A dose‐finding study of once‐daily oral telbivudine in HBeAg‐positive patients with chronic hepatitis B virus infection

Current therapy for chronic hepatitis B is suboptimal as a result of limited durable response rates, cumulative viral resistance, and/or poor tolerability. Telbivudine has potent antiviral activity against hepatitis B virus (HBV) in vitro and in the woodchuck model and has a promising preclinical safety profile. In this first clinical study of telbivudine, safety, antiviral activity, and pharmacokinetics were assessed in 43 adults with hepatitis B e antigen–positive chronic hepatitis B. This placebo‐controlled dose‐escalation trial investigated 6 telbivudine daily dosing levels (25, 50, 100, 200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12 weeks' follow‐up. Serum HBV DNA levels were monitored via quantitative polymerase chain reaction. The results indicate that telbivudine was well tolerated at all dosing levels, with no dose‐related or treatment‐related clinical or laboratory adverse events. telbivudine plasma pharmacokinetics were dose‐proportional within the studied dose range. Marked dose‐related antiviral activity was evident, with a maximum at telbivudine doses of 400 mg/d or more. In the 800mg/d cohort, the mean HBV DNA reduction was 3.75 log10 copies/mL at week 4, comprising a 99.98% reduction in serum viral load. Correspondingly, posttreatment return of viral load was slowest in the high‐dose groups. Viral dynamic analyses suggested a high degree of efficiency of inhibition of HBV replication by telbivudine and helped refine selection of the optimal dose. In conclusion, these results support expanded clinical studies of this new agent for the treatment of hepatitis B. (HEPATOLOGY 2004;40:719–726.)