By Liz Highleyman

Standard therapies for chronic hepatitis B include a number of direct-acting oral antiviral drugs including lamivudine (Epivir-HBV), entecavir (Baraclude), and tenofovir (Viread), as well as pegylated interferon alfa-2a (Pegasys). The oral drugs are better tolerated and generally suppress HBV viral load better than pegylated interferon, but are less likely to produce serological response (loss of HBeAg or hepatitis surface B antigen [HBsAg]) and must be taken for a longer time. Although treatment for chronic hepatitis C virus requires combination therapy with pegylated interferon plus ribavirin, the latter drug is not typically used for hepatitis B.

Vincent Rijckborst and fellow investigators with the PARC Study Group designed a trial to assess whether adding ribavirin might reduce the high rate of relapse among HBeAg negative chronic hepatitis B patients treated with pegylated interferon.

The analysis included 138 participants who were randomly assigned to receive either 180?mcg/week pegylated interferon alfa-2a monotherapy with placebo, or else combination therapy with the same dose of pegylated interferon plus 1000-1200 mg/day weight-adjusted ribavirin for 48 weeks -- the same regimen used for genotype 1 or 4 chronic hepatitis C. About 80% of participants had HBV genotype D, which some studies have shown does not responds as well to interferon as other genotypes.

Participants were followed for 24 weeks after completion of therapy to see if they achieved a combined sustained response, defined as HBV DNA < 10,000?copies/mL (or < 1714?IU/mL) and normalized alanine aminotransferase (ALT). The modified intention-to-treat population included 133 patients after 5 were excluded from the analysis.

Results

	At the end of treatment, combined response rates were 36% in the pegylated interferon monotherapy group and 41% in the pegylated interferon/ribavirin combination therapy group, not a significant difference (P = 0.60).
	Post-treatment relapse was common in both treatment groups.
	At the end of follow-up, combined sustained response rates were 20% in the pegylated interferon monotherapy group and 16% in the combination therapy group, again not a significant difference (P = 0.49).
	Looking at HBV viral load alone, only about 8% of participants overall achieved sustained undetectable HBV DNA (< 400 copies/mL)
	Both groups experienced decreases in HBV DNA (mean change -3.9 vs -2.66 log copies/mL, respectively) and a small reduction in HBsAg (-0.56 vs -0.34 log IU/mL, respectively).
	HBV DNA rebounded after treatment ended, but HBsAg remained at end-of-treatment levels.
	No patients experienced HBsAg loss, indicating clearance of infection.
	Pegylated interferon/ribavirin combination therapy was generally well-tolerated, but was associated with a higher rate of anemia and neutropenia compared with pegylated interferon alone.

"Treatment with peginterferon alfa-2a resulted in a limited sustained response rate in HBeAg negative chronic hepatitis B patients," the study authors concluded. "Addition of ribavirin did not improve response to therapy."
"Pegylated interferon...has been recommended as a first-line therapy for [HBeAg] negative chronic hepatitis B; however, data supporting this recommendation are derived from a single randomized controlled trial," wrote Jules Dienstag from Harvard Medical School in an accompanying editorial. "This study challenges the value and limits the appeal of pegylated interferon therapy for HBeAg negative chronic hepatitis B."

"Ultimately, this important trial...in HBeAg negative chronic hepatitis B not only shows a lack of efficacy for the addition of ribavirin to pegylated interferon, but also challenges the entire premise that pegylated interferon should remain a first-line treatment for this category of chronic hepatitis B," he continued. "For both HBeAg reactive and negative chronic hepatitis B, the limited added efficacy of pegylated interferon over oral agents, its higher cost and resource consumption, and its substantially poorer tolerability all together reduce its appeal as treatment, let alone as a first-line choice."

Investigator Affiliations: Department f Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands; Department of Gastroenterohepatology, Istanbul University Medical School, Istanbul, Turkey; Department of Internal Medicine 3, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Department of Infectious Diseases, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey; Department of Gastroenterology, Turkiye Yuksek lhtisas Hospital, Ankara, Turkey; Department and Clinic of Infectious Diseases, Hepatology and Acquired Immune Deficiences, Medical University Wroclaw, Wroclaw, Poland; Second Medical Department, Aristototle University of Thessaloniki, Thessaloniki, Greece; Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey; Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, Netherlands; Department of Epidemiology and Biostatistics, Erasmus MC, University Medical Center, Rotterdam, Netherlands.

9/17/10

References

V Rijckborst, MJ ter Borg, Y Cakaloglu, and others (PARC Study Group). A Randomized Trial of Peginterferon ?-2a With or Without Ribavirin for HBeAg-Negative Chronic Hepatitis B. American Journal of Gastroenterology 105(8): 1762-1769 (Abstract). August 2010.

J Dienstag. Peginterferon Therapy for HBeAg-Negative Chronic Hepatitis B: Less Than Meets the Eye (Editorial). American Journal of Gastroenterology 105(8): 1770-1772 (Free full text). August 2010.