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.