Prior exposure to lamivudine increases entecavir - resistance risk 1 in chronic hepatitis

44 The efficacy of entecavir (ETV) in chronic hepatitis B (CHB) patients who were 45 exposed to lamivudine (LAM), but had no detectable LAM-resistance (LAM-R) is not 46 well evaluated. In this study, we aimed to evaluate whether the probability of 47 developing genotypic resistance to ETV in LAM-exposed patients with/without LAM-R 48 is comparable to that in antiviral-naïve patients. This retrospective cohort study 49 included 500 consecutive patients with CHB who started ETV monotherapy at a single 50 tertiary hospital in Korea. The patients were divided into three groups: NA-naïve 51 patients (group 1, n=142), patients who were ever exposed to LAM with no currently or 52 previously detected LAM-R (group 2, n=233), and patients with LAM-R when starting 53 ETV (group 3, n=125). Overall median ETV treatment duration was 48.7 months. 54 The probabilities of virologic breakthrough were significantly increased not only in 55 group 3 (hazard ratio [HR]=14.4, P < 0.001) but also in group 2 (HR=5.0, P < 0.001), 56 compared to group 1. Genotypic ETV-resistance (ETV-R) was more frequently 57 developed in group 2 (HR=13.0, P = 0.013) as well as group 3 (HR=43.9, P < 0.001) than 58 in group 1: the probabilities of developing ETV-R in groups 1, 2 and 3 were <1.0, 8.0, 59 and 28.2%, respectively, at month 48. This study indicates that ETV-R occurred more 60 frequently in LAM-exposed patients, even though they had no detectable LAM-R, than 61 in NA-naïve patients. Therefore, LAM-exposed CHB patients, regardless of LAM-R, 62 should be monitored more cautiously for the development of ETV-R during ETV 63