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, including a history and physical examination, blood and urine tests, 24-hour urine collection, chest X-ray, electrocardiogram (EKG), abdominal ultrasound and a liver biopsy if one has not been done within the last year. This procedure involves obtaining a small sample of liver tissue through a needle placed in the liver.

One to 2 weeks after the evaluation, patients will be randomized to begin taking 100 milligrams/day of lamivudine and 10 mg/day of adefovir, both in pill form or 10 mg of 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. The visits will involve a history and physical examination and blood tests. At the end of 1 year, patients will be evaluated in the Clinical Center with the same tests done at the beginning of the study. 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 with blood tests for HBV levels and liver enzymes. 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 to the Clinical Center for another medical evaluation and liver biopsy 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.

Condition	Treatment or Intervention	Phase
HBV Hepatitis B Hepatitis Liver	Drug: Adefovir Dipivoxil	Phase II

Further Study Details: 

Expected Total Enrollment:  80

Aims: To assess the safety, antiviral activity and clinical benefit of the combination of lamivudine and adefovir dipivoxil vs adefovir alone in up to 80 patients with chronic hepatitis B for up to five years.

Background: Adefovir dipivoxil and lamivudine are oral antiviral agents that have been shown to have potent activity against HBV in vitro and in vivo. Both drugs have been used extensively in patients with HIV infection and more recently in controlled trials as monotherapy in patients with chronic hepatitis B. Lamivudine is currently approved as therapy of hepatitis B and has been evaluated extensively both as a one-year course of treatment as well as long-term continuous therapy. Lamivudine monotherapy induces a transient improvement in viral levels and liver histology, but viral resistance develops in a large proportion of patients with re-appearance of HBV DNA in serum in high levels associated with mutations in the YMDD motif of the HBV polymerase gene and worsening of the hepatitis. Adefovir monotherapy was recently approved by the FDA and in contrast, has not been shown to be associated with development of viral resistance even when given for up to two years. When given as monotherapy for 1 year, adefovir leads to improvement in histology of hepatitis B in approximately 50% of patients. At present, the long-term efficacy of adefovir has not been shown.

Protocol: Up to 80 patients with chronic hepatitis B who have raised serum ALT levels, HBV DNA in serum (above 1 million copies per ml by quantitative PCR) and active liver disease on liver biopsy will be enrolled and started on the combination of lamivudine (100 mg daily) and adefovir dipivoxil (10 mg daily) or adefovir alone (10 mg daily). Patients will be monitored carefully during therapy for adverse events, clinical symptoms and signs of liver disease, biochemical, and hematological parameters, and HBV serology at 2 to 4 week intervals. The primary endpoint of therapy will be a maintained combined response (a combination of virological, biochemical, and histological response) with major timing of end-points being at 1 and 4 years. Secondary endpoints will include loss of HBeAg, the individual types of maintained responses (virological, biochemical and histological), the development of lamivudine resistance, and improvement in symptom scores and quality of life assessments at 1 and 4 years.

Conclusions: This study will assess the effects of the combination of lamivudine and adefovir dipivoxil compared to adefovir alone in suppressing hepatitis B and prevention of lamivudine resistant mutants that arise during long-term therapy with lamivudine alone.

Genders Eligible for Study:  Both

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 or AST 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 as defined by the presence of both anti-HDV in serum and HDV antigen in liver
Co-infection with HCV as defined by the presence of both anti-HCV and HCV RNA in serum.
Co-infection with HIV 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 antitypsin 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: 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

Maryland
      National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  010246; 01-DK-0246
Record last reviewed:  July 23, 2004
Last Updated:  November 23, 2004
Record first received:  September 3, 2001
ClinicalTrials.gov Identifier:  NCT00023309
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08