Increased risk of hepatocellular carcinoma in HBeAg-negative indeterminate phase compared to HBeAg-negative chronic infection

Background & Aims: The outcomes and benefits of antiviral therapy in patients with indeterminate phase HBeAg-negative chronic hepatitis B (CHB) are not well described in treatment guidelines. We examined hepatocellular carcinoma (HCC) risk among these patients. Approach & Results: We identified all non-cirrhotic treatment-naïve patients with HBeAg-negative CHB who received ≥1 test for hepatitis B virus (HBV) DNA and HBeAg. HBeAg-negative indeterminate phase included abnormal alanine aminotransferase (ALT ≥40 IU/L) and low HBV DNA (<2,000 IU/mL), or normal ALT (<40 IU/L) and high HBV DNA (≥2,000 IU/mL). Cox model evaluated relationship between HBV phase and HCC risk, with antiviral therapy as time-dependent variable. In 17,287 patients (mean age 54.1 years, 50% male), 4,071 (24%) transitioned to HBeAg-negative chronic hepatitis, 8,722 (50%) remained in the indeterminate phase, and 4,494 (26%) moved to HBeAg-negative chronic infection over a median follow-up of 55.1 [interquartile range 21.3-105.4] months. Patients in the indeterminate phase had a significantly higher HCC risk than those in chronic infection (adjusted hazard ratio [aHR] 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 (aHR 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 CHB, 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.