Distinguishing True Immune Tolerant Hepatitis B Patients: Insights From Long‐Term Clinical Outcomes

The long-term prognosis of immune tolerant (IT) phase patients remains unclear. This study aimed to identify true IT-phase patients with favourable outcomes and distinguish grey-zone IT patients. We retrospectively analysed 1064 chronic hepatitis B (CHB) patients (516 clinically inclusive IT, 548 antiviral-treated immune active [AVT-IA]). Clinically inclusive IT-phase was defined as HBeAg-positive, no cirrhosis, HBV DNA ≥ 10^6 IU/mL, and ALT < 80 U/L. Favourable prognosis was defined as the absence of HCC development and IA progression during follow-up. IT-phase patients had significantly lower 10-year HCC rates compared to AVT-IA patients (1.7% vs. 2.7%). Among the clinically inclusive IT group, favourable prognosis was associated with younger age (< 35 years), female gender, stringent low ALT (< 35 U/L for males, < 25 U/L for females), high HBV DNA (> 10^8 IU/mL), and no family history of HCC. Patients meeting these criteria showed no HCC cases and had a lower likelihood of progression to IA (~50%) within 10 years. The strict criteria demonstrated 90.3% specificity for identifying true IT-phase patients within the clinically inclusive IT group. Family history of HCC was an independent risk factor for HCC development (HR 6.059, p = 0.019), while stringent low ALT, younger age, and female gender were linked to lower IA progression risk (HR 0.32, p ≤ 0.001). This study highlights the importance of applying strict criteria in distinguishing true IT-phase patients from grey-zone patients. True IT patients are at minimal risk of HCC or progression to IA, while identifying grey-zone patients is crucial, as they may require early antiviral therapy.