Lamivudine (LVD) Epivir-HBV Zefﬁx (Asia) Name Interferon alpha -2b Adefovir Dipivoxil (ADV) Entecavir (ETV) Pegylated Interferon Alpha-2a Telbivudine (TLV or LdT)) 610 Chae and Hann who developed LVD resistance (Nunez et al 2002; Ristig et al 2002). Based on these experiences, TDF has been used off label for those with severe LVD resistance before the ap- proval of ADV in 2002. Furthermore, TDF has recently been compared with ADV in 40 patients with CHB who became LVD resistant. Patients in the TDF group exhibited a more rapid decline in HBV DNA during the treatment period, with a mean reduction of –4.8 and –6.6 log10 copies/mL at 3 and 6 months, compared to a mean reduction of .97 and –1.72 log10 copies/mLat 3 and 6 months respectively in the ADV group. (Van Bommel et al 2003, 2004). Hann et al (2006) have also observed the similar differences. Of 109 patients who developed LVD resistance, 65 were placed on ADV and 44 on TDF. At 12 months on either therapy, the HBV DNA log reduction was 5.03 ± 1.64 for TDF and 2.36 ± 2.37 for ADV treated patients (p = 0.001). Furthermore, HBV DNA reduction 3 log at 12 month was observed in 63% and 28 % of the TDF and ADV arms, respectively (p = 0.013). Table 1 Characteristics of FDA approved drugs for treatment of hepatitis B Characteristics of individual FDA approved drugs are listed in Table 1. Combination therapy With more antiviral agents becoming available, the future directions of CHB treatment may involve combination therapy, with the goals of reducing drug resistance, mini- mizing toxicities and maximizing efﬁcacy. Ideal synergistic regimen may be combination of two drugs with different mechanism. Potential combinations need to be studied in large well designed clinical trials. Although there were suggestions initially that the combina- tion of LVD and IFN-α may have an additive beneﬁt this has not yet been conﬁrmed in a large scale study (Marcellin et al 2004). Also the combination of LdT and LVD was not shown to be more efﬁcacious than LdT monotherapy (Lai et al 2005). The combination of emtricitabine and ADV showed more improved therapeutic effect and less frequent viral resistance (Conjeevaram and Lok 2003; Marcellin et al 2004; Lau et al 2005; Chae and Hann 2006; Lai et al 2006; Colonno et al 2007) Trade name Intron A Hepsera Baraclude Pegasys Tyzeka Strong points • Finite duration of treatment • Durable response post- treatment (for responders) • No known resistance • Oral • Safe with negligible side effects • Least expensive • Effective for ADV resistant HBV • Oral • Effective against LVD-resistant HBV and ETV-resistant HBV • Low resistance: 0 at yr 1, 2% at yr 2, 7% at yr 3, 15% at yr 4 • Oral • Potent viral suppression: greater than LVD or ADV • Effective for LVD-resistant HBV • Resistance: 0.8% at yr 4 for treatment-naïve patients, 39.5% at yr 4 for LVD-resistant HBV • Finite duration of treatment • Once weekly injection • Durable response post-treatment (for responders) • No known resistance • Oral • Potent viral suppression • Resistance: 4% for HBeAg(+) CHB (cf. 9.1% for LVD), 2.7% for HBeAg(-) CHB (cf. 9.8% for LVD) Weak points • Signiﬁcant side effects • 65%–70% fail to respond • Needle injection • High cost • Long-term treatment may be needed • High incidence of resistance: 9.1%–20% at yr 1, 70% at yr 5 (esp. those with high baseline HBV DNA) • Long-term treatment may be needed • Long-term renal toxicity unknown • 30% fail to respond • Less potent than LVD or ETV • Long-term safety and efﬁcacy unknown • Risk of carcinogenicity in rodents (in very high doses) • Cost ADV TLV LVD • Needle injection • Signiﬁcant side effects • 65%–70% fail to respond • High cost • Long-term safety and efﬁcacy beyond 1 year unknown • Efﬁcacy to LVD-resistant HBV unknown Approved 1991 1998 2002 2005 2005 2006 Therapeutics and Clinical Risk Management 2007:3(4)