Determinants for Spontaneous HBsAg Seroclearance in Persons with Chronic Hepatitis B Virus Infection By Bianca Malcolm Candidate for the Master of Public Health Degree Community-Based Master’s Project Oral Defense May 8, 2006 Faculty Chair: Longjian Liu, M.D., Ph.D., MSc Community Preceptor: Alison Evans, Sc.D.

Acknowledgements I would like to take this opportunity to thank Alison Evans, my community preceptor, and Gang Chen of Fox Chase Cancer Center for providing me with the data for my analysis and assisting me with my analysis. I also thank Dr. Longjian Liu, my faculty advisor, of the Department of Epidemiology and Biostatistics at Drexel University School of Public Health who provided me innumerable support and guidance during my Community Based Master’s Project. Finally, I would like to thank all participants in the original study for making this secondary data analyses possible.

Overview Abstract Statement of the Problem Introduction Background and Significance Project Aims Research Design and Methods Results Discussion Conclusions Recommendations Value to the Community

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 ( ) to undergo further testing of viral markers and HBsAg-status. Of those 1863 subjects, 341 (18.30%) had apparently cleared HBsAg by 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 %; 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 sequelae, most notably liver cancer and cirrhosis. Universal childhood hepatitis B vaccination programs have dramatically reduced the incidence, mortality, and morbidity of HBV in the U.S. and Western Europe. However, HBV is increasingly prevalent worldwide, especially in Asian countries where the disease is endemic.

Introduction Chronic HBV infection is when a person remains positive for HBsAg for more than six months. These persons usually remain HBsAg positive indefinitely. However, a significant portion of chronic carriers (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. This analysis used a large series of Chinese persons to investigate the relationship of baseline factors to the occurrence of spontaneous HBsAg seroclearance.

Background and Significance Worldwide Hepatitis B statistics: –> 2 billion people (1/3 of the world’s population) have been infected –800 million infected persons –350 million chronic carriers –50 million new cases/year –Accounts for 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)

How Hepatitis B Progresses

Previous Studies’ Findings Liaw, et al. (1991) found that subjects who were HBeAg negative or older than 40 years of age at entry had higher incidences of delayed HBsAg clearance. Kato, et al. (2000) also found that spontaneous HBsAg seroclearance was dependent on age. Furusyo, et al. (1999) found that persons older than 50 years of age and/or HBeAg-negative were more likely to clear HBsAg than other subjects.

Project Aims This 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 scarce literature on HBsAg seroclearance. Two main hypotheses are: 1)Persons infected with chronic HBV who are ≥ 50 years of age at cohort entry are more likely to undergo HBsAg seroclearance than their counterparts who are < 50 years of age at entry. 2)Persons infected with chronic HBV who are negative for hepatitis B e antigen (HBeAg) at cohort entry are more likely to achieve spontaneous HBsAg seroclearance than those who are HBeAg- positive at cohort entry.

Research 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 ( ), for further serum testing of viral markers and HBsAg-status. Of those 1863 patients, 341 (18.3%) had apparently cleared HBsAg by Statistical analysis was conducted by the x 2 test, Student’s t test, and logistic regression by SAS v.8 statistical analysis software.

Demographics of the Study Population

Univariate Analysis for Clearance of HBsAg

Significant Factors for Clearance of HBsAg

Non-Significant Factors for Clearance of HBsAg

Multivariate Analysis for Clearance of HBsAg

Odds Ratios of Significant Factors for Clearance of HBsAg

Odds Ratios of Non-Significant Factors for Clearance of HBsAg

Discussion Age and HBeAg-status significantly influenced the incidence of spontaneous HBsAg clearance, which is consistent with previous evidence on HBsAg clearance. Older persons may be more likely to clear HBsAg because they have had the virus longer in their systems. Clearance of HBeAg means that virus replication has stopped, therefore, HBeAg-negative persons are in a better position to clear HBsAg than HBeAg-positive persons. Although males have higher incidences of chronic HBV infection and females are more likely to clear HBeAg, sex did not significantly influence HBsAg clearance.

Discussion (cont’d) Strengths of the study: –Large series of patients provides lots of power for study results. –11 years of follow-up is a long enough period to sufficiently observe HBsAg clearance in population. Limitations of the study: –Initial chronic HBV infection is unknown. –Exact time of HBsAg clearance, if applicable, is unknown. –Unable to compare baseline factors of original cohort of chronically infected persons with this sample => decreased validity.

Conclusions Results suggest that the age of patients and HBeAg-status are determinants for clearance of HBsAg. Persons older than or 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 found to be 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, if applicable. Hepatitis B vaccination is the most efficient method of preventing HBV and HBV-related illnesses (1st anti- cancer vaccine), 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, especially in Asian populations.

Value to the Community The Asian and Pacific Islander community (domestic and abroad) have notoriously low rates for HBV vaccination and series completion. The results from this study can be used by researchers, public health officials, and clinicians to inform future research and interventions for hepatitis B, especially future efforts to vaccinate API children. Fox Chase Cancer Center can also use this study to further investigate the benefits of HBsAg clearance in persons with chronic hepatitis B infection.

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): Asian Liver Center at Stanford University. (2005). Retrieved February 19, 2006 from Centers for Disease Control. (2005). CDC: Hepatitis B Fact Sheet. Retrieved October 18, 2005 from 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): 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): Gilead Sciences, Inc. (2004). An Overview of Chronic Hepatitis B. Retrieved October 18, 2005 from Community ISO 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): Kawsar M and Goh BT. (2002). Hepatitis B virus infection among Chinese residents in the United Kingdom. Sexually Transmitted Infections. 78(3): Lavanchy D. (2004). Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. Journal of Viral Hepatitis, 11(2): 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): Lok A and McMahon BJ. (2001). Chronic hepatitis B. Hepatology. 34: 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): 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):

Questions