Clinical trial NCT02364336: Add-on Peginterferon Following Nucleos(t)Ide Analogue Treatment
Official title: Mechanisms Associated With Favorable Response to Peginterferon-Alpha Add-on Therapy Following Long-term Nucleos(t)Ide Analogue Treatment in Patients With Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis B
Keywords: Chronic Hepatitis B
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2015-02-18
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Primary outcomes:
measure: Change in Interferon-stimulated-gene (ISG) Expression
timeFrame: 6 hours after first injection of peginterferon
Secondary outcomes:
measure: Hepatitis B e Antigen (HBeAg) Loss
timeFrame: End of treatment, 24 weeks, and 48 weeks
measure: Hepatitis B s Antigen (HBsAg) Loss
timeFrame: End of treatment, 24 weeks, and 48 weeks
measure: Change in Natural Killer (NK) Cell Frequency
timeFrame: 6 hours after first injection of peginterferon and baseline
measure: Change in Natural Killer (NK) Cell Degranulation
timeFrame: 6 hours after first injection of peginterferon and baseline
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Marc G Ghany, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008 Jul;8(7):559-68. doi: 10.1038/nri2314.
citation: Ouzan D, Penaranda G, Joly H, Khiri H, Pironti A, Halfon P. Add-on peg-interferon leads to loss of HBsAg in patients with HBeAg-negative chronic hepatitis and HBV DNA fully suppressed by long-term nucleotide analogs. J Clin Virol. 2013 Dec;58(4):713-7. doi: 10.1016/j.jcv.2013.09.020. Epub 2013 Sep 29.