High rates of transition to immune active disease in a cohort of strictly defined immune tolerant patients with chronic hepatitis B: results from the RADICAL consortium.

BACKGROUND: Patients with immune tolerant (IT) chronic hepatitis B (CHB) have high viral loads, minimal inflammation and minimal fibrosis. Nevertheless, the benign nature of this phase and the need for antiviral therapy remain controversial. OBJECTIVE: We explored the natural history of IT patients by assessing the risk of transition to immune active (IA) disease, fibrosis progression and hepatocellular carcinoma (HCC). DESIGN: This international multicentre study from the RADICAL consortium includes mono-infected patients with CHB from sites around the world. The IT-phase was strictly defined as persistently (1) hepatitis B e-antigen (HBeAg)-positive, (2) alanine aminotransferase (ALT) ≤40 U/L, (3) HBV DNA >7 log10 IU/mL and (4) F0-1 during the first year after baseline. We assessed the probabilities of transition to IA disease (ALT ≥50 U/L), the risk of significant fibrosis (≥F2) and HCC. RESULTS: In total, 951 IT patients were included with a median age of 33, 40% were male with a median follow-up of 13 years. Median ALT and HBV DNA at baseline were 25.5 U/L and 8.4 log10 IU/mL.The probability of transitioning to IA disease was 51%, 67% and 72% before 5 years, 10 years and 15 years. A high-normal ALT was associated with an increased risk of IA disease (subdistribution hazard ratio (sHR): 20-30 U/L: 1.744, p<0.001, sHR: >30U/L: 3.130, p<0.001). IT patients had a low risk of progression to significant fibrosis (15 years: 6.3%), and HCC (15 years: 1.1%). CONCLUSION: The majority of this large cohort of well-defined IT patients transition to IA disease within 5 years of follow-up, with the highest risk observed in those with a high-normal ALT, suggesting that these patients may benefit from either more frequent monitoring or pre-emptive therapy.