Large scale longitudinal study of chronic hepatitis B patients with hepatitis B surface antigen seroclearance

Abstract

BACKGROUND AND AIM: Seroclearance of hepatitis B surface antigen (HBsAg) is a rare event in chronic hepatitis B patients. We conducted a large scale longitudinal study investigating the virological, histological and clinical aspects, including the risk of development of hepatocellular carcinoma (HCC) in patients with HBsAg seroclearance. PATIENTS AND METHODS: Two hundred and ninety-eight patients (211 male and 87 female; median age on presentation: 43.1 years) with HBsAg seroclearance were recruited and followed up every 3 – 6 months for clinical assessment. Intrahepatic HBV DNA and covalently closed circular DNA (cccDNA) were measured by real-time PCR. Serum HBV DNA was measured by the Artus HBV RG Test (QIAGEN, Germany). Liver stiffness was assessed by FibroScan (Echosens, France). RESULTS: The median age of HBsAg seroclearance was 49.6 years. The median follow-up duration was 108.9 months and the median follow-up duration after HBsAg seroclearance was 36.4 months. Liver biopsies were performed on 29 patients (median time of biopsy: 48.6 months after HBsAg seroclearance). All have detectable intrahepatic HBV DNA (median: 1.68 copies/cell), and cccDNA were detectable in 23 patients (79.3%, median: 0.03 copies/cell). Of the 29 patients with liver biopsy, 9 and 16 patients had sera available within 1 year and between 5 – 10 years after HBsAg seroclearance, respectively, for HBV DNA analysis. All 9 patients had undetectable HBV DNA (<1.1 IU/mL) within 1 year of HBsAg seroclearance, and 4/16 patients had detectable HBV DNA levels between 5 – 10 years of HBsAg seroclearance (median: 2.37 IU/mL). Of the 26 patients with adequate liver tissues for histological examination, 4 had mild fibrosis (F1) and 5 had minimal necroinflammation. FibroScan was performed on 76 and 78 patients who had HBsAg seroclearance at age <50 and ≥50 years respectively. Significant fibrosis (liver stiffness > 8.1 kPa) was observed only in 7.9% (6/76) patients with HBsAg seroclearance at age <50 compared to 29.5% (23/78) patients with HBsAg seroclearance at age ≥50 (p = 0.001). Seven patients developed HCC (median age: 69.3). Kaplan-Meier analysis showed that the chance of HCC development in patients with HBsAg seroclearance at age <50 was significantly less than those with HBsAg seroclearance at age ≥50 (p = 0.004). Conclusion: Although serum HBV DNA was detectable in only a small proportion of patients with HBsAg seroclearance, intrahepatic HBV DNA was still present in all patients. Nevertheless, patients who cleared HBsAg at age <50 had significantly less fibrosis and lower chance of HCC development than those with HBsAg seroclearance at ≥50 years.