Increased risk of HCC in HBeAg-negative indeterminate phase compared with HBeAg-negative chronic infection

Background and Aims: The outcomes and benefits of antiviral therapy in patients with indeterminate phase HBeAg-negative chronic hepatitis B are not well described in treatment guidelines. We examined HCC risk among these patients. Approach and Results: We identified all non-cirrhotic treatment-naïve patients with HBeAg-negative chronic hepatitis B who received ≥1 test for HBV DNA and HBeAg. HBeAg-negative indeterminate phase included abnormal ALT (≥40 IU/L) and low HBV DNA (<2000 IU/mL), or normal ALT (<40 IU/L) and high HBV DNA (≥2000 IU/mL). Cox model evaluated the relationship between HBV phase and HCC risk, with antiviral therapy as a time-dependent variable. In 17,287 patients (mean age 54.1 y, 50% male), 4071 (24%) transitioned to HBeAg-negative chronic hepatitis, 8722 (50%) remained in the indeterminate phase, and 4494 (26%) moved to HBeAg-negative chronic infection over a median follow-up of 55.1 (IQR: 21.3–105.4) months. Patients in the indeterminate phase had a significantly higher HCC risk than those in chronic infection (adjusted hazard ratio: 1.587, 95% CI: 1.262–1.995). Among patients in the indeterminate phase, those with normal ALT and high HBV DNA had a higher HCC risk than those with abnormal ALT and low HBV DNA (adjusted hazard ratio: 1.377, 95% CI: 1.007–1.883, p =0.045). The 5-year cumulative HCC incidence showed no significant difference between treated and untreated patients in either group. Conclusions: In patients with indeterminate phase HBeAg-negative chronic hepatitis B, those with normal ALT and high HBV DNA showed a higher HCC risk than those with abnormal ALT and low HBV DNA, with no difference between treated and untreated patients in either group. Close monitoring with timely antiviral treatment may suffice to mitigate HCC risk in untreated patients.