Interferon Alfa-2b Alone or in Combination With
Ribavirin as Initial Treatment for Chronic Hepatitis C
[Medscape Gastroenterology, 1999]
Abstract
John G. McHutchison, Stuart C. Gordon, Eugene R. Schiff,
Mitchell L. Shiffman, William M. Lee, Vinod K. Rustgi, Zachary D.
Goodman, Mei- Hsiu Ling, Susannah Cort, Janice K. Albrecht, for the
Hepatitis Interventional Therapy Group. N Engl J Med
339(21):1485-1492, November 19, 1998
Background
Only 15 to 20 percent of patients with chronic hepatitis C have a
sustained virologic response to interferon therapy. We compared the
efficacy and safety of recombinant interferon alfa-2b alone with
those of a combination of interferon alfa-2b and ribavirin for the
initial treatment of patients with chronic hepatitis C.
Methods
We randomly assigned 912 patients with chronic hepatitis C to
receive standard-dose interferon alfa-2b alone or in combination
with ribavirin (1000 or 1200 mg orally per day, depending on body
weight) for 24 or 48 weeks. Efficacy was assessed by measurements
of serum hepatitis C virus (HCV) RNA and serum aminotransferases
and by liver biopsy.
Results
The rate of sustained virologic response (defined as an
undetectable serum HCV RNA level 24 weeks after treatment was
completed) was higher among patients who received combination
therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48
weeks (87 of 228 patients, 38 percent) than among patients who
received interferon alone for either 24 weeks (13 of 231 patients,
6 percent) or 48 weeks (29 of 225 patients, 13 percent) (P less
than 0.001 for the comparison of interferon alone with both 24
weeks and 48 weeks of combination treatment). Among patients with
HCV genotype 1 infection, the best response occurred in those who
were treated for 48 weeks with interferon and ribavirin. Histologic
improvement was more common in patients who were treated with
combination therapy for either 24 weeks (57 percent) or 48 weeks
(61 percent) than in those who were treated with interferon alone
for either 24 weeks (44 percent) or 48 weeks (41 percent). The drug
doses had to be reduced and treatment discontinued more often in
patients who were treated with combination therapy. Conclusions: In
patients with chronic hepatitis C, initial therapy with interferon
and ribavirin was more effective than treatment with interferon
alone.
Expert Commentary
An increasing number of patients infected with hepatitis C virus
are being identified in the US. The treatment for patients with
ongoing liver injury caused by the virus (as defined by elevated
liver transaminases, detectable viral RNA in the blood, or
inflammatory activity on liver biopsy) has been with interferon 3
million units injected three times a week. If the therapy is
continued for a year, about 10%-15% of patients will have a
sustained virologic response (no detectable viral RNA in the blood
6 months after completion of therapy). Most of these patients that
have sustained responses to the treatment will maintain the
responses indefinitely and demonstrate histologic improvements on
liver biopsy. However, because there is such a low response rate,
important factors have been identified to predict a favorable
response. These factors are non-genotype 1 (about 30% sustained
response rate), low serum viral RNA level (less than 2 million
copies/mL), and absence of cirrhosis. In the US, 75%- 80% of
hepatitis C patients are infected with HCV genotype 1 and the
average viral load is approximately 2.9 million copies/mL, thus
explaining the low response rate. There are many clinical trials
evaluating better therapies for hepatitis C, and this present study
is the result of a large multicenter randomized, controlled trial
using interferon and ribavirin combined as initial treatment for
chronic hepatitis C.
Methods. Nine hundred and twelve patients with chronic hepatitis
C who had never received treatment were randomized to treatment
with either interferon alfa-2b alone (INF; Intron A,
Schering-Plough, Kenilworth, NJ) or in combination with ribavirin
(Rebetron, Schering- Plough) for 24 or 48 weeks. Efficacy was
assessed by measurement of serum hepatitis C RNA and transaminases
and also by liver biopsy.
Results. The overall sustained response rates for the four
treatment arms showed that interferon combined with ribavirin had
response rates 3-5 times higher than interferon alone (see Table I,
below). Although the response rates were similar for combination
therapy given for 24 weeks versus 48 weeks overall (31% versus
38%), there were subgroups of patients who had higher response
rates with 48 weeks of treatment.
Table I SUSTAINED RESPONSE
INF INF + Ribavirin INF INF + Ribavirin
24 wk. 24 wk. 48 wk. 48 wk.
13/231 70/228 29/225 87/228
6% 31% 13% 38%
In patients with HCV genotype 1, the sustained response rate was
higher when treated with combination therapy for 48 weeks than for
24 weeks (28% versus 16%). In patients with high viral load, a
slightly higher response rate occurred in those who were treated
with combination therapy for 48 weeks than in those treated for 24
weeks (36% versus 27%). In patients with cirrhosis, combination
treatment for 48 weeks had a higher response rate than treatment
for 24 weeks (38% versus 29%).
Conclusion. The authors concluded that in patients with chronic
hepatitis C, combination therapy with interferon and ribavirin is
more effective than initial therapy with interferon alone.
In an editorial in the same issue, Dr T. Jake Liang of the
National Institutes of Health addressed two different issues
arising from the study. In previous studies of interferon treatment
for hepatitis C, most of the patients who had sustained responses
had an early viral RNA clearance after initiating interferon
therapy. Currently, most physicians treating patients with
hepatitis C would agree that detectable viral RNA after 12 weeks of
interferon therapy is evidence of no response to treatment, and
that in these cases therapy should be terminated to decrease
morbidity and cost. Interestingly, McHutchison and colleagues found
that up to 50% of the sustained responders in both the interferon
alone and the combination therapy treatment groups had a late viral
clearance (after 12 or 24 weeks). These findings need to be
considered and re-examined in order to determine the duration of
therapy given before patients are considered nonresponders.
The other question is the duration of combination therapy. The
same group of patients who had factors associated with poor
response to interferon alone (genotype 1, high viral load,
cirrhosis) had improved response rates with longer combination
therapy (48 weeks). However, the toxicity and side effects of
combination therapy caused 21% of patients in the 48-week treatment
group to withdraw. These potential adverse events need to be
considered and discussed at length with each patient before
starting therapy.
This study along with many previous smaller studies clearly
shows that interferon and ribavirin together have much better
results than interferon alone for hepatitis C. The FDA has also
recently approved this regimen as initial therapy. We would like to
propose an algorithm to help select the least toxic and costly
treatment for each patient. All patients will have genotype, viral
load, and the presence/absence of cirrhosis determined prior to
treatment. Patients with genotype 1 or high viral load or the
presence of cirrhosis who have no contraindications for treatment
should receive interferon and ribavirin combination therapy as
initial treatment; if the viral RNA becomes undetectable after 24
weeks, therapy should continue for 48 weeks unless intolerable side
effects occur. Patients without these factors should receive
interferon alone for 12 weeks, and if viral RNA is detectable at 12
weeks, these patients should be switched to combination therapy
with ribavirin for 24 weeks.
We are anxiously awaiting better therapy that includes improved
response rates along with less toxicity and side effects.
Preliminary data with consensus interferon induction therapy may
offer a hopeful alternative; perhaps clinical trials using
consensus interferon along with ribavirin or other antiviral agents
will be forthcoming.
Gloria Sze, MD; Assistant Professor
Viktor Eysselein, MD; Professor of Medicine, and Chief Division of
Gastroenterology; Harbor-UCLA Medical Center; Torrance, Calif.
Home | What is HCV | Transmission |
Future |
Complications |
Biopsy |
Treatment
| Lab |
Nutrition |
Patient |
Links | Transplant |
Webrings |
guestbookbook |
Awards |
FAQ
|