We performed an independent meta-analysis of all available blind, placebo-controlled trials confirmed the efficacy of this randomized clinical trials of interferon alfa-2b in patients with agent in normalizing alanine aminotransferase (ALT) values chronic hepatitis C. Articles published between 1986 and and improving histological features of disease activity. [3][4][5][6] 1996 had to include previously untreated patients who were
Based on these studies, in 1991 the Food and Drug Adminrandomly allocated to therapy with at least 2 million units istration approved a formulation of recombinant alpha inter-(MU) of interferon alfa-2b three times weekly for 24 weeks. feron, interferon alfa-2b (Intron A; Schering Plough Corpora-A total of 32 trials met the inclusion criteria. Of these, 20 tion, Kenilworth, NJ) in a dose of 3 million units (MU) compared interferon-treated patients to placebo recipients or subcutaneously three times weekly for 6 months as treatment untreated patients and were used in the primary meta-analysis for patients with chronic non-A, non-B hepatitis (hepatitis that compared rates of end-of-treatment and 6-month post-C). This dose and duration of interferon alfa-2b therapy has treatment sustained biochemical (normal alanine aminotransbeen the standard of care for treatment of patients with ferase [ALT] levels) responses, end-of-treatment and 6-month chronic hepatitis C in the United States until recently.
sustained virological responses (absence of hepatitis C virus
Interferon alfa-2b has been used widely in the United [HCV] RNA), and end-of-treatment histological responses in States, Europe, and Asia. Multiple clinical trials have subsepatients with paired biopsies. An additional 12 trials comquently been performed in patients with acute and chronic pared different doses, duration, or strategies of treatment. In hepatitis C. 7 A number of recent meta-analyses have concomparison with no treatment, interferon alfa-2b therapy was firmed the efficacy of interferon therapy in patients with associated with significant improvement in all end points meaacute and chronic hepatitis C. 7-10 However, none dealt exclusured. End-of-treatment biochemical responses were seen in sively with interferon alfa-2b.
47% of treated patients compared with 4% of controls (odds
As part of the National Institutes of Health Consensus ratio, 25.1; P Γ΅ .0001). The biochemical responses were sus-Development Conference on the treatment of hepatitis C, we tained for at least 6 months in 23% of treated patients comwere asked to perform an independent meta-analysis of all pared with 2% of controls (odds ratio, 17.8; P Γ΅ .0001). available randomized clinical trials of interferon alfa-2b in End-of-treatment virologic responses were observed in 29% chronic hepatitis C performed over the past decade. of treated patients compared with 5% of controls (odds ratio, 9.4; P Γ΅ .001) and 6-month sustained virologic responses
PATIENTS AND METHODS
were documented in 8% of treated patients compared with 1% of controls (odds ratio, 8.6; P Γ΅ .001). Histological re-To be considered for this analysis, published articles had to include the following: 1) patients with chronic hepatitis (non-A, non-sponses were recorded in 73% of treated patients compared B, or C); 2) patients with no previous treatment with interferon; with 38% of controls (odds ratio, 4.8; P Γ΅ .0001). Extended 3) patients who were 18 years of age or older; 4) random allocation therapy for 12 to 24 months resulted in significant improveof patients into at least two treatment groups; 5) treatment with ment in 6-month sustained responses: 27% versus 14% (odds interferon alfa-2b with a dose of at least 2 MU three times weekly ratio, 2.9; P Γ΅ .001). Higher dose therapy also resulted in for a minimum of 24 weeks; and 6) adequate information to assess modest increases in end-of-treatment (61% vs. 52%; odds raend points. tio, 1.8; P Γ΅ .02) and 6-month sustained responses (28% vs.
The quest for pertinent trials was initiated with a MEDLINE 19%; odds ratio, 2.2; P Γ΅ .01). (HEPATOLOGY 1997;26(Suppl search for all randomized controlled trials of interferon therapy in 1):83S-88S.) chronic hepatitis C, performed by Dr. Willis Foster at the National Institute of Diabetes and Digestive and Kidney Diseases. This was supplemented by a search of Current Contents in early 1997. In Preliminary studies performed at the Clinical Center of addition, relevant articles and previous meta-analyses were scoured the National Institutes of Health in the 1980s suggested the for additional trials, references, and follow-up articles. Only trials potential benefit of alpha interferon in patients with chronic published between 1986 and December 1996 were included. non-A, non-B hepatitis. 1,2 A series of randomized, double-A total of 198 articles was retrieved with the computerized searches or appeared of sufficient interest to require review. From these, 32 clinical trials met the inclusion criteria established for the meta-analysis. A log was kept of all articles retrieved and the reason Abbreviations: ALT, alanine aminotransferase; MU, million units; HCV, hepatitis C virus; CI, confidence interval; PCR, polymerase chain reaction.
for rejection. The majority were eliminated because they included From the Departments of Medicine and Biostatistics, University of Washington, other forms of interferon or were review articles. The primary rea-Seattle, WA. sons for rejecting trials using interferon alfa-2b included inadequate