Entecavir at Five Years Shows Long-Term Maintenance of High Genetic Barrier to Hepatitis B Virus Resistance

Aims: Entecavir (ETV) provides both potent viral suppression and a high genetic barrier to resistance, requiring ≥3 resistance substitutions. As a result, in nucleoside-naïve patients, ETV resistance (ETVr) was rare through 4 years. The genetic barrier in lamivudine(LVD)-refractory patients was reduced.

Methods: All patients receiving continuous therapy in phase II/III trials were monitored for resistance through year 5. Detectable patient HBV DNA (≥300 copies/mL) was sequenced in each year. Cumulative probabilities of resistance were determined through year 5.

Results: In years 1 through 5, respectively, 663, 278, 149, 120 and 108 nucleoside-naïve patients were treated and monitored, with 93% in year 5 having HBV DNA <300 copies/mL. No patients with year 5 detectable virus showed emerging ETVr at T184, S202 or M250±LVD resistance (LVDr) M204I/V±L180M. The cumulative probability of genotypic ETVr remained 1.2% through 5 years. Among LVD-refractory patients treated with ETV, 187, 146, 80, 53 and 33 were monitored in years 1 through 5, respectively. The cumulative probabilities of genotypic ETVr at years 1 through 5 were 6%, 15%, 36%, 46% and 51%, respectively, and virologic breakthrough with ETVr was 43% through year 5. Among 68 LVD-refractory patients who achieved undetectable HBV DNA on ETV, 1 subsequently developed ETVr with virologic breakthrough.

Conclusions: ETVr remains rare (1.2%) in nucleoside-naive patients through 5 years. LVDr patients have a reduced barrier to ETV resistance and may benefit from combination therapy.