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Adding pegylated interferon to entecavir improves hepatitis B treatment response

Liz Highleyman
13 December 2012
Milan Sonneveld, Erasmus University Medical Centre, Rotterdam © Liz Highleyman /

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 presentation at The Liver Meeting 2012, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) last month in Boston. A related study found that hepatitis B surface antigen (HBsAg) levels during treatment can predict response.

Nucleoside/nucleotide analogue antiviral drugs are standard treatment for chronic hepatitis B. They perform well at lowering HBV viral load, but only a minority of patients have serological response including HBeAg and HBsAg loss or seroconversion.

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.



An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.


A shortage of neutrophils, a type of white blood cell that fights bacterial infections.


A low level of platelets in the blood. In people with hepatitis, this may be due to cirrhosis or interferon treatment.

Milan Sonneveld from Erasmus University Medical Centre in Rotterdam and the ARES study team conducted a controlled trial that enrolled 184 HBeAg-positive participants 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 0.5mg/day entecavir monotherapy for 48 weeks. The other group received the same dose of entecavir, but after 24 weeks of monotherapy they added 180mcg/week pegylated interferon alfa-2a (Pegasys) and continued on triple therapy through to week 48.

At 48 weeks, 74% of participants in the entecavir monotherapy group and 83% in the interferon add-on group achieved HBV DNA below 200 IU/mL, but the difference did not reach statistical significance; 53 and 61%, respectively, reached HBV viral load below 20 IU/mL, again not significant.

Fewer than half as many people in the entecavir-only group experienced HBeAg loss than in the add-on group (8 vs 18%), which fell just short of statistical significance (P=0.07).

The only factors independently associated with combined virological and serological response in a multivariate analysis were lower HBsAg level at baseline and addition of pegylated interferon, which nearly quadrupled the likelihood of response (odds ratio=3.78). 

Adding pegylated interferon to entecavir was generally safe, though it led to increased side-effects. Five people experienced serious adverse events, including three with 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 and two people developed severe neutropenia while on pegylated interferon. No one in either treatment group developed anaemia.

"Addition of pegylated interferon alfa-2a to entecavir monotherapy increases HBV DNA, HBeAg, and HBsAg decline," the researchers 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 at 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.

The researchers noted as background that several factors are associated with response to interferon, including HBV genotype, baseline viral load, ALT level and possibly IL28B gene variants, which 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 by-product of viral replication – so serum HBsAg levels during treatment may predict sustained response.

This pooled analysis included 803 participants in three trials. Treatment response was defined as both virological response (HBV DNA below 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 had HBV genotype C, followed by 25% with genotype B. For treatment, 58% used pegylated interferon monotherapy while the rest used pegylated interferon plus lamivudine (Epivir).

HBsAg decline during treatment varied strongly according to HBV genotype, with genotype 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 all genotypes, however, the researchers observed that responders had sustained lower HBsAg levels than non-responders, whose levels returned nearly to baseline values after finishinging treatment. 

At 12 weeks, both HBsAg level and HBsAg decline predicted treatment response. There were 45% of patients with HBsAg <1500 IU/mL, 22% with HBsAg 1500-20,000 IU/mL and 6% with HBsAg >20,000 IU/mL who went on to experience combined response six months post-treatment.

Overall, people who experienced HBsAg decline at 12 weeks were about twice as likely to achieve combined response (26 vs 14%, respectively). 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 combined response than HBsAg decline. There were 46% of participants with HBsAg <1500 IU/mL, 16% with HBsAg 1500 to 20,000 IU/mL and only 3% with HBsAg >20,000 IU/mL who experienced combined response six months after finishing treatment.

Again, people who experienced HBsAg decline at 24 weeks were about twice as likely to achieve combined response (25 vs 12%, respectively). But at this time point, negative predictive values were 96% for HBV genotype A and 100% for genotypes B, C and D, so genotype-specific stopping rules were not necessary.

Overall, the researchers concluded that the chances of combined response were best for people with HBsAg below 20,000 IU/mL at week 24 of treatment, supporting a stopping rule that all patients with HBsAg above 20,000 IU/mL at that point should discontinue treatment.


Sonneveld M 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 Disease, Boston, abstract 19, 2012.

Sonneveld M 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 Disease, Boston, abstract 23, 2012.

View the abstracts on the conference website.