Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: A randomized open-label pilot study☆
Introduction
Despite the enormous advances that have been achieved in the treatment of chronic hepatitis C over the last decade [1], there is still a need for improved therapies, especially for the difficult-to-treat patients such as HCV-genotype 1 infected individuals, patients with liver cirrhosis, or patients who did not respond to a previous interferon alfa (IFN)-based therapy [2]. Even the new standard therapy of pegylated interferon alfa (PEG-IFN) in combination with ribavirin is not very effective for the so called non-responder patients. Relapse patients may benefit from re-treatment but patients infected with HCV-genotype 1 who were true non-responders to IFN and ribavirin demonstrated only 12% sustained virological response (SVR) with PEG-IFN and ribavirin [3], [4]. Thus, there is currently no generally accepted therapeutic strategy for this patient population. One approach, currently evaluated in clinical trials, is the long-term maintenance therapy with PEG-IFN in non-responders with advanced fibrosis or cirrhosis to prevent hepatocellular carcinoma and/or decompensation (EPIC3, HALT-C, COPILOT trials [3], [4], [5]). However, viral eradication should be still the first achievable goal whenever possible. Some study results suggest that consensus interferon (CIFN), which is a ‘consensus’ molecule of the type-1 interferons with a higher biological activity in vitro [6], [7], may be more effective than standard IFN for the difficult-to-treat HCV-genotype 1 patients [8], [9], [10]. CIFN monotherapy demonstrated a substantial SVR in non-responder patients [11]. To mimic the half-life of PEG-IFN, CIFN has to be administered on a daily basis. Recently, one study showed that daily dosing of 9 μg CIFN significantly increased the SVR compared to a 9 μg tiw regimen [12]. Preliminary data from a single center study presented in abstract form, suggested that daily dosing of CIFN in combination with ribavirin can achieve SVRs of 38–45% in non-responder patients to standard IFN and ribavirin depending on the CIFN dose [13]. High-dose-induction, although not effective in studies with standard IFN [14], [15], [16], seemed to have further improved the SVR in this study [13]. Cotler and colleagues [17] assessed the first-phase viral kinetics in 20 previous non-responders after a single dose of 15 or 30 μg CIFN and demonstrated a significantly sharper decline of the HCV-RNA with the higher dose after 24 h (0.8 and 1.5, respectively). Whether high-dose-induction with CIFN may serve as an option to further increase the SVR in difficult-to-treat patients remains unknown.
Here, we initiated an open-label pilot study to assess the efficacy of daily dosing of CIFN in combination with ribavirin on the first- and second-phase of viral kinetics, sustained virological response, and histological response in patients with chronic hepatitis C who did not respond to a prior IFN based therapy. Additionally, we tested if a short-term induction with a double dose of CIFN would further enhance the SVR.
Section snippets
Selection of patients
Adult patients (18–65 years) with chronic hepatitis C infection were eligible for the study if they were virological non-responders to a previous therapy with IFN or IFN plus ribavirin (HCV-RNA positive after at least 3 MU IFN alfa tiw for 24 weeks). Non-response was further classified as flat non-response (<1 log10 reduction of HCV-RNA), flat partial response (>1 log10<2 log10 reduction of HCV-RNA), and partial response with a significant reduction of viral load (>2 log10 reduction of HCV-RNA).
Study design
The study was an open-label trial with a central randomization procedure performed in Hannover. Seventy-seven patients were randomly assigned into two groups without further stratification using sequentially numbered cards in sealed envelopes. Patients in Group A were treated with 9 μg CIFN daily for 48 weeks whereas patients in Group B received an induction therapy of 18 μg CIFN daily for the first 8 weeks followed by 9 μg CIFN daily for the remaining 40 weeks. In both groups, ribavirin was given
Assessment of efficacy
The primary endpoint was sustained virological response (SVR), defined as undetectable HCV-RNA in serum 24 weeks after the end-of-treatment (EOT). Secondary endpoints were early virological response (EVR: HCV-RNA decline>2 log10 before week 12) and absence of serum HCV-RNA at the EOT and normalization of serum ALT at the end of follow-up. Therapy was discontinued once the HCV-RNA was detectable at week 24 of treatment. The first-phase of early viral kinetics was assessed by the log10 decay
Statistical analysis
Data were described by rates, means with standard deviation, medians, and ranges. Furthermore, groups were compared by χ2 test, Fishers exact test, Man–Whitney and Kruskal–Wallis test as appropriate. In addition, multivariate step-wise logistic regression was used to identify independent predictors from baseline characteristics which were associated with SVR in univariate analysis. All p values reported were two-sided and p values below 5% were considered significant.
Patients
Between March 2000 and September 2001, 77 patients were randomized (Group A=38, Group B=39 and treated at eight different sites (Hannover, Bad Oeynhausen, Berlin, Bochum, Braunschweig, Bielefeld, Kassel, Koblenz). The baseline characteristics are shown in Table 1. The only significant difference between the treatment groups was found in baseline ALT as Group B tended to have lower ALT levels (p=0.048).
Safety
The spectrum of side effects of daily CIFN therapy was comparable to previous trials with IFN
Discussion
Currently, there are no recommendations how to manage patients with chronic hepatitis C who did not respond to a prior IFN/ribavirin therapy. Here, we investigated a daily dosing regimen with CIFN in combination with ribavirin. As expected for non-responders, our 77 patients showed baseline characteristics that are associated with a poor treatment response (Table 1). The treatment with daily dosing of CIFN plus ribavirin resulted in surprisingly high EVR of more than 80% but after the end of
Study group
Medizinische Hochschule Hannover (M.P. Manns, M. Cornberg, H. Wedemeyer, J. Hadem, M. Bastürk, A. Schüler, H.L. Tillmann, C. Trautwein), Krankenhaus Bad Oeynhausen (F. Schuppert, O. Becker, W. Steuber), Charité Berlin (E. Gentz, A. Roske, J. Jetschmann, H.H.-J. Schmidt), Ruhr-Universität Bochum (W. Schmiegel, M. Reiser), Praxis Braunschweig (O. Marschal), Franziskus-Hospital Bielefeld (M. Steffen, R. Müller), Klinikum Kassel (J. Pausch), Praxis Koblenz (G. Hermesdorf).
Acknowledgements
The study was supported by an unrestricted research grant from Yamanouchi Pharma GmbH (now Astellas Pharma GmbH), Germany, the German competence network for viral hepatitis (Kompetenznetz Hepatitis), and the clinical research unit (KFO 129, supported by the Deutsche Forschungsgemeinschaft). M.P. Manns is a consultant to companies marketing alfa-interferons. We thank N. Kothe, P. Magerstedt, Hannover, and K.H. Schweickert for technical assistance, and L.A. Wilkinson and F.S. Saccoccio for
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The authors have declared that they received funding from the drug companies involved to carry out their research.