We are grateful to Drs. Xin and Xuan for their interest in our study, in which the long-term outcome of 1965 hepatitis B surface antigen (HBsAg) carriers with antibody against hepatitis B e antigen (anti-HBe) and normal alanine aminotransferase at baseline were studied.1 The authors had three comments or questions on our article:

  • 1
    As described in the section of Patients and Methods, all study patients did not receive antiviral or immunomodulatory therapy before entry and during follow-up, so all 24 patients with reactivation of hepatitis B had “spontaneous” HBsAg seroclearance 3–20 years after the onset of hepatitis B.
  • 2
    The number of patients with age at entry of 60–69 years and ≥70 years were very small, so they were grouped together with those with age at entry of 50–59 years as patients with age at entry ≥50 years.
  • 3
    Many authors have divided the natural course of perinatally acquired chronic hepatitis B virus infection into four phases: immune tolerance, immune clearance, inactive carrier state, and reactivation of hepatitis B. However, as seen in the current study, only 16% (314/1965) of anti-HBe–positive carriers had reactivation of hepatitis B during a long-term follow-up of more than 20 years. The cumulative probabilities of reactivation of hepatitis B in this series were 9.7%, 17.1%, 19.6%, and 21.5%, respectively, after 5, 10, 15, and 20 years.1 These findings indicated that reactivation of hepatitis B tended to occur much more frequently during the first 10 years of follow-up and became relatively uncommon 15 years later. Furthermore, the natural course following spontaneous hepatitis B e antigen (HBeAg) seroconversion has been studied in two different cohorts from our unit, one involving 283 patients with HBeAg-positive chronic hepatitis B2 and the other involving 240 HBeAg-positive carriers.3 The annual rates of reactivation of hepatitis B were 3.3% and 2.2% per year, respectively.2, 3 The cumulative probability of HBeAg-negative chronic hepatitis B after 15 years was about 23%.2 Reactivation of hepatitis B occurred much more frequently during the first 10 years after HBeAg seroconversion.2 On the basis of the data of these studies, the overall incidence of reactivation of hepatitis B following HBeAg seroconversion was estimated to be as high as 25%. Accordingly, in Taiwan, following HBeAg seroconversion, only 25% of HBsAg carriers will go through the fourth phase, while the other 75% of HBsAg carriers will stop at the third phase as inactive carriers with lifelong sustained remission of hepatitis. Perhaps the incidence of reactivation of hepatitis B may be much lower for HBsAg carriers from low-endemic or intermediate-endemic areas.4 Therefore, we preferred to divide the natural course of chronic hepatitis B virus infection into three phases, because the division of the natural course of chronic hepatitis B into four phases likely will give us a misimpression that all or the majority of HBsAg carriers will go through the four phases.


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  • 1
    Chu CM, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. HEPATOLOGY 2007; 45: 11871192.
  • 2
    Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. HEPATOLOGY 2002; 35: 15221527.
  • 3
    Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med 2004; 116: 829834.
  • 4
    de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993; 118: 191194.

Chia-Ming Chu M.D.*, * Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.