Combination Therapy of Pegylated Interferon Alfa-2a and Tenofovir Versus Tenofovir Monotherapy in Chronic Hepatitis B (HBRN)

• Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 240 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 228 ] [ Designated as safety issue: No ]

• Cumulative HBsAg loss [ Time Frame: Week 192 ] [ Designated as safety issue: No ]
• Cumulative HBsAg loss [ Time Frame: Week 228 ] [ Designated as safety issue: No ]
• Serious Adverse Events [ Time Frame: up to 240 weeks ] [ Designated as safety issue: No ]
• Adverse events [ Time Frame: up to 240 weeks ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: week 192 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: week 228 ] [ Designated as safety issue: No ]
• HBeAg loss [ Time Frame: week 240 ] [ Designated as safety issue: No ]
• HBsAg seroconversion [ Time Frame: week 192 ] [ Designated as safety issue: No ]
• HBsAg seroconversion [ Time Frame: week 228 ] [ Designated as safety issue: No ]
• HBsAg seroconversion [ Time Frame: week 240 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: week 192 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: week 228 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: week 240 ] [ Designated as safety issue: No ]
• Normalization of Alanine Transaminase(ALT) levels [ Time Frame: week 192 ] [ Designated as safety issue: No ]
  males ≤30 IU/L, females ≤20 IU/L
• Normalization of Alanine Transaminase(ALT) levels [ Time Frame: week 228 ] [ Designated as safety issue: No ]
  males ≤30 IU/L, females ≤20 IU/L
• Normalization of Alanine Transaminase(ALT) levels [ Time Frame: week 240 ] [ Designated as safety issue: No ]
  males ≤30 IU/L, females ≤20 IU/L
• Proportion with HBV DNA ≤1000 IU/mL [ Time Frame: week 192 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA ≤1000 IU/mL [ Time Frame: week 228 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA ≤1000 IU/mL [ Time Frame: week 240 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA <20 IU/mL [ Time Frame: week 192 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA <20 IU/mL [ Time Frame: week 228 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA <20 IU/mL [ Time Frame: week 240 ] [ Designated as safety issue: Yes ]
• Absence of detectable antiviral drug-resistance HBV mutations [ Time Frame: week 192 ] [ Designated as safety issue: No ]
• Stable or improved Ishak fibrosis score compared to pre-treatment [ Time Frame: Week 192 ] [ Designated as safety issue: No ]
• Improved necroinflammation defined by HAI reduction of ≥2 points (compared to pre-treatment). [ Time Frame: week 192 ] [ Designated as safety issue: No ]
• Sustained HBV DNA <1000 IU/ml AND "mild" histology defined as HAI ≤3 AND improvement in Ishak fibrosis score by ≥ 1 [ Time Frame: week 192 ] [ Designated as safety issue: No ]

• Time to HBsAg loss [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) seroconversion [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBsAg) seroconversion [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
• Normalization of Alanine Transaminase(ALT) levels [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
  males ≤38 IU/L females ≤25 IU/L
• Alanine transaminase (ALT) ≤1.25 X ULN [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
  For males ≤38 IU/L and females ≤25 IU/L)
• Proportion with HBV DNA ≤1000 IU/mL [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
• Proportion with HBV DNA <20 IU/mL [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
• Absence of detectable antiviral drug-resistance HBV mutations [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
• Stable or improved Ishak fibrosis score [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
  This will be compared with Ishak fibrosis score recorded at baseline visit.
• Improved necroinflammation defined by HAI reduction of ≥2 points [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
  This will be compared to necroinflammation that was recorded at baseline visit.
• Sustained HBV DNA ≤1000 IU/ml PLUS "mild" histology [ Time Frame: at week 192 ] [ Designated as safety issue: No ]
  This is defined as HAI ≤3 AND improvement in Ishak fibrosis by ≥ 1.
• Time to HBsAg loss [ Time Frame: at week 228 ] [ Designated as safety issue: No ]
• Time to HBsAg loss [ Time Frame: at week 240 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 228 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 240 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBsAg) seroconversion [ Time Frame: at week 228 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBsAg) seroconversion [ Time Frame: at week 240 ] [ Designated as safety issue: No ]
• Normalization of Alanine Transaminase(ALT) levels [ Time Frame: at week 228 ] [ Designated as safety issue: No ]
• Normalization of Alanine Transaminase(ALT) levels [ Time Frame: at week 240 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA ≤1000 IU/mL [ Time Frame: at week 228 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA ≤1000 IU/mL [ Time Frame: at week 240 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA <20 IU/mL [ Time Frame: at week 228 ] [ Designated as safety issue: Yes ]
• Proportion with HBV DNA <20 IU/mL [ Time Frame: at week 240 ] [ Designated as safety issue: Yes ]

This clinical trial compares the efficacy of peginterferon plus tenofovir for 24 weeks followed by monotherapy with tenofovir for a further 3.5 years to the efficacy of tenofovir alone given for 4 years in patients with chronic hepatitis B. The primary measure of outcome will be sustained HBsAg loss in serum one year after stopping all antiviral therapy (sustained off-treatment response).

The objective of this study is to compare the long-term efficacy of treatment with combination therapy with peginterferon plus tenofovir versus tenofovir monotherapy in the treatment of chronic hepatitis B.

This is a randomized (1:1) parallel group design trial comparing (i) Tenofovir DF 300 mg daily for 192 weeks (4 years) and (ii) peginterferon alfa-2a 180 µg weekly for 24 weeks plus Tenofovir DF 300 mg daily for 192 weeks (4 years). Enrolled participants will be stratified by HBeAg status (positive/negative), genotype (A vs. all others) and cirrhosis (present vs. absent). After 192 weeks of treatment, participants meeting criteria for treatment discontinuation will stop treatment and be followed for 48 weeks (total duration of treatment and follow up is 240 weeks). A liver biopsy will be obtained at the end-of-treatment (week 192) to assess improvement in histology. Emtricitabine/tenofovir coformulated as Truvada, approved for treatment of HIV but not for treatment of HBV infection, will be offered to patients with primary nonresponse, partial virological response or confirmed virologic breakthrough.

• Drug: Tenofovir
  300 mg daily for 192 weeks (4 years)
  Other Name: Hepatitis B, tenofovir, Viread
• Drug: Combination of peginterferon alfa 2a and tenofovir
  A combination of peginterferon alfa 2a 180 µg weekly plus tenofovir 300 mg daily for 24 weeks and then only tenofovir 300 mg daily for 168 weeks.
  Other Name: PEGASYS, peginterferon alfa 2a, Viread, and tenofovir

• Experimental: Tenofovir
  Tenofovir 192 weeks
  Intervention: Drug: Tenofovir
• Experimental: Peginterferon and tenofovir
  A combination of peginterferon alfa 2a plus tenofovir for 24 weeks and then tenofovir only for 168 weeks
  Intervention: Drug: Combination of peginterferon alfa 2a and tenofovir

Inclusion criteria:

• Participant is enrolled in the HBRN Cohort Study (NCT01263587) and has completed the baseline evaluation
• 18 years or older

• Chronic hepatitis B infection as evidenced by either of the following:

  1. HBsAg positive result at screening (within 8 weeks prior to randomization) and another time at least 24 weeks prior to randomization with no HBsAg negative result in between.
  2. HBsAg positive plus absence of detectable anti-HBc IgM in serum at screening (within 8 weeks prior to randomization).
• Hepatitis B e antigen positive or negative
• Serum HBV DNA ≥1000 IU/mL on 2 occasions at least 4 weeks, and no more than 24 weeks, apart with the second being within 8 weeks of randomization
• Two elevated serum ALT levels 4 weeks apart, and no more than 24 weeks apart, with the second being within 8 weeks of randomization
• Treatment Naive for the last 48 weeks
• Compensated liver disease
• No evidence of HCC
• Liver biopsy (done as standard of care) that shows findings consistent with chronic hepatitis B with histology activity index (HAI) ≥5 (necroinflammatory component only) or Ishak fibrosis score ≥2 or both, as assessed by the local study pathologist on review of a liver biopsy done within 96 weeks of randomization
• Females of child bearing potential must agree to use an adequate method of contraception throughout the study and must have a negative pregnancy test immediately prior to the start of treatment

Exclusion criteria:

• Serum ALT ≥450 IU/L for males and ≥300 IU/L for females
• History of hepatic decompensation including but not limited to ascites, variceal bleeding, or hepatic encephalopathy
• Liver biopsy with ≥3+/4 iron in hepatocytes by Prussian blue stain
• Known allergy or intolerance to any of the study medications
• Females who are pregnant or breastfeeding
• Previous organ transplantation including engrafted bone marrow transplant
• Any other concomitant liver disease, including hepatitis C or D; Participants with severe steatohepatitis will be excluded (participants with non-alcoholic fatty liver disease [NAFLD] with steatosis only and/or mild to moderate steatohepatitis are acceptable)
• Positive anti-HIV
• Renal insufficiency with calculated (by MDRD method) creatinine clearance <50 mL/min, at the screening visit
• Platelet count <90,000 /mm3, hemoglobin <13 g/dl (males) or <12 g/dl (females), absolute neutrophil count <1500 /mm3 (<1000/mm3 for African-Americans) during the screening visit
• History of active alcohol or drug abuse within 48 weeks of screening.
• Pre-existing psychiatric condition(s), including but not limited to: Current moderate or severe depression as determined by the study physician, history of depression requiring hospitalization within past 10 years, history of suicidal or homicidal attempt within the past 10 years, or history of severe psychiatric disorders including but not limited to schizophrenia, psychosis, bipolar disorder
• 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
• Any medical condition that would be predicted to be exacerbated by therapy or that would limit study participation
• Any medical condition requiring or likely to require chronic systemic administration of corticosteroids or other immunosuppressive medications during the course of this study
• Evidence of active or suspected malignancy, or a history of malignancy within the last 144 weeks (except adequately treated carcinoma in situ and basal cell carcinoma of the skin)
• Need for ongoing use of any antivirals with activity against HBV during the course of the study
• Any other condition that in the opinion of the investigator would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the study.
• Participation in any other clinical trial involving investigational drugs within 30 days of randomization or intention to participate in another clinical trial during this study.