Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (K_i) for adefovir diphosphate for HBV DNA polymerase was 0.1 βM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with K_i values of 1.18 βM and 0.97 βM, respectively.

Antiviral Activity

The concentration of adefovir that inhibited 50% of viral DNA synthesis (EC₅₀) in HBV transfected human hepatoma cell lines ranged from 0.2 to 2.5 µ M. The combination of adefovir with lamivudine showed additive anti-HBV activity.

Resistance

Clinical isolates with genotypic changes conferring reduced susceptibility in cell culture to nucleoside analog reverse transcriptase inhibitors for the treatment of HBV infection have been observed. Long-term resistance analyses performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA demonstrated that amino acid substitutions rtN236T and rtA181T/V have been observed in association with adefovir resistance. In cell culture, the rtN236T substitution demonstrated 4- to 14-fold, the rtA181V substitution 2.5- to 4.2-fold, and the rtA181T substitution 1.3- to 1.9-fold reduced susceptibility to adefovir.

In HBeAg-positive nucleoside-naïve patient isolates (study GS-98-437, N=171), no adefovir resistance-associated substitutions were observed at week 48. Sixty-five patients continued on long term treatment after a median duration on adefovir dipivoxil of 235 weeks (range 110–279 weeks). Isolates from 16 of 38 (42%) patients developed adefovir resistance-associated substitutions in the setting of virologic failure (confirmed increase of ≥ 1 log₁₀ HBV DNA copies/mL above nadir or never suppressed below 10³ copies/mL). The substitutions included rtN236T (n=2), rtA181V (n=4), rtA181T (n=3), rtA181T+rtN236T (n=5), and rtA181V+rtN236T (n=2). In HBeAg-negative nucleoside-naïve patients (study GS-98-438), isolates from 30 patients were identified with adefovir resistance-associated substitutions with a cumulative probability of 0%, 3%, 11%, 19%, and 30% at 48, 96, 144, 192, and 240 weeks, respectively. Of those 30 patients, 22 had a confirmed increase of ≥ 1 log₁₀ HBV DNA copies/mL above nadir or never achieved HBV DNA levels below 10³ copies/mL; an additional 8 patients had an adefovir resistance-associated substitutions without virologic failure.

In an open-label study of pre- and post-liver transplantation patients (study GS-98-435), isolates from 129 patients with clinical evidence of lamivudine-resistant hepatitis B virus at baseline were evaluated for adefovir resistance-associated substitutions. The incidence of adefovir resistance-associated (rtN236T or rtA181T/V) substitutions was 0% at 48 weeks. Isolates from four patients developed the rtN236T substitution after 72 weeks of adefovir dipivoxil therapy. Development of the rtN236T substitution was associated with serum HBV DNA rebound. All 4 patients who developed the rtN236T substitution in their HBV had discontinued lamivudine therapy before the development of genotypic resistance and all 4 lost the lamivudine resistance-associated substitutions present at baseline. In a study of 35 HIV/HBV co-infected patients with lamivudine-resistant HBV (study 460i) who added adefovir dipivoxil to lamivudine, no adefovir resistance-associated substitutions were observed in HBV isolates from 15/35 patients tested up to 144 weeks of therapy.

Clinical resistance in pediatric patients

In a Phase 3 pediatric study GS-US-103-518, HBV isolates from 49 of 56 pediatric subjects (aged 12 to 17 years) had serum HBV DNA > 169 copies/mL and were evaluated for adefovir resistance-associated substitutions. rtN236T and/or rtA181V adefovir resistance-associated substitutions were not observed at Week 48. However, the rtA181T substitution was present in baseline and Week 48 isolates from 2 pediatric patients.

Cross-resistance

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