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Chronic hepatitis B patients with high viral loads are at increased risk of cirrhosis and hepatocellular carcinoma (HCC). In patients with low viral loads, higher hepatitis B surface antigen (HBsAg) levels have been shown to predict HCC development. However, little is known about the difference in risk for other hepatitis B virus (HBV)-related adverse outcomes with varying HBsAg levels. A total of 1,068 Taiwanese hepatitis B e antigen (HBeAg)-negative HBV carriers with serum HBV DNA level <2,000 IU/mL at baseline were followed for a mean duration of 13.0 years. Patients were categorized based on their HBsAg levels, and the relationships between HBsAg level and development of HBeAg-negative hepatitis, hepatitis flare, and cirrhosis were investigated. Of the 1068 patients with low viral loads, 280 developed HBeAg-negative hepatitis, with an annual incidence rate of 2.0%. HBsAg level, but not HBV DNA level, was found to be a risk factor for HBeAg-negative hepatitis. Multivariate analysis showed that the adjusted hazard ratio in patients with an HBsAg level !1,000 versus <1000 IU/mL was 1.5 (95% confidence interval, 1.2-1.9). The positive correlation was present when evaluating other endpoints, including hepatitis flare and cirrhosis, and remained consistent when the study population was restricted to those with normal alanine aminotransferase (ALT) level at baseline. The annual incidence rate of HBeAg-negative hepatitis was lowered to 1.1% in patients with low levels of HBV DNA, HBsAg, and ALT. Conclusion: In HBeAg-negative patients with low viral loads and genotype B or C virus infection, a higher HBsAg level can predict disease progression. HBsAg <1,000 IU/mL in combination with low levels of HBV DNA and ALT help define minimal-risk HBV carriers. (HEPATOLOGY 2013;57:441-450) H epatitis B virus (HBV) infection is a global health problem, resulting in more than 1 million deaths per year.1 Patients with chronic HBV infection are at risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), with an estimated lifetime risk of 25%-40% in carriers who acquire the virus early in life.

Loss of hepatitis B surface antigen (HBsAg) usually indicates the cure of hepatitis B virus (HBV) infection. In spontaneous hepatitis B e antigen (HBeAg) seroconverters, lower serum HBsAg and HBV DNA levels have been shown to be associated with HBsAg loss over time. However, little is known about their impacts on HBsAg loss in HBeAg-negative patients with limited viral replication. A total of 688 HBeAg-negative patients with baseline serum HBV DNA levels <2000 IU/mL were enrolled in Taiwan. The relationships of HBsAg and HBV DNA levels with subsequent HBsAg loss were investigated. In a mean follow-up of 11.6 years, the average annual rate of HBsAg loss was 1.6%. Baseline HBsAg and HBV DNA levels were inversely associated with subsequent HBsAg loss. When compared to patients who had HBsAg levels >1000 IU/mL, the rates of HBsAg loss were significantly higher in patients with HBsAg levels of 100-999, 10-99, and <10 IU/mL, with hazard ratios of 2.5 (95% confidence interval [CI], 1.6-4.0), 2.8 (95% CI, 1.6-5.0), and 13.2 (95% CI, 8.1-21.5), respectively. Multivariate analysis showed that HBsAg level, but not HBV DNA, remained as an independent factor. The adjusted hazard ratio of HBsAg loss was 13.2 (95% CI, 7.8-22.1) for HBsAg level <10 versus !1000 IU/mL. When compared to HBV DNA level by receiver operating characteristic curve analysis, HBsAg level served as a better predictor of both 5-year and 10-year HBsAg loss. Conclusion: In HBeAgnegative patients with HBV genotype B or C infection who have HBV DNA level <2000 IU/mL, HBsAg level <10 IU/mL is the strongest predictor of HBsAg loss. (HEPATOLOGY 2012;55:68-76) H epatitis B virus (HBV) infection is a global health problem, resulting in more than one million deaths per year. 1 Patients with chronic HBV infection are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). [1][2][3] It is estimated that in HBV carriers who acquire the virus early in life, the lifetime risk of developing these complications is 25%-40%. 3,4 The REVEAL-HBV (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer HBV) Study has indicated that in patients with chronic HBV infection, HBV DNA level is a major driver of disease progression. 5,6 Of particular note is that patients with serum HBV DNA levels !2000 IU/mL start to have an increased risk of developing adverse outcomes, including hepatitis, cirrhosis, HCC, and liver-related death. [5][6][7][8] In contrast, those individuals with HBV DNA levels <2000 IU/mL have a higher likelihood of becoming inactive carriers, and some clear hepatitis B surface antigen (HBsAg) during the follow-up, 9,10

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Background and objective Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis. Methods 251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case–control study, which included 184 patients with biopsy-proven liver fibrosis stages. Results In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant ≥45% compared to <45% in the longitudinal cohort; this finding was validated by the case–control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67). Conclusions A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection.