Two-step evolution of the hepatitis B drug-resistant mutations in a patient who developed primary entecavir resistance



Guan-Huei Lee, Department of Gastroenterology and Hepatology, National University Health System, 1E, Kent Ridge Road, Level 10, Singapore 119228

Tel: +65 67725595

Fax: +65 67751518




Few cases of primary entecavir resistance in chronic hepatitis B patients have been reported to date. The serial profiling of the HBV polymerase gene mutations from a treatment-naive patient who developed drug resistance after 32 months of entecavir therapy is presented here.


Serum samples were collected at multiple time points from before the start of therapy to virological and biochemical breakthrough. The evolution of the hepatitis B virus polymerase gene mutations was analysed with commercial line probe assay and pyrosequencing.


Drug resistance mutation analysis by pyrosequencing revealed a two-step process in the selection of drug resistance. The patient had a good initial response to entecavir 0.5 mg/day. A partially resistant HBV strain first emerged as the predominant species from as early as 2 weeks. After a period of non-compliance to therapy, there was virological breakthrough, which resolved on restarting entecavir. Shortly after, there was secondary failure of entecavir therapy, caused by a new resistant strain carrying all three mutations required.


In this patient, pre-existence of minor population of partially resistant viral strains and treatment non-compliance probably contributed to his development of primary entecavir resistance.