Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults with Chronic Hepatitis B (HBRN Immune Tolerant A)

General Description

The Hepatitis B Research Network Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults with Chronic Hepatitis B (HBRN Immune Tolerant A) study sought to determine the efficacy of treatment with 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon in the treatment of chronic hepatitis B in hepatitis B “e” antigen (HBeAg) positive adults who were in the immune tolerant phase. Additionally, the study evaluated the safety and sustained responses after treatment with entecavir and peginterferon alfa-2a in the treatment of chronic hepatitis B in HBeAg positive adults in the immune tolerant phase.

Objectives

The study’s primary objective was to evaluate the safety and efficacy of treatment with a combination of entecavir plus peginterferon alfa-2a in immune-tolerant adults with chronic hepatitis B.

Outcome Measure

The primary outcome measures for evaluation of drug efficacy were HBeAg loss (lack of detectable HBeAg) and HBV DNA levels ≤1,000 IU/mL at 96 weeks. The number, type, and rate of adverse or serious events through end of treatment at 48 weeks and end of follow-up at 96 weeks were assessed as the primary outcome measures for safety. Secondary outcome measures, evaluated at 48 and 96 weeks, included hepatitis B surface antigen (HBsAg) loss, HBeAg loss, HBeAg seroconversion, alanine aminotransferase (ALT) levels, and HBV DNA levels

Criteria

Individuals of at least 18 years of age who met the following criteria were eligible for the study:

• Enrolled in the HBRN Adult Cohort Study or completed necessary components of the cohort baseline evaluation.
• Documented chronic hepatitis B infection, as evidenced by detection of HBsAg in serum for ≥24 weeks prior to baseline visit OR at least one positive HBsAg & negative anti-HBc IgM within 24 weeks prior to baseline visit OR at least one positive HBsAg & two positive HBV DNA over a period of ≥24 weeks prior to baseline visit.
• Presence of HBeAg in serum at last screening visit within 6 weeks of baseline visit.
• Serum HBV DNA level >10˄7 IU/mL on at least two occasions at least 12 weeks apart during the 52 weeks before baseline visit. One of the two HBV DNA levels must be within 6 weeks of baseline visit.
• ALT levels persistently ≤45 IU/L in males, ≤30 IU/L in females (approx. 1.5 times the upper limit of normal [ULN] range) as documented by at least three values: one taken 28-52 weeks before baseline visit, one taken 6 to 24 weeks before the baseline visit, & the final value within 6 weeks prior to baseline visit.
• No evidence of hepatocellular carcinoma (HCC)

Exclusion criteria are documented in the study protocol.

Outcome

At 48 weeks post end of treatment, no participants met the primary endpoint of both HBeAg loss and HBV DNA ≤1,000 IU/mL and HBV DNA rebounded to baseline levels in all participants while ALT values returned to near baseline levels in all but four participants. The lead-in treatment strategy of 8 weeks of entecavir followed by combination peginterferon and entecavir for 40 weeks had limited efficacy in adults in the immune tolerant phase of chronic hepatitis B infection.