Natural History and Prognosis of Chronic Hepatitis B Patients in the Indeterminate Phase

ABSTRACT Background and Aims In chronic hepatitis B (CHB), an indeterminate phase exists outside the typical predefined phases. Our study investigates this indeterminate phase's natural history and prognosis, focusing on antiviral treatment outcomes. Methods We conducted a retrospective cohort study to compare the risk of transitioning to immune active phase between inactive and indeterminate CHB and the incidence of hepatocellular carcinoma (HCC) and cirrhosis between untreated patients with indeterminate CHB (at baseline and throughout follow‐up) and those who received treatment, following standard AASLD 2018 guidance. Results The risk of transitioning to the immune active phase over 3, 5, and 10 years was 6.3%, 8.9%, and 14.2%, respectively, for inactive phase patients ( n = 104). For HBeAg‐negative indeterminate phase patients ( n = 194), the risk was significantly higher at 23.0%, 31.9%, and 38.2%, and for HBeAg‐positive indeterminate phase patients ( n = 140), it was 40.4%, 52.0%, and 55.0% ( p < 0.001). Inverse probability of treatment weighting (IPTW) was utilized to balance the groups of treated and untreated indeterminate patients. Following IPTW adjustment, the Kaplan–Meier curve analysis indicates that the risk of HCC and cirrhosis among untreated patients ( n = 294) is higher than that among treated patients ( n = 76), ( p = 0.015 and 0.007, respectively). In the multivariable analysis, antiviral therapy remained an independent predictor of a reduced risk of HCC (aHR 0.128, 95% CI 0.031–0.522, p = 0.005) and cirrhosis (aHR 0.148, 95% CI 0.044–0.496, p = 0.002). Conclusion The indeterminate phase patients had a high‐risk transition to active phase, and antiviral therapy can reduce the incidence of developing HCC and cirrhosis.