Current issues of ACP Journal Club are published in Annals of Internal Medicine


A higher dose and longer duration of interferon α-2a reduced the incidence of cirrhosis in chronic hepatitis C

ACP J Club. 1999 Mar-April;130:37. doi:10.7326/ACPJC-1999-130-2-037

Source Citation

Degos F, Daurat V, Chevret S, et al., and the Multicentre GER-CYT-04 Group. Reinforced regimen of interferon alfa-2a reduces the incidence of cirrhosis in patients with chronic hepatitis C: a multicentre randomised trial. J Hepatol. 1998 Aug;29:224-32.



In patients with chronic hepatitis C, is an increased dose and longer duration of interferon α-2a (INF) therapy more effective than standard doses for preventing the development of cirrhosis?


Randomized controlled trial with 18-month follow-up.


15 university hospitals in France.


244 patients (mean age 37 y, 64% men) positive for antibodies to the hepatitis C virus (HCV) (confirmed hepatitis C). Exclusion criteria were previous treatment for hepatitis C, other viral infection, pregnancy, hemophilia, chronic alcohol abuse, uncontrolled drug addiction, abnormal laboratory values, thyroid dysfunction, and history of severe psychiatric disease. Follow-up was 82%.


124 patients were allocated to the re-inforced regimen (INF, 6 MU/d for 12 d, 6 MU 3 times/wk for 22 wk, and then 3 MU 3 times/wk for 24 wk). 120 patients were allocated to a standard regimen (3 MU 3 times/wk for 24 wk).

Main outcome measures

Sustained normal levels of alanine transaminase (ALT) at 18 months, sustained virologic response (undetectable HCV RNA and branched DNA [bDNA] < 0.2 × 106 by the end of treatment), and cirrhosis confirmed by liver biopsy at 18 months.

Main results

Patients in the reinforced group had a higher rate of maintaining normal levels of ALT (P = 0.003) and undetectable bDNA and HCV (P = 0.04) and a lower incidence of cirrhosis (P = 0.04) than did patients in the standard group. Patients in the reinforced group also had higher rates of flu-like syndrome (68% vs 54%, { P = 0.03}*), nausea or vomiting (60% vs 38%, { P < 0.001}*), and weight loss (96% vs 81%, { P < 0.001}*) but not thyroiditis, suicide attempts, or irritability.


Patients with chronic hepatitis C who received a reinforced regimen of interferon α-2a had a lower incidence of cirrhosis, a higher incidence of maintaining normal ALT levels and virologic responses, and a higher incidence of adverse effects than did patients who received a standard regimen.

Sources of funding: Direction des Hôpitaux and Délégation à la Recherche Clinique and Assistance Publique-Hôpitaux de Paris.

For correspondence: Dr. F. Degos, Service d'Hépatogastroentérologie 2, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110 Clichy, France. FAX 33-1-4739-6178.

*Numbers calculated from data in article.

Table. Reinforced vs standard interferon α-2a regimens for chronic hepatitis C†

Outcomes at 18 mo Reinforced Standard RRR (95% CI) NNT (CI)
Cirrhosis 1.0% 10.3% 91% (45 to 98) 11 (6 to 27)
Sustained normal ALT levels 18.4% 4.3% 327% (74 to 968) 8 (4 to 16)
Sustained normal virologic response 19.6% 6.9% 183% (30 to 529) 8 (5 to 28)

†ALT = alanine transaminase. Other abbreviations defined in Glossary; RRR, RBI, NNT, and CI calculated from data in article.


Considerable interest has been shown in devising drug treatments and schedules to improve outcomes in patients with chronic hepatitis C. Combined interferon and ribavirin therapy compared with interferon monotherapy resulted in an increase of approximately 30% in biochemical and virologic response rates (1). Treatment strategies under evaluation involve increasing the duration of therapy with an induction phase followed by maintenance therapy, modified interferons, and new antiviral agents.

Degos and colleagues attempt to determine the efficacy of a reinforced regimen, but the rationale for the drug schedule is unclear. The lack of the standard 12-month duration of treatment for the control group (2) makes interpretation of the results difficult. The lower frequency of cirrhosis in the reinforced therapy group is curious. The histologic data suggest modest improvement, considering that the mean fibrosis score in 39% of controls and 55% of the reinforced group remained unchanged in the 0, 1, and 3 score categories. About 17% of patients in both groups had unknown scores. Questions about the adequacy of the liver biopsy sample, fragmentation, and criteria for the diagnosis of cirrhosis need clarification. Most patients in the reinforced group experienced more side effects than controls, as expected, but only a few withdrew from the study, generally confirming the high motivation of these patients to pursue treatment for this recalcitrant disease.

Reinforced, augmented, induced, and prolonged therapy using interferon alone or in combination with other drugs will continue to be studied. The results will confirm whether we can effectively suppress hepatitis C, prevent cirrhosis, and even eliminate HCV. We await the results of these studies with hope.

Jacob Korula, MD
University of Southern California School of MedicineLos Angeles, California, USA


1. Schalm SW, Hansen BE, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers. J Hepatol. 1997;961-6.

2. National Institutes of Health Consensus Development Conference Panel Statement: Management of hepatitis C. Hepatology. 1997;26(suppl):2-10.