We aimed to determine the 2-year outcomes of entecavir followed by lamivudine in patients with undetectable viral load (<12 IU/mL) and normal alanine aminotransferase (ALT) after initial entecavir treatment for at least 6 months. Patients were randomly assigned 1:1 to continue with entecavir or switch to lamivudine. Liver biochemistry and hepatitis B virus (HBV) DNA were determined at weeks 0, 4, 12, 24, 48, 72, and 96. Mutational analysis using line-probe assay were performed at weeks 0, 24, 48, and 96 and at the time of HBV DNA relapse. There was no elevation of ALT observed in any patients up to 96 weeks. At 96 weeks of follow-up, 19/25 (76%) patients in the lamivudine arm had persistently undetectable HBV DNA, compared with 25/25 (100%) patients in the entecavir arm. Six patients in the lamivudine arm had HBV DNA >20 IU/mL, occurring at a range of 12 to 96 weeks. Of these, four patients had HBV DNA of less than 100 IU/mL during rebound (three had undetectable HBV DNA after switching back to entecavir), and the remaining two patients had HBV DNA levels of 7,973 and 699 IU/mL. Three patients (12%) had evidence of drug-resistant mutations, of which two patients had rtM204I mutation and one patient had rtM204V mutation. One of these three patients had previous lamivudine exposure before entecavir treatment and one patient had questionable drug compliance. Conclusion: Sequential therapy using entecavir followed by lamivudine resulted in virological rebound in 24% of patients after 96 weeks. Prior optimal viral suppression with entecavir did not confer any significant advantage in patients who switched to lamivudine. (HEPATOLOGY 2011;53:1148-1153) C hronic hepatitis B (CHB) affects 400 million people worldwide, constituting an important health burden in areas where hepatitis B virus (HBV) infection is endemic. Up to 40% of CHB patients may develop cirrhosis and its complications, including hepatocellular carcinoma (HCC). 1 Lamivu-dine (LAM) was the first oral nucleoside analog available for the treatment of CHB, and is effective in retarding disease progression, including liver decompensation and HCC in both patients with cirrhosis and without cirrhosis. 2,3 Unfortunately, long-term LAM therapy is associated with high rates of drug-resistance, with 76% after 8 years of treatment. 3 Previous studies have identified early viral suppression to be a predictor of long-term outcomes including the development of drug resistance. In a study of 159 hepatitis B e-antigen (HBeAg)-positive CHB patients treated with LAM, viral suppression at 24 weeks was predictive of long-term resistance risks with a median follow-up of 29 months. 4 In those patients who achieved undetectable HBV DNA by real-time polymerase chain reaction (PCR) assay at week 24, the long-term resistance risk was only 8% compared to 64% for those with HBV DNA of >4 log copies/mL. Similar findings have also been shown in other antiviral agents including adefovir (ADV) and telbivudine. 5,6