priming of HBV DNA polymerase as well as the synthesis of the first and second strand of HBV DNA. In a recent study of 715 patients with HBeAg(+)CHB, the mean reduction in serum HBV DNA from baseline to week 48 was greater with ETV 0.5 mg than with LVD 100 mg (6.9 vs. 5.4 log10 copies/mL, p 0.001) (Chang et al 2006b). However, HBeAg seroconversion (or HBeAg loss) at 48 weeks between the two arms were similar; 21% (22%) for ETV and 18% (20%) for LVD. Histologic improve- ment after 48 weeks was observed more frequently in the ETV group (72%) and than in the LVD group (62%). Virological rebound during the first years of drug therapy was observed in 2% of the ETV group compared with 18% of LVD group. Genotype analysis of isolates obtained at week 48 from the six ETV-treated patients revealed no emerging substitutions compared with baseline samples. No resistance to ETV was reported 48 weeks in treatment naïve patients and less than 1% at year 3. In a study of 648 patients with HBeAg(–) CHB, more patients in the ETV group than in the LVD group had undetectable HBV DNA at week 48 (90% vs. 72%). Patients treated with ETV had statistically significant improvements in the mean reduction of serum HBV DNA levels from baseline to week 48 when compared with patients on LVD therapy (5.0 vs 4.5 log10 copies/ml, p 0.001) (Lai et al 2006). ETV has also been shown to be effective against both LVD-resistant HBV and wild type. One mg is the most effective dose for patients who failed to respond to LVD as shown in a study with 182 subjects (Chang et al 2005 ). ETV resistance emergence in ETV-treated nucleoside naïve patients over a 4-year period was only 0.8%. However, the rate of ETV resistance increased to 1, 10, 32 and 39.5% at year 1, 2, 3, and 4 in lamivudine refractory patients (Colonno et al 2007). In a recent study patients with CHB were randomized to receive open label ETV 0.5 mg/day and ADV 10 mg/day and assessed for reductions in HBV DNA levels (Leung et al 2006). By week 24, ETV-treated patients achieved a mean log HBV DNA reduction of 6.97 compared to 4.84 for ADV treated patients. Undetectable HBV DNA ( 300 copies/mL by PCR) was achieved by week 24 in 45% of ETV-treated and 13% of ADV-treated patients. A recent 3 year ETV study demonstrated that by week 144, 90% of 122 patients in the study showed unde- tectable HBV DNA ( 300 copies/ml by PCR), 80% had normalization of ALT (ALT 1 × ULN), 33% and 16% of patients achieved HBeAg loss and HBeAg seroconversion, respectively (Chang et al 2006a). Therapeutics and Clinical Risk Management 2007:3(4) Time for an active therapy for HBV Telbivudine (LdT or TLV) Telbivudine (LdT or TLV) is a beta -L-2’deoxythymidine which acts as a speciﬁc inhibitor of HBV polymerase. In a three-arm trial, LdT monotherapy was compared with LVD monotherapy and the combination of LdT and LVD in patients with HBeAg(+) CHB (Lai et al 2005). At week 52, LdT monotherapy produced a signiﬁcantly greater mean log HBV DNA reduction (6.09 vs 4.57 log10 copies/ml), undetectable HBV DNA (61% vs 32%) and normalization of ALT (86% vs 63%) (all, p 0.05) compared to LVD monotherapy. The combination treatment was not better than LdT alone. HBeAg seroconversion was 31% for LdT and 22% for LVD. Viral breakthrough was 4.5% compared to 15.8% for LVD. (Lai et al 2005). In the GLOBE Trial 1,367 patients with 921 HBeAg(+) and 446 HBeAg(–) CHB from 20 different countries were randomized to receive LdT or LVD (Lai et al 2006). Patients who received LdT had statistically signiﬁcant HBV DNA reduction than those who received LVD regardless of HBeAg status. Drug resistance for HBeAg(+) group was 4.4% for LdT and 9.1% for LVD; for HBeAg(–) CHB patients, 2.7% of LdT and 9.8% of LVD developed drug resistance. Interestingly, LdT resistance mutations were solely M204I whereas LVD resistance mutations were a mixture of M204V, M204I and M204V + L180M double mutants. The efficacy of LdT and ADV was studied in 135 patients with HBeAg(+) compensated CHB. The HBV DNA reduction at week 24 was far better for LdT than for ADV (Bzowej et al 2006). Another recent study which included both HBeAg(+) and (–) compensated CHB patients, investigated whether patients receiving LVD therapy would benefit from switching to LdT. Patients were randomized to either continue LVD (n = 124) or switch to LdT (n = 121) for 1 year. In patients with per- sistent viremia during LVD therapy, switching to LdT was associated with a significantly improved HBV sup- pression (Gane et al 2006). Tenofovir disoproxil fumarate (TDF) TDF is an acyclic nucleoside phosphonate (nucleotide) ana- logue of adenosine 5’-monophosphate. It inhibits HBV DNA polymerase and HIV reverse transcriptase, with close chemi- cal similarity to ADV. At the present time, TDF is FDA-ap- proved for the treatment of patients with HIV and not for those with HBV. The activity of TDF in LVD-resistant HBV has been observed in patients coinfected with HIV and HBV 609