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

Abstract

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.

Keywords: Chronic hepatitis B; Entecavir; Japanese; Lamivudine refractory; Lamivudine resistant.

Figures

Fig. 1

Lamivudine-refractory, long-term treatment cohort. Eighty-two patients completed 52 weeks of treatment in study ETV-052 and entered rollover study ETV-060, with no interruption or gap in treatment. Sixty-five patients remained on treatment (entecavir 1.0 mg daily) through 96 weeks in study ETV-060, for a total entecavir treatment time of 148 weeks

Fig. 2

Distribution of HBV DNA over time in the lamivudine-refractory, long-term treatment cohort. The proportion of patients with HBV DNA of >400 copies/mL increased through ETV-060 week 96 (148 weeks of total entecavir treatment time)

Fig. 3

Proportions of patients with normal ALT (ALT ≤ 1.0 × ULN) over time in the lamivudine-refractory, long-term treatment cohort. Seventy-eight patients had abnormal ALT (ALT > 1.0 × ULN) at pretreatment baseline. At week 96 of study ETV-060, patients had received a total of 148 weeks of entecavir therapy

Fig. 4

Proportions of patients with HBeAg loss and HBe seroconversion over time in the lamivudine-refractory, long-term treatment cohort. Sixty-two patients were HBeAg positive at pretreatment baseline. At week 96 of study ETV-060, patients had received a total of 148 weeks of entecavir therapy

Fig. 5

Distribution of Knodell necroinflammatory scores (a) and Knodell fibrosis scores (b) at baseline, year 1 (48 weeks), and year 3 (148 weeks) for the 16 patients who had evaluable liver biopsies at all 3 time points