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Interferon Alfa-2b Alone or in Combination With Ribavirin as Initial Treatment for Chronic Hepatitis C
[Medscape Gastroenterology, 1999]

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

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.

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.

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.

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