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TITLE: "A New Approach to HCV Therapy: Results with Interferon alfa-2b and Ribavirin in Patients Who Failed to Respond to Interferon"

AUTHOR: Michael P. Manns, MDProfessor of Medicine, Department of Gastroenterology and HepatologyHannover Medical School, Germany; SOURCE: 1998 Update on Liver Disease and Hepatitis Conference

Learning Objectives:
Retreatment of relapse patients with chronic hepatitis C with interferon alpha-2b and ribavirin results in sustained response rates up to 50% of patients

Retreatment of patients who failed to respond to interferon with the standard regime of 3 MU interferon alpha-2b for 6 months in combination with ribavirin is successful only in very small proportion of patientsNew treatment options are urgently needed for primarynon-responders.

Abstract: Interferon alpha-2b (IFN) monotherapy has resulted in sustained response rates of only 10% to 25% of patients with hepatitis C. Retreatment of primary non-responders with IFN alone is unsuccessful in most cases. Pilot studies of retreatment for relapsed patients with interferon alpha-2b in combination with ribavirin were very promising, but efficacy of combination therapy in primary non-responders is discussed controversially. Brillanti and coworkers reported in 1994 the successful retreatment of interferon relapse in a small group of patients. Other small studies from Italy and Sweden confirmed these results. Therefore, in the spring of 1996, a placebo controlled, international multicenter trial of retreatment of interferon relapse in chronic hepatitis C was started. A total of 345 patients were enrolled at 52 study sites. Patients were treated with interferon alpha-2b tiw in combination with ribavirin (1000/1200 mg per day) or placebo for six months. Follow up was six months. At the completion of treatment, HCV RNA was undetectable in 82% of patients receiving combination therapy and 47% of those treated with IFN-placebo (p less than 0.001). HCV remained undetectable at the end of follow up in 49% of the combination group, but in only 5% of the IFN alone group (p less than 0.001). HCV RNA level and viral genotype influenced response to combination therapy. Histological improvement occurred in both treatment groups, but was greater after combination therapy and was associated with loss of HCV RNA. The first pilot studies of retreatment of primary non-responder with IFN and ribavirin were published in 1995. Schvarz and coworkers reported therapy of 10 patients with IFN and ribavirin for six months.

Four patients had biochemical and virological end of treatment (EOT) response, three of those were HCV-RNA negative during follow up of 24 weeks. In 1997, a meta-analysis of individual patient data from European centers was published by Schalm and coworkers. This study included 42 previous non-responders receiving combination therapy. Sustained response rates were seen in 19% of the patients. On the other hand, there had been multiple smaller studies, describing response rates upon retreatment of primary non-responders of less than 10%. Most of these studies were presented in abstract form at the AASLD 1997 in Chicago and at the EASL 1998 in Lisbon. Overall, we analysed data on 517 patients. In general, the treatment regime was interferon alpha-2b 3 MU tiw for six months in combination with ribavirin in a dose of 1000 mg or 1200 mg per day. With this approach, an end-of-treatment response could be achieved in 39.6%, whereas sustained response was reported for only 26 out of 379 patients (6.9%). Prolonged therapy up to 12 months or increasing the dose of interferon alpha-2b to 6 MU tiw did not markedly improve the results.

Alternative approaches for non-responders might be high dose interferon induction therapy (10 MU QD) in combination with ribavirin or triple therapy with IFN, ribavirin and amantadine. Large trials are needed or already ongoing to confirm the efficacy and safety of these treatment options. The combination results in a fall in hemoglobin which requires close monitoring, but otherwise has a safety profile similar to interferon alone.

Conclusions: Combination therapy of interferon alpha-2b and ribavirin is highly effective in relapse patients with chronic hepatitis C and increases sustained response rates nearly 10-fold. 49% of patients were still HCV-RNA negative after six months of follow up in this group of patients. In contrast to naive and relapse patients, combination therapy of interferon alpha-2b and ribavirin in patients previously not responding to interferon alone is successful only in a very small proportion of patients. The standard interferon regime (3 MU tiw for 6 months) is not recommended as a regular therapy for non-responders.

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