Dimou et al undetectable serum HBV DNA ( 0.7Meq/mL by the b-DNA assay) and ALT levels below 1.25 times the upper limit of normal (ULN) and non response as a serum HBV DNA levels 0.7 Meq/mL. Treatment was discontinued at week 52 both in responders and non-responders. Patients with only virologic response ( = undetectable serum HBV DNA levels 0.7 Meq/mL) and ALT levels 1.25xULN were offered continued therapy for up to 96 weeks. Histologic improve- ment (reduction of necroinﬂammation) occurred at week 48 in signiﬁcantly more patients in the ETV than in the LAM group (70% vs 61%, p = 0.01). Undetectable serum HBV DNA levels by PCR and ALT normalization were observed in 90% and 78% and in 72% and 71% of patients treated with ETV and LAM, respectively (Lai et al 2006b). Eighty-ﬁve percent of patients in the ETV group and 78%, (p = 0.04) in the LAM group had responded at week 48 while 10% and 11% of each group had only virologic response. At the end of 24 weeks follow-up the response was sustained in 48% and 35% of the patients in the LAM and ETV group, respec- tively. There was no evidence of ETV resistance at week 48, in paired samples from 211 randomly selected patients in the ETV group but 5 (2%) of these patients experienced virologic rebound. Genotypic analysis from these patients revealed no emerging substitutions that confer resistance to ETV. Twenty-ﬁve patients (8%) in the LAM group had a virologic rebound during the treatment period (Lai et al 2006b). The adverse events between the two treatment groups were similar. Three patients in the ETV group experienced ALT ﬂares, associated with a reduction of HBV DNA levels by at least 2 log10, that resolved spontaneously, while such ﬂares occurred in 5 patients in the LAM group. In two of these 5 patients alanine aminotransferase ﬂares were associated with a reduction of HBV DNA levels by at least 2 log10 and in the other 3 with increasing HBV DNA levels. One of the last experienced the development of ascites. Post-treatment ALT ﬂares occurred in 8% of the patients in the ETV and in 11% in the LAM group (Lai et al 2006b). Twenty-six patients in the ETV and 28 in the LAM group continued therapy up to week 96 (Shouval et al 2006). The cumulative virologic response through week 96 was 94% and 77%, (p 0.0001) among ETV and LAM treated patients respectively, while biochemical response occurred in 89% and 84% of them (Shouval et al 2006). In Table 1 the response rates at year 1 and 2 in HBeAg- positive and HBeAg-negative patients treated by ETV or LAM are depicted. It is obvious that ETV is superior to LAM in terms of liver histology improvement, HBV DNA suppression, ALT normalization and the viral resistant 1082 strains development rate. Moreover despite the higher rate of HBV DNA suppression in ETV group the rate of HBeAg seroconversion was similar between the two groups for the treatment period. Data from the above studies also indicated that response rate to ETV did not differ between patients with and without cirrhosis on liver biopsy (Schiff et al 2005). Although the number of cirrhotic patients was small in the two studies, histologic improvement occurred in a similar rate between patients with or without cirrhosis on liver biopsy at baseline, 76% vs 72% in HBeAg-positive and 74% vs 70% in HBeAg- negative patients, respectively (Schiff et al 2005). Efﬁcacy of entecavir in patients with lamivudine- and adefovir-resistant HBV mutants The efﬁcacy and safety of ETV in LAM-resistance patients were initially evaluated in a double-blind randomized dose-ranging trial. In this study, 182 patients with HBeAg- positive and -negative CHB and LAM-resistant HBV were enrolled and treated with 3 different daily doses of ETV (0.1 mg, 0.5 mg and 1 mg) in comparison to LAM 100 mg daily (Chang et al 2005). A signiﬁcant higher proportion of patients in the ETV 1 mg (79%) and 0.5 mg (51%) groups achieved serum HBV DNA levels 0.7 Meq/mL (by bDNA assay) compared to the LAM group (13%, p 0.0001), after 24 weeks of treatment (Chang et al 2005). Moreover the proportion of patients with undetectable serum HBV DNA by PCR assay was higher in ETV 1 mg (26%) and 0.5 mg (26%) groups compared to LAM (4%, p 0.01) at 48 weeks of treatment. HBeAg seroconversion was achieved in a minority of HBeAg-positive patients in all treatment groups (Chang et al 2005). The rate of biochemical remission at week 48 was superior in ETV 1 mg (68%) and 0.5 mg (59%) than in LAM (6%, p 0.001). In this study superiority of ETV at dose of 1 mg for the treatment of LAM-resistant patients was revealed. At baseline, 87% of the patients had lamivudine resistance-associated substitutions and at week 48, 80% of them retained this substitution, regardless of treat- ment group. Entecavir-associated resistance substitutions (rtT184, rtS202 and rtM250) were detected in 6 patients at baseline and emerged in 2 entecavir-treated patients (1 receiv- ing 0.5 mg and 1 receiving 0.1 mg) during treatment period, but only one patient experienced viral rebound at week 48 (Chang et al 2005). Viral rebound was also observed in 5 ETV treated patients, but genotypic analysis could not reveal any entecavir-resistance mutations (Chang et al 2005). Therapeutics and Clinical Risk Management 2007:3(6)