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Peginterferon Alfa-2b and Ribavirin for 12 versus 24 Weeks in HCV Infection
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     To the Editor: Mangia and coworkers (June 23 issue)1 report that the course of combination therapy can be shortened from 24 to 12 weeks with minimal loss of efficacy in patients infected with hepatitis C virus (HCV) genotype 2 or 3 who have early clearance of HCV RNA. Nevertheless, three issues should be considered before these findings in patients in Italy can be extrapolated to U.S. patients.

    First, the study used doses of peginterferon alfa-2b (1.0 μg per kilogram of body weight per week) and ribavirin (1000 or 1200 mg daily) that differ from those usually recommended in the United States (1.5 μg per kilogram per week and 800 mg daily, respectively).2 Second, the results of this treatment for hepatitis C are usually better in European settings than in U.S. settings. In a Food and Drug Administration analysis of the use of peginterferon and ribavirin, sustained response rates were 49 percent in U.S. centers as compared with 57 percent in non-U.S. centers, and the difference was not attributable to known confounding factors (e.g., HCV genotype, body-mass index, sex, or race).3,4 Finally, patients in this study have features more favorable for a response than typical U.S. cohorts: the average body-mass index (the weight in kilograms divided by the square of the height in meters) was 25 to 26, half of the patients were women, and all were white. In typical U.S. studies, the average body-mass index is 29 to 30, two thirds are men, and blacks are included.5 Before recommendations are made for these easy-to-treat patients, U.S. experience with an abbreviated course of therapy would be helpful.

    Brian B. Borg, M.D.

    Jay H. Hoofnagle, M.D.

    National Institute of Diabetes and Digestive and Kidney Diseases

    Bethesda, MD 20892

    References

    Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609-2617.

    Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147-1171.

    Biologic license supplement: peginterferon -2b and ribavirin for treatment of chronic hepatitis C. December 20, 2001. (Accessed August 26, 2005, at http://www.fda.gov/ohrms/dockets/ac/01/slides/3819s1_01_cber/index.htm.)

    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982.

    Shiffman ML, Di Bisceglie AD, Lindsay KL, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126:1015-1023.

    To the Editor: Mangia et al. provide evidence that infection with HCV genotype 2 can be treated with a 12-week course of peginterferon and ribavirin, provided that serum HCV RNA is undetectable in the serum at 4 weeks, with results as good as those achieved with the current standard 24-week course. Halving the course of therapy will allow significant cost savings and spare patients months of debilitating side effects. Results in patients infected with HCV genotype 3, however, are less impressive. The 23 percent difference in sustained response rates (100 percent with 24 weeks of therapy vs. 77 percent with 12 weeks) and nonoverlapping confidence intervals belie the authors' conclusion that patients with genotype 3 infection (and undetectable HCV RNA at 4 weeks) do not require 24 weeks of therapy. Although this study provides sufficient impetus for me to offer patients with genotype 2 infection a 12-week course of therapy if serum HCV RNA is undetectable at week 4, patients with HCV genotype 3 infection would appear to be best served with a 24-week course. Further studies are needed.

    Michael J. Henry, M.D.

    Gundersen Lutheran

    La Crosse, WI 54601

    mjhenry@gundluth.org

    The authors reply: We agree with Drs. Borg and Hoofnagle that before truncated courses of therapy for HCV genotype 2 or 3 can be recommended, more studies are needed, especially in U.S. cohorts of patients with demographic characteristics that differ from those of Italian patients. They correctly remark on our treatment regimen, in which the doses of both peginterferon alfa-2b and ribavirin differed from those usually recommended (1.0 μg per kilogram per week vs. the usual recommended dose of 1.5 μg per kilogram per week and 1000 mg or 1200 mg daily vs. 800 mg daily, respectively). As we mention in our report,1 in the registration trial by Manns et al.2 the benefit of a high-dose regimen was most apparent in patients with HCV genotype 1 infection, whereas those with HCV genotype 2 or 3 had similar response rates with high-dose and low-dose regimens of peginterferon alfa-2b. Furthermore, an uncontrolled study in Norway recently found favorable rates of sustained virologic response in patients with a rapid response (at four weeks) with the use of the recommended dose of 1.5 μg per kilogram per week in combination with ribavirin (800 to 1200 mg).3 Finally, in pooled data from the Italian and Norwegian3 studies on shortened treatment of patients infected with HCV genotype 2 or 3, the dose of peginterferon alfa-2b was not significantly associated with either rapid or sustained virologic response. Consequently, we are confident that these patients may be safely treated with low doses of peginterferon alfa-2b, even for a short period (12 to 14 weeks).

    Dr. Henry's perception that patients infected with HCV genotype 3 would be best served by a 24-week course of antiviral treatment is derived from the 100 percent rate of sustained virologic response after 24 weeks of therapy as compared with 77 percent after 12 weeks. However, only 17 patients infected with HCV genotype 3 received the standard 24-week course in our study, and these numbers should be cited with caution. In a German study of shortened treatment with peginterferon alfa-2a and ribavirin, the rate of sustained virologic response was 93 percent among patients with HCV genotype 3 infection who had a rapid response (at week 4) and who were treated for a period of 16 weeks and 84 percent among those who were treated for 24 weeks.4 Therefore, even patients infected with HCV genotype 3 who are HCV RNA–negative at week 4 may be safely treated with a short-duration regimen. Conversely, patients infected with HCV genotype 3 in whom viremia persists at week 4 of therapy may be candidates for more than 24 weeks of therapy, because the rate of sustained virologic response in such patients is as low as 46 percent.

    Alessandra Mangia, M.D.

    Angelo Andriulli, M.D.

    Casa Sollievo della Sofferenza Hospital

    71013 San Giovanni Rotondo, Italy

    a.mangia@tin.it

    References

    Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609-2617.

    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-965.

    Dalgard O, Bjoro K, Hellum KB, et al. Treatment with pegylated interferon and ribavirin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004;40:1260-1265.

    von Wagner M, Huber M, Berg T, et al. Peginterferon-alpha-2a (40kd) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005;129:522-527.