Similar compliance and effect of treatment in chronic ... - Rega Institute

Original article 159

Similar compliance and effect of treatment in chronic hepatitis C resulting from intravenous drug use in comparison with other infection causes Geert Robaeysa, Hans Van Vlierbergheb, Catharina Matheı¨c, Marc Van Ranstd, Liesbeth Bruckerse and Frank Buntinxc on behalf of the members of the BASL Steering Committee and the Benelux Study Group Objectives There is some reluctance to treat intravenous drug users (IVDUs) with chronic hepatitis C (CHC) because of presumed lower compliance and response to antiviral therapy. We intended to evaluate the compliance and response to antiviral treatment for CHC in IVDUs compared with non-IVDUs. Methods A retrospective cohort study — secondary analysis of the results of a treatment trial — was performed in Belgium and The Netherlands. A total of 406 previously untreated CHC patients, including 98 (24%) IVDUs, were studied for compliance (presentation at the end of treatment), complete response (alanine aminotransferase within normal limits and serum hepatitis C virus polymerase chain reaction negative) at the end of therapy and sustained virological response (SVR). Results Non-compliance (8.2%) in IVDUs was not different from non-IVDUs (6.8%) (relative risk = 1.20; 95% confidence interval = 0.55–2.62). Complete response after controlling for hepatitis C virus was similar (relative risk = 1.19; 95% confidence interval = 0.89–1.60). Controlling for treatment arm, age, sex, presence of cirrhosis or hepatitis C virus viral load before treatment did not change these results. There was a marginally significant difference in the sustained virological response between IVDUs (46.6%) and non-IVDUs (34.6%) (relative risk = 1.35; 95% confidence interval = 1.00–1.81), also disappearing after adjusting for

Introduction In industrialized countries, intravenous drug use has been the major source of new hepatitis C virus (HCV) infections since the 1990s. Thirty-seven percent to 98% of intravenous drug users (IVDUs) are seropositive for HCV [1–10]. Former drug users are defined as having stopped drug use for 6 months. Complete remission rates after antiviral treatment for chronic hepatitis C virus (CHC) infections have increased significantly during the past 10 years, from around 7% initially with interferon to around 47% with interferon and ribavirin [11–15]. Nevertheless, there is some reluctance to treat HCVinfected IVDUs, partially because of a widespread belief that compliance of IVDUs would be lower in comparison with non-IVDUs, and also because evidence

genotype. No difference in compliance or sustained virological response was found between active and nonactive IVDUs or between IVDU patients in or without a methadone maintenance program. Conclusions In this group of Benelux patients, IVDUs showed similar compliance and response to treatment with interferon and ribavirin compared with other patients with CHC infection. Therefore, it is no longer justifiable to withhold treatment to chronic hepatitis C patients who use intravenous drugs. Eur J Gastroenterol Hepatol c 2006 Lippincott Williams & Wilkins. 18:159–166 European Journal of Gastroenterology & Hepatology 2006, 18:159–166 Keywords: hepatitis C, substance abuse, intravenous, patient compliance, treatment outcome, cohort study a Department of Gastroenterology and Hepatology, Ziekenhuis Oost Limburg, Genk, bDepartment of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, cDepartment of General Practice, Katholieke Universiteit Leuven, Leuven, dLaboratory of Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute and University Hospitals, Katholieke Universiteit Leuven, Leuven and eCenter for Statistics, Limburgs Universitair Centrum, Diepenbeek, Belgium

Correspondence and requests for reprints to Dr Geert Robaeys, Ziekenhuis Oost Limburg, Department of Gastroenterology and Hepatology, Schiepse Bos 6, B 3600 Genk, Belgium Tel: + 32 89 32 65 05; fax: + 32 89 32 79 16; e-mail: [email protected] Received 14 July 2004 Accepted 22 September 2005

about the effect of treatment in IVDUs is scarce [16–22]. It has been reported that the antiviral response is higher in patients with a non-1 HCV genotype compared with genotype 1, and IVDUs tend to harbor a non-1 genotype more frequently. Information about the combined influence of IVDU status and HCV genotype on treatment response is scarce [16–22]. We therefore aimed at studying possible differences in treatment effect between IVDUs and non-IVDUs. We compared both compliance and response to treatment of IVDUs and non-IVDUs in a large group of CHC patients, including CHC patients with ongoing actual intravenous drug use and IVDUs who had stopped intravenous drug use for a longer period. While examining the treatment response, the interaction between IVDU

c 2006 Lippincott Williams & Wilkins 0954-691X

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Methods We specifically analyzed differences with respect to both compliance and response to treatment between IVDUs and non-IVDUs participating in a treatment randomized clinical trial evaluating the efficacy of an induction dose of interferon in a large group of CHC patients treated with interferon and ribavirin. Previously untreated CHC patients were treated with daily interferon alpha 2b induction at 5 MU subcutaneously during 8 weeks (group A) or with interferon alpha 2b at 5 MU subcutaneously thrice weekly (group B) followed by the standard dose of interferon alpha 2b (3 MU three times a week). In both groups, a total dose of 1000 or 1200 mg ribavirin was added at week 5, twice daily to patients whose weight was approximately 75 kg. Details and the main results are reported elsewhere [23]: no difference was found between the arm with and without an induction dose. Patients

Previously untreated patients, 18 years or older, with compensated chronic HCV infection, a serum alanine aminotransferase level above the upper limit of normal, and positive serum HCV RNA were eligible for the study. Compensated chronic HCV infection was defined as CHC infection without cirrhosis-related ascites, encephalopathy or portal hypertension. All patients underwent a liver biopsy showing chronic hepatitis within 12 months before enrolment. They were required to use effective birth control. Criteria for exclusion included alcohol abuse, decompensated cirrhosis, a hemoglobin concentration less than 12 g/dl in women and less than 13 g/dl in men, a leukocyte count less than 3000/mm3, a neutrophil count less than 1500/mm3, a platelet count less than 100,000/mm3, human immunodeficiency virus infection, prior organ transplantation, severe psychiatric conditions, seizure disorder, cardiovascular disease, renal insufficiency, hemoglobinopathy, poorly controlled diabetes mellitus, or immunologically mediated diseases (inflammatory bowel disease such as Crohn’s disease, ulcerative colitis), idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, and clinical cryoglobulinemia. Risk factors for HCV transmission were registered as community-acquired HCV infection, parenteral drug addiction, history of transfusion, and occupational exposure. The drug-use status was collected by information directly from the patient, from urinary testing or both. Actual drug use was initially intended to be an exclusion characteristic but, as in other studies [16], this proved not to be feasible. Active IVDU was defined as

intravenous drug use during treatment. Non-active drug users did not use any intravenous drugs during treatment. Separately, patients were classified as either following a methadone maintenance program or not. Sources of infection were transfusion of blood and blood products (37%), parenteral (23%), sporadic (36%) and sexual transmission (4%). Alcohol abuse was defined as using more than 3 U (37.5 g) a day for men and 2 U (25 g) a day for women. Study design and treatment regimens

The objective of the trial originally undertaken [23] was to determine the efficacy of daily interferon alpha 2b induction at 5 MU subcutaneously during 8 weeks (group A) as compared with interferon alpha 2b at 5 MU subcutaneously three times weekly (group B) followed by the standard dose of interferon alpha 2b (3 MU three times a week) in previously untreated CHC patients. In both groups, at week 5 a total dose of 1000 or 1200 mg ribavirin was added for patients whose weight was less than or more than 75 kg, respectively. Patients were assigned to treatment by a randomization ratio of 1:1, and assessed as outpatients for tolerance and efficacy at months 1, 3, 5 and 12 during treatment and at month 6 after therapy. The original trial results have been previously reported [23]. A secondary analysis reported here compared patients infected after intravenous drug use and patients infected in another way with respect to their relative compliance and response to treatment, irrespective of the treatment arm. HCV patients infected after intravenous drug use were defined as patients who were HCV-positive and who injected drugs intravenously at least once. Patients who remained HCV RNA-positive by polymerase chain reaction (PCR) at week 20 were taken off therapy and considered non-responders. When adverse events other than anemia were reported as intolerable by the patient, therapy was stopped. The dose of ribavirin was adjusted on the basis of hemoglobin levels. Ribavirin therapy was reduced to 600 mg/day when hemoglobin levels fell below 10 g/dl, and discontinued when values dropped below 8.5 g/dl. Biochemical testing was performed monthly during therapy, and every 3 months after therapy. Qualitative HCV RNA was tested at month 5, at the end of therapy, and at the end of follow-up (6 months after the end of treatment). The sera were stored in optimal conditions at –801C and transported on ice. Testing for HCV RNA was carried out in a single laboratory for all patients by means of a PCR by Roche Amplicor (Roche Molecular Systems, Pleasanton, Oregon, USA). Quantitative HCV RNA was measured by Roche monitor (Roche Molecular Systems). For HCV genotyping, Innolipa (Innogenetics, Zwijnaarde, Belgium) was used. The lower limits of detection of qualitative and


Therapy of chronic hepatitis C in IVDU Robaeys et al. 161

quantitative HCV RNA tests were respectively 50 and 600 IU/ml. Outcome measures

A complete response was defined as an alanine aminotransferase level within the normal limits and a negative HCV PCR serum. The end-of-treatment virological response was determined as an undetectable HCV RNA level at the end of the treatment period. Sustained virological response (SVR) was determined as an undetectable HCV RNA level at the end of a 6-month follow-up period. Compliance was determined as presentation for HCV PCR testing at the end of treatment. As a sensitivity analysis, attendance at the scheduled appointments was registered in all IVDU patients. For analysis, this proportion was categorized higher than or lower than 2/3. Ethical aspects

All patients gave written informed consent. Ethical approval was obtained from the ethical committee of each centre participating in the study.

Background characteristics of IVDUs and non-IVDUs

Of the 406 patients who started treatment after randomization, 98 (24%) were IVDUs (Fig. 1). They were all Caucasians and predominantly males (84.4%). The mean age at the start of treatment was 37.8 years. There was no statistical difference in age between the males and females (Table 1). Thirty-nine IVDU patients with genotype 1 started treatment: the viral response could be measured in 37 patients at end of treatment and in 34 patients after 6 months (sustained viral response). Forty-eight IVDU patients with a non-1 genotype effectively started therapy: the viral response could be measured in 44 patients at the end of treatment and in 32 patients after 6 months of follow-up. Background details about actual intravenous drug use were available for 87 (89%) of the patients. Only 66 (76%) IVDU patients did not use intravenous drugs during antiviral therapy; 21 (24%) were using intravenous drugs during antiviral therapy. Of 87 patients for whom the information was available, 21 (24%) were on a methadone maintenance program (10/21 in active IVDUs and 11/66 in non-active IVDUs).

Analysis

Comparison of the proportion of compliance or response between IVDUs and non-IVDUs was performed by calculating relative risks (RRs) and their 95% confidence intervals (CIs). Multivariate analysis with up to three dichotomous dependent variables was performed using a stratified analysis according to Mantel–Haenszel. Response was initially examined in compliant patients only (data available at outcome measure event). In order to comply with the intention-to-treat requirement, a sensitivity analysis examined the effect if all noncompliers were considered non-responders for all major end points.

Almost one-half of the IVDUs were infected by HCV genotype 3a (43.7%). Genotype 1a (26.4 %) and genotype 1b (11.5%) were less frequent. Seven percent (six patients) showed a co-infection of genotype 1a/1b. Only 4% had another genotype than genotypes 1, 2 and 3. Almost two-thirds of the IVDUs had a high viral load ( Z 200 000 copies/ml) (65.6%). Data regarding the viral load were absent in eight patients. Most of the patients had no cirrhosis (92.6%). Although the mean age was marginally higher in patients with cirrhosis (37 versus 41 years), the difference was not significant.

Results

Of the 406 patients, 308 were non-IVDUs. In the nonIVDUs the mean age was 46.7 years. There were more women (42.3%). Data about sex were missing in eight persons. Genotype 1 was more frequently present (76.9%) and more patients had cirrhosis (12.8%). Data about genotype were missing, respectively, in 22 nonIVDUs and 11 IVDUs. Viral load was higher (73.6%) as compared with IVDUs, but this was not statistically different. Data about viral load were absent in 16 patients.

Four hundred and fifty-four patients were enrolled for the initial trial from November 1996 to December 1998. Forty-eight patients never started treatment because they did not attend after randomization. Six of these belonged to the group of IVDUs. Four hundred and six patients participated in the study. Of these, 209 patients (51.5%) were randomized in group A (induction therapy) and 197 patients (48.5%) were randomized in group B (standard therapy).

Two hundred and twenty-two non-IVDU patients with genotype 1 started treatment. Viral response could be measured in 211 patients at the end of treatment and in 196 patients after 6 months (sustained viral response). Sixty-four non-IVDU patients with a non-1 genotype effectively started the therapy: the viral response could be measured in 60 patients at the end of treatment and in 52 patients after 6 months of additional follow-up.

The power of the available number of patients was sufficient to significantly identify a RR of 1.5 between IVDUs and non-IVDUs with a power of 85% (a = 0.95). We used Epi-Info (version 3.3.2; CDC, Atlanta, Georgia, USA) and SPSS software (version 12, SPSS Inc., Chicago, Illinois, USA) for the calculations.


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Fig. 1

Randomized in study

n= 454

Excluded: did not present for participation: n = 48 (10%)

Started in study

n = 406 IVDU n= 6

IVDU n = 98

NonIVDU n= 42

Non-IVDU n =308

Number at start of study

Genotype 1 n= 39

Genotype non-1 n = 48

Genotype 1 n= 222


Viral response at end of study: number available

Genotype 1 n= 37


Genotype 1 n = 211

Genotype non-1 n= 60

SVR: viral response after 6 months of follow-up: number available

Genotype 1 n =34


Genotype 1 n = 196

Genotype non-1 n= 52

Flow diagram of the patients included in the study. IVDU, intravenous drug user; SVR, sustained viral response.

Table 1 Patient characteristics at baseline of intravenous drug users (IVDUs) and non-IVDUs treated for chronic hepatitis C virus infection

Age (years) [mean ± SD] Sex (male) [n (%)] Genotype [n (%)] 1 1b/3a 1b/5a 2 3 4 5a Viral load [n (%)] < 200 000 Z 200 000 Cirrhosis [n (%)]

IVDUs

Non-IVDUs

37.8 ± 9.3 81 (84.4)

46.7 ± 11.6 173 (57.7)

39 (45)

220 1 1 17 22 15 10

6 38 2 2

0 (7) (43.7) (2.3) (2.3)

31 (34.4) 59 (65.6) 7 (7.4)

(76.9) (0. 3) (0.3) (6) (8) (5) (3.5)

77 (26.4) 215 (73.6) 38 (12.8)

Compliance to treatment

Ninety-eight IVDUs and 308 non-IVDUs started the treatment. Non-compliance in IVDUs (n = 8; 8.2%) was

not different from non-IVDUs (n = 21; 6.8%) (RR = 1.20; 95% CI = 0.55–2.62) (Table 2). Of the IVDU patients that were compliant according to this definition, 92% attended more than two-thirds of all scheduled appointments. Within the IVDUs there was no difference between patients following a methadone maintenance program and those who did not (P = 0.16), nor between active and non-active IVDUs (n = 0.33). Response to treatment

Table 2 also presents the complete response rate at the end of treatment in IVDUs and non-IVDUs. IVDUs treated with interferon and ribavirin had a better complete response than non-IVDUs (RR = 1.39; 95% CI = 1.07–1.81). This result was similar if all noncompliant patients (no end-to-treatment data available) were considered non-responders (RR = 1.31; 95% CI = 0.99–1.73). However, the better response on antiviral treatment disappeared when controlled for genotype (RR = 1.19; 95% CI = 0.89–1.60). Controlling for



Table 2

Compliance, complete response and viral response in intravenous drug users (IVDUs) versus non-IVDUs

Non-compliance Complete response at end of treatment All patients Genotype 1 patients Genotype non-1 patients Viral response at end of treatment All patients Genotype 1 patients Genotype non-1 patients Sustained viral response All patients Genotype 1 patients Genotype non-1 patients

n

IVDUs [n/total n (%)]

Non-IVDUs [n/total n (%)]

Relative risk (95% confidence interval) in IVDUs versus non-IVDUs

406

8/98 (8.2)

21/308 (6.8)

1.20 (0.55–2.62)

362 241 100

42/83 (50.6) 10/34 (29.4) 28/41 (68.3)

101/279 (36.2) 62/ 207(30.0) 30/59 (50.8)

1.39 (1.07–1.81) 0.98 (0.56–1.72) 1.34 (0.97–1.85)

377 248 104

55/90 (61.1) 15/37 (40.5) 35/44(79.5)

139/287 (48.4) 86/211 (40.8) 41/60(68.3)

1.26 (1.03–1.55) 0.99(0.65–1.52) 1.16(0.93–1.46)

333 230 84

34/73 (46.6) 10/34 (29.4) 21/32(65.6)

90/260 (34.6) 56/196 (28.6) 28/52(53.8)

1.35 (1.00–1.81) 1.02 (0.47–2.23) 1.22 (0.85–1.74)

The numbers mentioned in the first column (n) indicate the number of patients in which the data were available to perform the mentioned analysis.

Table 3

Differences in outcome between active and non-active intravenous drug users (IVDUs)

Non-compliance Viral response at end of treatment Sustained viral response

Active IVDUs [n/total n (%)]

Non-active IVDUs [n/total n(%)]

Relative risk (95% confidence interval)a

0/21 (0) 10/21 (48.0) 5/16 (31)

5/66 (7.6) 37/61 (61) 27/54 (50)

0 (0.02–4.81) 0.79 (0.48–1.28) 0.63 (0.29–1.36)

a

Relative risk (95% confidence interval) in active IVDUs versus non-active IVDUs.

treatment arm, age, sex, presence of cirrhosis, viral load before treatment, and type of infection (IVDU versus non-IVDU) did not change these results.

became marginally significant (RR = 1.35; 95% CI = 1.00–1.81) and lost significance during a similar sensitivity analysis (RR = 1.11; 95% CI = 0.81–1.53).

IVDU patients with genotype 1 responded less at end of therapy (29.4%) compared with a non-1 genotype (68.3%) (Table 2), resulting in a relative risk of complete response at the end of treatment of 0.43 (95% CI = 0.25– 0.75) for genotype 1 versus non-1. Complete response at the end of treatment according to genotype was found in 31% (genotype 1a), 32% (genotype 1b), 39% (genotype 2a), 100% (genotype 2b), 60% (all genotype 1 and 2), 71% (genotype 3a), 24% (genotype 4) and 50% (genotype 5). In non-IVDUs the proportion complete response was 30% for genotype 1 and 50.8% for non-1 genotype patients, resulting in a RR of 0.59 (95% CI = 0.43–0.82).

A similar sensitivity analysis for the subgroup analysis according to genotype was also performed. However, relative risks remained largely similar and statistical significance was never reached, in whatever direction.

The complete response was less after 6 months of followup (n = 289): 28.8% (n = 17) in IVDUs and 20.4% (n = 47) in non-IVDUs. The initial difference between both groups was no longer significant (RR = 1.41; 95% CI = 0.88–2.27). Viral response followed the same pattern as complete response (Table 2) with a significantly larger response in IVDUs compared with non-IVDUs at the end of treatment (RR = 1.26; 95% CI = 1.03–1.55), which lost significance after adjusting for genotype (RR = 1.09; 95% CI = 0.88–1.35). It became marginally significant during sensitivity analysis in which all non-compliers were considered non-responders (RR = 1.24; 95% CI = 1.00– 1.54), but also this analysis was not significant after adjusting for genotype (RR = 1.08; 95% CI = 0.86–1.35). The SVR when evaluated after 6 months of follow-up also

Comparison between active and non-active IVDUs

Within IVDUs there was no relevant difference in compliance between those who used intravenous drugs during treatment and those who did not (RR for noncompliance = 0; 95% CI = 0.02–4.81). Sustained viral response was not different either between those who did use intravenous drugs during antiviral therapy and those who did not (respectively, 31 and 50%) (RR = 0.63; 95% CI = 0.29–1.36) (Table 3). In order to estimate the effect of the possible missing information in the comparison of active IVDUs and nonactive IVDUs, we performed two sensitivity analyses for each of the outcome measures. In the first analysis all patients that could not be classified as belonging to one of both subgroups were considered active users. In the second analysis they were considered non-active. Although the relative risks slightly changed, the main results remained similar and in none of the comparisons statistical significance was even approached. Other subgroups of IVDUs

Although the numbers are low, alcohol abuse seems to decrease the proportion of patients who develop a SVR:


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only one out of seven patients abused alcohol, and 15 out of 29 (52%) did not abuse alcohol. Following a methadone maintenance program does not seem to be very influential: 33% SVR (5/15) in patients included in a methadone maintenance program and 43% (21/49) in those patients not using methadone (P = 0.96). In seven patients the dose of methadone was increased during therapy. The SVR did not decrease in those patients (57%).

Discussion In this study IVDUs showed a similar compliance to treatment with interferon and ribavirin as other patients with CHC infection: they presented as frequently for the final blood sample at the end of treatment as non-IVDUs. Of the IVDU patients that were compliant according to this definition, 92% attended more than two-thirds of all scheduled appointments. IVDU patients did not respond less to antiviral treatment than other chronic HCV-positive patients. After controlling for HCV genotype the initially higher response was similar in both IVDUs and non-IVDUs. This is due to the fact that more than one-half of the IVDUs (51%) are infected by genotypes 3 and 2, and that these genotypes respond very well to therapy. IVDUs were predominantly men and younger than non-IVDUs. This was not of influence on the response to therapy. These data suggest that IVDUs can be treated with the same compliance and the same response rate as CHC patients infected in a different way. This is in contrast with the presumed lower response and compliance with treatment in IVDUs, mentioned in the past. Indeed, some published guidelines recommend that persons who use illicit drugs should not be offered treatment for HCV infection until they had stopped all such use for at least 6 months [24–27]. This results from doubt about compliance with treatment and concern about re-initiation of drug use and possible re-infection. Our finding that there is no difference in compliance in IVDUs compared with patients infected in another way is also quite remarkable, because one-half of the patients were treated in the induction arm with an even higher dose of interferon than in actual standard conditions. Additionally, this high compliance was reached at the end of the 1990s (1996– 1998) when it was not clear that an individualized approach and a comprehensive psychological assessment increased compliance [28–34]. Only few studies reported results of attempts to treat HCV infection in active drug users [16–22]. In studies concerning compliance in drug users to other therapies, IVDU patients were less likely than other persons to adhere to medical therapy, although in other studies between 40% and more than 80% of drug users adhered to

different treatment regimens [28]. In one study in patients with substance abuse treated with interferon, a three times higher loss to follow-up was noticed [29]. Moreover, sustained virologic response to interferonbased therapy seemed less likely in HCV-infected patients with substance abuse than in other HCVinfected patients [30]. In our study, we demonstrated in a large group of patients that the response to treatment with interferon and ribavirin in IVDUs was as high as in the other patients with CHC viral infection. This was independent of the use of methadone or of active drug use. These data were comparable with other treatment studies with a smaller group of patients [16,17], a shorter treatment period [32] or no comparison group [16,17,19]. Our IVDU study group was a mixed group in which 24% were using intravenous drugs during therapy. Clinicians decided for themselves on a case-by-case basis which of them was included, probably resulting in some degree of inter-doctor variation. However, in a subgroup analysis comparing IVDUs who actively used intravenous drugs during therapy and those who did not, we did not find any difference for any of the three outcome measures. This is in contrast to the study of Schaefer et al. [33], who found a low rate of SVR in former drug users. They also found, however, a high drop-out rate. Those patients were not treated with methadone. It is possible that in our study the higher compliance may be due to treatment with methadone in many of these patients. We found analogous results to Van Thiel et al. [34], who performed a retrospective study in individuals with a history of intravenous drug use. They also found a similar rate of SVR in patients with intravenous drug abuse and patients without intravenous drug abuse. Recent use of illicit drugs within a 6-month period of starting interferon therapy or continued methadone use during treatment did not seem to impair the response to interferon when the results were compared with those of a matched cohort of non-drug-abusing controls [34]. Their study was performed in one centre. Our study was performed in multiple centers. This suggests that also in a setting where patients were treated in different circumstances the response to therapy can be comparable with nondrug-abusers. The drug users included in this study lived in the Benelux. They all had access to a well-established medical health system as is present in Europe. There were no important financial or social limits to be treated with methadone or other medications if this was needed. Most patients were in a reasonably good general physical health. This may differ from the situation elsewhere in the world. It could be argued that IVDU patients who became RNAnegative could re-infect themselves again. This could be considered an argument against treatment. We are



following those patients and we hope to confirm their status after 5 years. However, only a small amount of reinfection has been noted up to now [17,20,32].

N. Bourgeois, R. Brenard, I. Colle, J. Delwaide, J. Henrion, Y. Horsmans, P. Michielsen, F. Nevens, G. Robaeys.

Because our results add to the present knowledge of the possibilities for the treatment of IVDUs in Europe, it seems indeed that the recommendations of the European Association for the Study of the Liver guidelines [27] must be questioned. Our results are in favor of the recent changes that were made in the National Institutes of Health consensus [31]. It is no longer justifiable to withhold treatment for hepatitis C illicit drug users and methadone-substituted patients in Europe because of lack of compliance and response. Moreover, former addicted patients can be treated properly. Injection drug use has been the largest risk factor for HCV infection during the past 10 years and it is important not to deny access to potentially lifesaving treatment for HCV infection in an early stage of the disease. In addition, appropriate treatment may help containing the HCV epidemic that is now being described in IVDUs all over the world [2].

The Benelux Study Group: B. Bastens (Lie`ge, Belgium), N. Bourgeois (ULB, Belgium), J.T. Brouwer (Rotterdam, The Netherlands), I. Colle (RUG, Belgium), R.J. de Knegt (Groningen, The Netherlands), W. Deloof (Ieper, Belgium), M. Delhaye (ULB, Belgium), J. Delwaide (Lie`ge, Belgium), J.W. den Ouden-Muller (Rotterdam, The Netherlands), De Vaere (Braine-L’Alleud, Belgium), De Vries (Arnhem, The Netherlands), P. Druez (Gilly, Belgium), E. Francois (ULB, Belgium), J.M. Go¨tz (Assen, The Netherlands), Ph. Golstein (ULB, Belgium), A. Hayani (Charleroi, Belgium), J. Henrion (Jolimont, Belgium), J. Holvoet (Antwerpen, Belgium), P. Lammens (Brussel, Belgium), V. Lefe`bvre (Namur, Belgium), P. Michielsen (Antwerpen, Belgium), Nakad (Tournai, Belgium), F. Nevens (Leuven, Belgium), H. Orlent (Rotterdam, The Netherlands), G. Robaeys (Genk, Belgium), C.M.J. van Nieuwkerk (VU Amsterdam, The Netherlands), O. Le Moine (ULB, Belgium), H. Reynaert (VUB, Belgium), B. Servais (Seraing, Belgium), H.A.R.E. Tuynman (Alkmaar, The Netherlands), S. Vandenhazel (AZN, The Netherlands), H. Van Vlierberghe (Gent, Belgium).

It can be expected that in the near future the good compliance and response will increase even further. The administration of pegylated interferon once a week will probably increase compliance rates. Finally, an individualized approach, enrolment in interdisciplinary programs and good collaboration between the hepatologist and an expert in the assessment and treatment of substance abuse may promote adherence to antiviral therapy. Careful multidisciplinary follow-up of the patients is of paramount importance in this respect. Additional clinical research is needed to study the compliance of drug users during those new treatment regimens. It can be expected that additional evidence will become available from such experiments that will enable further improvements of the treatment guidelines for IVDUs infected by the hepatitis C virus.

Acknowledgement The authors are indebted to Prof. Dr J. Fevery, PhD, for critical review during the preparation of the manuscript. Conflict of interest The initial treatment effect trial was organized by the Belgian Association for the Study of the Liver and was sponsored by an unconditional grant of Shering-Plough, who also provided logistic help. No other conflicts of interest declared. Authors’ contributions Geert Robaeys conceived the study, collected and analysed data, presented and discussed results, and wrote the paper. Hans Van Vlierberghe conceived the study and criticized the paper. Catharina Matheı¨ and Marc Van Ranst provided clinical expertise, managed the proposals, appraised the results and criticized the paper. Liesbeth Bruckers analysed the results and critiqued the paper. Frank Buntinx conceived and directed the study, analysed the results and critiqued the paper.

Appendix A Members of the Steering Committee of the Belgian Association for the Study of the Liver (BASL):

References 1

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