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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 prolonged 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
prolonged 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 prolonged
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 prolonged
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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