Dimou et al of resistance ( 1,000-fold reduction in ETV susceptibility) (Tenney et al 2004). It is obvious that the pattern of ETV- resistance is more complicated than LAM or ADV resistance because 3 or 4 substitutions in the polymerase region are required. Moreover, LAM-resistance substitutions are neces- sary for the development of ETV resistant mutant. Until now three patterns of ETV resistance have been detected in LAM resistant strains: (1) substitutions rtI169T and rtM250V, (2) substitutions rtS184G and rtS202I and (3) substitutions rtS202G (Villet et al 2005). In vitro studies have shown that ETV-resistant strains have no effect on the susceptibility to ADV. In 2 patients with ETV-resistance, ADV was administered in a dose of 10 mg daily with marked reduction in the viral load (Tenney et al 2004). Thus, on clinical grounds ADV seems quite effec- tive in patients with HBV mutants resistant to ETV and is probably the treatment of choice. No evidence of resistance up to week 96 has been reported among ETV-treated nucleoside naïve patients (Gish et al 2005; Chang et al 2006a; Colonno et al 2006a; Lai et al 2006b; Shouval et al 2006). However, data from a recent study of 3 years of ETV treatment have shown that the previous con- cept of no-resistance in naive patients on ETV monotherapy is under question (Colonno et al 2006b). In this study, 3 HBeAg-positive patients experienced a virologic breakthrough with genotypically conﬁrmed resistance in the third year of treatment. Although this data, obtained under a complex study design, are compatible with a rate of resistance lower than 1% at the third year of treatment, this has to be conﬁrmed fol- lowing a wide use of the drug in clinical practice (Figure 3). Moreover, while ETV genotypic resistance in LAM resistant mutants has been reported to be very low (6%) during the ﬁrst year of therapy increasing to approximately 14% at year two, new calculations on genotypic resistance have disclosed a cumulative rate of more than 30% at year 3 (Figure 3) (Colonno et al 2006b). Though a number of these patients may remain in low serum HBV-DNA levels, viral rebound increases from 1% at the ﬁrst to 10% at the second and 25% at the third year of treatment. For the time being the rate of biochemical resis- tance remains unknown because the deﬁnition of biochemical breakthrough (ALT 2x baseline or 10xULN) applied in this study (Colonno et al 2006b) actually refers to biochemical ﬂares and not to biochemical breakthroughs which represent increase of normal ALT values to 1.25xULN. As in the case of ETV therapy, patients with LAM- resistant HBV mutants treated with Adefovir monotherapy 32% 40 ) 30 % ( E C N A T S IS20 E R R I V A C E TN10 E 0 <1% 1 NAÏVE LAM-R <6% <1% 2 14% <1% 3 YEARS Figure 3 The rate of Entecavir resistance in Naïve and Lamivudine-resistance chronic hepatitis B patients during 3 years of treatment. Colonno RJ.AASLD 2006.Abstract 110. 1084 Therapeutics and Clinical Risk Management 2007:3(6)