Dimou et al CH2 Figure 2 The chemical structure of entecavir. rebound of viremia in the post treatment follow-up period was observed with the 0.5 and 1 mg of ETV compared with the other two lower doses (p 0.05) (De Man et al 2001). During the post-treatment period, 9% of ETV treated patients experienced hepatic ﬂares deﬁned as elevation in ALT greater than twice the baseline level and more than 10 times the upper limit of normal. None of these ﬂares were associated with elevated bilirubin levels and were not clinically signiﬁcant. This study has showed that ETV is a potent inhibitor of HBV in humans, but longer duration dosing trials should be performed before deﬁnite conclusions about the safety and the role of ETV in the treatment of chronic hepatitis B infection are made. In another double-blind randomized study, the safety and efﬁcacy of 3 doses of ETV were evaluated and compared to LAM in patients with CHB (Lai et al 2002). Entecavir doses of 0.01 mg, 0.1 mg, 0.5 mg and LAM 100 mg daily were administered for 24 weeks. Complete response was deﬁned as undetectable serum HBV DNA by bDNA (cut-off 0.7 Meq/mL) at week 22, with normal ALT and undetectable HBeAg for HBeAg-positive patient at baseline. Treatment was discontinuated in individuals with complete response and they were followed-up for 12 weeks. Partial response was deﬁned as undetectable serum HBV DNA by bDNA assay at week 22, but without loss of HBeAg for HBeAg-positive patients or with elevated ALT for HBeAg-negative patients at baseline. In these patients, LAM 100 mg were given for 48 weeks. The nonresponders (detectable HBV DNA by bDNA) were managed after week 24 by their physician and followed-up for 12 weeks. One hundred sixty-nine patients (81% HBeAg-positive) completed 24 weeks of treatment period. At the end of therapy a signiﬁcantly higher proportion (83.7%) of patients receiving 0.5 mg of ETV had undetectable 1080 HBV DNA levels (bDNA 0.7Meq/mL) compared to LAM 100 mg (57.5%, p = 0.008), while the response to the ETV 0.1 mg dose was similar with LAM (61.8% vs 57.5%). Serum HBV DNA undetectable by the b-DNA assay and ALT normalization were observed in 23.1% and 50%, 61.8% and 83.3%, 83.7% and 69%, 57.5% and 59.1% at the 0.01, 0.1, 0.5 mg ETV and the 100 mg LAM, doses respectively (Lai et al 2002). Complete or partial response occurred in 23%, 62%, 84% and 57% of patients in the 0.01 mg, 0.1 mg and 0.5 mg ETV and LAM group, respectively. After discontinu- ation of treatment, ALT elevation 3xULN was observed in 21% of patients in the 0.01 mg ETV group compared to 10.5% in the LAM group and in 3% and 4.5% in the 0.1 and 0.5 mg ETV groups respectively. On the basis of the results of this study it was considered that the optimal dose of ETV for the treatment of naïve patients should be 0.5 mg daily (Lai et al 2002). Efﬁcacy in HBe-positive patients In a randomized phase III double-blind trial, 715 treatment- naïve, HBeAg-positive (+) CHB patients were assigned to receive either 0.5 mg of ETV or 100 mg of LAM once daily for a minimum period of 52 weeks (Chang et al 2006a). Accord- ing to the study protocol clinical-management decisions were made at week 52 on the basis of the results of HBV DNA lev- els (b-DNA) and HBeAg assays on serum samples obtained at week 48. Patients who had a complete response deﬁned as undetectable serum HBV DNA levels ( 0.7 Meq/mL) and HBeAg loss and the nonresponders deﬁned by serum HBV DNA levels 0.7 Meq/mL discontinued treatment at week 52. Patients who achieved only virologic response [unde- tectable serum HBV DNA levels ( 0.7 Meq/mL), without HBeAg loss] were continued on therapy up to 96 weeks Therapeutics and Clinical Risk Management 2007:3(6)