A Comprehensive Monograph on Adefovir Dipivoxil: Pharmacology, Clinical Efficacy, and Therapeutic Context

Executive Summary

Adefovir dipivoxil is an orally administered diester prodrug of adefovir, classified as an acyclic nucleotide analog reverse-transcriptase inhibitor (ntRTI). Its primary therapeutic indication is the treatment of chronic hepatitis B (CHB) infection in adults and adolescents aged 12 years and older. The drug functions by undergoing intracellular conversion to its active diphosphate metabolite, which then competitively inhibits the hepatitis B virus (HBV) DNA polymerase and terminates viral DNA chain synthesis, thereby suppressing viral replication.

The development history of adefovir dipivoxil is a notable case study in pharmaceutical repurposing. Initially investigated by Gilead Sciences as a treatment for HIV infection under the brand name Preveon, it failed to gain regulatory approval due to significant dose-limiting nephrotoxicity at the high doses required for anti-HIV efficacy. However, the compound was successfully repurposed for CHB, for which a much lower and better-tolerated dose of 10 mg daily proved effective. It received FDA approval in 2002 under the brand name Hepsera®, representing a significant therapeutic advance at the time, particularly for patients with lamivudine-resistant HBV, as it possessed a higher genetic barrier to resistance than first-generation nucleoside analogs.

Despite its initial success, the therapeutic role of adefovir dipivoxil has been largely superseded by newer, more potent agents such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV). Clinical evidence from multiple head-to-head trials and meta-analyses has conclusively demonstrated the superiority of these agents in achieving virologic suppression.