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ObjectiveIn clinical practice, a substantial proportion of chronic hepatitis B virus (HBV) infections that do not fit into any of the usual immune states are considered to be in the “grey zone (GZ)”. This study aimed to investigate the effect of the change in antiviral therapy indication on identifying significant hepatic injury among GZ patients.MethodsPatients with chronic HBV infections and a persistent normal alanine aminotransferase (ALT) level (PNALT) who underwent ultrasonography-guided percutaneous liver biopsy were examined retrospectively. Evidenced hepatic injury (EHI) was defined as an inflammation grade ≥2 (≥G2) and/or fibrosis stage ≥2 (≥F2). Complete clinical data, liver inflammation, and fibrosis grades were collected, and the levels of cytokines were detected by the Luminex technique, all of which were analysed to investigate the immune and histopathology states of the liver.ResultsA total of 347 patients with chronic HBV infections and PNALT were categorized into immune tolerant (IT, n = 108), inactive HBV surface antigen (HBsAg) carrier (IHC, n = 61), GZ-1 (HBeAg positive in GZ, n = 92), and GZ-2 (HBeAg negative in GZ, n = 68) phases. Among them, 51.3% were in the GZ phase, and 50.1% presented with EHI. The IL-6 levels were higher in the EHI group than in the non-EHI group (2.77 vs. 1.53 pg/ml, Z = −13.32, p = 0.028). The monocyte chemoattractant protein 1 (MCP-1) level was positively correlated with HBV DNA (R = 0.64, p < 0.001) and HBeAg (R = 0.5, p < 0.001) but negatively correlated with fibrosis grade (R = −0.26, p = 0.048). The ratio of EHI in the GZ phase was 60.55%, which was significantly higher than that in patients in the IT (39.8%) and IHC phases (37.7%) (χ2 = 10.4, p = 0.006). A total of 46.69% of all patients exceeded the new ALT antiviral treatment threshold (30 U/L for men and 19 U/L for women). The EHI values in the IT and IHC phases below the new ALT threshold were 32.6% and 37.8%, respectively, whereas higher EHI values of 67.4% and 68.4% were seen in GZ-1 and GZ-2 patients, respectively, exceeding the new ALT threshold, and the difference was statistically significant (χ2 = 11.13, p < 0.001; χ2 = 14.22, p = 0.002). The median age in our cohort was 38.91 years, and only 21.03% were less than 30 years old. The EHI values in the IT and IHC patients

Antiviral therapy is not routinely recommended for CHB patients with ALT ≤ ULN (CHB-NALT), based on current international guidelines. However, it is debatable if antiviral treatment should be offered for CHB-NALT patients, because significant liver injury is observed from liver biopsy of some CHB-NALT patients. Quantification of anti‐HBc (qAnti‐HBc) can predict antiviral response in CHB patients, while its role in CHB-NALT patients remains to be explored. To determine if it is reliable that the novel non-invasive model based mainly on qAnti‐HBc and other conventional biomarkers for providing objective value among CHB-NALT patients with antiviral therapy, in direct comparison with liver biopsy. 542 or 110 liver biopsied CHB-NALT patients from 2015 to 2020 or in 2021 were included in training set or validation set. Circulating IL-1β, IL-2, IL-4, IL-12p70, IL-17, TNF and IFNα were determined in the training set. A non-invasive model was developed based on qAnti-HBc and other conventional biomarkers. Among 423/542 (78%) patients with significant liver injury in the training set, 47% were in grey-zone. Circulating IL-1β, IL-12p70, IL-17 in the CHB-NALT patients with liver injury was significantly higher than these without liver injury in the training set (p < 0.01). No significant difference of IL-1β, IL-12p70, IL-17 was observed between CHB-NALT patients with significant liver injury and active CHB with elevated ALT in the training set. There was inverse correlation between liver injury grades and IFNα, IL-4, or IL-2 in these patients (p < 0.05). Serum qAnti‐HBc level was significantly higher with CHB-NALT patients with liver injury than these without in the training set (P < 0.01). ALT/ULN, AST, PLT and qAnti-HBc were identified as independent predictors for significant liver injury. Furthermore, our current model demonstrated a good performance in predicting significant liver injury, i.e. AUROCs of 0.95 or 0.86 in training set or validation set. The model cut-off value for anti-viral therapy at ≥1.471. qAnti-HBc appears to be well correlated with the hepatic damage, in direct comparison with liver biopsy from CHB-NALT patients. The novel model developed seems to be reliable for predicting liver injury in CHB-NALT patients. Such model also provides objective value for decision making of antiviral therapy. [ABSTRACT FROM AUTHOR]