Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

Purpose: Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudine-refractory Japanese patients treated with entecavir for 3 years. Methods: Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples. Results: After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55% (36/65) of patients had hepatitis B virus (HBV) DNA of >400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of ≤1 × upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion. A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of >400 copies/mL, 84% (27/32) had ALT of ≤1 × ULN, and 15% (4/27) achieved HBe seroconversion. Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares. Conclusions: Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.