Incidence and Factors Associated With HBV Relapse After Cessation of Entecavir or Tenofovir in Patients With HBsAg Below 100 IU/mL

BACKGROUND & AIMS: We investigated the incidence and factors associated with relapse of hepatitis B virus (HBV) infection in patients with levels of HB surface antigen (HBsAg) less than 100 IU/mL after cessation of entecavir or tenofovir disoproxil fumarate (TDF) treatment. METHODS: We collected data from patients with chronic HBV infection without cirrhosis treated with entecavir from 2007 through 2015 or TDF from 2011 through 2016 in Taiwan. We identified 135 patients with levels of HBsAg less than 100 IU/mL at the end of treatment (79 entecavir and 56 TDF) and collected data from them for a median of 87 weeks (interquartile range, 48-161 wk) for use as the development set. We collected data from 108 patients from separate medical centers in Taiwan, followed up for a median of 126 weeks (interquartile range, 61-214 wk), and used these as the validation group. Post-treatment virologic relapse was defined as a serum HBV DNA level greater than 2000 IU/mL, and clinical relapse was defined as an alanine aminotransferase level greater than 80 U/L and a HBV DNA level greater than 2000 IU/mL. RESULTS: In the development group, the 5-year incidences of virologic relapse, clinical relapse, and HBsAg loss were 40.9%, 32.5%, and 47%, respectively. The baseline HBV DNA and end-of-treatment levels of HBsAg were associated independently with relapse. In the development group, 17.3% of patients with end-of-treatment HBsAg levels less than 40 IU/mL had a virologic relapse within 5 years, whereas 67.6% of patients with a HBsAg level of 40 IU/mL or more had a virologic relapse within 5 years (P < .001); proportions of patients with clinical relapses were 10.2% (HBsAg <40 IU/mL) and 57.6% (HBsAg >= 40 IU/mL; P < .001). In the validation groups, for patients with end-of-treatment HBsAg levels less than 40 IU/mL or 40 IU/mL or more, the rates of virologic relapse at 5 years were 31.1% and 80.5% (P < .001), and rates of clinical relapse were 14.2% and 50.3% (P < .001), respectively. Rates of virologic and clinical relapse within 5 years were low (<10%) in patients with a combination of end-of-treatment HBsAg level less than 40 IU/mL and baseline HBV DNA level less than 5 3 104 IU/mL, or baseline hepatitis B core-related antigen level less than 4 log U/mL in the development group. CONCLUSIONS: An end-of-treatment HBsAg level of 40 IU/mL or less is optimal for stopping nucleos(t)ide analog therapy. Waiting to stop therapy until patients have a combination of baseline HBV DNA level of 5 3 104 IU/mL or hepatitis B core-related antigen of 4 log U/mL and end-of-treatment HBsAg level of 40 IU/mL might reduce the risk of HBV relapse.