Hepatitis B Immune Globulin (HBIg) to Restore Immune Control in People With Chronic Hepatitis B

Up to 300 subjects with hepatitis B e antigen (HBeAg) negative chronic hepatitis B who are
inactive carriers (specified as those with HBV DNA levels <2,000 IU/ml over a 6-month period
with ALT levels <1.5 X upper limit of normal and HBsAg level <1500 U/mL) will be screened and
25 enrolled in a randomized trial of hepatitis B immune globulin (HBIg) for 12 weeks followed
by peginterferon alfa for 24 weeks versus peginterferon alfa alone for 24 weeks. The focus of
the study is to understand mechanistically what effect the removal of HBsAg will have on the
immune response and action of peginterferon alfa-2a. Chronic hepatitis B is characterized by
immune exhaustion, which is felt to be caused by ongoing exposure of immune cells to high
levels of viral antigens such as HBsAg. Presence of viral antigen results in continuous
immune cell stimulation leading to functional exhaustion and progressive loss of immune
function. In this study, we will attempt to achieve elimination of circulating HBsAg from the
blood of chronically infected patients by administering high doses of hepatitis B
immunoglobulin followed by peginterferon. A control arm consisting of peginterferon alone
will be included to allow for assessment of the effect of HBIg on response to peginterferon.
We will investigate whether this strategy will result in restoration of adaptive and innate
immunity leading to HBsAg clearance and development of long-lasting protective immunity. The
proposed study will be conducted in three phases with pre-specified stopping rules to ensure
subjects are responding appropriately at the end of each phase before moving to the next
phase. The primary endpoint of the trial will be clearance of HBsAg and restoration of the
HBV-specific T-cell response.

- INCLUSION CRITERIA:

1. Age >18, male or female

2. Known serum HBsAg positive with a level <1,500 IU/mL at the time of screening

3. Hepatitis B e antigen negative; anti-HBe positive at the time of screening

4. HBV DNA levels <2000 IU/mL on two occasions at least 24 weeks apart with the
second being at time of screening

5. ALT level less than or equal to 1.5 ULN based on at least two determinations
taken at least 24 weeks apart during the 24 weeks before study entry with the
second being at time of screening

6. Written informed consent

EXCLUSION CRITERIA:

1. Any treatment for HBV within the last 48 weeks

2. Co-infection with HDV as defined by the presence of anti-HDV in serum.

3. Co-infection with HCV as defined by the presence of anti-HCV with HCV RNA in serum.

4. Co-infection with HIV as defined by the presence of anti-HIV in serum.

5. Presence of anti-HBs in serum

6. Cirrhosis either diagnosed by a prior liver biopsy at any time or if not available by
a transient elastography score >13 kPa.

7. Decompensated liver disease as defined by serum bilirubin >2.5 mg/dL (with direct
bilirubin > 0.5 mg/dL), prothrombin time of greater than 2 seconds prolonged, a serum
albumin of less than 3.5 g/dL, or a history of ascites, variceal bleeding or hepatic
encephalopathy.

8. Presence of other causes of liver disease, (i.e. hemochromatosis, Wilson disease,
alcoholic liver disease, alpha-1-anti- trypsin deficiency).

9. A history of organ transplantation, or in the absence of organ transplantation any
medical condition requiring the chronic use of more than 5 mg of prednisone (or its
equivalent) daily.

10. Severe IgA deficiency

11. Severe allergic reaction to any human immunoglobulin product

12. Significant systemic illness other than liver diseases including congestive heart
failure, renal failure, chronic pancreatitis and diabetes mellitus with poor control,
that in the opinion of the investigator may interfere with therapy.

13. Pregnancy or inability to practice 2 forms of contraception in women capable of
bearing children

14. Lactating women.

15. Hepatocellular carcinoma (HCC), or the presence of a mass on imaging studies of the
liver that is suggestive of HCC, or an alpha-fetoprotein level of greater than 500
ng/mL.

16. eGFR < 50 ml/min, serum creatinine > 1.3 mg/dl

17. History of hypersensitivity to pegylated interferon-alpha

18. Platelet count <90 mm(3)/dL

19. Hgb <12 g/dL for males and <11 g/dL for females

20. Active ethanol/drug abuse/psychiatric problems such as major depression,
schizophrenia, bipolar illness, obsessive- compulsive disorder, severe anxiety, or
personality disorder that, in the investigator s opinion, might interfere with
participation in the study.

21. History of malignancy or treatment for a malignancy within the past 3 years (except
adequately treated carcinoma in situ or basal cell carcinoma of the skin).

22. 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.

23. Presence of conditions that, in the opinion of the investigators, would not allow the
patient to be followed in the current study.