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

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 safety and 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 single arm treatment study 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 alanine aminotransferase (ALT) levels and high serum levels of hepatitis B virus
(HBV) DNA ("immune tolerant" HBeAg-positive chronic hepatitis B). All participants followed
for 48 weeks after treatment discontinuation (week 96 for those who completed treatment).

Inclusion Criteria:

- Enrolled in & completed the baseline evaluation for NCT01263587 or completed the
necessary components of NCT01263587 by the end of baseline visit.

- >18 years of age at the baseline visit (day 0). Patients >50 years of age at baseline
will need to have a liver biopsy as standard of care with hepatic activity index (HAI)
≤3 & Ishak fibrosis score ≤1 within 96 weeks prior to baseline visit.

- Documented chronic HBV infection as evidenced by detection of HBsAg in serum for ≥24
weeks prior to baseline visit OR at least one positive HBsAg & negative anti-hepatitis
B core (HBc) immunoglobulin (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 U/L in males, ≤30 U/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) based upon alpha-fetoprotein (AFP) ≤20
ng/mL at screening visit (up to 6 weeks prior to baseline visit). a. Participants who
meet American Association for the Study of Liver Diseases (AASLD) criteria for HCC
surveillance must have negative liver imaging as shown by ultrasound, computerized
tomography (CT) or magnetic resonance imaging (MRI) within 28 weeks prior to baseline
visit. b. Participants with AFP >20 ng/mL must be evaluated clinically with additional
imaging & shown not to have HCC on CT or MRI before they can be enrolled.

Exclusion Criteria:

- History of hepatic decompensation

- Evidence of decompensated liver disease prior to or during screening, including direct
bilirubin >0.5 mg/dL, international normalization ratio (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 last
screening visit.

- Previous treatment with medications that have established activity against HBV
including interferon & nucleos(t)ide analogs ≥24 weeks. Patients with <24 weeks of
prior HBV treatment & 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 baseline visit.

- Previous liver or other organ transplantation (including engrafted bone marrow).

- Any other concomitant liver disease, including hepatitis C or D. Non-alcoholic fatty
liver disease (NAFLD) with steatosis &/or mild to moderate steatohepatitis is
acceptable but NAFLD with severe steatohepatitis is exclusionary.

- Presence of anti-hepatitis D virus (HDV) or anti-hepatitis C virus (HCV) (unless HCV
RNA negative) in serum on any occasion in the 144 weeks prior to baseline visit.
Presence of anti-HIV (test completed within 6 weeks prior to baseline visit).

- 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 baseline visit (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 the baseline visit or intention to participate in another clinical trial
involving investigational drugs during participation in this study.