Protocol Number: 01-DK-0246

Title:

Combination of Lamivudine and Adefovir Dipivoxil for Treatment of Chronic Hepatitis B

Number:

01-DK-0246

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, 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.

Sponsoring Institute:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

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 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

Special Instructions: Currently Not Provided

Keywords:

Adefovir Dipivoxil

Lamivudine

3TC

Nucleoside/Nucleotide Analogue

Chronic Hepatitis B

Hepatitis B Mutants

Liver Biopsy

Recruitment Keywords:

Hepatitis B

Hepatitis

HBV

Liver

Conditions:

HBV

Hepatitis B

Hepatitis

Liver

Investigational Drug(s):

Adefovir Dipivoxil

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B

Chronic hepatitis B virus infection: treatment strategies for the next millennium

The treatment of chronic viral hepatitis

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

Search The Studies | Help | Questions |
Clinical Center Home | NIH Home

Warren Grant Magnuson Clinical Center (CC)
National Institutes of Health (NIH)
Bethesda, Maryland 20892. Last update: 10/15/2004