[show abstract][hide abstract] ABSTRACT: In view of the findings that high hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is associated with increased risk of chronic hepatitis B (CHB)-related complications, disease progression in CHB patients in the immune-tolerant phase is uncertain. We evaluated disease progression in 57 immune-tolerant CHB patients with high HBV DNA. Each subject underwent an initial liver biopsy. In those who remained in the immune-tolerant phase, a follow-up liver biopsy was performed after 5 years of follow-up. Patients who developed elevated serum alanine aminotransferase (ALT) levels were discontinued from the study after a follow-up liver biopsy. Disease progression was defined as a 1-point increase in fibrosis stage. Initial liver biopsies showed the median fibrosis stage of the study patients was 1 (range 0-1). By the end of follow-up, 9 of the 57 patients (15.8%) had developed elevated serum ALT. In those who remained in the immune-tolerant phase, follow-up fibrosis stage was comparable with the initial fibrosis stage (P = 0.58). However, disease progression was greater in patients who developed elevated serum ALT when compared with those who remained in the immune-tolerant phase (5 of 9 vs. 3 of 48, respectively, P = 0.001). The median rate of fibrosis progression of patients who remained in the immune-tolerant phase was lower than that of patients with high serum ALT (0 U/year [range -0.40-0.20 U/year] versus 0.21 U/year [range 0-1.11 U/year], respectively, P = 0.04). CONCLUSION: CHB patients in the immune-tolerant phase have mild disease. In those who remained in the immune-tolerant phase in the present study, disease progression was minimal. However, immune-tolerant patients who progressed to the immune clearance phase often faced disease progression.