Hepatitis - Treatment of the Non responder

Non response to antiviral therapy is defined as the persistence of detectable HCV RNA throughout therapy, with detectable serum HCV RNA at the end of the therapeutic course. The sustained response to re-treatment of non responders to any form of antiviral therapy has been disappointing.

Re-treatment of non responders to IFN mono therapy was evaluated in several small studies. In the consensus interferon trial, non responders to IFN mon otherapy showed a 13% sustained virologic response rate at 48 weeks of therapy with IFN-alfa con-1. The use of combination IFN and ribavirin therapy in FN non responders has resulted in sustained response rates ranging from 0% to 15%. Of interest, a recent trial reported a 42% sustained response to intravenous recombinant IFN-bEIA in previous IFN non responders.

Approximately 60% of all patients treated with combination IFN and ribavirin are non responders. The approach to this group represents a growing challenge to the treating clinician. Although it seems reasonable that higher doses of IEN plus ribavirin or a weight-based system of ribavirin dosing should improve response to treatment in these patients, there are little if any published data to support such an approach. The peginterferons may, however, prove useful in combination with IFN and ribavirin, and clinical trials designed to test this notion are currently ongoing.

Virologic non responders to antiviral therapy may derive some benefit from re-treatment that is aimed at preventing histologic disease progression. Patients with underlying bridging fibrosis or cirrhosis are at a greater risk for developing complications of cirrhosis than are those without fibrosis. In addition to its antiviral effect, IFN was shown to have anti proliferative and anti fibrotic activity through its down regulation of transforming growth factor b. Recent studies showed improvement in underlying histology in non responders to antiviral therapy. Several studies have also demonstrated a significant reduction in the relative risk of developing HCC among non responders to IFN mono therapy.

These studies have brought the issue of IFN maintenance therapy for prevention of fibrotic progression to the fore. Shiffman and colleagues’95’ reported that a 2-year course of IFN mono therapy administered to non responders stabilized fibrosis and improved inflammation on serial biopsies. This concept has now led to the launch of a National Institutes of Health-sponsored trial -- the Hepatitis C Antiviral Long-term Treatment against Cirrhosis or HALT-C trial -- to evaluate the effect of long-term peginterferon-alfa2a therapy in patients with advanced fibrosis or cirrhosis who did not respond to combination pegylated IEN plus ribavirin.