In a randomized phase III trial, in HBeAg-positive CHB patients with LAM-resistant HBV, ETV 1 mg daily was compared with LAM 100 mg daily for at least 52 weeks (Sherman et al 2006). In this study clinical management decisions were again made at week 52, based on week 48 results. Responders deﬁned by serum HBV DNA levels 0.7 Meq/mL by bDNA assay and HBeAg loss at week 48 and nonresponders (HBV DNA levels 0.7 Meq/mL) discontin- ued treatment and followed-up for 24 weeks period. Patients with only virologic response at week 48 as deﬁned by serum HBV DNA levels 0.7 Meq/mL by bDNA assay, without HBeAg loss, continued study medication until week 96 (Sherman et al 2006). At week 48, histologic improvement observed in a higher proportion of patient in the ETV than in LAM group (55% vs 28%, p 0.001) (Table 2). Moreover the rates of virological response ( by PCR assay) and return of ALT to normal were higher in the ETV than in the LAM treated patients, 19% vs 1%, (p 0.0001) and 61% vs 15%, (p 0.0001), respectively. The rate of HBeAg seroconver- sion did not differ between the two groups (ETV group 8% and LAM group 3%, p = 0.06). At baseline 18 (6%) of lamivudine-refractory patients had substitutions that confer resistance to lamivudine and entecavir. Genotypic analysis of paired baseline and week 48 samples were performed for 134 of the 141 ETV-treated patients and reveled 7 patients with mutations associated with ETV resistance at baseline. None of these patients exhibited virologic rebound during the ﬁrst year of therapy. Two other patients (1.4%) experienced a virologic rebound during ETV-treatment and genotypic analysis revealed mutations that confer resistance to ETV (Sherman et al 2006). A number of patients in the ETV and the LAM groups continued treatment for a second year (Yurdaydin et al 2006). The cumulative conﬁrmed virologic, serologic (HBeAg seroconversion) and biochemical response at week 96 in the ETV and LAM groups were 30% and 1%, (p 0.0001), 16% and 4%, (p = 0.0011) and 85% and 29%, (p 0.0001), respectively. Nine percent of the ETV treated patients exhib- ited viral rebound due to ETV resistant mutations (Yurdaydin et al 2006). After several years of use of adefovir dipivoxil, HBV resistance to this compound has been recognized among patients under long-term ADV monotherapy particularly after the second year of treatment with genotypic ADV resistance reaching 29% at year ﬁve. In vitro studies have shown that ETV inhibits effectively the replication of ADV resistant HBV mutants (Brunelle et al 2005). However, clinical studies on the efﬁcacy of ETV in patients with ADV-resistant HBV Therapeutics and Clinical Risk Management 2007:3(6) Table 2 Comparison of entecavir vs lamivudine in HBeAg positive lamivudine-resistance patients with chronic hepatitis B (CHB) Undetectable HBV DNA ALT Normal HBeAg seroconversion Histologic improvement ETV resistance Week 48 ETV 19% 61% 8% 55% 6% LAM 1% 15% 3% 28% Entrcavir in hepatitis B Week 96 ETV 30% 85% 16% 9% LAM 1% 29% 4% Abbreviations: ETV, entecavir; LAM, lamivudine;ALT, alanine aminotransferase; NA, non applicable; vs, versus. (Sherman et al 2006;Yurdaydin et al 2006) mutants have not been performed yet, but in one recent report ETV treatment in two patients with ADV resistance showed a 3 log10 decline of HBV DNA levels after 6 months of therapy (Fung et al 2005). Entecavir resistance Entecavir resistance was ﬁrst been identiﬁed in two patients with LAM-resistant strains, who experienced virologic breakthrough after more than 1 year of ETV therapy (Tenney et al 2004). Genotypic analysis of the polymerase region before the initiation of ETV treatment, had shown substitu- tions conferring HBV resistance to LAM therapy: rtL180M, rtM204V, rtV173L in both patients. Genotypic analysis of the polymerase region after virologic breakthrough under ETV treatment showed that in addition to the LAM-resistance substitutions, the unique substitutions rtI169T (domain B) and rtM250V (domain E) in the ﬁrst patient and the rtS184G (domain B) and rtS202I (domain C) in the second one emerged (Tenney et al 2004). Phenotypic analysis of recom- binant HBV genomes, containing patients’ RT domains or speciﬁc mutations, was performed. Substitution rtI169T alone or in combination with LAM-resistance substitutions did not decrease the susceptibility to ETV. Substitution rtM250V alone conferred a low level of ETV resistance, while in combination with LAM-resistance substitutions, a 1,000-fold reduction in ETV susceptibility was observed. Substitutions rtS184G and rtS202I alone did not confer resis- tance to ETV, while either substitution in combination with LAM-resistance substitutions slightly reduced the suscepti- bility to ETV. HBV containing all 4 substitutions rtL180M, rtM204V, rtS184G and rtS202I exhibited the highest level 1083