Abstract Background: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance is a rare event in patients with chronic hepatitis B virus (HBV) infections and there is little available literature on it. Objective: This study intended to identify determinants for HBsAg seroclearance in persons with chronic HBV using a large cohort of Chinese patients with 11 years of follow-up. Design/Methods: This secondary data analysis used the database of a prospective cohort study of 1863 subjects who had returned 11 years after initial cohort entry (1992-93) to undergo further testing of viral markers and HBsAg-status. Of those 1863 subjects, 341 (18.30%) had apparently cleared HBsAg by 2003. Spontaneous HBsAg seroclearance was investigated in terms of its relationship to age, HBeAg-status, gender, HBV-DNA viral load, and history of clinical hepatitis. Results: Of the 365 persons who were 50 years and older, 93 (25.47%) spontaneously cleared HBsAg. In contrast, only 248 (16.56%) of the 1498 subjects younger than 50 years of age cleared HBsAg (p<.0001). The incidence of HBsAg seroclearance was also significantly higher in persons who were HBeAg-negative compared to persons who were HBeAg-positive (21.52% vs. 13.17%; p <.0001). And HBsAg seroclearance incidence was higher in persons with a low-positive (21.37%) HBV-DNA viral load than in persons with either a negative (16.77%) or a high-positive (14.13%) viral load (p=.0009). Conclusions: Results suggest that the age of patients, HBeAg-status, and HBV-DNA viral load are determinants for spontaneous HBsAg seroclearance. However, gender and history of clinical hepatitis did not significantly influence the occurrence of HBsAg seroclearance.

Statement of the Problem Hepatitis B virus (HBV) infection is a major global public health concern because it is closely associated with serious outcomes, most notably liver cancer and cirrhosis. Worldwide Hepatitis B statistics: > 2 billion people (1/3 of the world’s population) have been infected at some point in their lives 800 million current infected persons 350 million current chronic carriers 75% of all chronic carriers are in Asia 50 million new cases/year Accounts for 60-80 percent of liver cancer cases (the leading cause of liver cancer) Accounts for 500,000 to 1.2 million deaths per year (10th leading cause of death worldwide)

Background and Significance Most (90%) HBV infections are acute and self-limited; Hepatitis B surface antigen (HBsAg) is cleared from the infected person’s blood within 6 months. And, 10% of all HBV infections become chronic (lifelong); HBsAg remains detectable in the blood. Still, a significant portion of the chronic hepatitis B population (~0.1-2%) spontaneously clears serum HBsAg per year. Previous studies have shown that certain factors (e.g. age, gender, HBeAg-status, HBV-DNA viral load) may influence the incidence of spontaneous clearance of HBsAg in the blood.

Project Aims Study seeks to identify determinants that will increase the incidence of spontaneous HBsAg seroclearance and, subsequently, decrease the occurrence of poor outcomes. Contribute to current scant literature on HBsAg seroclearance. Main hypotheses: Persons infected with chronic HBV who are ≥ 50 years of age at cohort entry will be more likely to spontaneously clear HBsAg than their counterparts who are < 50 years of age at cohort entry. Persons infected with chronic HBV who are HBeAg-negative at cohort entry will be more likely to spontaneously clear HBsAg than those who are HBeAg-positive at cohort entry.

Study Design and Methods This is a secondary data analysis performed on the database of a prospective cohort study. In 2003, 1863 randomly-selected Chinese chronic HBV carriers (out of an initial 18,000) returned, 11 years after initial entry into the study (1992-93), for further serum testing of viral markers and HBsAg-status. Of those 1863 patients, 341 (18.3%) had apparently cleared HBsAg by 2003. Statistical analysis was conducted by the x2 test, Student’s t test, and logistic regression by SAS v.8 statistical analysis software.

How Hepatitis B Progresses Persons infected with chronic HBV greatly suffer from liver cancer (5-10%), cirrhosis (30%), and liver failure (23%). Moreover, 1 in 4 of all chronically infected persons die from HBV-related illnesses. Increasing the incidence of clearance of HBsAg may decrease the occurrence of HBV-caused mortality and morbidity.

Demographics of Study Population

Significant Factors for Clearance of HBsAg

Non-significant Factors for Clearance of HBsAg

Odds Ratios for Clearance of HBsAg

Conclusions Results suggest that the age of patients and HBeAg-status are determinants for clearance of HBsAg. Persons older than 50 years of age and/or HBeAg-negative were more likely to spontaneously clear HBsAg than any other group. Although the % differences for clearance of HBsAg were significant for HBV-DNA viral load, this variable was not independent of other study variables. Gender and history of clinical hepatitis did not significantly influence the occurrence of spontaneous HBsAg seroclearance.

Recommendations Future studies should concentrate on determining the exact time infected persons contract chronic hepatitis B and the exact time they clear the virus. Hepatitis B vaccination is the most efficient method of preventing HBV and HBV-related illnesses, therefore, future policy should focus on: Preventing mother-to-infant transmission through the administration of HBV vaccines at birth Increasing child vaccination coverage; and Increasing adult vaccination coverage, especially in Asian populations. Future policy should also focus on improving medical services, detection, and treatment for chronic HBV carriers, specially in Asian populations.

References Ahn SH, Park YN, Park JY, Chang HY, Lee JM, Shin JE, Han KH, Park C, Moon YM, and Chon CY. (2005). Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. Journal of Hepatology. 42(2): 188-94. Asian Liver Center at Stanford University. (2005). Retrieved February 19, 2006 from http://liver.stanford.edu/Edu/Edu_stat.php. Centers for Disease Control. (2005). CDC: Hepatitis B Fact Sheet. Retrieved October 18, 2005 from http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htm. Chen G. Lin W. Shen F. Iloeje UH. London WT. Evans AA. (2005). Chronic hepatitis B virus infection and mortality from non-liver causes: results from the Haimen City cohort study. International Journal of Epidemiology. 34(1): 132-7. Furusyo N. Hayashi J. Sawayama Y. Kishihara Y. Kashiwagi S. (1999). Hepatitis B surface antigen disappearance and hepatitis B surface antigen subtype: a prospective, long-term, follow-up study of Japanese residents of Okinawa, Japan with chronic hepatitis B virus infection. American Journal of Tropical Medicine and Hygiene, 60(4): 616-22. Gilead Sciences, Inc. (2004). An Overview of Chronic Hepatitis B. Retrieved October 18, 2005 from Community ISO 9660. Kato Y. Nakao K. Hamasaki K. Kato H. Nakata K. Kusumoto Y. Eguchi K. (2000). Spontaneous loss of hepatitis B surface antigen in chronic carriers, based on a long-term follow-up study in Goto Islands, Japan. Journal of Gastroenterology, 35(3): 201-205. Kawsar M and Goh BT. (2002). Hepatitis B virus infection among Chinese residents in the United Kingdom. Sexually Transmitted Infections. 78(3): 166-8. Lavanchy D. (2004). Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. Journal of Viral Hepatitis, 11(2): 97-107. Liaw YF. Sheen IS. Chen TJ. Chu CM. Pao CC. (1991). Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology, 13(4): 627-631. Lok A and McMahon BJ. (2001). Chronic hepatitis B. Hepatology. 34: 1225-1241. Mast EE. Margolis HS. Fiore AE. Brink EW. Goldstein ST. Wang SA. Moyer LA. Bell BP. Alter MJ. (2005). A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP) Part 1: Immunization of Infants, Children, and Adolescents. Morbidity and Mortality Weekly Report, 54(RR16): 1-23. Yuen MF. Wong DK. Yuan HJ. Sum SM. Lai CL. (2004). HBsAg seroclearance in Chinese patients receiving lamivudine therapy for chronic hepatitis B virus infection. Journal of Clinical Microbiology. 42(10): 4882-4.