Lamivudine and Adefovir to Treat Chronic Hepatitis B
Condition: HBV (Hepatitis B Virus); Hepatitis B; Hepatitis
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic
Intervention: Lamivudine and adefovir; Adefovir alone
Intervention description: Lamivudine (100 mg/day) and adefovir (10 mg/day); Adefovir (10 mg/day)
Intervention MeSH terms: Lamivudine; Adefovir; Adefovir dipivoxil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Adefovir Dipivoxil; Lamivudine; Nucleoside/Nucleotide Analogue; Chronic Hepatitis B; Hepatitis B Mutants; Liver Biopsy; Hepatitis B; Hepatitis; HBV; Liver

Summary:

      This study will evaluate the safety and effectiveness of lamivudine plus adefovir versus
      adefovir alone to treat chronic hepatitis B infection. The Food and Drug Administration has
      approved lamivudine for the treatment of hepatitis B. However, the drug is not effective in
      all patients, and many of those in whom it initially works develop resistance after 1 to 3
      years. Adefovir is an experimental drug that inhibits replication of the hepatitis B virus
      (HBV). Adefovir used alone may be adequate to provide sustained suppression of the virus and
      improvement in liver disease. However combining two anti-viral agents may be superior to
      using one alone, similar to the strategy employed for the treatment of AIDS. This study will
      test whether the combination of lamivudine and adefovir is better than adefovir alone for the
      treatment of chronic hepatitis B.

      Patients 18 years of age and older, who have been infected with HBV for at least 6 months,
      may be eligible for this study. Candidates may not have received lamivudine treatment in the
      past 6 months or prior treatment with adefovir and must not be taking other anti-viral
      treatments for their hepatitis. They will have a blood test to confirm HBV infection.

      Participants will be admitted to the NIH Clinical Center for 2 to 3 days for a medical
      evaluation. One to 2 weeks after the evaluation, patients will be randomized to begin taking
      lamivudine and adefovir, or adefovir alone. Therapy will continue for at least 12 months.
      Follow-up clinic visits will be scheduled weekly for the first month, then every 4 to 8 weeks
      for the rest of the treatment period. Patients will be evaluated at the end of 1 year.
      Patients who have not improved with treatment will stop taking the treatment and will be
      evaluated in the clinic once every 4 weeks for another 6 months. Patients who show an
      improvement in their liver injury may continue taking lamivudine and adefovir or adefovir
      alone for 4 more years, as long as they continue to improve with the medication. Progress
      will be evaluated. If the test results show no continued improvement or are negative for
      hepatitis B antigens, therapy will be stopped.

      Patients who continue treatment for 5 years will be readmitted at year 4 for another medical
      evaluation to assess the effects of treatment at that time. After the 5 years all patients
      will stop therapy at and be followed with regular clinic visits for at least 6 months.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Age greater than 18 years and above, male or female

        Known serum HBsAg positivity for at least 6 months

        Detectable HBV-DNA in serum above 1 million copies per ml, as detected by quantitative PCR
        (Roche Cobas Assay)

        Serum ALT (alanine aminotransferase) or AST (aspartate aminotransferase)levels above the
        upper limit of normal based on two determinations taken at least one month apart during the
        6 months before entry

        Liver biopsy within 2 years consistent with chronic hepatitis and with a histology activity
        index score (HAI) of 6 or more (out of a total possible score of 22) and an "Ishak"
        fibrosis score of at least 1 (out of a total possible score of 6). For patients with
        lamivudine resistance the liver biopsy may be performed either on or off lamivudine.

        Written informed consent.

        EXCLUSION CRITERIA:

        Previous or current treatment with adefovir or tenofovir.

        Co-infection with HDV (Hepatitis D Virus) as defined by the presence of both anti-HDV in
        serum and HDV antigen in liver

        Co-infection with HCV (Hepatitis C Virus) as defined by the presence of both anti-HCV and
        HCV RNA in serum.

        Co-infection with HIV (Human immunodeficiency virus) as defined by the presence of anti-HIV
        in serum.

        Decompensated liver disease as defined by serum bilirubin greater than 2.5 mg%, prothrombin
        time of greater than 2 seconds prolonged, a serum albumin of less than 3.0 gm%, or a
        history of ascites, variceal bleeding, or hepatic encephalopathy.

        Presence of other causes of liver disease (i.e., hemochromatosis, Wilson's disease,
        alcoholic liver disease, non-alcoholic steatohepatitis, alpha-1 antitrypsin deficiency)

        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.

        Significant systemic illnesses other than liver diseases including congestive heart
        failure, renal failure, chronic pancreatitis, diabetes mellitus with poor control that in
        the opinion of the investigators might interfere with therapy.

        Pregnancy or inability to practice contraception in patients capable of bearing or
        fathering children

        Pre-existing bone marrow suppression: White Blood Cells (WBC) less than 2,000 cells/mm(3),
        hematocrit less than 30%, or platelets less than 50,000 cells/mm(3).

        History of clinically apparent pancreatitis or evidence of subclinical pancreatitis as
        shown by serum amylase values twice the upper limits of the normal range and abnormalities
        of the pancreas on CT or other imaging studies of the abdomen

        Prior interferon treatment within 6 months of entry

        Sensory or motor neuropathy apparent from medical history and physical examination

        Creatinine clearance less than 50 ml/min or serum creatinine greater than 1.5 mg/dl;
        creatinine clearance will be determined on a 24 hour urine specimen. Accuracy of collection
        will be ensured by documenting appropriate total creatinine excretion in the 24 hour urine
        specimen (15 mg/kg) and correcting for the patient's age and gender.

        Concurrent use of nephrotoxic agents (e.g., aminoglycosides, amphotericin B, vancomycin,
        foscarnet, cis-platinum, pentamidine, nonsteroidal anti-inflammatory agents) or competitors
        of renal tubular excretion (e.g., probenecid) within 2 months prior to study screening or
        the expectation that the subject will receive these during the course of the study

        History of hypersensitivity to nucleoside/nucleotide analogues

        Active ethanol/drug abuse/psychiatric problems that, in the investigator's opinion, might
        interfere with participation in the study

        History of seizure disorder

        History of renal tubular acidosis

        History of malignancy or treatment for a malignancy within the past 5 years