Miriam E. Tucker

April 17, 2014

LONDON, United Kingdom — Adding pegylated interferon to nucleos(t)ide analog therapy boosts viral decline and response rates in patients with hepatitis B e antigen-positive chronic hepatitis B, the results of a global randomized trial suggest.

In the 14-center, investigator-initiated, 96-week ARES trial, the addition of peginterferon alpha-2a to the nucleos(t)ide analog entecavir resulted in higher hepatitis B e antigen and surface antigen response rates than entecavir monotherapy.

"Peginterferon add-on appeared to prevent relapse and may, therefore, facilitate the discontinuation of nucleos(t)ide analog therapy," said Willem Pieter Brouwer, MD, from the Department of Gastroenterology and Hepatology at the Erasmus MC University Medical Center in Rotterdam, the Netherlands.

The results of the trial were presented here at the European Association for the Study of the Liver (EASL) International Liver Congress 2014.

Hepatitis B is a major cause of hepatocellular cancer worldwide, and is responsible for up to 75% of hepatocellular cancer cases in the Far East and in sub-Saharan Africa. Although entecavir is a potent nucleos(t)ide analog that maintains viral suppression in more than 90% of patients during continuous therapy, the majority of patients relapse after stopping treatment.

"Hepatitis B surface antigen loss is achieved in only approximately 10% of patients during nucleos(t)ide analog treatment; therefore, newer treatment strategies are required," Dr. Brouwer said.

Sustained Response

The ARES study involved 185 treatment-naïve adults with hepatitis B e antigen-positive chronic hepatitis B and compensated liver disease, and with alanine aminotransferase (ALT) levels more than 1.3 times the upper limit of normal. After 24 weeks of entecavir monotherapy, the remaining 182 patients were randomized to receive add-on peginterferon therapy or to continue receiving entecavir monotherapy.

About two-thirds of the cohort was Asian and about one-third white, 70% was male, and mean age was 32 years. Of the cohort, 7% had hepatitis B genotype A, 19% had genotype B, 42% had genotype C, and 32% had genotype D.

The primary end point — hepatitis B e antigen loss with HBV DNA below 200 IU/mL at week 48 — was achieved by more patients in the add-on group than in the monotherapy group, but did not quite reach statistical significance (19% vs 10%; P = 0.095).

However, in a prespecified multivariate analysis adjusted for differences in HBV DNA at the start of the randomized therapy phase, add-on peginterferon was significantly associated with a 4.78-fold increase in response rate (P = .004).

Patients who responded to therapy at 48 weeks continued on entecavir for another 6 months and then stopped all treatment at week 72. Nonresponders continued on entecavir for another year.

At 96 weeks, the decline in hepatitis B surface antigen was greater in the add-on group than in the monotherapy group (P = .001), as was the decline in e antigen (P = .009) and HBV DNA (P = .087). Significantly more patients in the add-on group achieved hepatitis B e antigen seroconversion and an HBV DNA level below 200 IU/mL (24% vs 11%; P = .029).

In addition, more patients in the add-on group than in the monotherapy group achieved hepatitis B surface antigen levels below 1000 IU/mL (26% vs 14; P = .059).

Response at week 96 was also better in the add-on group (31% vs. 20%; P = .107). On multivariate analysis, after adjustment for the difference in HBV DNA levels at 24 weeks, it reached statistical significance (odds ratio, 3.07; P = .007).

This suggests that the "peginterferon add-on is independently associated with response at 96 weeks," Dr. Brouwer reported.

Sustained off-treatment response was also better with add-on peginterferon. Immune control (hepatitis B e antigen-negative, normal serum ALT, and HBV DNA below 2000 IU/mL) was better in the 14 patients in the add-on group who stopped treatment at 72 weeks than in the monotherapy group (79% vs 25%).

Tolerability of Peginterferon

The combination therapy was generally well tolerated. As expected, grade 3 adverse events were slightly more common in the add-on group than in the monotherapy group, including neutropenia (28% vs 0%; P < .001) and leukopenia (9% vs 0%; P = .003).

Only 8 patients experienced severe adverse events. Two were cases of severe (grade 4) neutropenia in the add-on group. The other 6 were either numerically greater in the monotherapy group or were not related to treatment, Dr. Brouwer reported.

During the press briefing, Cihan Yurdaydin, MD, chief of the Hepatology Institute at the University of Ankara Medical School in Turkey, and EASL governing board member, was asked to explain why adding peginterferon is desirable in hepatitis B but is being phased out of treatment regimens for hepatitis C.

"In hepatitis C, we have the luxury of getting rid of peginterferon," he said. "If we had that same luxury in hepatitis B, we certainly would do it. We don't have that."

Direct-acting antivirals specific to the hepatitis C life cycle don't work in hepatitis B, and it's far more difficult to develop them for hepatitis B, Dr. Yurdaydin explained. Peginterferon, in contrast, works nonspecifically on the immune system, so it works for both types of hepatitis.

To date, there no clinical studies of direct-acting antivirals for hepatitis B, he added. "There are other studies, but it is unlikely there will be the robust effect you see in hepatitis C."

Cost Savings

Discontinuing nucleos(t)ide analog therapy could save money, particularly in countries where governments don't adequately reimburse for hepatitis B treatment, Dr. Yurdaydin pointed out.

"With nucleos(t)ide analogs, you have a very effective treatment, but you have to continue, continue, continue — and that means cost. If there is any way to shorten treatment duration, it would be very important," he said.

The ARES study was sponsored and initiated by the Rotterdam Foundation for Liver Research, with financial support from Bristol-Myers Squibb and Roche Diagnostics. Dr. Brouwer has disclosed no relevant financial relationships. Dr. Yurdaydin reports receiving consulting and speaker fees from Roche and Gilead.

European Association for the Study of the Liver (EASL) International Liver Congress 2014: Abstract 3: Presented April 10, 2014.

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