Some individuals who are chronically infected with hepatitis B virus (HBV) eventually lose hepatitis B surface antigen (HBsAg). Hepatocellular carcinoma (HCC) has been demonstrated to occur in a few patients after loss of HBsAg. Neither factors associated with loss of HBsAg nor the incidence of HCC thereafter have been clearly elucidated. We performed a prospective population-based cohort study in 1,271 Alaska Native persons with chronic HBV infection followed for an average of 19.6 years to determine factors associated with loss of HBsAg and risk of developing HCC thereafter. HBsAg loss occurred in 158 persons for a rate of HBsAg clearance of 0.7%/year. Older age, but not sex, was associated with clearance of HBsAg, and loss of HBsAg was not associated with any particular HBV genotypes (A, B, C, D, and F) found in this population. Participants were followed for an average of 108.9 months after HBsAg loss. Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P < 0.001]). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance. Conclusion: HCC can occur in persons with chronic hepatitis B who have lost HBsAg, even in the absence of cirrhosis. These persons should still be followed with periodic liver ultrasound to detect HCC early. (HEPATOLOGY 2010;51:1531-1537.)
H epatitis B (HBV) infection is a major worldwide health problem, and it is estimated that 350 to 400 million persons are chronically infected with this virus. 1 Perinatal or horizontal infection early in childhood is the main route of HBV transmission. After acute hepatitis B, most persons achieve complete immune clearance of the virus, yielding lifelong immunity. However, up to 90% of infants, 30% of children under 5 years of age, and between 5% and 10% of adults develop chronic infection. 2 Chronic HBV infection is confirmed by the presence of hepatitis B surface antigen (HBsAg) in serum for at least 6 months and is characterized by several clinical phases: the immune tolerant, immune active, or clearance and inactive phases. 3 The immune tolerant phase usually follows perinatal infection and is characterized by the presence of hepatitis B e antigen (HBeAg), high levels of HBV DNA, normal levels of alanine aminotransferase (ALT), and minimal or