Microbiology

Mechanism of Action

Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β,and δ and mitochondrial DNA polymerase γ with K_i values ranging from 18 to > 160 µM.

Antiviral Activity

Entecavir inhibited HBV DNA synthesis (50% reduction, EC₅₀) at a concentration of 0.004 µM in human HepG2 cells transfected with wild-type HBV. The median EC₅₀ value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 µM (range 0.010-0.059 µM).

The coadministration of HIV nucleoside reverse transcriptase inhibitors (NRTIs) with BARACLUDE is unlikely to reduce the antiviral efficacy of BARACLUDE against HBV or of any of these agents against HIV.In HBV combination assays in cell culture,abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations.In HIV antiviral assays, entecavir was not antagonistic to the cell culture anti-HIV activity of these six NRTIs at > 4 times the Cmax of entecavir.

Antiviral Activity against HIV

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical human immunodeficiency virus type 1 (HIV-1) isolates using a variety of cells and assay conditions yielded EC₅₀ values ranging from 0.026 to > 10 µM; the lower EC₅₀ values were observed when decreased levels of virus were used in the assay.In cell culture, entecavir selected for an M184I substitution in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations.HIV variants containing the M184V substitution showed loss of susceptibility to entecavir.

Resistance

In Cell Culture

In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions ( > 70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V and/or rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV polymerase.

Clinical Studies

Nucleoside-naive subjects: Genotypic evaluations were performed on evaluable samples ( > 300 copies/mL serum HBV DNA) from 562 subjects who were treated with BARACLUDE for up to 96 weeks in nucleoside-naive studies (AI463022, AI463027, and rollover study AI463901). By Week 96, evidence of emerging amino acid substitution rtS202G with rtM204V and rtL180M substitutions was detected in the HBV of 2 subjects (2/562 = < 1%),and 1 of them experienced virologic rebound ( ≥ 1 log₁₀ increase above nadir). Emerging amino acid substitutions at rtM204I/V ± rtL180M, rtL80I, or rtV173L, which conferred decreased phenotypic susceptibility to entecavir, were detected in the HBV of 3 subjects (3/562 = < 1%) who experienced virologic rebound.

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