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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