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

Abstract

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 log 10 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 log 10 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.