AASLD 2014: Pegylated Interferon + Tenofovir Improves Odds of HBsAg Loss in Hepatitis B Patients

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People with chronic hepatitis B virus (HBV) infection are more likely to experience favorable treatment response, as indicated by hepatitis B surface antigen (HBsAg) loss, if they add pegylated interferon to tenofovir -- although even then the cure rate falls short of 10%, researchers reported at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting this week in Boston.

Antiviral therapy using nucleoside/nucleotide analogs such as tenofovir (Viread) or entecavir (Baraclude) is the mainstay of hepatitis B treatment. While antivirals are effective at suppressing HBV viral load over the long term, they rarely lead to a cure, indicated by the loss of hepatitis B surface antigen and seroconversion, or development of anti-HBs antibodies. Several studies have looked at combining antivirals with pegylated interferon -- which stimulates the body's natural immune responses against HBV -- but results have been inconsistent.

Hepatitis B is difficult to cure because bits of HBV DNA can integrate into the genome of liver cells (although HBV does not insert a full set of viral genetic instructions into latent cells, as HIV does). Interferon is better known as the standard treatment for hepatitis C before the arrival of highly effective direct-acting antivirals. Since HCV does not integrate its genetic material into host cells, it is now possible to cure hepatitis C with a combination of potent oral antivirals taken for as little as 8 weeks without interferon, which often causes difficult side effects.

Joerg Petersen from the University of Hamburg, on behalf of an international team of collaborators, presented findings from a study of tenofovir plus pegylated interferon alfa-2a (Pegasys or PegIntron) for chronic hepatitis B, with the primary endpoint being HBsAg loss with a finite course of treatment. Unlike most previous research, this large trial was adequately powered to compare outcomes that occur in only a small proportion of patients.

This open-label study enrolled a total of 740 people with chronic hepatitis B. 60% were hepatitis B "e" antigen (HBeAg) positive -- which is somewhat easier to treat -- while the rest were HBeAg negative. About two-thirds were men, three-quarters were Asian, and the mean age was approximately 37 years. The HBV genotype distribution reflected a largely Asian population, with most having genotype C (43%), B (28%), or D (21%). The mean baseline HBV DNA level was approximately 7.0 log IU/ml and the mean HBsAg level was about 3.9 log IU/ml. People with advanced bridging fibrosis or cirrhosis were excluded.

Participants were randomly assigned to received one of the following regimens:

Petersen reported results after 72 weeks of follow-up; patients will continue to be followed through 120 weeks. People in the arms that stopped treatment at week 48 could restart tenofovir after completing their assigned therapy if they met certain safety criteria.

HBsAg Loss

Other Endpoints

Safety

"Combination therapy with [tenofovir] plus [pegylated interferon] for 48 weeks led to higher rates of HBsAg loss compared with either monotherapy in chronic hepatitis B patients without cirrhosis," the researchers concluded. They suggested that "consolidation therapy" after HBsAg loss may be important for maintaining responses.

While outcomes were clearly better with extended tenofovir plus pegylated interferon compared with either taken alone, the desired response of HBsAg loss remained unlikely.

"At the end of the day, is 7.3% that good -- is it worth the effort?" asked AASLD president Adrian di Bisceglie, who chose this as one of a dozen Liver Meeting presentations highlighted at his opening press conference. "The answer is it may be, but the real answer is we need new treatments for hepatitis B."

Di Bisceglie also noted that people with hepatitis B "on average seen to tolerate pegylated interferon better" than those with hepatitis C, though we don't understand why.

11/14/14

Reference

P Marcellin, S-H Ahn, X Ma, J Petersen, et al. HBsAg Loss With Tenofovir Disoproxil Fumarate Plus Peginterferon Alfa-2a in Chronic Hepatitis B: Results of a Global Randomized Controlled Trial. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract 193.