Entecavir Two-Year Resistance Update

Entecavir (ETV) [Baraclude] is a potent inhibitor of hepatitis B virus (HBV) with proven clinical efficacy. High level ETV resistance (ETVr) requires pre-existing lamivudine (LVD)-resistance (LVDr) substitutions and additional changes at HBV RT residues rtT184, rtS202 or rtM250.

Patients receiving ETV for 1 year showed no evidence of emerging ETVr in nucleoside-naïve patients and virologic rebounds due to ETVr in only 1% of LVD refractory patients.

Virologic rebounds (confirmed ³1 log increase from nadir by PCR) observed in patients from studies AI463-022 & AI463-027 (nucleoside naïve), AI463-014 & AI463-026 (LVD refractory), and AI463-901 (extended treatment) were analyzed for emerging ETVr.

Genotypic analysis compared patient HBV RT sequences with those at study entry and with wild type (WT) HBV.

Phenotypes of emerging substitutions were determined using antiviral assays measuring

HBV DNA yields from HepG2 cells transfected with plasmids expressing patient RT sequences.

Results:

• Among >650 nucleoside naïve, HBeAg pos & HBeAg neg patients completing at least 24 wk of ETV therapy, 93% achieved HBV DNA reductions to <300 copies/ml. Over 200 patients completed ≥ 90 wks of therapy.
• Genotypic analysis of the 18 observed virologic rebounds (2 year treatment period) failed to show any evidence of emerging ETVr substitutions, with population phenotypes at the time of rebound essentially unchanged from baseline or WT.
• Four additional patients failing to achieve HBV DNA reductions <100,000 copies/ml on ETV also had HBV fully susceptible to ETV.
• Therefore, there is no evidence of ETVr emerging in nucleoside naïve patients treated with ETV.
• Virologic rebounds due to resistance were observed in 10% of LVD refractory patients treated with ETV for 2 years.
• In all cases, ETVr variants had pre-existing LVDr substitutions and emerging changes at residues rtT184 and/or rtS202.
• Of the 12 patients exhibiting a rebound, 2 had been on suboptimal ETV therapy (0.5 mg) and 3 others received ETV/LVD combination therapy.
• Subsequent analysis of baseline viral samples demonstrated selection of ETVr substitutions during prior LVD treatment.

Conclusions

There was no evidence of emerging ETVr in nucleoside treatment naïve subjects undergoing 2 years of ETV therapy, coinciding with substantial suppression of viral DNA levels.

Among LVD refractory patients, 10% experienced virologic rebounds due to emerging ETVr by the 2nd yr of therapy. Phenotypic ETVr required the presence of pre-existing LVDr substitutions, which can be selected with exposure to LVD. Therefore, LVD treatment results in frequent emergence of LVDr and may negatively impact future HBV treatment options.

R Colonno and others. Entecavir Two Year Resistance Update: No Resistance Observed in Nucleoside Naïve Patients and Low Frequency Resistance Emergence in Lamivudine Refractory Patients. Abstract 962

11/16/05

Reference

R Colonno and others. Entecavir Two Year Resistance Update: No Resistance Observed in Nucleoside Naïve Patients and Low Frequency Resistance Emergence in Lamivudine Refractory Patients. Abstract 962. Program and Abstracts of the 56^th annual meeting of the American Association for the Study of Liver Diseases. November 11-15, 2005. San Francisco, CA.