Add-on Peginterferon Following Nucleos(t)Ide Analogue Treatment
Add-on Peginterferon Following Nucleos(t)Ide Analogue Treatment
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.
Chronic hepatitis B virus (HBV) infection is a leading cause of liver associated morbidity
 and mortality. Currently available first-line therapies for treatment of chronic hepatitis B
 include pegylated interferon-alpha and the nucleos(t)ide analogues (NUCs) entecavir and
 tenofovir. These were shown to effectively suppress viral replication, but their ability to
 induce durable off-treatment response is limited to a small subset of patients. Combination
 treatment with peginterferon and NUCs has been attempted in several randomized controlled
 trials, with no apparent advantage over either agent given alone. In these studies however,
 treatment with peginterferon was initiated either simultaneously or shortly after NUCs
 administration. The efficacy of peginterferon following long-term viral suppression with NUCs
 was only tested in one small pilot study, nevertheless showing 60% hepatitis B s antigen
 (HBsAg) loss rate.

 The underlying mechanisms responsible for improved efficacy of peginterferon in this setting
 are unknown and warrant further investigation. In this single arm study we propose to
 evaluate the efficacy and mechanisms associated with response to peginterferon add-on therapy
 following a minimum of 192 weeks of viral suppression induced by NUCs in a group of chronic
 HBV infected patients. Sixty patients with either hepatitis B e antigen (HBeAg) positive
 (n=30) or negative (n=30) chronic HBV infection will be enrolled to this study. After medical
 evaluation and pretreatment liver biopsy, treatment with subcutaneous injections of pegylated
 interferon alpha-2a 180 g per week will be given for a total of 24 weeks, followed by an
 off-treatment evaluation period of 48 weeks. A second liver biopsy will be performed six
 hours following the first peginterferon injection. Primary end-point for this study will be
 the change in interferon-stimulated-genes response before and after first interferon
 injection in responders versus non-responders to treatment. The responsiveness to IFN-based
 therapy of treatment responders vs nonresponders will additionally be evaluated by studying
 intrahepatic and peripheral blood natural killer cells. The study will also assess HBeAg and
 HBsAg loss and seroconversion rates in comparison to historical controls treated with either
 peginterferon or NUCs monotherapy. Finally, we will assess whether treatment responders
 develop an HBV-specific T cell response similar in quantity and quality to that of patients
 who spontaneously resolve HBV infection.
-  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.