are also at signiﬁcantly higher risk to develop ADV resistant HBV mutants than LAM-naïve patients (Fung et al 2005, 2006; Villet et al 2005; Yim et al 2006). On the other hand no patient with LAM-resistant strains treated by the com- bination of ADV with LAM for up to 4 years, has hitherto developed ADV resistant HBV mutants (Lampertico et al 2005; Rapti et al 2007). It is therefore reasonable to suggest that in patients with LAM-resistance HBV mutants sequential nucleos(t)ide monotherapy should be avoided and combina- tion therapy be applied by 2 potent antiviral agents with different resistant proﬁles as is the case of combination of ETV with adefovir and preferable with tenofovir. Conclusions The high anti-HBV potency of entecavir, its impressive efﬁcacy in terms of rapid HBV suppression to undetectabil- ity of HBV DNA by most sensitive PCR assays, combined with its high genetic barrier to HBV resistance, make ETV monotherapy a very attractive option as ﬁrst line treatment in lamivudine-naïve CHB patients both HBeAg-positive and HBeAg-negative. However, the hitherto duration of ETV phase III trials is short, their extension design com- plex and appropriate long-term studies are needed before reaching deﬁnite conclusions on its very long-term safety and resistance. In the setting of cirrhosis and liver transplantation, exist- ing data are promising but limited. 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