Early HBsAg Decline Predicts Sustained Response to Pegylated Interferon; Extended Treatment Can Improve Outcomes

SUMMARY: Chronic hepatitis B patients who experience an early decrease in hepatitis B surface antigen (HBsAg) starting before week 24 of therapy are more likely to achieve sustained response to pegylated interferon alfa-2a (Pegasys), according to an analysis presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) this month in Boston. Another study showed that extending pegylated interferon treatment to 72 weeks for hepatitis B "e" antigen (HBeAg) positive patients who did not achieve a response at week 48 could lead to HBeAg seroconversion and HBsAg clearance.

By Liz Highleyman

Two types of treatment are approved for chronic hepatitis B: directly targeted oral antiviral agents such as lamivudine (Epivir-HBV), and conventional or pegylated interferon, which stimulate immune response to HBV.

M.R. Brunetto and a team of European colleagues investigated patterns of on-treatment HBsAg decline in patients with HBeAg negative chronic hepatitis B treated with pegylated interferon, with or without lamivudine, and their influence on post-treatment sustained response rates.

A 48-week course of pegylated interferon alfa-2a produces on-treatment reduction of serum HBsAg in chronic hepatitis B patients, the researchers noted as background. Since HBsAg decline is associated with sustained response, monitoring on-treatment HBsAg levels might help identify patients most likely to benefit from this therapeutic approach.

The investigators measured quantitative serum HBsAg levels at baseline and at weeks 12, 24, 48, and 72 in patients treated with 180 mcg/week pegylated interferon alfa-2a for 48 weeks, with or without 100 mg once-daily lamivudine. Post-treatment response was assessed at 6 months in 155 patients and at 5 years in 120 patients who entered a long-term observational study. HBsAg decline was defined as a 10% reduction from baseline level.

Results

	52% of patients experienced a continuous HBsAg decline from baseline to week 24 and to week 48.
	16% experienced no HBsAg decline at week 24, but had a late decline by week 48.
	5% were relapsers, experiencing HBsAg decline at week 24 but not at week 48.
	29% experienced no HBsAg decline at week 24 or at week 48.
	The overall sustained virological response rate at 6 months post-treatment was 45%.
	Virological response was highest in patients with continuous (60%) or late (48%) HBsAg decline, compared with HBsAg relapse (29%) or no decline (20%).
	At 5 years post-treatment, virological response was more durable among patients with continuous decline (38%) compared with late decline (21%), relapse (17%), or no decline (9%).
	24% of patients with continuous decline, 10% with late decline, 17% with relapse, and 0% with no decline achieved HBsAg clearance at 5 years.

"On-treatment HBsAg decline is associated with sustained post-treatment response to Pegasys with highest response rates in those with continuous decline in HBsAg levels," the investigators concluded.

"Long-term post-treatment response appeared to be less durable in patients with late HBsAg decline starting after week 24; however some patients with a late decline achieved HBsAg clearance," they added.

Based on these findings, they recommended, "Further studies are warranted to determine if patients with a late HBsAg decline may benefit from extending Pegasys treatment beyond the standard 48-week course."

UO Epatologia, Azienda Ospedaliero Pisana, Pisa, Italy; Service d'Hepatologie and Centre de Recherches Biologiques Beaujon, University of Paris, Clichy, France; Direzione Scientifica, Foundation IRCCS, Policlinico di Milano and University of Pisa, Pisa, Italy; Abbott GmbH & Co, Wiesbaden, Germany; IST GmbH , Mannheim, Germany; Hoffman-La Roche Ltd, Basel, Switzerland.

Extended Therapy

In a related study, X.P. Chen from China assessed the potential benefits of extending pegylated interferon therapy to 72 weeks in chronic hepatitis B patients who did not respond after 48 weeks of treatment.

In this open-label study, 67 HBeAg positive patients with normal or mildly elevated ALT were randomly assigned to receive either 180 mcg/week pegylated interferon alfa-2a for 48 weeks or the oral antiviral drug entecavir (Baraclude) at 0.5 mg/day for 72 weeks.

A total of 12 patients in the pegylated interferon arm who did not achieve HBeAg seroconversion, HBV DNA < 1000 copies/mL, or HBsAg < 1500 IU/mL by week 48 continued on the same regimen for a further 24 weeks (for a total of 72 weeks).

Results

	At week 72, 44% of patients in the pegylated interferon arm achieved HBeAg seroconversion, compared with 18% in the entecavir arm.
	15% and 3%, respectively, experienced HBsAg clearance.
	72 week HBeAg seroconversion response rates were higher among pegylated interferon recipients with elevated baseline ALT compared than among those with normal ALT (52% vs 23%, respectively).
	High rates of HBeAg seroconversion were observed in patients with HBsAg < 1500 IU/mL at weeks 12 and 24 (75% and 67%, respectively).

"Pegasys was superior to entecavir in achieving HBeAg seroconversion and HBsAg clearance at week 72," the investigators concluded. "Patients without a response to pegylated interferon at week 48 achieved HBeAg seroconversion and HBsAg clearance when therapy was extended."

Guangdong Academy of Medical Science, Guangdong General Hospital, Guangzhou, China.

11/17/09

References

MR Brunetto, P Marcellin, F Bonino, and others. HBsAg decline in HBeAg-negative patients treated with peginterferon alfa-2a is associated with sustained response up to 5 years post-treatment: patients with continuous HBsAg decline starting before week 24 achieve highest rates of response. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 452.

XP Chen, X Chen, J Huang, and others. Extending peginterferon alfa-2a therapy in patients with HBeAg-positive chronic hepatitis B who did not achieve a response at week 48 can lead to HBeAg seroconversion and HBsAg clearance. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 410.