Heterogeneity Analysis of HBeAg-Positive Chronic Hepatitis B Patients with Ultra-High Viral Load (HBV DNA ≥ 7.0 log10 IU/mL).

Background/Objectives: HBeAg-positive chronic hepatitis B (CHB) patients with very high viral replication are often clinically considered a homogeneous, low-risk population. However, substantial biochemical, virological, and fibrosis-related heterogeneity may exist. This study aimed to characterize this heterogeneity in treatment-naive, HBeAg-positive CHB patients with ultra-high viral loads (HBV DNA ≥ 7.0 log10 IU/mL). Furthermore, we sought to identify predictors of significant fibrosis and detect clinically relevant discordant phenotypes, such as silent disease progression despite normal alanine aminotransferase (ALT) levels. Methods: This single-center, retrospective, cross-sectional study analyzed consecutively screened eligible patients. A liver stiffness measurement (LSM, kPa) and controlled attenuation parameter (CAP, dB/m) were obtained via transient elastography. Significant fibrosis was defined as an LSM ≥ 7.0 kPa. Statistical evaluations included Spearman's correlation, multivariable regression, ALT-LSM stratification, and K-means clustering. Results: Among 413 included patients, age and aspartate aminotransferase (AST) emerged as independent risk factors for significant fibrosis, whereas log10 HBV DNA and log10 HBsAg were independent negative predictors. Patients with HBsAg ≥ 25,000 IU/mL exhibited significantly lower LSM values than those with lower HBsAg levels. Notably, 18.4% of patients with strictly normal ALT (≤40 U/L) presented with an LSM ≥ 7.0 kPa, indicating silent progression. Cluster analysis further identified two distinct patient phenotypes characterized by differing age, ALT, viral load, and fibrosis profiles. Conclusions: An ultra-high viral load in HBeAg-positive CHB does not guarantee a uniformly benign clinical state. By quantifying biochemical, virological, and fibrotic heterogeneity, this study highlights a critical subgroup with silent fibrosis progression that risks being overlooked by ALT-based assessments alone.