In: Main23 Jun 2010
The leading cause of cirrhosis and hepatocellular carcinoma around the world is chronic hepatitis B virus (HBV) infection. Approximately 10% of patients who carry the human immunodeficiency virus (HIV) in the U.S. are co-infected with HBV and face decreased survival rates. Worldwide, 400 million people are chronically infected with hepatitis B.
Interferon alfa-2b (Intron® A, Scher-ing) and lamivudine (GlaxoSmithKline) have been approved by the Food and Drug Administration (FDA) for the treatment of chronic HBV infection. Fewer than 50% of the patients with chronic HBV, however, are candidates for interferon alfa-2b, and this therapeutic option has shown only modest success. Among co-infected patients, resistance develops in about 24% of patients after one year of therapy, in 47% after two years of therapy, and in 67% after four years of therapy.
The limited number of approved agents for the treatment of chronic HBV infection and the increase in the number of patients co-infected with HIV and HBV have reinforced the need for safe and effective new therapies. On September 20, 2002, the FDA approved the nu-cleotide reverse transcriptase inhibitor (NRTI) adefovir dipivoxil (Hepsera™, Gilead). Although this drug had previously been considered for the treatment of HIV, at higher dosing levels it was found to be associated with significant renal disease. At lower—and apparently safer—doses, adefovir has proved to be effective in the treatment of HBV in mono-infected patients, in HIV/HBV co-infected patients, and in lamivudine-resistant co-infected patients.
Hepsera™ is a diester prodrug of ade-fovir, which is an acyclic nucleotide analogue of adenosine monophosphate. Through cellular kinases, adefovir is phosphorylated to the active metabolite, adefovir diphosphate. Adefovir diphos-phate inhibits HBV deoxyribonucleic acid (DNA) polymerase by competing with the natural substrate deoxyadeno-sine triphosphate and by causing DNA chain termination after its incorporation into viral DNA.
Up to week 48, studies have shown no mutations in the HBV DNA polymerase gene that might grant reduced vulnerability to adefovir. As a result of the lack of data showing a resistance to adefovir, its efficacy has been found to be greater than that of lamivudine canadian.
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