• Analysis of 40KDA Peginterferon Alfa-2a (Pegasys) in Combination with Ribavirin, Mycophenolate Mofetil, Amantadine or Amantadine Plus Ribavirin in Patients That Relapsed or Did Not Respond to Rebetron Therapy: A Report of Two Randomized Mulitcenter Efficacy and Safety Studies
  Authored by Nezam Afdhal, et al.

The development of long-acting, or pegylated, interferon represents a significant advance in the treatment of viral hepatitis. However, it has become apparent that pegylated interferon is most effective in treating hepatitis C infection when used in combination with ribavirin in treatment-naive patients. The role of pegylated interferon in the treatment of patients who have previously failed antiviral therapy is controversial.

The combination of pegylated interferon with other antivirals, such as amantadine, may enhance efficacy with potentially less side effects. Based on its mechanism of action, mycophenolate mofetil may be synergistic with pegylated interferon in the treatment of hepatitis C infection. While mycophenolate mofetil does not have direct antiviral activity, it inhibits the same enzyme as ribavirin and hypothetically could enhance interferon's antiviral activity. The use of these novel agents in combination with pegylated interferon may achieve viral remission in patients with hepatitis C infection who previously failed conventional therapy with interferon alone or combination interferon plus ribavirin.

At the 52nd Annual meeting of the American Association for the Study of Liver Diseases, Dr. Nezam Afdhal, from the Beth Israel Deaconess Medical Center in Boston, presented interim results of clinical research looking at the efficacy of pegylated interferon alfa-2a (Pegasys) in combination with ribavirin, amantadine or amantadine + ribavirin. The patients enrolled in this study had previously been treated with interferon monotherapy or combination interferon + ribavirin for at least 12 weeks and failed to achieve a sustained response. The results presented at this meeting represent end-of-treatment data; sustained viral response data is not yet available.

Enrolled patients were labelled as either non-responders or relapsers to prior antiviral therapy and were randomly allocated to one of four treatment groups:

1. pegylated interferon alfa-2a 180µg weekly plus 800 to 1,000mg of ribavirin based on weight;

2. pegylated interferon alfa-2a 180µg weekly plus mycophenolate mofetil 1g twice a day;

3. pegylated interferon alfa-2a 180µg weekly plus amantadine 100mg twice a day; or

4. pegylated interferon alfa-2a, ribavirin 800-1,000mg daily and amantadine 100mg twice a day.

Patients were treated for 48 weeks. However, those who were virus positive at 24 weeks were considered treatment failures and their treatment was discontinued.

Virologic response during treatment, and at the end of treatment (week 48), among patients who previously failed antiviral therapy was as follows:

These results indicate that the addition of amantadine to pegylated interferon alfa-2a does not benefit patients who previously failed or relapsed after antiviral therapy. The addition of mycophenolate mofetil to pegylated interferon alfa-2a appears to achieve similar results as the combination of ribavirin and pegylated interferon alfa-2a. The fewer number of patients withdrawing from the group receiving mycophenolate mofetil, compared to the ribavirin group, suggests that the combination of mycophenolate mofetil and Pegasys may be better tolerated than ribavirin and Pegasys. Finally, the use of triple therapy (Pegasys, amantadine and ribavirin) achieved a better end-of-treatment virologic response among patients who had failed prior antiviral therapy. This difference was not noted in the prior relapse group.

There are several limitations to this paper that must be discussed. The results reported here are only end-of-treatment responses and not sustained viral responses. It is unknown how many of these patients will relapse once therapy is discontinued. The enhanced antiviral effect of triple therapy may disappear if most of these patients relapse after therapy. In addition, only about 30 patients were randomized to each group; this relatively small number of patients increases the chance that the results may not be representative of what can be achieved among a larger number of patients.

We look forward to the final results of this study which will probably be available in February or March of 2002. In the meantime, these results demonstrate that patients who have failed prior therapy may benefit from retreatment with pegylated interferon alfa-2a in combination with ribavirin, mycophenolate mofetil or triple therapy. Larger studies looking at triple therapy will be needed before we can adopt this approach as a treatment for hepatitis C infection.

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