Add-on Peginterferon Following Nucleos(t)Ide Analogue Treatment
Condition: Chronic Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic
Intervention: Peginterferon alfa-2a
Intervention MeSH terms: Peginterferon alfa-2a
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Chronic Hepatitis B

Summary:

      Background:

      - Chronic hepatitis B is caused by a virus that infects the liver. Cure is not possible but
      the virus can be controlled with the use of antiviral medicines,. Researchers think that
      adding a second antiviral medicine might help.

      Objective:

      - To understand how peginterferon might help treat people with chronic hepatitis B. Also, to
      see if peginterferon is safe to use with other antiviral medications.

      Eligibility:

      - Adults age 18 and older who have chronic hepatitis B and had therapy with 1 or more oral
      medicines for hepatitis B for at least 4 years.

      Design:

        -  Participants will be screened with physical exam and medical history. They will complete
           health questionnaires about their levels of fatigue and pain. They will have blood and
           urine tests. They may have an eye exam.

        -  Participants also will have a Fibroscan. A test to measure how stiff your liver is.

        -  Eligible participants will have a liver biopsy. Blood will be drawn.

        -  Participants will be admitted to the NIH Clinical Center. They will be injected with the
           study drug. Then they will have a second liver biopsy. They will be discharged 24 hours
           later.

        -  Participants will give themselves study drug injections under the skin weekly for 24
           weeks.

        -  Participants will have 5 clinic visits during the 24-week treatment period. Then they
           will have follow-up visits every 12 weeks for 48 weeks.

        -  During visits, participants may have a physical exam and medical history. They may have
           blood and urine tests. They may have a Fibroscan and complete questionnaires. At the
           final visit, they will also have a Fibroscan.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Inclusion criteria: HBeAg positive group

          1. Age >18 years and older, male or female.

          2. Known serum HBsAg and HBeAg positivity at the time of screening.

          3. Ongoing treatment with one or more NUCs for at least 192 weeks before study entry.
             Subjects may have a brief interruption of treatment for medical reasons (e.g. breast
             feeding) not to exceed 8 weeks and none within the 48 weeks before study entry.

          4. HBV DNA levels <100 IU/mL, measured at least 12 months prior to, and upon enrollment
             to the study.

          5. ALT level less than or equal to 2 ULN based on at least two determinations taken at
             least one month apart during the 24 weeks before study entry with the second being at
             time of screening

          6. Written informed consent

        Inclusion criteria: HBeAg negative group

          1. Age >18 years and older, male or female.

          2. Known serum HBsAg positivity and HBeAg negativity at the time of screening.

          3. Ongoing treatment with one or more NUCs for at least 192 weeks before study entry.
             Subjects may have a brief interruption of treatment for medical reasons (e.g. breast
             feeding) not to exceed 8 weeks and none within the 48 weeks before study entry.

          4. HBV DNA levels <100 IU/mL, measured at least 12 months prior to, and upon enrollment
             to the study

          5. ALT level less than or equal to 2 ULN based on at least two determinations taken at
             least one month apart during the 24 weeks before study entry with the second being at
             time of screening

          6. Written informed consent

        EXCLUSION CRITERIA:

        Exclusion criteria (for both eAg positive and negative patients)

          1. Co-infection with HDV as defined by the presence of anti-HDV in serum and/or HDV
             antigen in the liver.

          2. Co-infection with HCV as defined by the presence of HCV RNA in serum.

          3. Co-infection with HIV as defined by the presence of anti-HIV in serum.

          4. 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 g/dL, or a history of ascites, variceal bleeding or hepatic
             encephalopathy.

          5. Presence of other causes of liver disease, (i.e. hemochromatosis, Wilson disease,
             alcoholic liver disease, severe nonalcoholic steatohepatitis defined as the presence
             of marked ballooning injury on liver biopsy, alpha-1-anti-trypsin deficiency).

          6. A history of organ transplantation or in the absence of organ transplantation, any
             immunosuppressive therapy requiring the use of more than 5 mg of prednisone (or its
             equivalent) daily.

          7. 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.

          8. Pregnancy or inability to practice contraception in patients capable of bearing or
             fathering children

          9. Lactating women.

         10. 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.

         11. eGFR < 50 ml/min, serum creatinine > 1.3 mg/dl or urine protein >1 gram/24-hours

         12. History of hypersensitivity to pegylated interferon-alpha

         13. Platelet count <70 mm(3)/dL

         14. Hgb <12 g/dL for males and <11 g/dL for females

         15. 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.

         16. 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).

         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. 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.

         19. Presence of conditions that, in the opinion of the investigators, would not allow the
             patient to be followed in the current study for at 1 year.

         20. For subjects who interrupt therapy, documentation of a viral load >1,000 IU/ml while
             off therapy.