Chae and Hann of normal (ULN), 1–2 × ULN and 2 × ULN, respectively. However, these differences were not statistically signiﬁcant. Also, in both HBeAg(+) and HBeAg(–) patients, there were no signiﬁcant differences in the loss of HBV DNA among the three ALT groups. Resistance to lamivudine (LVD) Lamivudine (LVD) treatment of greater than 1 year has been associated with a steady increase in LVD resistance with reported rates of resistance of 38% and 65% at 2 and 5 years, respectively (Lok et al 2003) For LVD-resistant patients it is generally recommended to overlap ADV with LVD for some time during the switch to ADV. The role of continuing LVD treatment in patients with LVD-resistant HBV who are receiving adefovir is controversial. A pooled study of 467 patients with LVD resistant HBV demonstrated that resistance to ADV was seen only in those who stopped LVD (Snow et al 2005). Lee et al (2006) also found 18% ADV resistance in LVD resistant CHB patients who received ADV monotherapy. In recent reports on both HBeAg(+) and HBeAg(–) LVD-resistant CHB patients, the combination of LVD and ADV showed a superior virologic response when compared to ADV monotherapy (Barbon et al 2006; Lampertico et al 2006). Prolonged treatment: beneﬁts and limitations Prolonged treatment with LVD is generally well tolerated. In patients with HBeAg(–) CHB. Prolonged LVD therapy (3.8 ± 1.4 years) has been associated with improved sur- vival and reduction in the risk of liver related complica- tions, seemingly equivalent to that observed in sustained responders to IFN-α therapy (Papatheodoridis et al 2005). A major problem complicating prolonged or long-term therapy with LVD, however, is the progressive increase in drug resistance. Recent study by Chae and Hann (2006), however, suggested that patients with a baseline HBV DNA level 6 log10 copies/mL have a much lower incidence of LVD resistance; 3% at 1 year, 9% at 2 years and 32% at 3 years of LVD therapy. In contrast, patients with a baseline HBV DNA 6 log10 copies developed LVD resistance at a rate of 10% at 1 year, 36% at 2 years and 74% at 3 years. Therefore, patients with low baseline HBV DNA may still beneﬁt from long-term LVD therapy. LVD is also the least expensive among all antiviral drugs. The majority of HBV patients live in HBV endemic countries and these countries are also economically disadvantaged. Given that CHB management required long-term therapy, the cost of 608 treatment can become an important personal and national issue (especially in hyperendemic regions). Adefovir dipivoxil (ADV) Adefovir dipivoxil (ADV) is the acyclic analogue of dAMP. In 2002, ADV received FDA approval for the treatment of patients with HBeAg(+) and HBeAg(–) CHB. It is a prodrug with enhanced oral availability. ADV has activity in vitro against both wild type and LVD-resistant HBV strains. For this reason, ADV has been used to treat patients with LVD resistance. Monotherapy with ADV 10 mg/day for HBeAg(+) patients leads to marked decrease in HBV DNA levels (by 3 to 4 log10 units), improvements in serum ALT and hepatic histol- ogy and increased rates of HBeAg seroconversion (Marcellin et al 2003). After 3 years of treatment HBeAg loss was 51%, HBeAg seroconversion 43% and 56% of patients had unde- tectable HBV DNA (Marcellin et al 2005). Similar trials have been carried out in patients with HBeAg(–) CHB, in whom improvements in serum ALT and liver histology occurred in more than 60% of patients (Hadziyannis et al 2005a). Long-term treatment of adefovir (ADV) Prolonged treatment with ADV has been reported to be associated with an increasing virologic response in HBeAg(+) and HBeAg(–) CHB and has been found to be generally safe. ADV treatment for 3 years results in an increase in HBeAg seroconversion (12 % at year 1, 29 % year 2, and 43% at year 3) (Marcellin et al 2005). Three years of continuous treatment also has been associated with a progressive decline in serum HBV DNA and an increase in the percentage of patients becoming HBV DNA negative by PCR in HBeAg(–) CHB (Hadziyannis et al 2005b). Serum creatinine should be monitored as slight elevations in serum creatinine have been observed in less than 2% of patients treated with 10 mg daily for 2 to 3 years and rarely require discontinuation of drug. (Hadziyannis et al 2005b). The resistance proﬁle of ADV is better than that of LVD. Hadziyannis et al (2005a), in a study of 185 HBeAg(–) patients, reported ADV-resistance rates of 3% of patients at year 2, 11% at year 3, 18% at year 4 and 29% at year 5. However, others in a smaller study reported a higher cumulative prob- ability of resistance to ADV of 22% after 2 years (Fung et al 2006). The N236T and A181V/T ADV resistant mutants have been reported, both of which are sensitive to LVD therapy. Entecavir (ETV) Entecavir (ETV) is a cyclopentyl guanine nucleoside analogue. ETV blocks HBV replication by inhibiting the Therapeutics and Clinical Risk Management 2007:3(4)