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.
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. While lamivudine monotherapy induces a
transient improvement in viral levels and liver histology, 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 Tyrosine-methionine-aspartate-aspartate (YMDD) motif of the
HBV polymerase gene and worsening of the hepatitis. Adefovir monotherapy, 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 (alanine
aminotransferase) 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 stratified into one of four groups of 20 patients for
randomization: (A) Lamivudine naive and HBeAg positive, (B) Lamivudine naive and HBeAg
negative (C) previous lamivudine therapy and HBeAg positive and (D) previous lamivudine
therapy and HBeAg negative. 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.
- 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.
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
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
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
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