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  From BMS Briefing document for FDA Advisory Drug Hearing.
6.1 In Vitro Resistance
In transient HBV culture systems, ETV displayed potent antiviral activity against both WT and LVDR HBV. ETV inhibited the replication of LVDR HBV, but at 8-fold higher concentrations than for the WT virus. Despite the decreased susceptibility of LVDR HBV to ETV, the potency of ETV was still greater than that of either LVD or ADV for LVDR strains of HBV.5 Also, at extracellular concentrations representative of plasma levels in ETV-treated patients, intracellular ETV-TP accumulated to levels that are expected to inhibit the enzymatic activity of the LVDR HBV polymerase. Finally, there was no in vitro evidence for cross-resistance between ADV and ETV18,19 nor for any functional interference between ETV and other nucleoside/nucleotide analogues used for the treatment of either HBV or HIV.
6.2 Clinical Resistance
Early clinical information about ETV resistance was obtained from two Phase 2 patients who developed rising viremia while on extended (> 1 year) ETV treatment. Both patients were nucleoside-experienced prior to their treatment with ETV, and isolates from both had LVDR substitutions (rtL180M, rtM204V/I) present at baseline. Investigations using on-treatment isolates from these two patients demonstrated genotypic changes at residues rtT184, rtS202, and/or rtM250, which proved to be associated with decreased ETV susceptibility. However, further in vitro work demonstrated that introduction of these particular substitutions into recombinant viruses resulted in significant reductions in susceptibility to ETV only when LVDR substitutions were also present.18 This clinical information, together with the earlier in vitro work showing that LVDR substitutions result in an 8-fold reduction in HBV susceptibility to ETV, provided guidance for the resistance investigations in the Phase 3 studies.
Current understanding regarding the frequency of ETV resistance in the clinical setting is based on analyses of baseline and on-treatment specimens from >700 patients treated with ETV in four studies. Data for nucleoside-naive patients were derived from AI463022 and AI463027, while data for LVD-refractory patients were derived from AI463026 and AI463014 (ETV 1.0-mg group). Sampling from the nucleoside-naive studies used baseline and Week 48 samples from >530 (>80%) of the nucleoside-naive ETV-treated patients and was supplemented by samples from all patients with viral rebound (defined as any increase in HBV DNA by ≥ 1 log10 by PCR from on-treatment nadir). Resistance testing in the LVD-refractory studies was performed on all available patient samples.
None of the nucleoside-naive patients had either genotypic or phenotypic evidence for ETV resistance emergence through the earlier of the last study visit or the Week 48 visit. Fourteen (2.1%) of ETV-treated nucleoside-naive patients (6 from AI463022 and 8 from AI463027) experienced a viral rebound on treatment, although none showed genotypic or phenotypic evidence for emerging ETV resistance. Among the 183 LVD-refractory, ETV-treated patients, 5 (2.7%) exhibited a virologic rebound during the first year of treatment, with rebounds in only 2 of 4 cases examined attributable to the presence of substitutions associated with ETVR.
ETVR substitutions can be selected by LVD, as they preexisted in at least 29 patients (including 6 detected using a highly sensitive detection assay) harboring LVDR virus, but in none of the nucleoside-naive patients. ETV does not select for LVDR substitutions de novo or for other novel substitutions beyond those at residues rtT184, rtS202, and rtM250 that are associated with increased phenotypic resistance to ETV. There was a strong correlation between the population wildtype phenotype (EC50 of ≦ 3 nM) of viruses at baseline and the maximal ETV antiviral efficacy in treated patients. Patients experiencing virologic rebound due to the emergence of resistance harbored viruses at Week 48 with ETV population susceptibility phenotypes of 87 and 986 nM; thus, a population susceptibility phenotype of approximately 100 nM may represent a potential threshold for clinically relevant resistance.
6.3 Summary of Resistance Evaluation
In transient HBV culture systems, ETV was the most potent nucleoside antiviral against LVDR HBV, despite its reduced susceptibility to ETV relative to WT HBV. These cell-based assays demonstrated that the presence of LVDR substitutions rtL180M and rtM204V in HBV clones resulted in an 8-fold decrease in viral susceptibility to ETV.
Addition of ETVR substitutions at rtT184, rtS202, rtM250V or the combination of rtT184G and rtS202I substitutions reduced ETV susceptibility 16 to 70, 11 to 100, 113-242, and > 741-fold, respectively. Treatment with ETV did not result in the emergence of viral resistance, either to ETV or LVD, in nucleoside-naive patients following 48 weeks of treatment. ETV was effective in patients harboring LVDR HBV, despite the reduced susceptibility of LVDR virus. Although genotypic changes associated with resistance to ETV can be present among patients who are LVD-refractory, the rate at which this occurs is limited and virologic rebounds due to resistance were infrequently observed (1%) during the first year of treatment.

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