Telbivudine versus entecavir in patients with undetectable hepatitis B virus DNA: a randomized trial.

Background: Telbivudine has been suggested to induce hepatitis B surface antigen (HBsAg) decline to the similar degree as pegylated interferon. We aimed to investigate whether telbivudine could further decrease HBsAg titer in patients who maintain undetectable serum hepatitis B virus (HBV) DNA after initial entecavir treatment. Methods: In this open-label trial, patients who had serum HBsAg and HBV DNA levels >= 1,000 IU/mL and <60 IU/mL, respectively, following entecavir (0.5 mg/day) treatment for HBeAg-positive chronic hepatitis B were randomized to either switch treatment to telbivudine (600 mg/day, n = 47) or continue entecavir (n = 50) for 48 weeks. Results: The baseline characteristics were comparable between groups including HBsAg levels (median, 3.41 log(10) IU/mL). All patients had undetectable HBV DNA and normal alanine aminotransferase level. At week 48, the mean change in serum HBsAg levels was not significantly different between the telbivudine and entecavir groups (-0.03 log(10) IU/mL vs. -0.05 log(10) IU/mL; P = 0.57). No patient experienced HBsAg seroclearance or HBsAg decline >0.5 log(10) IU/mL. Eleven patients (23.4%) in the telbivudine group, but none in the entecavir group, experienced virologic breakthrough (P < 0.001). Seven patients (14.9%) exhibited genotypic resistance mutations (M204I +/- L180M) during the virologic breakthrough. Conclusion: Sequential therapy with entecavir followed by telbivudine resulted in a high rate of virologic breakthrough and drug-resistance without any beneficial effect on HBsAg decline. These results do not support the use of low genetic barrier drugs as a switch treatment strategy in patients who achieve virologic response with high genetic barrier drugs.This study was supported by funding from Novartis; the Korean National Health Clinical Research (NHCR) Project, Ministry of Health and Welfare (HC15C3380); the Korean Health Technology R&D Project, Ministry of Health & Welfare (HI14C1061), Republic of Korea; and the Proteogenomic Research Program through the National Research Foundation of Korea funded by the Korea government (MSIP). Novartis was permitted to review the manuscript and suggest changes but had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. The final decision on content was exclusively retained by the authors. None of other funding bodies played any role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript