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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): Peginterferon alfa-2a
Intervention type(s): Drug
Intervention MeSH terms: Peginterferon alfa-2a
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic Hepatitis B