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 lamivudinerefractory 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 C1 9 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 C1 9 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 123Hepatol Int (2010) 4:414-422 DOI 10.1007/s12072-009-9162-x 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.

Improvement in liver histology among Asian patients with chronic hepatitis B after long‐term treatment with entecavir

“…These observed improvements in liver histology during longterm ETV therapy were associated with high rates of virological, biochemical and serological responses. Our findings are notable because in Asians, CHB is associated with a different morbidity and prognosis because of mostly perinatal infection with HBV genotypes B and C. The results from the current study confirm and extend previous observations in Japanese patients (5)(6)(7) showing that Asian patients obtain a substantial benefit for improved liver histology and virological, biochemical and serological outcomes with long-term ETV therapy. Therefore, the long-term efficacy and safety of ETV in Asian patients with predominantly HBV genotype B or C infection is comparable to the experience in the overall CHB population (3).…”

Antiviral Drug Resistance Testing in Patients with Chronic Hepatitis B

“…Clinicians may continue entecavir or step up the dose to 1 mg daily as this was the dose used in previous long-term studies. In contrast, although primary entecavir resistance is rare, entecavir resistance may develop rapidly in patients with pre-existing lamivudine resistance [22,23]. Therefore, it is important to switch lamivudine to antiviral drugs with high genetic barrier to resistance in case of suboptimal viral suppression [24].…”

Do different lamivudine‐resistant hepatitis B genotypes carry the same risk of entecavir resistance?

“…In a subgroup analysis of a 3‐year Japanese study [Suzuki et al, 2009], all the patients (5 out of 19 patients) who developed entecavir‐resistant HBV mutants had developed the rtM204V mutation in the presence or absence of rtM204I, but none with rtM204I alone. Karino et al [2010] and Cho et al [2010] reported similar entecavir‐resistance rates in previous lamivudine‐refractory patients. Karino et al [2010] (n = 82, ETV 0.5 mg and 1.0 mg for 3 years) did not report on the influence of the types of baseline lamivudine‐resistant mutation on subsequent outcome.…”

“…Karino et al [2010] and Cho et al [2010] reported similar entecavir‐resistance rates in previous lamivudine‐refractory patients. Karino et al [2010] (n = 82, ETV 0.5 mg and 1.0 mg for 3 years) did not report on the influence of the types of baseline lamivudine‐resistant mutation on subsequent outcome. In the study by Cho et al [2010] (n = 40, ETV 1.0 mg for 48 weeks), only patients with rtM204V at week 48 had high viral load.…”