BackgroundDespite its status as a potential biomarker of hepatitis B virus (HBV) response to interferon treatment, the changes in hepatitis B surface antigen (HBsAg) levels over the natural course of HBV carriers have not been analyzed sufficiently.MethodsA total of 101 HBV carriers were followed prospectively from 1999 to 2009. HBsAg level was measured yearly during the followed period.ResultsHBsAg levels at baseline ranged from −1.4 to 5.32 log IU/ml, with a median value of 3.2 log IU/ml. Lower HBsAg levels were significantly associated with higher age and lower HBV replication status. The rate of change of HBsAg levels showed two peaks, with a cut-off value of −0.4 log IU/year. Based on this, patients were tentatively classified into rapid decrease (rate of change <−0.4 log IU/year) and non-rapid decrease groups. All baseline levels of HBsAg, HB core-related Ag, and HBV DNA were lower in the rapid decrease group than in the non-rapid decrease group. Patients with persistently positive HBeAg were all classified into the non-rapid decrease group. In patients with persistently negative HBeAg, HBV DNA levels were significantly (P = 0.028) lower in the rapid decrease group than in the non-rapid decrease group.ConclusionsLower baseline HBsAg levels were significantly associated with older age and lower viral activity. Both a loss of HBeAg detection as well as inactive replication of HBV are suggested to be fundamental factors contributing to a rapid decrease in HBsAg over the natural course of HBV infection.