Entecavir and Peginterferon for Immune-Tolerant Adults With Chronic Hepatitis B

Adult patients with chronic hepatitis B who are in the immuntolerant phase of the disease
(characterized by high HBV DNA level, HBeAg positivity and normal ALT level) will be
enrolled in a multicenter study to evaluate the efficacy of treatment with 8 weeks of
entecavir followed by 40 weeks of both entecavir and peginterferon alfa-2a. Eligible
subjects must be enrolled in the Hepatitis B Research Network Cohort Study, be between 18
and 40 years of age and HBeAg positive for at least 24 weeks prior to enrollment with an ALT
level < 1.5 times the upper limit of normal and HBV DNA level > 107 IU/ml. Subjects who
qualify for enrollment will be randomized to receive 8 weeks of entecavir followed by 40
weeks of both entecavir and peginterferon alfa-2a or no therapy. Participants in this 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.

The primary outcome will be to compare the efficacy of combination therapy of entecavir and
peginterferon alfa-2a versus no treatment in achieving HBeAg loss (lack of detectable HBeAg)
and HBV DNA levels less than or equal to 1000 IU/mL 48 weeks after stopping therapy.
Secondary outcomes will be to evaluate off treatment sustained virological, serological
and biochemical responses.

The 13 participating sites will enroll 250 patients. The Liver Diseases Branch will plan to
enroll up to 20 patients. There will be an almost identical study performed in the pediatric
population. This will be an important study to define whether patients with chronic
hepatitis B in the immune tolerant phase of the disease will benefit from therapy.

- INCLUSION CRITERIA:

1. Enrolled in and completed the baseline evaluation for the Hepatitis B Research
Network (HBRN) Cohort Study.

2. 18-40 years of age at time of randomization (day 0).

3. Documented chronic HBV infection as evidenced by detection of HBsAg in serum for
greater than or equal to 24 weeks prior to randomization OR at least one
positive HBsAg and negative anti-HBc

IgM within 24 weeks prior to randomization.

4. Presence of HBeAg in serum at the last screening visit within 6 weeks of
randomization AND greater than or equal to 24 weeks prior to randomization.

5. Serum HBV DNA level > 107 IU/mL on at least two occasions at least 12 weeks
apart during the 48 weeks before randomization. One of the two HBV DNA levels
should be from the last of the screening visits (within 6 weeks of
randomization).

6. ALT levels persistently less thanor equal to 60 IU/L in males, less thanor equal
to 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 24-48 weeks before
randomization, one taken 6 to 24 weeks before randomization, and the final value
within 6 weeks prior to randomization AND a biopsy done as standard of care with
HAI less thanor equal to 3 and Ishak fibrosis score less thanor equal to 1
within 24 weeks prior to randomization.

No biopsy is required if ALT levels are persistently less than or equal to 45
IU/L in males, less than or equal to 30 IU/L in females (approximately 1.5 times
the upper limit of the normal [ULN] range) as documented by at least three
values: one taken 24-48 weeks before randomization, one taken 6 to 24 weeks
before randomization, and the final value within 6 weeks prior to randomization.

7. No evidence of HCC based upon alpha-fetoprotein (AFP) less than or equal to 20
ng/mL at the screening visit (up to 6 weeks prior to randomization):

1. Participants who meet AASLD criteria for HCC surveillance must have
negative liver imaging as shown by ultrasound (US), computerized tomography
(CT) or magnetic resonance imaging (MRI) within 24 weeks prior to
randomization as part of standard of care.

2. 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.

8. Provide informed consent and agree to adhere to the requirements of the study.

EXCLUSION CRITERIA:

1. History of hepatic decompensation, including but not limited to ascites, variceal
bleeding, or hepatic encephalopathy.

2. 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.

3. 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.

4. Previous treatment with medications that have established activity against HBV
including, but not limited to, interferon and nucleos(t)ide analogs. Brief and
episodic use of famciclovir or valacyclovir for herpes infection is not exclusionary.

5. Known allergy or intolerance to any of the study medications.

6. Females who are pregnant or breastfeeding.

7. Females of childbearing potential unable or unwilling to use a reliable method of
contraception during the treatment period.

8. Renal insufficiency with calculated creatinine clearance < 50 mL/min at the last
screening visit.

9. History of alcohol or drug abuse within 48 weeks of randomization.

10. Previous liver or other organ transplantation including engrafted bone marrow
transplant.

11. 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.

12. Presence of anti-HDV or anti-HCV (unless HCV RNA negative) in serum on any occasion
in the 96 weeks prior to randomization.

13. Presence of anti-HIV (test to be completed within 6 weeks prior to randomization).

14. Pre-existing psychiatric condition(s), including, but not limited to:

1. Current moderate or severe depression as determined by the study physician

2. History of depression requiring hospitalization within past 10 years

3. History of suicidal or homicidal attempt within the past 10 years

4. History of severe psychiatric disorders including, but not limited to
schizophrenia, psychosis, bipolar disorder as determined by a study physician.

15. 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.

16. 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.

17. Any medical condition requiring, or likely to require, chronic systemic
administration of corticosteroids or other immunosuppressive medications during the
course of this study.

18. 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).

19. Expected need for ongoing use of any antivirals with activity against HBV during the
course of the study.

20. Concomitant use of complementary or alternative medications purported to have
antiviral activity.

21. 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.

22. Any other condition or situation that in the opinion of a study physician would make
the participant unsuitable for enrollment or could interfere with the participant
participating in and completing the study.