By Liz Highleyman

Pegylated interferon alfa is approved for the treatment of both chronic hepatitis B and C. When used to treat hepatitis C, the standard of care calls for it to be combined with ribavirin, which has been shown to reduce the risk of relapse after completing therapy and improve the odds of achieving sustained virological response (SVR).

In a poster presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers reported results from a study assessing whether addition of ribavirin improves response in hepatitis B patients.

Individuals with hepatitis B "e" antigen (HBeAg) negative chronic hepatitis B are at particularly high risk of viral relapse after discontinuing antiviral therapy, which, in addition to pegylated interferon, may also include oral agents such as lamivudine (Epivir-HBV), adefovir (Hepsera), entecavir (Baraclude), telbivudine (Tyzeka), and tenofovir (Viread).

The investigators suggested that the combination of pegylated interferon alfa plus ribavirin might be more effective than pegylated interferon alone or in combination with the aforementioned nucleoside/nucelotide analogs, because ribavirin not only inhibits viral replication by interfering with viral messenger RNA, but also plays a role in modulating the immune response to HBV.

In an international multicenter trial, 133 HBeAg negative chronic hepatitis B patients were randomly assigned to receive 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus either 1000-1200 mg/day ribavirin or placebo for 48 weeks (the same regimen as the chronic hepatitis C standard of care). Patients were followed for 24 weeks after completing treatment to assess SVR. Liver biopsies were performed at baseline and week 72.

Baseline characteristics were similar in the 2 treatment arms. About three-quarters were men, the mean age was 42 years, and most (80%) had HBV genotype D.

Results

• Using an intent-to-treat analysis, end-of-treatment (EOT) and sustained response rates were similar in the pegylated interferon/ribavirin and pegylated interferon/placebo arms:

• HBV DNA < 10,000 copies/mL at week 48 (EOT): 55% in the ribavirin arm vs 67% in the placebo arm;

• HBV DNA < 400 copies/mL at week 48 (EOT): 28% vs 52%, respectively (P < 0.005).

• HBV DNA < 10,000 copies/mL at week 72 (SVR): 19% vs 20%, respectively.

• HBV DNA < 400 copies/mL at week 72 (SVR): 6% vs 9%, respectively.

• ALT normalization occurred in about 52% of patients in the ribavirin arm at both 48 and 72 weeks, compared with 41% in the placebo arm.

• Looking at a composite response endpoint, the rates were 41% with ribavirin and 36% with placebo at week 48, and 16% and 20%, respectively, at week 72.

• Hepatitis B surface antigen (HBsAg) seroconversion occurred in 1 patient (1.6%) receiving ribavirin and none receiving placebo.

• A > 2 point decrease in Ishak necroinflammatory score was observed in 49% of patients in the ribavirin arm and 53% in the placebo arm.

• A > 1 point decrease in Ishak fibrosis score occurred in 26% and 31%, respectively.

• Similar proportions of patients prematurely discontinued treatment or follow-up in both arms.

• Except for the < 400 copies/mL results at week 48 -- which indicated that ribavirin worked less well than placebo -- none of the differences between treatment arms reached statistical significance.

Based on these findings, the investigators concluded that, "For HBeAg negative chronic hepatitis B the addition of ribavirin to pegylated interferon alfa-2a for 48 weeks of treatment did not improve response rates compared to pegylated interferon alfa-2a monotherapy."

Other studies have shown, however, than combining pegylated interferon with one of the directly targeted anti-HBV agents can lead to better response rates.

Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Istanbul University Medical School, Istanbul, Turkey; Medical University of Vienna, Vienna, Austria; Istanbul University Cerrahpasa Medical School, Istanbul, Turkey; Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey; Medical University Wroclaw, Wroclaw, Poland; Aristotle University of Thessaloniki, Thessaloniki, Greece; Ankara University School of Medicine, Ankara, Turkey.

11/14/08

Reference
HL Janssen; V Rijckborst, Y Cakaloglu, and others. 48 Weeks of Peginterferon Alfa-2a alone or in Combination with Ribavirin for HBeAg-negative Chronic Hepatitis B: Addition of Ribavirin does not improve Response Rates. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 991.