Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic Hepatitis B Virus (HBV) Infection

• Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBsAg loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBeAg loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBeAg seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• HBsAg seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBsAg seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Alanine aminotransferase (ALT) ≤ 40 U/L for males, ≤ 35 U/L for females [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• ALT ≤ 40 U/L for males, ≤ 35 U/L for females [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• HBV DNA ≤1000 IU/mL [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBV DNA ≤1000 IU/mL [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• HBV DNA < 20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• HBV DNA < 20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
• Absence of detectable antiviral drug-resistance HBV mutations [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
• Growth parameters [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  weight, height, Body Mass Index, Tanner scores
• Growth parameters [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  weight, height, Body Mass Index, Tanner scores

• Hepatitis B surface antigen (HBeAg) seroconversion [ Time Frame: at weeks 48,84 & 96 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at weeks 48, 84, & 96 ] [ Designated as safety issue: No ]
• Hepatitis B e antigen (HBeAg) seroconversion [ Time Frame: weeks 48, 84, & 96 ] [ Designated as safety issue: No ]
• Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48, 84, & 96 ] [ Designated as safety issue: No ]
• Normalization of Alanine Transaminase (ALT) levels [ Time Frame: at weeks 48, 84, and 96. ] [ Designated as safety issue: Yes ]
  ALT levels ≤40 IU/L for males, ≤35 IU/L for females
• Proportion with hepatitis B DNA ≤1000 IU/mL [ Time Frame: at weeks 48,84, & 96 ] [ Designated as safety issue: No ]
• Proportion with hepatitis B DNA <20 IU/mL [ Time Frame: at weeks 48, 84, & 96 ] [ Designated as safety issue: No ]

This multicenter, randomized, controlled study will be conducted by the pediatric centers within the NIDDK-sponsored Hepatitis B Research Network (HBRN). Children age 3-<18 years with immunotolerant chronic hepatitis B (CHB) infection who fulfill the entry criteria will receive entecavir as monotherapy for 8 weeks and then combination therapy with entecavir and pegylated interferon by weekly subcutaneous injection until week 48. Children will be followed for 96 weeks which is 48 weeks after discontinuation of therapy.

Assessment will be undertaken at baseline, weeks 4, 8, 10, 12, 14, & 16, then every 4 weeks until week 48, and then at week 52, 56, 60, 72, 84 and 96. Data collected will describe baseline demographics, symptoms of liver disease, intercurrent illnesses, and findings on physical examination. Blood work will be drawn to measure markers of viral and liver disease status, assessment of drug adverse effects, and for research biospecimen banking.

Participants will continue on therapy until week 48 and complete the full study follow-up protocol thereafter, including those who undergo seroconversion to anti-HBe or anti-HBs before reaching week 48. Participants who experience a sustained elevation of ALT will be eligible to receive treatment as recommended by their hepatologist and will continue to complete the study follow-up protocol. Participants who exhibit adverse effects of therapy will undergo dose adjustment or discontinuation of therapy as detailed in the protocol, and will continue to complete the study follow-up protocol.

Inclusion Criteria:

• Enrolled in & completed the baseline evaluation in NCT01263600 OR completed necessary components of NCT01263600 baseline evaluation by the end of the baseline visit.
• 3 to <18 years at time of randomization (day 0).
• Documented chronic HBV infection as evidenced by detection of HBsAg in serum for ≥ 24 weeks prior to baseline OR positive HBsAg and negative anti-HBc IgM within 24 weeks of baseline visit.
• Presence of HBeAg in serum at the last screening visit within 6 weeks of baseline visit.
• Serum HBV DNA level >10^7 IU/mL on at least 2 occasions at least 12 weeks apart during the 52 weeks before baseline visit. The HBV DNA levels must be within 6 weeks of baseline visit.
• ALT ≤60 U/l in males or ≤40 U/l in females, measured on at least 2 occasions, at screening (within 6 weeks prior to baseline visit) & at least 12 weeks prior to the screening visit & within the 52 weeks prior to baseline visit.
• Compensated liver disease, with normal total bilirubin (except if Gilbert's syndrome), direct bilirubin ≤0.5 mg/dL, INR ≤1.5, and serum albumin ≥3.5 g/dL.
• Creatinine clearance 90 ml/min.
• Absence of hepatocellular carcinoma on liver ultrasound in the past 48 weeks.

Exclusion criteria:

• Presence of infection with HCV-RNA or anti-HCV, anti-HDV, or HIV at screening.
• Presence of another cause of liver disease or HCC (serum alpha-fetoprotein >50ng /ml).
• Evidence of decompensated liver disease (Childs B-C).
• History or other evidence of a medical condition associated with chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposures).
• Females who are pregnant or breastfeeding.
• Adolescent females unwilling or unable to use an acceptable method of contraception if sexually active during the treatment period.
• Children currently breastfeeding while their mother is taking lamivudine, or those who were exposed to lamivudine for ≥24 weeks via maternal lamivudine treatment during pregnancy and/or while breastfeeding.
• Previous liver or other organ transplantation including engrafted bone marrow transplant.
• Hematological abnormalities during the screening period that contraindicate full dosing with study drugs, e.g absolute neutrophil count < 1.5 x 10^9 cells/L or platelet count < 120 x 10^9 cells/L.
• Known allergy to study drugs; peginterferon alfa-2a or entecavir.
• Treatment with systemic acyclovir or famciclovir within the previous 6 months.
• Need for ongoing use of any antivirals with activity against HBV during the course of the study or history of receiving treatment for HBV.
• Any use of illegal drugs OR use of alcoholic beverages which in the opinion of a study physician is sufficient to prevent adequate compliance with study procedures or increase the risk of pancreatitis or hepatotoxicity.
• History of immunologically mediated disease (e.g. inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune haemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis).
• History or other evidence of bleeding from esophageal varices or consistent with decompensated liver disease.
• History or other evidence of chronic pulmonary disease associated with functional limitation.
• History of significant cardiovascular diseases.
• History of a severe seizure disorder or current anticonvulsant use.
• History or other evidence of severe retinopathy.
• History of thyroid disease poorly controlled on prescribed medications. Participants with elevated thyroid stimulating hormone concentrations with elevation of antibodies to thyroid peroxidase and any clinical manifestations of thyroid disease are excluded.
• Concomitant use or use during ≤ 6 months prior to the first dose of study drug of anti-neoplastic, immunosuppressive, nephrotoxic or hepatotoxic medication, methadone, theophylline or medications that may affect renal excretion or hepatic metabolism are not permitted.
• Concomitant use of complementary or alternative medications purported to have antiviral activity.
• A participant may not be co-enrolled in another clinical trial where an investigational drug is administered.
• Any other condition or situation that in the opinion of a study physician would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the study.