Telbivudine Versus Lamivudine in Chinese Patients with Chronic Hepatitis B: Results at 1 Year of a Randomized, Double-Blind Trial HEPATOLOGY 2008;47:447-454

Background →current therapies : efficacy limitations, chronic HBV infection end stage hepatitis B complications cirrhosis, HCC : for over 1 million/yr deaths worldwide →linked to high levels of circulating HBV DNA →current therapies : efficacy limitations, tolerability issues, or the emergence of resistance → new antiviral agents continue to be needed to maximize longer term suppression of HBV replication and improve therapeutic outcomes.

Telbivudine orally bioavailable 1-nucleoside analogue specific and potent inhibitor of HBV replication in vitro no evidence of significant organ toxicity, genotoxicity, carcinogenicity, mitochondrial toxicity in vitro, teratogenicity, or embryofetal toxicity. rapid and profound reductions in serum HBV DNA levels →the GLOBE study

AIM (1) to gain additional phase III data on telbivudine in Chinese patients with chronic hepatitis B (2) to compare telbivudine and lamivudine in the relatively homogeneous Chinese patient population (effects of ethnic variation could be minimized) (3) to assess direct antiviral effect, reflected by serum HBV DNA reduction, as the primary efficacy measure

Patients and Methods multicenter, double-blind, randomized phase III trial for 2 years (104 weeks) 16 ~70 years randomly assigned in a 1:1 ratio (once daily) →600 mg of telbivudine + lamivudine placebo →100 mg of lamivudine + telbivudine placebo Inclusion criteria active viral replication (positive serum HBsAg) HBeAg(+) compatible with chronic hepatitis B HBeAg(+) or HBeAg(-) s-HBV DNA ≥ 6 log10 copies/mL s-ALT levels ≥ 1.3 times ULN (but <10 times ULN ) liver Bx within 12 months prior to randomization

Primary efficacy endpoint : s-HBV DNA reduction at 1 year (52 wks) →with treatment continuing for a second year to assess longer term efficacy and safety Secondary efficacy measures proportions of patients with s-HBV DNA reduction < 5 log10 copies/mL on two successive visits HBV DNA reductions to PCR-undetectable levels ALT normalization HBeAg loss and seroconversion(for HBeAg-positive patients) therapeutic response HBeAg(+) : HBV DNA reduced <5 log10 copies/mL coupled with HBeAg loss or ALT normalization HBeAg(-) : HBV DNA reduced < 5 log10 coupled with serum ALT normalization

Table 1. Baseline Demographic and Disease Features

Fig. 1. Reduction of serum HBV DNA from baseline P<0.001

Table 2. Efficacy in HBeAg-Positive Patients Therapeutic response 100% vs 82% Primary treatment failure 0% vs 5%

Fig. 2. Time to PCR-undetectable serum HBV DNA

Efficacy differences also generally favored telbivudine Discussion Efficacy differences also generally favored telbivudine in the much smaller HBeAg-negative subpopulation. The proportion of eligible HBeAg-negative patients was expected to be relatively low Resistance to telbivudine after 1 year was less than half that observed with lamivudine consistent with the previous phase III GLOBE trial did not reach statistical significance in the present study →presumably because of the more limited sample size in comparison with the GLOBE study

Conclusion In Chinese patients with chronic hepatitis B, telbivudine treatment for 52 weeks provided greater antiviral and clinical efficacy than lamivudine, with less resistance.