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The impact of barriers to hepatitis C virus treatment in recovering heroin users maintained on methadone
Journal of Substance Abuse Treatment 29 (2005) 159 – 165
The impact of barriers to hepatitis C virus treatment in recovering heroin users maintained on methadone Diana L. Sylvestre, (M.D.)a,b,T, Alain H. Litwin, (M.D., M.P.H.)c,d, Barry J. Clements, (P.A.-C.)b, Marc N. Gourevitch, (M.D., M.P.H.)e,1 a
Department of Medicine, University of California, San Francisco, CA, USA Organization to Achieve Solutions in Substance Abuse (OASIS), Oakland, CA, USA c Division of Substance Abuse, Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, USA d Department of Medicine, Montefiore Medical Center Albert Einstein College of Medicine, Bronx, NY, USA e Division of General Internal Medicine, Department of Medicine, New York University School of Medicine, New York, NY, USA b
Received 22 August 2004; received in revised form 1 November 2004; accepted 10 November 2004
Abstract Although most cases of hepatitis C virus (HCV) infection are associated with injection drug use, there are few data regarding the impact of putative barriers such as psychiatric disease and intercurrent drug use on HCV treatment outcomes. To define the impact of characteristics often cited as reasons for withholding HCV treatment, we studied HCV treatment in a real world sample of 76 recovering heroin users maintained on methadone. Overall, 21 (28%) had a sustained virological response and 18 (24%) discontinued treatment early. Although there was a modest decrement in response rates in patients reporting a preexisting psychiatric history ( p = .01), neither intercurrent drug use nor short duration of pretreatment drug abstinence led to significant reductions in virological outcomes ( p = .09 and p = .18, respectively.) We conclude that injection drug users can be safely and effectively treated for HCV despite multiple barriers to treatment when they are treated in a setting that can address their special needs. D 2005 Elsevier Inc. All rights reserved. Keywords: Hepatitis C; Barrier; Psychiatric disease; Drug use; Abstinence
1. Introduction Although most prevalent and incident cases of hepatitis C virus (HCV) infection in the United States are associated with injection drug use (Alter, 1997; Alter & Moyer, 1998), there are few data regarding HCV treatment in this population or on the impact of barriers such as psychiatric disease and intercurrent drug use on HCV treatment outcomes (Backmund et al., 2001; Dalgard et al., 2002; Jowett et al., 2001). T Corresponding author. Organization to Achieve Solutions in Substance Abuse (OASIS), 520 27th St., Oakland, CA 94612, USA. Tel.: +1 510 834 5442; fax: +1 510 834 0916. E-mail address: [email protected] (D.L. Sylvestre). 1 Dr. Gourevitch performed much of this work while with the Division of Substance Abuse, Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY. 0740-5472/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jsat.2005.06.002
Until recently, drug users have as a group been considered poor candidates for HCV treatment because of concerns regarding adherence, psychiatric disease, and reinfection. Currently, however, the importance of case-by-case determination of eligibility for treatment has gained acceptance (National Institutes of Health [NIH], 2002). In making such determinations, physicians must consider the potential impact of factors such as psychiatric comorbidity, extent of active drug or alcohol use, family and job responsibilities, and motivation to undertake a challenging treatment regimen (Edlin, 2002; Schaefer et al., 2003). Yet the specific impact of these factors on response to HCV treatment among drug users has not been quantified, leaving clinicians without the data they need to inform individualized treatment planning. A case in point is a history of psychiatric illness, generally considered to be a relative contraindication to HCV treatment
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because interferon, a mainstay of HCV treatment, elicits neuropsychiatric toxicities that may be exacerbated in patients with a preexisting mental illness (Fontana, 2000; Lerner et al., 1999; Trask et al., 2000; Zdilar et al., 2000). A proscription against treating patients with a psychiatric history disproportionately affects substance users, more than half of whom report symptoms of a psychiatric disorder (Regier et al., 1990). However, an increasing body of evidence has shown that patients with a history of psychiatric illness can be successfully treated for HCV, although they may develop depression and other neuropsychiatric toxicities at higher rates (Pariante et al., 1999; Van Thiel et al., 1995, 1998; Zdilar et al., 2000). Such information has broadened access to HCV treatment for patients with psychiatric conditions, but its relevance to substance users with a history of mental illness is unclear. The impact of intercurrent drug use on HCV treatment outcomes and the optimal duration of abstinence before initiating HCV treatment are also undefined. Concerns that drug use during HCV therapy will reduce medication adherence and increase the risk of reinfection with HCV are often cited as reasons for withholding HCV treatment from persons using drugs (Davis & Rodrigue, 2001). The fact that interferon is taken by injection might possibly pose a risk to recovery from injection drug use, particularly when abstinence has been brief, and the flu-like systemic side effects of interferon may resemble those of opioid withdrawal and foster the resumption of drug use as a means of side effect management. Yet, unlike for alcohol consumption (Schiff, 1999), no data show that drugs of abuse reduce the efficacy of interferon/ribavirin treatment. In addition, the impact of only a brief period of pretreatment abstinence on outcomes is unknown. To define the impact of specific characteristics often cited as reasons for withholding HCV treatment from drug users on treatment outcomes, we studied HCV treatment in a real world sample of recovering heroin users receiving methadone maintenance treatment. We hypothesized that participation in long-term outpatient opioid agonist replacement therapy would provide a context within which HCV could be successfully treated, allowing us to define and measure those characteristics associated with HCV treatment outcomes.
provided on-site at each location. Although geographically quite removed, the study was undertaken in these two settings because both provide comparable care under the direction of physicians with comparable approaches to treatment. 2.2. Eligibility Men and women aged 18 years and older were considered eligible if they had been maintained on methadone for a period of 3 months or longer, had a positive HCV polymerase chain reaction (PCR), and were willing to undergo treatment for HCV. Patients with non-HCV-related liver disease or decompensated liver disease were excluded. Those whose depression was felt to be unstable based on the judgment of the treating clinician were excluded until antidepressant treatment was initiated and the patients’ condition had stabilized. At the inception of the study, patients with active heroin, cocaine, amphetamine, and/or alcohol abuse on baseline evaluation were excluded. However, based on our experience in treating patients with active drug use, this criterion was eliminated as an exclusion after the first 25 patients had been enrolled. Thereafter, patients who maintained at least 75% attendance at our weekly clinics for at least 2 months were considered eligible for enrollment irrespective of concurrent drug use if no other contraindication was present. Use of marijuana before or during treatment was not an exclusion. All experimental procedures were followed in accordance with the Helsinki Declaration of 1975 as revised in 1983 and were approved by the Ethical Review Committee (Kansas City, MO, USA) and the institutional review boards of the Albert Einstein College of Medicine and the Montefiore Medical Center. 2.3. Medications Hepatitis C virus treatment consisted of standard thriceweekly interferon alfa-2b injections and ribavirin capsules administered at recommended doses. Patients with genotypes 2 and 3 received 24 weeks of therapy; the others were treated for 48 weeks. Medications were self-administered unless patients specifically requested otherwise. 2.4. Procedures
2. Materials and methods 2.1. Study setting Recruitment took place at two sites. The Organization to Achieve Solutions in Substance Abuse is a community-based nonprofit clinic providing medical and psychiatric treatment to substance users in Oakland, California. The Division of Substance Abuse of the Albert Einstein College of Medicine is a network of nine community-sited methadone maintenance treatment programs in the Bronx, New York. Comprehensive primary medical and psychiatric care are
After providing written informed consent, participants completed a questionnaire that elicited baseline demographic, psychosocial, psychiatric, and substance use characteristics. The duration of HCV infection was estimated as one less than the number of years since injection drug use was initiated. Because of its demonstrated impact on HCV treatment outcomes (NIH, 2002), heavy alcohol use was defined as average daily consumption of two or more alcoholic beverages (20 g). Liver biopsy was suggested but not required in patients with a baseline platelet count of N100,000/mm 3 . Patients with a platelet count of b100,000/mm3 were considered to be at greater risk for
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bleeding and thus biopsy was not performed on them. Biopsy specimens were examined by a pathologist unfamiliar with each patient and fibrosis was scored on the METAVIR scale of 0–4 (0 = none, 1 = minimal–mild, 2 = mild–moderate, 3 = moderate–severe, and 4 = cirrhosis). Patients were monitored for treatment-related neutropenia, thrombocytopenia, and hemolytic anemia using standard published algorithms (Pianko & McHutchison, 2000). Drug and alcohol consumption were assessed by monthly selfreport questionnaires, and monthly random urine drug test results were obtained from the subjects’ methadone treatment program. The Beck Depression Inventory was performed every 12 weeks as an indication of worsening psychiatric disease, which was treated with antidepressants. Selective serotonin reuptake inhibitors were used as first-line agents because of their efficacy and acceptable side effect profile. An HCV RNA PCR was performed at baseline, at 6 months, at the end of treatment, and at 6 months after the completion of therapy. Active participation in peer support/education groups throughout the treatment course was encouraged. Substance use during HCV therapy was actively discouraged but did not result in treatment discontinuation unless a patient became unreliable in attending appointments or the clinician felt that it represented a safety risk. The interferon dose was adjusted or discontinued for clinically significant thrombocytopenia or neutropenia, and the ribavirin dose was adjusted for the development of a hemoglobin level b10 mg/dl using standard published guidelines (Pianko & McHutchison, 2000). Patients experiencing symptoms attributed to opioid withdrawal were encouraged to request an increase in their methadone dose. Hepatitis C virus treatment was discontinued if requested by the patient or for severe cases of cytopenia, uncontrolled and/or worsening psychiatric conditions, or decompensating liver disease. 2.5. Outcome measures The primary study end point was sustained virological response (SVR), as demonstrated by undetectable levels of HCV RNA on analysis 6 months after the completion of therapy using a Bayer versant HCV RNA bDNA 3.0 assay (Bayer Diagnostics, Berkeley, CA), with a lower limit of detection of 550 IU/ml. Patients were classified as sustained virological responders at this time point if they had no detectable virus or as nonresponders if the PCR was positive. All analyses were performed on an intent-to-treat basis. 2.6. Adherence Adherence to interferon was assessed by the timing of returned empty interferon vials and by a monthly questionnaire that assessed the number of missed doses of medication. Adherence to ribavirin therapy was assessed by pill counting and by query during a monthly questionnaire. Using adherence criteria developed by others, we considered patients to be adherent to the HCV treatment regimen if they
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took z80% of prescribed interferon and z80% of prescribed ribavirin for at least 80% of the projected treatment course (McHutchison et al., 2002). 2.7. Statistical analysis All data were compiled in and analyzed using SPSS version 11.0.1 for Windows (SPSS, Inc., Chicago, Ill). Associations between SVR and sociodemographic characteristics and drug and alcohol use were determined using Pearson’s or Spearman’s correlation coefficients for continuous variables and Student’s t or Wilcoxon’s signed rank test for categorical variables, depending on the normality of the distribution of data. Bivariate analysis of categorical data was performed with v 2 and Fisher’s exact tests. p Values b.05 in two-tailed comparisons were considered statistically significant. Logistic regression was used to assess for statistical independence among variables that showed a univariate association with a p value of V.20.
3. Results Seventy-six methadone-maintained patients were enrolled at the two sites. Their average age was 50 years; of the patients, 46 (61%) were male, 54 (71%) were Caucasian, 10 (13%) were African American, and 12 (16%) were Latino. The mean estimated duration of HCV exposure of the patients was 28 F 9 years. The median dose of methadone was 71 mg (range, 19–160 mg), and the median duration of continuous methadone maintenance was 5 years (range, 0.25–28 years). Overall, the mean duration of lifetime heroin use by the patients was 21 years (range, 3–50 years); 44 of the patients (64%) reported a history of heavy alcohol use for a median of 12 years (range, 1– 43 years). The median duration of abstinence from illicit drug use by the patients was 1 year (range, 0–18 years); 23 of the patients (30%) had been abstinent for b6 months. One patient was known to be HIV seropositive. Forty-five patients (59%) reported a previous psychiatric diagnosis: 33 (43%) reported depression; 6 (8%), mixed depression and anxiety; 2, anxiety disorder; 1, schizophrenia; 1, bipolar disorder; 1, obsessive–compulsive disorder; and 1, dysthymia. Although there was no difference in age or liver histology between those with and those without psychiatric history (data not shown), patients reporting a psychiatric history were more likely to be female (53% vs. 19% of those without a psychiatric history [ p = .004]) and to have genotype 1 (52% vs. 23% without a psychiatric history [ p = .02.]) There was also a trend toward fewer African Americans in the psychiatric cohort (7% vs. 24% [ p = .08]). Forty-five patients (60%) had genotype 1, 10 (13%) had genotype 2, and 19 (25%) had genotype 3. One patient had genotype 8a and another patient could not be genotyped. Thirty-five patients underwent liver biopsy. Among these, the mean METAVIR inflammation grade was 2.4 (range,
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Fig. 1. Hepatitis C treatment outcomes in patients maintained on methadone (N = 76). ETR indicates end-of-treatment response.
1.5–3.5) and the mean fibrosis stage was 2.8 (range, 0 – 4). Of the remaining 41 patients, 20 had platelet counts of b100,000/mm3. Overall, 23 of the 76 study patients (30%) had Stage 4 fibrosis or a platelet count of b75,000 mm3. Thirty-seven patients (49%) were end-of-treatment responders and 21 (28%) had an SVR (Fig. 1). During HCV treatment, 15 of the 76 patients (20%) reported some degree of alcohol consumption, but only 1 reported heavy (N20 g/day) ingestion. Overall, 45 (59%) used illicit drugs during treatment: 18 (24%) used marijuana only and 27 (36%) used heroin, cocaine, or methamphetamine during treatment. The methadone dose of 33 patients (45%) was increased during HCV treatment by a median of 15 mg (range, 0 –180 mg). Of the 76 patients, 18 (24%) discontinued treatment early whereas 58 (76%) completed therapy. The most common reason for early treatment discontinuation, as reported by 8 patients, was intolerable systemic side effects: specific reasons for discontinuity included psychiatric reasons (n = 4), unresponsive depression (n = 3), and development of psychosis (n = 1). In addition, 2 patients discontinued for medical reasons, 1 because of subacute bacterial peritonitis and 1 for intractable psoriasis. One patient was felt to have become
unstable owing to excessive alcohol consumption and the treating physician discontinued his treatment. Moreover, 2 patients relocated and were unable to access medications and 1 was incarcerated. Based on medical assessment, 36 of the 76 study patients (47%) were taking antidepressants at the time of HCV treatment initiation. This number included 27 of the 45 patients (60%) who reported a preexisting psychiatric condition and 9 of the 31 patients (29%) who did not ( p = .025). By the end of HCV treatment, 65 of the 76 study patients (86%) were taking antidepressants: 40 (89%) of those with a psychiatric history and 25 (81%) of those who did not report one ( p = .34). The association of a preexisting psychiatric diagnosis with treatment outcomes is shown in Fig. 2. Of the 31 patients, 11 (35%) who did not report a prior psychiatric condition had a sustained viral response, as compared with 10 of the 45 patients (22%) who reported a psychiatric history. Multivariate logistic regression analysis taking sex, race, and genotype into account revealed that this finding was statistically significant ( p = .01). There was no difference in dropout rates between the two groups: 11 of the 45 patients (24%) reporting a prior psychiatric condition and 7 of the 31 patients (23%) without a prior psychiatric condition discontinued treatment. Similarly, adherence rates were comparable between the groups, with 30 of the 45 patients (67%) who reported a pretreatment psychiatric diagnosis and 22 of the 31 patients (71%) without a psychiatric diagnosis demonstrating adherence to the medication regimen ( p N .5). The association of the duration of abstinence from drug use with HCV treatment outcomes is also shown in Fig. 2. Of the 53 patients, 16 (30%) who had been abstinent from drug use for at least 6 months before initiating HCV treatment had an SVR, as compared with 5 of the 23 patients (22%) who had a more limited duration of abstinence. This difference was not statistically significant ( p = .18).
Fig. 2. Sustained virological response rates versus psychiatric history ( p = .01), duration of pretreatment abstinence ( p = .18), and intercurrent drug use ( p = .09). Occ indicates occasional; Reg, regular; *, statistical difference.
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Overall, 27 of the 76 patients used heroin, cocaine, or methamphetamine at least once during HCV treatment. Of them, 12 used heroin only, 6 used cocaine only, 3 used methamphetamine only, and 6 used multiple substances. Most drug users used these substances rarely or infrequently; of the 27 patients who used drugs, 11 used them three or fewer times and 8 used them on an occasional basis. However, an additional 8 patients used drugs at least everyday or every other day for a minimum of 1 month and were categorized as bregularQ drug users; all of the regular drug users injected heroin, with 2 additionally using cocaine and 1 using methamphetamine. The association of drug use with HCV treatment outcomes is shown in Fig. 2. There appeared to be a decrement in treatment outcomes as the intensity of drug use increased; the sustained response rate was 35% among patients who were abstinent, 21% among those who did not use drugs regularly, and 0% among the regular drug users. However, these results did not achieve statistical significance ( p = .09).
4. Discussion Our results indicate that methadone-maintained patients can be successfully treated for HCV in an outpatient setting that can address their special needs for psychiatric and medical care. Although the overall SVR rate (28%) was somewhat lower than the 40– 41% response rates reported for large studies of standard interferon/ribavirin combination therapy in non-addicted patients (McHutchison et al., 1998; Poynard et al., 1998), those studies were conducted on highly selected patient populations and specifically excluded patients maintained on methadone as well as those with psychiatric conditions and those with a significantly advanced liver disease. Our real world cohort was much more challenging; therefore, our results should be considered in the context of the relatively advanced liver disease, lengthy disease exposure, and the presence of multiple potential treatment barriers in our study population. With this perspective, it appears that the overall impact of barriers such as mental illness, limited duration of pretreatment abstinence, and continuing drug use among patients maintained on methadone had a relatively modest effect on HCV treatment response. Interestingly, a preexisting psychiatric diagnosis was more clearly associated with poorer HCV treatment outcomes than was short duration of pretreatment abstinence or moderate intervening drug use. The high rate of antidepressant use in our treated cohort highlights the impact of interferonmediated neuropsychiatric toxicity in our cohort and may also speak of the substantial prevalence of undiagnosed mental illness. Although nearly a quarter of those who reported a history of mental illness had successful treatment outcomes, our results are similar to those of others demonstrating lower HCV treatment response rates in these patients (Capuron et al., 2003; Ho et al., 2001). The etiology of this phenomenon remains unclear.
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Our study did not reveal statistically significant differences in dropout rates or in medication adherence rates between the two groups, nor were psychiatric patients more likely to exhibit demographic or histological differences that might be associated with reduced treatment response rates. At the same time, the failure to find statistical significance between these groups on these important measures may be due at least in part to the relatively low power imposed by our small number of subjects. Significant differences in the rates of pretreatment antidepressant use raise the possibility that P450-related pharmacokinetic interactions may have led to unfavorable changes in interferon or ribavirin metabolism. However, such metabolic interactions are unlikely and there were no significant differences in the rates of antidepressant therapy overall by the end of the HCV treatment. Our study sample was not large enough to permit examination of the potential impact of different antidepressant regimens on treatment outcomes. Other possible explanations for different treatment responses by psychiatric history are highly speculative and may relate to alterations in the hypothalamic-pituitary-adrenal axis that have been previously demonstrated in patients with depression (Raison & Miller, 2001) or the impact of depressionrelated immunological derangements (Raison & Miller, 2001). Obviously, further study is warranted. Our findings that neither a short duration of pretreatment abstinence from drug use nor intermittent drug use during HCV treatment significantly reduced treatment outcomes offer further support for making treatment decisions on a case-by-case basis. However, caution should be urged in interpreting these results in a study with a relatively small sample size. In addition, it should be emphasized that study patients received HCV treatment in settings and by clinicians experienced at providing treatment for addictive disorders. Patients who relapsed to drug use during HCV treatment thus had immediate access to addiction treatment if needed. Providing HCV treatment in settings closely associated with substance abuse treatment services may minimize the impact of drug use on HCV treatment outcomes. Indeed, another study of recovering heroin users whose HCV treatment was initiated during an inpatient methadone detoxification also demonstrated HCV treatment outcomes similar to those of non-addicted patients, even in the setting of relapse to drug use (Backmund et al., 2001). None of the 8 patients in our study who relapsed to regular drug use during HCV treatment had a sustained viral response. Although this finding did not achieve statistical significance, it would appear that patients who relapse to regular drug use during HCV treatment are less likely to have a virological response. Consideration should therefore be given to engaging such patients in alternate models of care such as a residential setting or in an intense outpatient setting with daily individual and group therapies. Because HCV is generally not an emergency to treat, stabilizing substance use behaviors before initiating HCV treatment might help improve HCV treatment outcomes for many patients whose
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drug use is uncontrolled. However, it should be emphasized that up to 20% of patients with active HCV will develop cirrhosis after 20–30 years of infection (NIH, 2002). In this setting, HCV treatment becomes challenging or even impossible, and so it is important to evaluate and refer patients for intervention while the window of opportunity still exists. These results have a number of important implications for HCV-infected substance users. First, they suggest that the optimal duration of pretreatment abstinence should not be arbitrarily determined. Motivated patients who need treatment for HCV may start therapy before achieving 6 months of sobriety if clinically indicated and if appropriate resources are available. Second, our results also suggest a strategy for intervening if relapse to drug use occurs during HCV treatment. Although HCV treatment is often discontinued in such circumstances, our results suggest that intermittent drug use may have only a limited impact on treatment outcomes. Therefore, a strategy that incorporates early and aggressive interventions to prevent drug use from becoming regular should help preserve treatment continuity and outcomes. Third, although comorbid psychiatric conditions may be associated with reduced HCV treatment response rates, addicted patients with a history of depression or any other mental illness may be successfully treated as long as their condition has been stabilized before initiating HCV treatment. Our study has a number of limitations. First, we confined our study to recovering heroin users maintained on methadone, which has well-established stabilizing effects on drug use and behavior. Psychiatric conditions, limited duration of pretreatment abstinence, and intervening drug use may have a greater impact in patients who have not been so stabilized and/or are not undergoing methadone treatment. Second, our observations on the impact of psychiatric conditions on HCV treatment outcomes were made in part on the basis of a selfreported history of mental illness. These diagnoses may have been underreported in patients with more limited access to health care and may help explain the trend toward reduced psychiatric illness in our African American patients. Third, active drug users were not included at the inception of the study because of potential safety issues, potentially biasing enrollment toward abstinent patients and underrepresenting the true prevalence and impact of drug use on methadonemaintained patients treated for HCV. Fourth, settings that effectively integrate access to treatment for HCV, mental illness, and substance use are, unfortunately, relatively uncommon and may limit the generalizability of our study. Lastly, our modest study also did not permit us to ascertain the relative merits of different psychiatric medication regimens, nor did it allow us to determine whether differences in HCV treatment outcomes were associated with different drugs of abuse or routes of administration. Despite these limitations, our study begins to answer some of the key questions that arise when making decisions about treating HCV in substance users. Because a history of injection drug use accompanies a diagnosis of HCV in 60% of the 2.7 million chronically infected patients in the United
States (Alter & Moyer, 1998), these findings have implications for most patients with HCV. Hepatitis C virus treatment should not be withheld from patients in whom it is indicated unless it is unsafe or ineffective. Our results and the results of others suggest that injection drug users can tolerate and benefit from HCV treatment (Backmund et al., 2001; Dalgard et al., 2002). Our study of real world methadone patients with a relatively advanced liver disease and high rates of psychiatric comorbidity, intervening drug use, and limited pretreatment abstinence suggests that response rates are similar to those of non-drug-using populations. Further improvements in HCV outcomes in addicted patients may be expected using regimens that incorporate more effective pegylated interferons, particularly as strategies for addressing interferon-mediated neuropsychiatric toxicity are refined and as optimal models for delivering integrated services to these challenging patients are developed and defined.
Acknowledgments We thank Joan E. Zweben, PhD, for her thoughtful manuscript review and Schering Oncology Biotech and the San Francisco Foundation for providing educational grants in support of this study. Interim results of this study were published in Drug and Alcohol Dependence (2002).
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D.L. Sylvestre et al. / Journal of Substance Abuse Treatment 29 (2005) 159 – 165 Hepatitis Interventional Therapy Group. New England Journal of Medicine, 339, 1485 – 1492. McHutchison, J. G., Manns, M., et al. (2002). Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology, 123, 1061 – 1069. National Institutes of Health. (2002). National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002—June 10–12, 2002. Hepatology, 36(5 Suppl 1), S3 – S20. Pariante, C. M., Orru, M. G., et al. (1999). Treatment with interferon-alpha in patients with chronic hepatitis and mood or anxiety disorders. Lancet, 354, 131 – 132. Pianko, S., & McHutchison, J. G. (2000). Treatment of hepatitis C with interferon and ribavirin. Journal of Gastroenterology and Hepatology, 15, 581 – 586. Poynard, T., Marcellin, P., et al. (1998). Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet, 352, 1426 – 1432. Raison, C. L., & Miller, A. H. (2001). The neuroimmunology of stress and depression. Seminars in Clinical Neuropsychiatry, 6, 277 – 294.
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Regier, D. A., Farmer, M. E., et al. (1990). Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. Journal of the American Medical Association, 264, 2511 – 2518. Schaefer, M., Schmidt, F., et al. (2003). Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology, 37, 443 – 451. Schiff, E. R. (1999). The alcoholic patient with hepatitis C virus infection. American Journal of Medicine, 107, 95S – 99S. Trask, P. C., Esper, P., et al. (2000). Psychiatric side effects of interferon therapy: Prevalence, proposed mechanisms, and future directions. Journal of Clinical Oncology, 18, 2316 – 2326. Van Thiel, D. H., Friedlander, L., et al. (1995). Interferon-alpha can be used successfully in patients with hepatitis C virus-positive chronic hepatitis who have a psychiatric illness. European Journal of Gastroenterology & Hepatology, 7, 165 – 168. Van Thiel, D. H., Friedlander, L., et al. (1998). Treatment of chronic hepatitis C in individuals with pre-existing or confounding neuropsychiatric disease. Hepatogastroenterology, 45, 328 – 330. Zdilar, D., Franco-Bronson, K., et al. (2000). Hepatitis C, interferon alfa, and depression. Hepatology, 31, 1207 – 1211.
The impact of barriers to hepatitis C virus treatment in recovering heroin users maintained on methadone Diana L. Sylvestre, (M.D.)a,b,T, Alain H. Litwin, (M.D., M.P.H.)c,d, Barry J. Clements, (P.A.-C.)b, Marc N. Gourevitch, (M.D., M.P.H.)e,1 a
Department of Medicine, University of California, San Francisco, CA, USA Organization to Achieve Solutions in Substance Abuse (OASIS), Oakland, CA, USA c Division of Substance Abuse, Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, USA d Department of Medicine, Montefiore Medical Center Albert Einstein College of Medicine, Bronx, NY, USA e Division of General Internal Medicine, Department of Medicine, New York University School of Medicine, New York, NY, USA b
Received 22 August 2004; received in revised form 1 November 2004; accepted 10 November 2004
Abstract Although most cases of hepatitis C virus (HCV) infection are associated with injection drug use, there are few data regarding the impact of putative barriers such as psychiatric disease and intercurrent drug use on HCV treatment outcomes. To define the impact of characteristics often cited as reasons for withholding HCV treatment, we studied HCV treatment in a real world sample of 76 recovering heroin users maintained on methadone. Overall, 21 (28%) had a sustained virological response and 18 (24%) discontinued treatment early. Although there was a modest decrement in response rates in patients reporting a preexisting psychiatric history ( p = .01), neither intercurrent drug use nor short duration of pretreatment drug abstinence led to significant reductions in virological outcomes ( p = .09 and p = .18, respectively.) We conclude that injection drug users can be safely and effectively treated for HCV despite multiple barriers to treatment when they are treated in a setting that can address their special needs. D 2005 Elsevier Inc. All rights reserved. Keywords: Hepatitis C; Barrier; Psychiatric disease; Drug use; Abstinence
1. Introduction Although most prevalent and incident cases of hepatitis C virus (HCV) infection in the United States are associated with injection drug use (Alter, 1997; Alter & Moyer, 1998), there are few data regarding HCV treatment in this population or on the impact of barriers such as psychiatric disease and intercurrent drug use on HCV treatment outcomes (Backmund et al., 2001; Dalgard et al., 2002; Jowett et al., 2001). T Corresponding author. Organization to Achieve Solutions in Substance Abuse (OASIS), 520 27th St., Oakland, CA 94612, USA. Tel.: +1 510 834 5442; fax: +1 510 834 0916. E-mail address: [email protected] (D.L. Sylvestre). 1 Dr. Gourevitch performed much of this work while with the Division of Substance Abuse, Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY. 0740-5472/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jsat.2005.06.002
Until recently, drug users have as a group been considered poor candidates for HCV treatment because of concerns regarding adherence, psychiatric disease, and reinfection. Currently, however, the importance of case-by-case determination of eligibility for treatment has gained acceptance (National Institutes of Health [NIH], 2002). In making such determinations, physicians must consider the potential impact of factors such as psychiatric comorbidity, extent of active drug or alcohol use, family and job responsibilities, and motivation to undertake a challenging treatment regimen (Edlin, 2002; Schaefer et al., 2003). Yet the specific impact of these factors on response to HCV treatment among drug users has not been quantified, leaving clinicians without the data they need to inform individualized treatment planning. A case in point is a history of psychiatric illness, generally considered to be a relative contraindication to HCV treatment
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because interferon, a mainstay of HCV treatment, elicits neuropsychiatric toxicities that may be exacerbated in patients with a preexisting mental illness (Fontana, 2000; Lerner et al., 1999; Trask et al., 2000; Zdilar et al., 2000). A proscription against treating patients with a psychiatric history disproportionately affects substance users, more than half of whom report symptoms of a psychiatric disorder (Regier et al., 1990). However, an increasing body of evidence has shown that patients with a history of psychiatric illness can be successfully treated for HCV, although they may develop depression and other neuropsychiatric toxicities at higher rates (Pariante et al., 1999; Van Thiel et al., 1995, 1998; Zdilar et al., 2000). Such information has broadened access to HCV treatment for patients with psychiatric conditions, but its relevance to substance users with a history of mental illness is unclear. The impact of intercurrent drug use on HCV treatment outcomes and the optimal duration of abstinence before initiating HCV treatment are also undefined. Concerns that drug use during HCV therapy will reduce medication adherence and increase the risk of reinfection with HCV are often cited as reasons for withholding HCV treatment from persons using drugs (Davis & Rodrigue, 2001). The fact that interferon is taken by injection might possibly pose a risk to recovery from injection drug use, particularly when abstinence has been brief, and the flu-like systemic side effects of interferon may resemble those of opioid withdrawal and foster the resumption of drug use as a means of side effect management. Yet, unlike for alcohol consumption (Schiff, 1999), no data show that drugs of abuse reduce the efficacy of interferon/ribavirin treatment. In addition, the impact of only a brief period of pretreatment abstinence on outcomes is unknown. To define the impact of specific characteristics often cited as reasons for withholding HCV treatment from drug users on treatment outcomes, we studied HCV treatment in a real world sample of recovering heroin users receiving methadone maintenance treatment. We hypothesized that participation in long-term outpatient opioid agonist replacement therapy would provide a context within which HCV could be successfully treated, allowing us to define and measure those characteristics associated with HCV treatment outcomes.
provided on-site at each location. Although geographically quite removed, the study was undertaken in these two settings because both provide comparable care under the direction of physicians with comparable approaches to treatment. 2.2. Eligibility Men and women aged 18 years and older were considered eligible if they had been maintained on methadone for a period of 3 months or longer, had a positive HCV polymerase chain reaction (PCR), and were willing to undergo treatment for HCV. Patients with non-HCV-related liver disease or decompensated liver disease were excluded. Those whose depression was felt to be unstable based on the judgment of the treating clinician were excluded until antidepressant treatment was initiated and the patients’ condition had stabilized. At the inception of the study, patients with active heroin, cocaine, amphetamine, and/or alcohol abuse on baseline evaluation were excluded. However, based on our experience in treating patients with active drug use, this criterion was eliminated as an exclusion after the first 25 patients had been enrolled. Thereafter, patients who maintained at least 75% attendance at our weekly clinics for at least 2 months were considered eligible for enrollment irrespective of concurrent drug use if no other contraindication was present. Use of marijuana before or during treatment was not an exclusion. All experimental procedures were followed in accordance with the Helsinki Declaration of 1975 as revised in 1983 and were approved by the Ethical Review Committee (Kansas City, MO, USA) and the institutional review boards of the Albert Einstein College of Medicine and the Montefiore Medical Center. 2.3. Medications Hepatitis C virus treatment consisted of standard thriceweekly interferon alfa-2b injections and ribavirin capsules administered at recommended doses. Patients with genotypes 2 and 3 received 24 weeks of therapy; the others were treated for 48 weeks. Medications were self-administered unless patients specifically requested otherwise. 2.4. Procedures
2. Materials and methods 2.1. Study setting Recruitment took place at two sites. The Organization to Achieve Solutions in Substance Abuse is a community-based nonprofit clinic providing medical and psychiatric treatment to substance users in Oakland, California. The Division of Substance Abuse of the Albert Einstein College of Medicine is a network of nine community-sited methadone maintenance treatment programs in the Bronx, New York. Comprehensive primary medical and psychiatric care are
After providing written informed consent, participants completed a questionnaire that elicited baseline demographic, psychosocial, psychiatric, and substance use characteristics. The duration of HCV infection was estimated as one less than the number of years since injection drug use was initiated. Because of its demonstrated impact on HCV treatment outcomes (NIH, 2002), heavy alcohol use was defined as average daily consumption of two or more alcoholic beverages (20 g). Liver biopsy was suggested but not required in patients with a baseline platelet count of N100,000/mm 3 . Patients with a platelet count of b100,000/mm3 were considered to be at greater risk for
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bleeding and thus biopsy was not performed on them. Biopsy specimens were examined by a pathologist unfamiliar with each patient and fibrosis was scored on the METAVIR scale of 0–4 (0 = none, 1 = minimal–mild, 2 = mild–moderate, 3 = moderate–severe, and 4 = cirrhosis). Patients were monitored for treatment-related neutropenia, thrombocytopenia, and hemolytic anemia using standard published algorithms (Pianko & McHutchison, 2000). Drug and alcohol consumption were assessed by monthly selfreport questionnaires, and monthly random urine drug test results were obtained from the subjects’ methadone treatment program. The Beck Depression Inventory was performed every 12 weeks as an indication of worsening psychiatric disease, which was treated with antidepressants. Selective serotonin reuptake inhibitors were used as first-line agents because of their efficacy and acceptable side effect profile. An HCV RNA PCR was performed at baseline, at 6 months, at the end of treatment, and at 6 months after the completion of therapy. Active participation in peer support/education groups throughout the treatment course was encouraged. Substance use during HCV therapy was actively discouraged but did not result in treatment discontinuation unless a patient became unreliable in attending appointments or the clinician felt that it represented a safety risk. The interferon dose was adjusted or discontinued for clinically significant thrombocytopenia or neutropenia, and the ribavirin dose was adjusted for the development of a hemoglobin level b10 mg/dl using standard published guidelines (Pianko & McHutchison, 2000). Patients experiencing symptoms attributed to opioid withdrawal were encouraged to request an increase in their methadone dose. Hepatitis C virus treatment was discontinued if requested by the patient or for severe cases of cytopenia, uncontrolled and/or worsening psychiatric conditions, or decompensating liver disease. 2.5. Outcome measures The primary study end point was sustained virological response (SVR), as demonstrated by undetectable levels of HCV RNA on analysis 6 months after the completion of therapy using a Bayer versant HCV RNA bDNA 3.0 assay (Bayer Diagnostics, Berkeley, CA), with a lower limit of detection of 550 IU/ml. Patients were classified as sustained virological responders at this time point if they had no detectable virus or as nonresponders if the PCR was positive. All analyses were performed on an intent-to-treat basis. 2.6. Adherence Adherence to interferon was assessed by the timing of returned empty interferon vials and by a monthly questionnaire that assessed the number of missed doses of medication. Adherence to ribavirin therapy was assessed by pill counting and by query during a monthly questionnaire. Using adherence criteria developed by others, we considered patients to be adherent to the HCV treatment regimen if they
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took z80% of prescribed interferon and z80% of prescribed ribavirin for at least 80% of the projected treatment course (McHutchison et al., 2002). 2.7. Statistical analysis All data were compiled in and analyzed using SPSS version 11.0.1 for Windows (SPSS, Inc., Chicago, Ill). Associations between SVR and sociodemographic characteristics and drug and alcohol use were determined using Pearson’s or Spearman’s correlation coefficients for continuous variables and Student’s t or Wilcoxon’s signed rank test for categorical variables, depending on the normality of the distribution of data. Bivariate analysis of categorical data was performed with v 2 and Fisher’s exact tests. p Values b.05 in two-tailed comparisons were considered statistically significant. Logistic regression was used to assess for statistical independence among variables that showed a univariate association with a p value of V.20.
3. Results Seventy-six methadone-maintained patients were enrolled at the two sites. Their average age was 50 years; of the patients, 46 (61%) were male, 54 (71%) were Caucasian, 10 (13%) were African American, and 12 (16%) were Latino. The mean estimated duration of HCV exposure of the patients was 28 F 9 years. The median dose of methadone was 71 mg (range, 19–160 mg), and the median duration of continuous methadone maintenance was 5 years (range, 0.25–28 years). Overall, the mean duration of lifetime heroin use by the patients was 21 years (range, 3–50 years); 44 of the patients (64%) reported a history of heavy alcohol use for a median of 12 years (range, 1– 43 years). The median duration of abstinence from illicit drug use by the patients was 1 year (range, 0–18 years); 23 of the patients (30%) had been abstinent for b6 months. One patient was known to be HIV seropositive. Forty-five patients (59%) reported a previous psychiatric diagnosis: 33 (43%) reported depression; 6 (8%), mixed depression and anxiety; 2, anxiety disorder; 1, schizophrenia; 1, bipolar disorder; 1, obsessive–compulsive disorder; and 1, dysthymia. Although there was no difference in age or liver histology between those with and those without psychiatric history (data not shown), patients reporting a psychiatric history were more likely to be female (53% vs. 19% of those without a psychiatric history [ p = .004]) and to have genotype 1 (52% vs. 23% without a psychiatric history [ p = .02.]) There was also a trend toward fewer African Americans in the psychiatric cohort (7% vs. 24% [ p = .08]). Forty-five patients (60%) had genotype 1, 10 (13%) had genotype 2, and 19 (25%) had genotype 3. One patient had genotype 8a and another patient could not be genotyped. Thirty-five patients underwent liver biopsy. Among these, the mean METAVIR inflammation grade was 2.4 (range,
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Fig. 1. Hepatitis C treatment outcomes in patients maintained on methadone (N = 76). ETR indicates end-of-treatment response.
1.5–3.5) and the mean fibrosis stage was 2.8 (range, 0 – 4). Of the remaining 41 patients, 20 had platelet counts of b100,000/mm3. Overall, 23 of the 76 study patients (30%) had Stage 4 fibrosis or a platelet count of b75,000 mm3. Thirty-seven patients (49%) were end-of-treatment responders and 21 (28%) had an SVR (Fig. 1). During HCV treatment, 15 of the 76 patients (20%) reported some degree of alcohol consumption, but only 1 reported heavy (N20 g/day) ingestion. Overall, 45 (59%) used illicit drugs during treatment: 18 (24%) used marijuana only and 27 (36%) used heroin, cocaine, or methamphetamine during treatment. The methadone dose of 33 patients (45%) was increased during HCV treatment by a median of 15 mg (range, 0 –180 mg). Of the 76 patients, 18 (24%) discontinued treatment early whereas 58 (76%) completed therapy. The most common reason for early treatment discontinuation, as reported by 8 patients, was intolerable systemic side effects: specific reasons for discontinuity included psychiatric reasons (n = 4), unresponsive depression (n = 3), and development of psychosis (n = 1). In addition, 2 patients discontinued for medical reasons, 1 because of subacute bacterial peritonitis and 1 for intractable psoriasis. One patient was felt to have become
unstable owing to excessive alcohol consumption and the treating physician discontinued his treatment. Moreover, 2 patients relocated and were unable to access medications and 1 was incarcerated. Based on medical assessment, 36 of the 76 study patients (47%) were taking antidepressants at the time of HCV treatment initiation. This number included 27 of the 45 patients (60%) who reported a preexisting psychiatric condition and 9 of the 31 patients (29%) who did not ( p = .025). By the end of HCV treatment, 65 of the 76 study patients (86%) were taking antidepressants: 40 (89%) of those with a psychiatric history and 25 (81%) of those who did not report one ( p = .34). The association of a preexisting psychiatric diagnosis with treatment outcomes is shown in Fig. 2. Of the 31 patients, 11 (35%) who did not report a prior psychiatric condition had a sustained viral response, as compared with 10 of the 45 patients (22%) who reported a psychiatric history. Multivariate logistic regression analysis taking sex, race, and genotype into account revealed that this finding was statistically significant ( p = .01). There was no difference in dropout rates between the two groups: 11 of the 45 patients (24%) reporting a prior psychiatric condition and 7 of the 31 patients (23%) without a prior psychiatric condition discontinued treatment. Similarly, adherence rates were comparable between the groups, with 30 of the 45 patients (67%) who reported a pretreatment psychiatric diagnosis and 22 of the 31 patients (71%) without a psychiatric diagnosis demonstrating adherence to the medication regimen ( p N .5). The association of the duration of abstinence from drug use with HCV treatment outcomes is also shown in Fig. 2. Of the 53 patients, 16 (30%) who had been abstinent from drug use for at least 6 months before initiating HCV treatment had an SVR, as compared with 5 of the 23 patients (22%) who had a more limited duration of abstinence. This difference was not statistically significant ( p = .18).
Fig. 2. Sustained virological response rates versus psychiatric history ( p = .01), duration of pretreatment abstinence ( p = .18), and intercurrent drug use ( p = .09). Occ indicates occasional; Reg, regular; *, statistical difference.
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Overall, 27 of the 76 patients used heroin, cocaine, or methamphetamine at least once during HCV treatment. Of them, 12 used heroin only, 6 used cocaine only, 3 used methamphetamine only, and 6 used multiple substances. Most drug users used these substances rarely or infrequently; of the 27 patients who used drugs, 11 used them three or fewer times and 8 used them on an occasional basis. However, an additional 8 patients used drugs at least everyday or every other day for a minimum of 1 month and were categorized as bregularQ drug users; all of the regular drug users injected heroin, with 2 additionally using cocaine and 1 using methamphetamine. The association of drug use with HCV treatment outcomes is shown in Fig. 2. There appeared to be a decrement in treatment outcomes as the intensity of drug use increased; the sustained response rate was 35% among patients who were abstinent, 21% among those who did not use drugs regularly, and 0% among the regular drug users. However, these results did not achieve statistical significance ( p = .09).
4. Discussion Our results indicate that methadone-maintained patients can be successfully treated for HCV in an outpatient setting that can address their special needs for psychiatric and medical care. Although the overall SVR rate (28%) was somewhat lower than the 40– 41% response rates reported for large studies of standard interferon/ribavirin combination therapy in non-addicted patients (McHutchison et al., 1998; Poynard et al., 1998), those studies were conducted on highly selected patient populations and specifically excluded patients maintained on methadone as well as those with psychiatric conditions and those with a significantly advanced liver disease. Our real world cohort was much more challenging; therefore, our results should be considered in the context of the relatively advanced liver disease, lengthy disease exposure, and the presence of multiple potential treatment barriers in our study population. With this perspective, it appears that the overall impact of barriers such as mental illness, limited duration of pretreatment abstinence, and continuing drug use among patients maintained on methadone had a relatively modest effect on HCV treatment response. Interestingly, a preexisting psychiatric diagnosis was more clearly associated with poorer HCV treatment outcomes than was short duration of pretreatment abstinence or moderate intervening drug use. The high rate of antidepressant use in our treated cohort highlights the impact of interferonmediated neuropsychiatric toxicity in our cohort and may also speak of the substantial prevalence of undiagnosed mental illness. Although nearly a quarter of those who reported a history of mental illness had successful treatment outcomes, our results are similar to those of others demonstrating lower HCV treatment response rates in these patients (Capuron et al., 2003; Ho et al., 2001). The etiology of this phenomenon remains unclear.
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Our study did not reveal statistically significant differences in dropout rates or in medication adherence rates between the two groups, nor were psychiatric patients more likely to exhibit demographic or histological differences that might be associated with reduced treatment response rates. At the same time, the failure to find statistical significance between these groups on these important measures may be due at least in part to the relatively low power imposed by our small number of subjects. Significant differences in the rates of pretreatment antidepressant use raise the possibility that P450-related pharmacokinetic interactions may have led to unfavorable changes in interferon or ribavirin metabolism. However, such metabolic interactions are unlikely and there were no significant differences in the rates of antidepressant therapy overall by the end of the HCV treatment. Our study sample was not large enough to permit examination of the potential impact of different antidepressant regimens on treatment outcomes. Other possible explanations for different treatment responses by psychiatric history are highly speculative and may relate to alterations in the hypothalamic-pituitary-adrenal axis that have been previously demonstrated in patients with depression (Raison & Miller, 2001) or the impact of depressionrelated immunological derangements (Raison & Miller, 2001). Obviously, further study is warranted. Our findings that neither a short duration of pretreatment abstinence from drug use nor intermittent drug use during HCV treatment significantly reduced treatment outcomes offer further support for making treatment decisions on a case-by-case basis. However, caution should be urged in interpreting these results in a study with a relatively small sample size. In addition, it should be emphasized that study patients received HCV treatment in settings and by clinicians experienced at providing treatment for addictive disorders. Patients who relapsed to drug use during HCV treatment thus had immediate access to addiction treatment if needed. Providing HCV treatment in settings closely associated with substance abuse treatment services may minimize the impact of drug use on HCV treatment outcomes. Indeed, another study of recovering heroin users whose HCV treatment was initiated during an inpatient methadone detoxification also demonstrated HCV treatment outcomes similar to those of non-addicted patients, even in the setting of relapse to drug use (Backmund et al., 2001). None of the 8 patients in our study who relapsed to regular drug use during HCV treatment had a sustained viral response. Although this finding did not achieve statistical significance, it would appear that patients who relapse to regular drug use during HCV treatment are less likely to have a virological response. Consideration should therefore be given to engaging such patients in alternate models of care such as a residential setting or in an intense outpatient setting with daily individual and group therapies. Because HCV is generally not an emergency to treat, stabilizing substance use behaviors before initiating HCV treatment might help improve HCV treatment outcomes for many patients whose
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drug use is uncontrolled. However, it should be emphasized that up to 20% of patients with active HCV will develop cirrhosis after 20–30 years of infection (NIH, 2002). In this setting, HCV treatment becomes challenging or even impossible, and so it is important to evaluate and refer patients for intervention while the window of opportunity still exists. These results have a number of important implications for HCV-infected substance users. First, they suggest that the optimal duration of pretreatment abstinence should not be arbitrarily determined. Motivated patients who need treatment for HCV may start therapy before achieving 6 months of sobriety if clinically indicated and if appropriate resources are available. Second, our results also suggest a strategy for intervening if relapse to drug use occurs during HCV treatment. Although HCV treatment is often discontinued in such circumstances, our results suggest that intermittent drug use may have only a limited impact on treatment outcomes. Therefore, a strategy that incorporates early and aggressive interventions to prevent drug use from becoming regular should help preserve treatment continuity and outcomes. Third, although comorbid psychiatric conditions may be associated with reduced HCV treatment response rates, addicted patients with a history of depression or any other mental illness may be successfully treated as long as their condition has been stabilized before initiating HCV treatment. Our study has a number of limitations. First, we confined our study to recovering heroin users maintained on methadone, which has well-established stabilizing effects on drug use and behavior. Psychiatric conditions, limited duration of pretreatment abstinence, and intervening drug use may have a greater impact in patients who have not been so stabilized and/or are not undergoing methadone treatment. Second, our observations on the impact of psychiatric conditions on HCV treatment outcomes were made in part on the basis of a selfreported history of mental illness. These diagnoses may have been underreported in patients with more limited access to health care and may help explain the trend toward reduced psychiatric illness in our African American patients. Third, active drug users were not included at the inception of the study because of potential safety issues, potentially biasing enrollment toward abstinent patients and underrepresenting the true prevalence and impact of drug use on methadonemaintained patients treated for HCV. Fourth, settings that effectively integrate access to treatment for HCV, mental illness, and substance use are, unfortunately, relatively uncommon and may limit the generalizability of our study. Lastly, our modest study also did not permit us to ascertain the relative merits of different psychiatric medication regimens, nor did it allow us to determine whether differences in HCV treatment outcomes were associated with different drugs of abuse or routes of administration. Despite these limitations, our study begins to answer some of the key questions that arise when making decisions about treating HCV in substance users. Because a history of injection drug use accompanies a diagnosis of HCV in 60% of the 2.7 million chronically infected patients in the United
States (Alter & Moyer, 1998), these findings have implications for most patients with HCV. Hepatitis C virus treatment should not be withheld from patients in whom it is indicated unless it is unsafe or ineffective. Our results and the results of others suggest that injection drug users can tolerate and benefit from HCV treatment (Backmund et al., 2001; Dalgard et al., 2002). Our study of real world methadone patients with a relatively advanced liver disease and high rates of psychiatric comorbidity, intervening drug use, and limited pretreatment abstinence suggests that response rates are similar to those of non-drug-using populations. Further improvements in HCV outcomes in addicted patients may be expected using regimens that incorporate more effective pegylated interferons, particularly as strategies for addressing interferon-mediated neuropsychiatric toxicity are refined and as optimal models for delivering integrated services to these challenging patients are developed and defined.
Acknowledgments We thank Joan E. Zweben, PhD, for her thoughtful manuscript review and Schering Oncology Biotech and the San Francisco Foundation for providing educational grants in support of this study. Interim results of this study were published in Drug and Alcohol Dependence (2002).
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