7%) 12/46 (26.1%) 33/56 (58.9%) 13.57 (10.19) 49.17 (44.35) 33.70 (14.59)
0.024 0.57 59.49 (35.30) 21.41 (29.39) 73.15 (32.18) 14.88 (27.94) 58.23 (34.05) 19.94 (25.50) 34.63 (27.05) 38.86 (46.19) 34.98 (26.7) 35.45 (25.42)
% days abstinent (SD) Drinks/week (SD) Secondary outcomes Heavy drinking days (≥4 drinks) (SD) 30-day abstinence %CDT >2.1 EtG/EtS %positive BDI-II BSI (SD) PCL-C (SD)
69.91 (31.99) 13.35 (18.86)
MET MET EDU MET Primary outcomes
Baseline
Table 2 Drinking outcomes and effect size estimates at 6 months.
3 months
EDU
6 months
EDU
P
Mean difference between groups at 6 months (95% CI) 13.66 (1.4 to 25.9) −6.52 (−16.9 to 3.85)
Effect size d 0.45 0.23
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score was more than 17, indicating moderate depressive symptoms. Similarly, elevated BSI and PCL-C scores indicate significant anxiety and other psychiatric symptoms. The most common non-alcohol substance used was cannabis, but cocaine, methamphetamines and opioids were also used. Despite these significant symptoms, MET was helpful in increasing percentage of days abstinent. This suggests that MET will be helpful in the broader population of people with HCV and comorbid AUDs. The therapeutic effect of MET was most pronounced at 3 months, but drinking continued to decline at 6 months. Alcohol use in the control condition also decreased significantly at 3 months but plateaued at 6 months. This suggests that, unlike the health education intervention, MET is durable. In clinical practice, clinicians could consider adding more sessions to further enhance the effectiveness of MET in this population. However, further research is needed to determine whether adding more sessions would further reduce alcohol use. Overall initiation of antiviral treatment was low. This was not unexpected, as not all patients want antiviral therapy, and during the study new antiviral treatments with greater efficacy were in the process of becoming approved by the US Food and Drug Administration. Practitioners may have been waiting to initiate these new therapies with the expectation that they would be more efficacious. Although there was no overall difference in antiviral treatment initiation between groups, we found that MET was associated with greater initiation of antiviral therapy at the Minneapolis site. Prior data indicate that patients with significant alcohol problems can initiate and benefit successfully from antiviral therapy, but typically require multi-disciplinary support [40,41]. Our data are consistent with prior research indicating that initiation of antiviral therapy is influenced by patient, provider and system factors [42,43]. Future studies should determine whether efforts to reduce alcohol use increase initiation of antiviral therapy and outcomes such as a sustained virological response. There are several limitations to the current study. All subjects were Veterans and most were male, thus results may not apply to all people with HCV. However, many other characteristics of this group, including significant psychiatric and substance use symptoms, are typical of many people with HCV and thus the results have broader applicability. The only significant effect of MET was an increase in the percentage of days abstinent. It is possible that although we designed the control condition to be a neutral intervention with respect to alcohol use, it probably provided more support than a treatment-as-usual approach, thus diluting the effect of MET. Other factors, such as giving control subjects their liver function tests and rigorous assessment of alcohol use, may also have
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contributed to the reduction in alcohol use in the control condition. Although the biological measures of alcohol use (%CDT and EtG/EtS) were consistent with selfreported reductions in alcohol use, there were no significant differences between groups. The power to detect a difference between groups may have been hampered by our inability to collect samples from all subjects. Another limitation of the study is that it was not possible for participants to be blinded to the intervention condition. However, research assistants who completed the research follow-up visits were blinded to the intervention condition assignment, thus mitigating this concern. Although more than 84% of both groups had follow-up data at 6 months and analyses included all participants, attrition is a limitation of this study. Finally, findings are limited by the 6-month follow-up period. However, 6 months is a typical follow-up period used by hepatologists to monitor alcohol use, so results at 6 months have clinical relevance and help to determine antiviral treatment readiness. Future studies that examine long-term follow-up are needed, not only to examine the relationship between alcohol use reduction and antiviral treatment initiation, but also to examine the impact of MET and alcohol use reduction on morbidity and mortality. In summary, MET was more efficacious in increasing self-reported percentage of days abstinent than a control education condition in patients with HCV, comorbid AUDs and continued drinking. MET is a brief treatment that could be implemented widely. Systems that have ‘integrated’ care hepatology clinics (those who have access to mental health clinicians) or patient-aligned care teams would be ideal settings for such an intervention. Finally, MET interventions have the potential to increase access to antiviral therapy, reduce fibrosis progression and thereby reduce the significant morbidity and mortality associated with HCV. Trial registration Clinicaltrials.gov Identifier: NCT00596960. Declaration of interests E.D. has received research funding from the Department of Veterans Affairs and holds stock in Terras Irradiant and Genii. B.F. and P.H. have received research funding from the Department of Veterans Affairs. K.McM., R.L., P.T., C.I. and C.P. have no conflicts of interest. The authors have no affiliation with tobacco, alcohol, pharmaceutical or gaming industries or any body substantially funded by one of these organizations. Acknowledgements This study was supported by a grant from the Research Service of the Department of Veterans Affairs (Principle
Investigator: Eric Dieperink MD). The Department of Veteran Affairs had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this paper are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.
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