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

• HBeAg loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBeAg loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Time to HBsAg loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Time to HBsAg loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• ALT <45 IU/L for men, <30 IU/L for women (approximately 1.5 ULN) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• ALT <45 IU/L for men, <30 IU/L for women (approximately 1.5 ULN) [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• ALT normalization (men <30 IU/L, women <20 IU/L) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• ALT normalization (men <30 IU/L, women <20 IU/L) [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• HBV DNA ≤1000 IU/mL [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBV DNA ≤1000 IU/mL [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• HBV DNA <20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBV DNA <20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 96 ] [ Designated as safety issue: No ]

• Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBeAg) seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Time to hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Normalization of Alanine Transaminase (ALT) levels [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Proportion with hepatitis B DNA [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  ≤1000 IU/mL
• Proportion with hepatitis B DNA <20 IU/mL [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBeAg) seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Time to hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Normalization of Alanine Transaminase (ALT) levels [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Proportion with hepatitis B DNA [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  ≤1000 IU/mL
• Proportion with hepatitis B DNA <20 IU/mL [ Time Frame: at week 96 ] [ Designated as safety issue: No ]

The investigators propose to evaluate the safety and efficacy of a short lead-in course (8 weeks) of entecavir followed by combination of entecavir plus peginterferon alfa-2a for 40 weeks. The investigators hypothesize that using a potent nucleos(t)ide analogue will provide a higher rate of loss of HBeAg loss and suppression of HBV DNA.

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 are in the immune tolerant phase.

To evaluate "off treatment" sustained responses after treatment with entecavir and peginterferon alfa-2a in the treatment of chronic hepatitis B in HBeAg positive adults who are in the immune tolerant phase.

A randomized (1:1) controlled trial of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon alfa-2a in adults with HBeAg-positive chronic hepatitis B with normal or near normal ALT levels and high serum levels of HBV DNA ("immune tolerant" HBeAg-positive chronic hepatitis B) compared to no treatment. A similar study will be conducted in children. Participants in this adult study will be stratified according to age (18-30, >30-40) and center. All participants will be followed until week 96 (48 weeks after discontinuation of therapy in the treatment group) at which time the primary outcome will be measured.

• Experimental: Peginterferon and entecavir
  A combination of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon.
  Intervention: Drug: Entecavir and peginterferon
• No Intervention: Control

Inclusion Criteria:

• Enrolled in and completed the baseline evaluation for NCT01263587.

  ->18 years of age at time of randomization (day 0). Patients >50 years of age at randomization will need to have a liver biopsy as standard of care with HAI ≤3 and Ishak fibrosis score ≤1 within 24 weeks prior to randomization.

• Documented chronic HBV infection as evidenced by detection of HBsAg in serum for ≥24 weeks prior to randomization OR at least one positive HBsAg and negative anti-HBc IgM within 24 weeks prior to randomization.
• Presence of HBeAg in serum at the last screening visit within 6 weeks of randomization AND ≥24 weeks prior to randomization.
• Serum HBV DNA level >107 IU/mL on at least two occasions at least 12 weeks apart during the 52 weeks before randomization. One of the two HBV DNA levels should be from the last of the screening visits.
• ALT levels persistently ≤60 IU/L in males, ≤40 IU/L in females (approximately 2.0 times the upper limit of normal [ULN] range) as documented by at least three values: one taken 24-52 weeks before randomization, one taken 6 to 24 weeks before randomization, and the final value within 6 weeks prior to randomization. For patients with one of three ALT values between 61-90 in males and 41-60 in females, a biopsy done as standard of care with HAI ≤3 and Ishak fibrosis score ≤1 within 24 weeks prior to randomization is required.
• No evidence of HCC based upon alpha-fetoprotein (AFP) ≤20 ng/mL at the screening visit (up to 6 weeks prior to randomization (Participants who meet AASLD criteria for HCC surveillance must have negative liver imaging as shown by ultrasound, computerized tomography or magnetic resonance imaging within 24 weeks prior to randomization as part of standard of care and Participants with AFP >20 ng/mL must be evaluated clinically with additional imaging and shown not to have HCC on CT or MRI before they can be randomized).

Exclusion Criteria:

• History of hepatic decompensation
• Evidence of decompensated liver disease prior to or during screening, including direct bilirubin >0.5 mg/dL, INR >1.5, or serum albumin <3.5 g/dL.
• Platelet count <120,000/mm3, hemoglobin <13 g/dl (males) or <12 g/dl (females), absolute neutrophil count < 1500 /mm3 (<1000/mm3 for African-Americans) at the last screening visit.
• Previous treatment with medications that have established activity against HBV including, but not limited to, interferon and nucleos(t)ide analogs ≥24 weeks. Patients with <24 weeks of prior HBV treatment and a wash-out period >24 weeks are not excluded.
• Known allergy or intolerance to study medications.
• Females who are pregnant or breastfeeding. Females of childbearing potential unable or unwilling to use a reliable method of contraception during the treatment period.
• Renal insufficiency with calculated creatinine clearance <50 mL/min at screening.
• History of alcohol or drug abuse within 48 weeks of randomization.
• Previous organ or bone marrow transplant
• Any other concomitant liver disease, including hepatitis C or D. Non-alcoholic fatty liver disease (NAFLD) with steatosis and/or mild to moderate steatohepatitis is acceptable but NALFD with severe steatohepatitis is exclusionary.
• Presence of anti-HDV or anti-HCV (unless HCV RNA negative) in serum on any occasion in the 96 weeks prior to randomization. Presence of anti-HIV (test to be completed within 6 weeks prior to randomization).
• Pre-existing psychiatric condition(s), including, but not limited to: current moderate or severe depression, history of depression requiring hospitalization within the past 10 years history of suicidal or homicidal attempt within the past 10 years, history of severe psychiatric disorders as determined by a study physician.
• History of immune-mediated or cerebrovascular disease, chronic pulmonary or cardiac disease associated with functional limitation, retinopathy, uncontrolled thyroid disease, poorly controlled diabetes or uncontrolled seizure disorder, as determined by a study physician.
• Any medical condition that would, in the opinion of a study physician, be predicted to be exacerbated by therapy or that would limit study participation.
• Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids or other immunosuppressive medications during the course of this study.
• Evidence of active or suspected malignancy, or a history of malignancy within the 144 weeks prior to randomization (except adequately treated carcinoma in situ or basal cell carcinoma of the skin).
• Expected need for ongoing use of any antivirals with activity against HBV during the course of the study.
• Concomitant use of complementary or alternative medications purported to have antiviral activity.
• Participation in any other clinical trial involving investigational drugs within 30 days of randomization or intention to participate in another clinical trial involving investigational drugs during participation in this study.