Tenofovir DF With or Without Peginterferon for Chronic Hepatitis B

This is a randomized (1:1) parallel group design trial comparing (i) tenofovir DF 300 mg
daily for 192 weeks (4 years) and (ii) peginterferon alfa-2a 180 micrograms/g weekly for 24
weeks plus tenofovir DF 300 mg daily for 192 weeks (4 years). Enrolled participants will be
stratified by HBeAg status (positive/negative), genotype (A vs. all others) and cirrhosis
(present vs. absent). After 192 weeks of treatment, participants meeting criteria for
treatment discontinuation will stop treatment and be followed for 48 weeks (total duration
of treatment and follow up is 240 weeks). A liver biopsy will be obtained at the end-of
treatment (week 180-192) to assess improvement in histology. Emtricitabine/tenofovir
coformulated as Truvada, approved for treating HIV but not for treating HBV infection, will
be offered to participants with primary nonresponse, partial virological response or
confirmed virologic breakthrough.

- INCLUSION CRITERIA:

1. Enrolled in the Hepatitis B Research Network (HBRN) Cohort Study or completed
the necessary components of the Cohort baseline evaluation by the end of the
baseline visit for this study.

2. At least 18 years of age at the time of randomization (day 0).

3. Chronic HBV infection as evidenced by at least one of the following:

1. HBsAg positive result within 8 weeks prior to randomization and another
time at least 24 weeks prior to randomization with no HBsAg negative result
in between.

2. HBsAg positive plus absence of detectable anti-HBc IgM in serum within 8
weeks prior to randomization.

3. HBsAg positive within 8 weeks prior to randomization and HBV DNA greater
than or equal to 1,000 IU/mL on 2 occasions at least 24 weeks apart (can
include result from screening visit within 8 weeks of randomization).

4. HBsAg positive within 8 weeks prior to randomization plus evidence of
chronic hepatitis B infection as indicated by a liver biopsy within 144
weeks of randomization

4. HBeAg positive or negative.

5. Serum HBV DNA greater than or equal to 1000 IU/mL on 2 occasions at least 4
weeks apart within the 32 weeks prior to randomization (can include result from
screening visit within 8 weeks of randomization).

6. At least two elevated serum ALT levels (> 45 U/L for males and > 30 U/L for
females) at least 4 weeks, and no more than 32 weeks apart with the second being
within 8 weeks of randomization.

7. Compensated liver disease, with total bilirubin less than or equal to 2 mg/dL
(except if Gilbert s syndrome), direct bilirubin less than or equal to 0.5
mg/dL, INR less than or equal to 1.5, and serum albumin greater than or equal to
3.5 g/dL

8. No evidence of HCC based upon alpha-fetoprotein (AFP) less than or equal to
20ng/mL within 8 weeks prior to randomization:

1. Participants who meet AASLD criteria for HCC surveillance must have
negative liver imaging by ultrasound (US), computerized tomography (CT) or
magnetic resonance imaging (MR) within 28 weeks of 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.

9. Liver biopsy that shows findings consistent with chronic hepatitis B with the
Modified Ishak histology activity index (HAI) greater than or equal to 3
(necroinflammatory component only) or Ishak fibrosis score greater than or equal
to 1 or both, as assessed by the local consortium pathologist on review of a
liver biopsy done within 144 weeks of randomization. Slides must be available
for review by the local consortium pathologist and meet adequacy requirements.
If the participant had received previous treatment for hepatitis B, the biopsy
must have been done after discontinuation of treatment.

10. Females of child bearing potential must agree to use an adequate method of
contraception throughout the study and must have a negative pregnancy test
immediately prior to the start of treatment.

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

EXCLUSION CRITERIA:

1. Serum ALT > 450 U/L for males and > 300 U/L for females (participants are eligible
for re-screening if ALT levels fall to the range of eligibility).

2. Treatment with interferon or nucleos(t)ide analogues for hepatitis B within 48 weeks
of randomization.

3. More than 48 weeks of therapy with nucleos(t)ide analogues for hepatitis B at any
time in the past.

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

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

6. Females who are pregnant or breastfeeding.

7. Previous organ transplantation including engrafted bone marrow transplant.

8. Any other concomitant liver disease, including hemochromatosis or 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.

9. Positive anti-HIV (test to be completed within 8 weeks prior to randomization).

10. Renal insufficiency with calculated (by MDRD method) creatinine clearance < 60 mL/min
within 8 weeks prior to randomization.

11. Platelet count < 90,000 /mm3, hemoglobin < 13 g/dL (males) or < 12 g/dL (females),
absolute neutrophil count < 1500 /mm3 (< 1000/mm3 for African-Americans) within 8
weeks prior to randomization.

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

13. 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.

14. History of immune-mediated disease, or cerebrovascular, 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.

15. 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.

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

17. Evidence of active or suspected malignancy, or a history of malignancy within the
last 144 weeks prior to randomization (except adequately treated carcinoma in situ or
basal cell carcinoma of the skin).

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

19. 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.

20. Any other condition 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.