Mechanism of Action of Interferon and the Contribution of Prolonged Treatment in Chronic Hepatitis C

Alfredo Alberti, MD
Professor of Medicine
Department of Clinical and Experimental Medicine
University of Padova
Padova, Italy

Learning Objectives:

To review:
* Response kinetics during interferon therapy
* Strategies for inducing and maintaining the response
* The role of ed treatment in improving long-term outcomes
* Indications for retreatment with interferon

Abstract:

Interferon therapy has been used to treat chronic hepatitis C (formerly NANB) for more than ten years but the optimum regimen has not been yet defined. While the International Consensus suggests the use of 3 MU thrice weekly for at least 12 months as “standard” schedule for chronic hepatitis C, with an expected rate of sustained response between 15% and 25%, there is emerging evidence that other, more aggressive schedules may improve these results. Recent data indicate that virologic resistance or escape during the early phase of treatment are the major determinants of therapy failures.
Daily administration of interferon during the early “induction” phase may reduce the number of such failures being superior to tiw administration in inducing a more stable virologic response. On the other hand, several randomized trials and meta-analysis of published studies have clearly proven that extension of interferon therapy for at least 12 months is essential to reduce the risk of relapse after withdrawal of interferon. Thus, the rate of sustained response may be improved by using a higher initial dose to induce the response and a ed period of treatment to minimize the risk of relapse. In our own randomized trials, the use of 6 MU tiw for four to six months, followed by 3 MU to complete 12 months of treatment was superior to a fixed schedule of 3 MU tiw for 12 months as to long-term biochemical, virological and histological outcomes. Four years after therapy patients treated with this schedule showed a statistically significant reduction in progression to cirrhosis and in hepatic decompensation compared to cases treated with less aggressive schedules. The benefit of using this high dose regimen was more evidenced in patients infected with HCV-1 and in cases with more advanced liver disease. These observations and the preliminary results of an ongoing randomized trial would suggest that the treatment schedule (as to initial dose and total dose and duration) may be tailored according to pretreatment features. Prolonged interferon therapy was not associated with sustained response in patients remaining HCV-RNA positive after three months of treatment. In these cases some histologic improvement was observed at the end of therapy but this effect was not maintained after withdrawal suggesting that in these patients interferon monotherapy has only a suppressive effect on disease activity, and should be used on a long-term basis, according to clinical indications.

Retreatment with interferon was attempted in patients who had not achieved a permanent response with a first course of therapy. Retreatment was not effective in previous non-responders, independent of the schedule used. On the other hand, retreatment for at least 12 months induced a sustained response in 40% of patients who had relapsed after a six month course of interferon, indicating that ed retreatment may result in permanent cure in a significant proportion of such cases.

References:

1. Poynard T, Bedossa P, Chevallier M, et al. A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. Multicenter Study Group. N Engl J Med 1995;332(22):1457-62.
2. Reichard O, Foberg U, Fryden A, et al. High sustained response rate and clearance of viremia in chronic hepatitis C after treatment with interferon-alpha-2b for 60 weeks. Hepatology 1994;19:280-5.
3. Chemello L, Bonetti P, Cavalletto L, et al. Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C.
Hepatology 1995;22:700-6.
4. Kasahara A, Hayashi N, Hiramatsu N, et al. Ability of ed
interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: a multicenter randomized controlled trial. Hepatology 1995;21:291-7.
5. Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon recombinant trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996;24:778-89.
6. Alberti A, Chemello L, De Salvo GL, et al. Retreatment with alpha interferon of chronic hepatitis C. Hepatology (in press).
From: Update on Liver Disease and Hepatitis Conference June 1997

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