Lamivudine and Adefovir to Treat Chronic Hepatitis B

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.