Intravenous drug use is currently the main transmission

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1 A Prospective Controlled Study of Interferon-Based Therapy of Chronic Hepatitis C in Patients on Methadone Maintenance Stefan Mauss, 1 Florian Berger, 1 Joerg Goelz, 2 Bernhard Jacob, 3 and Günther Schmutz 1 We examined the feasibility of hepatitis C treatment in patients on opioid maintenance. One hundred patients with chronic hepatitis C, 50 on methadone maintenance, and 50 with no intravenous drug use or opioid maintenance for at least 5 years were prospectively matched for sex, age, hepatitis C virus (HCV) genotype and HCV RNA. The primary end point was undetectable HCV RNA at 24 weeks posttreatment. Treatment with peginterferon alfa-2b (1.5 g/kg per week) and ribavirin ( mg /day) was initiated for 24 weeks (HCV genotype 2, 3) or 48 weeks (HCV genotype 1, 4). Within the first 8 weeks of therapy, discontinuation due to noncompliance or patient request was observed in 22% (11/50) in the methadone group versus 4% (2/50) in the control group (P.02). After 8 weeks, there was no significant difference in discontinuation due to noncompliance or patient request (4/39 [10%] vs. 4/48 [8%]). There was no difference in discontinuation of therapy because of viral failure or adverse events (10/50 methadone vs. 6/50 control, P.41). At the end of treatment, 50% (25/50) in the methadone group and 76% (38/50) in the control group had undetectable HCV RNA (P.01). Sustained viral response was 42% (21/50) in the methadone group and 56% (28/50) in the control group (P.16). No serious psychiatric event occurred in either group. In conclusion, peginterferon and ribavirin seem reasonably safe and sufficiently effective in patients on methadone maintenance. Patients discontinuing therapy due to noncompliance or request did so early, thereby limiting the cost of an unsuccessful approach to treatment. (HEPATOLOGY 2004;40: ) Intravenous drug use is currently the main transmission route of hepatitis C virus (HCV) infection in the Western world. 1 5 The prevalence in intravenous drug users varies between 35% and 95%. 6 Thus, intravenous drug users with HCV represent a relevant public health problem. Combination therapy with pegylated interferon and ribavirin induces sustained viral responses in treatment-naive patients of 35% to 85%, depending on HCV genotype and HCV viral load. 7,8 Due to these success rates and the convenience of a once weekly injection of pegylated interferons, the acceptance of interferon based therapies has grown with physicians and patients, Abbreviation: HCV, hepatitis C virus. From the 1 Center for HIV and Hepatogastroenterology, Dusseldorf; 2 Praxiszentrum Kaiserdamm, Berlin; and 3 Municipal Methadone Outpatient Clinic, Dusseldorf, Germany. Received January 14, 2004; accepted March 23, Address reprint requests to: Dr. Stefan Mauss, Center for HIV and Hepatogastroenterology, Grafenberger Allee 128a, Dusseldorf, Germany. maussst@compuserve.com; fax: Copyright 2004 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience ( DOI /hep despite significant treatment-related adverse events. However, individuals with active substance abuse are generally not considered eligible for interferon-based therapy because of poor compliance and the priority of treating the addiction first. Yet some physicians treat patients on opioid maintenance therapy with interferon-based therapies despite the unavailability of clinical trial data to support this practice. Consequently, the present study examines, in a prospective controlled setting, the efficacy and tolerability of pegylated interferon plus ribavirin in patients with or without methadone maintenance. Patients and Methods Because a randomized trial in a setting comparing patients on opioid maintenance with patients not on opioid maintenance as controls is not feasible, we chose a prospectively matched population study design. To be included in the methadone maintenance group, patients had to have been on stable methadone maintenance without the concomitant use of illicit drugs for 6 months. To be enrolled in the control group, patients had to have no history of intravenous drug use, illicit drug use, or opioid 120

2 HEPATOLOGY, Vol. 40, No. 1, 2004 MAUSS ET AL. 121 Table 1. Baseline Characteristics (Median and Range) of Patients Characteristic Methadone N 50 Control N 50 Sex (male [female]) 44 (6) 44 (6) Age (y) 35 (22 50) 40 (23 53) Weight (kg) 80 (58 108) 78 (50 115) Body mass index (kg/m 2 ) 24.7 ( ) 25.1 ( ) HCV genotype 1 or 4 29 (58%) 29 (58%) HCV genotype 2 or 3 21 (42%) 21 (42%) HCV RNA at baseline (IU/mL) ( ) ( ) Methadone maintenance Duration (mo) 21 (6 96) Not applicable Daily dose (mg/d) 55 (6 140) Not applicable maintenance therapy for 5 years. Patients who had ongoing illicit drug use, a history of seizures, or a history of psychiatric disorders requiring hospitalization (other than for illicit drug use) were excluded from both groups. Concomitant drug use was excluded by weekly drug screening of urine. Fifty patients on methadone maintenance were enrolled consecutively; for each of these, a control patient was prospectively matched for sex, age, HCV genotype and HCV RNA. All patients were treated with pegylated interferon -2b (1.5 mg/kg body weight) and ribavirin dosed at 1000 mg ( 75 kg body weight) and 1200 mg ( 75 kg body weight). Treatment duration was 48 weeks for patients with HCV genotypes 1 and 4 and 24 weeks for HCV genotypes 2 and 3. Paracetamol was the preferred drug to treat flulike adverse effects of interferon based therapy; doxepin, citalopram, and paroxetine were the preferred antidepressants prescribed according to the judgment of the treating physician in cases of clinically relevant depressive mood disorders. The primary end point of the prospective controlled intent-to-treat analysis was sustained viral response to interferon-based therapy defined as an HCV RNA less than 50 IU/mL at 24 weeks posttreatment (AMPLICOR HCV v2.0, Roche Molecular Systems, Branchburg, NJ). The study was approved by the local ethics committee. All patients signed a consent form authorizing collection and analysis of the data. Statistical analysis was performed with software from SPSS (SPSS GmbH, Munich, Germany). For the comparisons of the methadone group with the control group, the 2-tailed nonparametric unpaired Mann Whitney U test was used. For comparisons within each group, the paired Wilcoxon test was applied. The statistical significance level was.05. Results In both groups, 44 patients were male, HCV genotype 1 or 4 was present in 29 patients (58%), and HCV genotype 2 or 3 in 21 patients (42%). The median age of methadone patients was 35 (range, 22-50) and 40 (range, 23-53) in control patients. The median HCV RNA in the methadone group was IU/mL (range, IU/mL) and IU/ml (range, IU/mL) in the control group. The median time on stable methadone maintenance at baseline was 21 months (range, 6-96), and median methadone dose was 55 mg per day (range, mg; Table 1). At the end of treatment, the proportion of patients responding in the methadone arm was 25 of 50 (50%); this was statistically inferior to the 38 of 50 (76%) observed in the control group (P.01). However, due to a higher relapse rate in control patients during the follow-up period, the sustained viral response was 28 of 50 (56%) in controls and did not differ statistically from the 21 of 50 (42%) in the methadone arm (P.16; Fig. 1). There was no statistical difference in response rate after stratifying patients according to HCV genotype (Table 2). The 10 patients experiencing a relapse in the control group showed no association with a specific genotype pattern (7/23 patients with HCV genotype 1, 4; 3/15 patients with HCV genotype 2, 3; P.71), and neither did the methadone patients (1/12 patients with HCV geno- Fig. 1. Virological response to treatment in patients on methadone maintenance (open bars) and in controls (filled bars), as defined by HCV RNA. EOT, end of treatment; SVR, sustained viral response (at end of follow-up).

3 122 MAUSS ET AL. HEPATOLOGY, July 2004 Table 2. Sustained Viral Response (SVR) and Association With HCV Genotype SVR Methadone Control P Value All HCV genotypes 21/50 (42%) 28/50 (56%).16 HCV genotype 1 or 4 11/29 (38%) 16/29 (55%).29 HCV genotype 2 or 3 10/21 (48%) 12/21 (57%).76 type 1, 4; 3/13 patients with HCV genotype 2, 3; P.76). In the methadone arm, an analysis of baseline characteristics did not demonstrate an association of the chosen variables with sustained viral response or treatment failure (Table 3). In total, 25 of 50 patients (50%) prematurely discontinued interferon-based therapy in the methadone group, compared to 12 of 50 (24%) in the control group (P.01; Fig. 2).This difference was driven by the discontinuation rate mainly due to noncompliance or patient request during the first 8 weeks of therapy: 11 of 50 (22%) in the methadone group versus 2 of 50 (4%) in the control group (P.02). Methadone patients who discontinued during the first 8 weeks of therapy showed no specific HCV-genotype pattern (7/29 patients with HCV genotype 1, 4 vs. 4/21 patients with HCV genotype 2, 3; P.74). After the first 8 weeks of therapy, there was no significant difference in discontinuation rate due to noncompliance or patient request in the remaining patients between the methadone arm (4/39 [10%]) and controls (4/48 [8%]; P.73). Discontinuation as a consequence of adverse treatment effects or viral treatment failure did not differ between the treatment groups: methadone (10/50 [20%]) versus control (6/50 [12%]); P.41). In the methadone group, 4 patients discontinued treatment due to adverse events Fig. 2. Number of patients discontinuing interferon-based therapy prematurely. Methadone patients (open symbols) and control patients (filled symbols). All discontinuations (squares); patients discontinuing due to noncompliance or their own request (triangles). (weight loss, impaired renal clearance, anemia, alcohol abuse). In the control group, 2 patients had to discontinue treatment because of adverse events (hypothyroidism, first manifestation of multiple sclerosis). Over time, the alanine aminotransferase profile did not differ between methadone patients and controls. The decrease in leukocytes, platelets, and hemoglobin was comparable in both groups (Table 4). At baseline, 4 of 50 patients in the methadone arm and 2 of 50 in the control arm were treated with antidepressants (P.68). During interferon-based therapy, 15 of 50 methadone patients and 10 of 50 control patients were being treated with antidepressants at any time (P.36). At the end of follow up, 3 of 50 methadone patients and 4 of 50 control patients were still on antidepressants (P 1.00). One patient had to discontinue treatment due to alcohol abuse, but no patient in the methadone group returned to using intravenous drugs. Table 3. Retrospective Comparison of Baseline Data (Median and Range) From Methadone Patients With Sustained Viral Response (SVR) and Patients With Viral Treatment Failure Characteristics Methadone Patients With SVR* (n 21) Methadone Patients Without SVR* (n 29) P Value Methadone maintenance Duration (y) 2 (0.5 8) 1 (0.5 8).28 Daily dose (mg) 60 (10 140) 45 (6 135).46 Age (y) 35 (24 50) 35 (22 49).94 Weight (kg) 82 (58 99) 80 (60 108).94 Body mass index (kg/m 2 ) 23.9 ( ) 24.8 ( ).72 HCV RNA (IU/mL) 481,500 (104,000 1,240,000) 771,000 (41,700 4,250,000).25 ALT (U/L: 25 C) 39 (15 102) 37 (10 73).16 Leukocytes (cells/nl) 7.7 ( ) 7.3 ( ).80 Platelets (cells/nl) 202 ( ) 229 (83 365).12 Hemoglobin (g/dl) 14.8 ( ) 15.1 ( ).80 NOTE. No association between the analyzed factors and SVR was observed. Abbreviation: ALT, alanine aminotransferase. *HCV RNA 50 IU/mL 24 weeks after end of treatment.

4 HEPATOLOGY, Vol. 40, No. 1, 2004 MAUSS ET AL. 123 Table 4. Comparison of Laboratory Results (Median and Range) at Beginning of HCV Therapy (Baseline), End of Treatment (EOT), and 24 Weeks Posttreatment Laboratory Value Methadone Control ALT (U/I: 25 C) Baseline 39 (10 102) 48 (14 218) EOT 12 (5 103) 16 (6 83) SVR 12 (7 62) 14 (5 80) Leukocytes (cells/nl) Baseline 7.6 ( ) 7.2 ( ) EOT 3.6 ( ) 3.3 ( ) SVR 6.9 ( ) 6.3 ( ) Platelets (cells/nl) Baseline 208 (83 356) 216 (93 353) EOT 129 (32 301) 149 (50 496) SVR 198 (72 361) 214 (92 342) Hemoglobin (g/dl) Baseline 14.8 ( ) 15.8 ( ) EOT 12.0 ( ) 12.2 ( ) SVR 14.4 ( ) 15.4 ( ) Abbreviations: ALT, alanine aminotransferase; SVR, sustained viral response. Methadone patients who completed interferon-based therapy did not increase the median daily methadone dose during interferon-based therapy (55 mg/day vs. 50 mg/day). In these patients, 24 weeks post-therapy, the median methadone dose (20 mg/day) was lower compared to baseline (55 mg/day); P.008 (Fig. 3). Discussion Illicit drug users represent a relevant proportion of patients with chronic hepatitis C. Patients on opioid maintenance are treated by some hepatologists, but this approach is largely based on personal experience rather than on the results of controlled studies. The present study provides data for the rationale of treating patients on stable methadone maintenance. The results suggest that the control group has a better chance of treatment response than the group on methadone maintenance, and this response is driven by increased compliance and reliability of the patients in the control group. However, the small sample size of the study precludes a firm conclusion. In a post hoc sample size calculation with the sustained viral response rate observed in this study, a sample size of 200 patients would have been necessary to detect a difference with 80% probability at P.05. Despite the increased premature discontinuation rate within the first 8 weeks, the patients on methadone maintenance achieved an overall sustained viral response rate of 42%. This response rate seems acceptable in this rather difficult-to-treat population compared to the 54% achieved in the pivotal study by Manns et al 8 and the 56% achieved in the present control group. In a retrospective observational study of treatment with conventional interferon plus ribavirin in abstinent drug users or patients on methadone maintenance, a sustained viral response rate of 36% in 50 patients was observed. 9 In another uncontrolled observational study of 50 patients with chronic hepatitis C on methadone maintenance, the response rate was 54% at the end of treatment with conventional interferon plus ribavirin. 10 In a different study scenario, patients enrolled during detoxification treatment and treated with interferon or interferon plus ribavirin had a sustained viral response rate of 36%. 11 In the present study, the sustained viral response rate of 42% in the methadone arm with the use of pegylated interferon -2b and ribavirin seems on a par with the treatment response reported in the other studies. Not unexpectedly, most methadone patients who discontinued therapy due to noncompliance or by their own request did so during the first 8 weeks, thereby limiting the costs for the health care system of an unsuccessful approach to treatment. Methadone patients who continued treatment beyond week 8 had similar adherence and sustained response rates as controls. The daily dose of methadone in patients who completed therapy was not substantially altered in patients during interferon-based treatment and was even lower 24 weeks posttreatment. In the present study, interferon-based therapy showed no unexpected serious adverse effects in patients on methadone maintenance, a population considered to have substantial psychiatric comorbidity. It may be important that all patients were seen daily by the physician who administered the methadone maintenance therapy and that pharmacological treatment with antidepressants was initiated when considered appropriate by the treating physician. It must be considered, however, that because of the limited sample size, rare adverse effects of interferonbased therapy might have been missed. Fig. 3. Median daily methadone dose in patients completing interferon-based therapy was not increased during HCV therapy and was reduced 24 weeks thereafter. EOT, end of treatment; SVR, sustained viral response.

5 124 MAUSS ET AL. HEPATOLOGY, July 2004 In conclusion, pegylated interferon in combination with ribavirin in our pilot study seems reasonably safe and sufficiently effective in patients with methadone maintenance. Additional studies are warranted to further identify a patient profile to provide guidance for successful and safe application of interferon-based therapy of chronic hepatitis C in this difficult-to-treat patient population. References 1. Alter MJ. Epidemiology of hepatitis C. HEPATOLOGY 1997;26(Suppl 1): 62S 65S. 2. Garfein RS, Vlahov D, Galai N, Doherty MC, Nelson KE. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health 1996;86: Hershow RC, Kalish LA, Sha B, Till M, Cohen M. Hepatitis C virus infection in Chicago women with or at risk for HIV infection: evidence for sexual transmission. Sex Transm Dis 1998;25: Garfein RS, Doherty MC, Monterroso ER, Thomas DL, Nelson KE, Vlahov D. Prevalence and incidence of hepatitis C virus infection among young adult injection drug users. J Acquir Immune Defic Syndr Hum Retrovirol 1998;18(Suppl 1):S11 S19 5. McCarthy JJ, Flynn N. Hepatitis C in methadone maintenance patients: prevalence and public policy implications. J Addict Dis 2001; 20: Edlin BR, Seal KH, Lorvick J, Kral AH, Ciccarone DH, Moore LD, et al. Is it justified to withhold treatment for hepatitis C from illicit-drug users? N Engl J Med 2001;345: Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358: Jowett SL, Agarwal K, Smith BC, Craig W, Hewett M, Bassendine DR, et al. Managing chronic hepatitis C acquired through intravenous drug use. Q J Med 2001;94: Sylvestre DL. Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend 2002;68: Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of hepatitis C infection in injection drug users. HEPATOLOGY 2001;34: