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AASLD 2012: Adding Pegylated Interferon to Entecavir Improves HBV Treatment Response


Intensifying entecavir (Baraclude) treatment for hepatitis B by adding pegylated interferon lowers HBV viral load and increases the likelihood of hepatitis B "e" antigen (HBeAg) loss, according to a report at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) last month in Boston. A related study found that hepatitis B surface antigen (HBsAg) levels during treatment can be used to predict response to interferon.

Nucleoside/nucleotideanalog antivirals that interfere with the hepatitis B virus (HBV) lifecycle are standard treatment for chronic hepatitis B. They perform well for lowering HBV DNA levels, but serological response, including HBeAg and HBsAg loss or seroconversion, occurs in only a minority of patients.

Interferon -- long the mainstay of hepatitis C treatment -- stimulates the natural immune response against viral infections and may contribute to improved outcomes for hepatitis B as well.

Milan Sonneveld from Erasmus University Medical Center in Rotterdam and the ARES study team conducted a controlled trial that enrolled 184 HBeAg positive patients with compensated liver disease at 15 sites in Europe and China. About 60% were of Asian ethnicity and all major HBV genotypes were represented.

One group was randomly assigned to take 0.5 mg/day entecavir monotherapy for 48 weeks; the other group received the same dose of entecavir, but after 24 weeks of monotherapy they added 180 mcg/week pegylated interferon alfa-2a (Pegasys) and continued on triple therapy through week 48.


  • 74% of participants in the entecavir monotherapy group and 83% in the interferon add-on group achieved HBV DNA < 200 IU/mL, but the difference did not reach statistical significance
  • 53% and 61%, respectively, reached HBV viral load > 20 IU/mL, again not a significant difference.
  • 8% of patients the entecavir-only group and 18% in the add-on group experienced HBeAg loss, which just missed being significant (P=0.068).
  • In a multivariate analysis, the only factors independently associated with combined response were:

o   HBsAg level at baseline: odds ratio 0.42, indicating that a lower level raised the likelihood of response;

o   Addition of pegylated interferon: odds ratio 3.78, or nearly quadruple the likelihood of response.

  • Adding pegylated interferon to entecavir was generally safe and well-tolerated.
  • 5 people experienced serious adverse events, including 3 ALT flares during the entecavir monotherapy phase.
  • Neutropenia (0% vs 23%) and thrombocytopenia (0% vs 8%) were significantly more common in the add-on group compared with the monotherapy group; no one in either arm developed anemia.
  • 2 people developed severe neutropenia while on pegylated interferon.

"Addition of pegylated interferon alfa-2a to entecavir monotherapy increases HBV DNA, HBeAg, and HBsAg decline," the reseachers concluded. "Addition of pegylated interferon alfa-2a to potent [nucleoside/nucleotide] analogue therapy may increase chances of finite therapy."

HBsAg Response-guided Therapy

In another presentation during the same oral session, Sonneveld described findings from a study of response-guided interferon therapy using stopping rules based on HBsAg levels (< 1500, 1500-20,00 or > 20,000 IU/mL) or HBsAg decline (yes or no) at 12 and 24 weeks.

As background, the researchers noted that several factors are associated with response to interferon treatment, including HBV genotype, baseline viral load, ALT level, and possibly variants of the IL28B gene, which plays a role in interferon responsiveness and predict response to interferon-based therapy for hepatitis C. Serum HBsAg levels appear to reflect the amount of covalently closed circular DNA(cccDNA) in the liver, a byproduct of viral replication.

This pooled analysis included 803 participants in 3 trials. Treatment response was defined as a combination of HBV DNA < 200 IU/mL and HBsAg loss at 24 weeks after the end of treatment. A majority of patients (75%) were men and about 80% were Asian. Nearly half (48%) had HBV genotype C, followed by 25% with genotype B. 58% used pegylated interferon monotherapy while the rest used pegylated interferon plus lamivudine (Epivir-HBV).


  • HBsAg decline varied strongly according to HBV genotype, with A showing the greatest decline followed by B, C, and D, in that order.
  • In all cases HBsAg levels were lowest at the end of treatment and then started to rise again, but did not reach baseline levels by the end of follow-up.
  • Across genotypes, however, the researchers observed that responders had a sustained lower HBsAg level than non-responders, whose HBsAg returned to near baseline after completing treatment.
  • At 12 weeks, both HBsAg level and HBsAg decline predicted 6-month post-treatment combined response rates:

o   45% with HBsAg < 1500 IU/mL;

o   22% with HBsAg 1500-20,000 IU/mL;

o   6% with HBsAg > 20,000 IU/mL

o   26% with HBsAg decline at 12 weeks;

o   14% with no HBsAg decline at 12 weeks.

  • However, the predictive value of the stopping rules varied by HBV genotype, necessitating genotype-specific algorithms at week 12.
  • At 24 weeks, HBsAg level was a better predictor of response than HBsAg decline:

o   46% with HBsAg < 1500 IU/mL;

o   16% with HBsAg 1500-20,000 Iu/mL;

o   3% with HBsAg > 20,000 IU/mL

o   25% with HBsAg decline at 12 weeks;

o   12% with no HBsAg decline at 12 weeks.

  • Week 24 negative predictive values were 96% for HBV genotype A and 100% for genotypes B, C, and D, so genotype-specific rules are not necessary.

Overall, the best stopping rule was HBsAg > 20,000 IU/mL at week 24 of treatment, supporting a recommendation that all patients with HBsAg > 20,000 IU/mL at that point should discontinue treatment.



MJ Sonneveld, Q Xie, N-P Zhang, et al. Adding peginterferon alfa-2a to entecavir increases HBsAg decline and HBeAg clearance - first results from a global randomized trial (ARES study). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 19.

MJ Sonneveld, BE Hansen, T Piratvisuth, et al. Response-guided peginterferon therapy in HBeAg-positive chronic hepatitis B using serum hepatitis B surface antigen levels: a pooled analysis of 803 patients. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 23.