Chronic hepatitis B virus (HBV) infection affects approximately 400 million people worldwide, and three-quarter of them are from Asia-Pacific region [1-3]. Nucleos(t)ide analogs treatment can suppress viral replication, delay cirrhotic complications and reduce the risk of hepatocellular carcinoma (HCC) [4-5].~Currently, five nucleos(t)ide analogs are approved for the treatment of chronic hepatitis B, namely lamivudine, adefovir dipivoxil, telbivudine, entecavir (ETV) and tenofovir disoproxil fumarate (TDF). ETV and TDF are recommended as first-line therapy by all regional guidelines due to their high anti-viral potency and low risk of inducing resistance [6-8].~ETV monotherapy for chronic HBV infection is highly effective in both HBeAg-positive and negative treatment-naïve patients [9-10]. The cumulative probability of maintained virologic suppression with undetectable HBV DNA at year 1, 2 and 3 were 76.5%, 83.0% and 88.3% respectively [11].~TDF is another potent anti-viral treatment for chronic hepatitis B. Up to 72% and 87% of HBeAg-positive and -negative patients achieved undetectable HBV DNA by week 144 of TDF monotherapy [12]. It is also effective in patients with prior exposure to other nucleo(s)tide analogs. Previous studies demonstrated that TDF can be used as an effective rescue therapy in lamivudine or adefovir-treated patients with incomplete virologic response [13-14].~The importance of complete viral suppression should be emphasized. In treatment-naïve patients, there is a positive correlation between HBV DNA level with risk of developing cirrhosis and HCC [15-17]. In a recent report on 372 ETV-treated patients, suppression of HBV DNA to less than 2000 IU/ml was associated with lower risk of disease progression among those with cirrhosis at baseline [18]. Therefore, suppressing HBV DNA to undetectable level should be the treatment target, especially in patients with established cirrhosis who are at the greatest risk of HCC.
Currently, five nucleos(t)ide analogs are approved for the treatment of chronic hepatitis B, namely lamivudine, adefovir dipivoxil, telbivudine, entecavir (ETV) and tenofovir disoproxil fumarate (TDF). ETV and TDF are recommended as first-line therapy by all regional guidelines due to their high anti-viral potency and low risk of inducing resistance.~ETV monotherapy for chronic HBV infection is highly effective in both HBeAg-positive and negative treatment-naïve patients. The cumulative probability of maintained virologic suppression with undetectable HBV DNA at year 1, 2 and 3 were 76.5%, 83.0% and 88.3% respectively.~TDF is another potent anti-viral treatment for chronic hepatitis B. Up to 72% and 87% of HBeAg-positive and -negative patients achieved undetectable HBV DNA by week 144 of TDF monotherapy. It is also effective in patients with prior exposure to other nucleo(s)tide analogs. Previous studies demonstrated that TDF can be used as an effective rescue therapy in lamivudine or adefovir-treated patients with incomplete virologic response.~However, the optimal treatment for patients with suboptimal response to ETV is uncertain. With this background, we will conduct a randomized controlled trial to evaluate the efficacy of TDF switch therapy in patients with incomplete virologic response to ETV treatment.