In HBeAg-positive CHB, HBeAg seroconversion was achieved in 12% of patients at the ﬁrst year, increasing to 29% and 43% at the second and third year of therapy respectively (Marcellin et al 2003, 2005). In HBeAg- negative CHB, long-term ADV therapy is associated with undetectable serum HBV DNA in 71%, 79%, 65% and 67% at year 2, 3, 4 and 5, respectively (Hadziyannis et al 2003, 2005a, 2005b, 2006). ADV resistance is delayed and infre- quent developing after the ﬁrst year of treatment. Genotypic HBV resistance may emerge in 3%, 11%, 18% and 29% of patients at years 2, 3, 4 and 5 of treatment, respectively (Hadziyannis et al 2003, 2005a, 2005b, 2006). However, virologic and biochemical breakthroughs at year 5 are restricted only to 16% and 11% respectively (Hadziyannis et al 2006). In patients with LAM-resistant HBV strains, treatment with ADV alone or in combination with LAM has similar rate of virological (26% vs 35%) and biochemi- cal response (47% vs 53%) at one year (Peters et al 2004). However, longer duration of treatment has shown that adding adefovir on lamivudine rather than switching from lamivudine to adefovir represents the treatment of choice in patients developing LAM-resistant HBV mutants (Fung et al 2005, 2006; Lampertico et al 2006; Rapti et al 2007). Telbivudine Telbivudine (LdT, β-L-2'-deoxythimidine, Idenix, Cambridge, MA) is an L nucleoside analogue of thymidine, approved by FDA on late 2006 for the treatment of chronic hepatitis B under the trade name of Tyzeka at a daily dose of 600 mg. It is a reverse transcriptase inhibitor and acts by competing with the natural substrate thymidine 5' triphosphate and its incorporation into viral DNA causes chain termination, resulting in inhibition of HBV replication. It is a potent anti-HBV agent inhibiting the synthesis both of the ﬁrst and the second DNA strand of the virus and in phase II studies it has been found to be more effective than lamivudine. In HBeAg-positive patients it achieved a greater reduction in HBV DNA levels (6.01 log10 vs 4.57 log10, p 0.05) as well as higher rates of HBV DNA undetectability (61% vs 32%, p 0.05) and normalization of ALT levels (86% vs 63%, p 0.05) (Lai et al 2004; Lai et al 2005a). The year 1 and 2 results of a very large registration trial in 1367 individuals with HBeAg-positive and -negative CHB, the GLOBE trial, have been reported in the 2005 AASLD (Lai et al 2005b) and the 2006 EASL (Thongsawat et al 2006) and AASLD (Lai et al 2006a) Meetings. The following important observations came out from the analyses of the results at weeks 52 and 104 of this pivotal LdT study: Therapeutics and Clinical Risk Management 2007:3(6) Entrcavir in hepatitis B 1. LdT is equally safe but more effective than lamivudine in terms of absolute HBV DNA reduction from baseline (HBeAg-positive: 6.5 log10 vs 5.5 log10 at week 52, p 0.05 and 5.7 log10 vs 4.4 log10, p 0.05, at week 104, respectively, HBeAg-negative: 5.2 log10 vs 4.4 log10, p 0.05 at week 52 and 5 log10 vs 4.2 log10, p 0.05 at week 104, respectively) and time of undetect- ability. However there is no signiﬁcant difference from LAM in HBeAg loss and seroconversion to anti-HBe (26% vs 23% at week 52, 35% vs 29% at week 104 and 22% vs 21% at week 52, 30% vs 25% at week 104, respectively) (Lai et al 2006b). 2. Treatment failures and HBV resistance are less frequent with LdT compared to LAM (treatment failure in HBeAg- negative patients 0.9% vs 7.6%, p 0.001 and in HBeAg- positive 6.8% vs 18.8%, p 0.001, respectively) (Lai et al 2006b). 3. Both in LdT and LAM treated HBeAg-positive patients, the rates of HBeAg seroconversion are signiﬁcantly increased if a profound and rapid HBV suppression to undetectability of serum HBV DNA at week 24 is achieved, this effect being also associated with enhanced T-cell reactivity to HBc protein (Cooksley et al 2006). Entecavir Entecavir, a novel carbocyclic analog of 2' deoxyguanosine (Figure 2), has been approved in 2005 in USA and in 2006 in Europe for naïve and lamivudine-resistant chronic hepatitis B treatment. Data on its safety, side effects, short- and long- term efﬁcacy and HBV resistance in the various subsets of HBV patients are critically reviewed in this article. In Figure 1 the HBeAg response rates achieved with one year of therapy by ETV, the other three approved nucleos(t)ides and pegylated interferon-alfa2a together with their potency in terms of log reduction in HBV DNA levels are shown in a comparative way. Entecavir in chronic hepatitis B Entecavir therapy in treatment-naïve patients with chronic hepatitis B The safety and efﬁcacy of ETV were initially evaluated in a randomized, placebo-controlled, dose-escalating study (De Man et al 2001). In patients with CHB, ETV was admin- istered at doses of 0.05 mg, 0.1 mg, 0.5 mg and 1 mg and compared to placebo for 28 days (De Man et al 2001). All patients were followed-up 24 weeks off therapy. All doses of ETV were well tolerated and were associated with a signiﬁ- cant decline in serum HBV DNA levels. However, a slower 1079