Gray zone and the need for expansion in chronic hepatitis B: From theory to clinical practice

Table 1 Comparative summary of studies supporting early antiviral therapy in gray zone patients

Publication year	Ref.	Country	Study sample characteristics	Key findings
2007	Chen et al[21]	Taiwan	3653 chronic hepatitis B patients without cirrhosis, followed for 11.1 years, mostly HBeAg (+), HBV DNA ≥ 2000 IU/mL	HBV DNA ≥ 2000 IU/mL increases cirrhosis risk (RR: 2.5) and HCC risk (RR: 9.9), independent of ALT
2023	Lee et al[22]	South Korea	2978 "GZ" patients, treated vs untreated, HBV DNA ≥ 2000 IU/mL, nationwide data	Untreated patients have higher fibrosis risk (HR: 1.8) and HCC risk (HR: 2.1) compared to the treated group
2023	Zhou et al[23]	China	194 HBeAg (-) patients, HBV DNA positive, normal ALT, treated vs untreated, followed for 54 months	Treatment reduces cirrhosis (2.3% vs 13.4%; P = 0.011) compared to the untreated group
2024	Zhang et al[24]	United States	324 "GZ" untreated patients, HBV DNA ≥ 2000 IU/mL, normal/Low ALT, liver biopsy performed	37% have significant histological disease: 19.2% severe fibrosis (F3-F6), 9% severe inflammation (G7-G18), despite normal ALT
2025	Lai et al[25]	International	103 studies (70 case-control: 18739 patients; 32 cohort: 15118 patients; 1 randomised controlled trial: 160 patients) with HBV cirrhosis	NAs improve survival (HR: 0.65; 95%CI: 0.56-0.76) and reduce HCC risk (RR: 0.78; 95%CI: 0.66-0.92)

ALT: Alanine aminotransferase; GZ: Grey zone; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HR: Hazard ratio; RR: Risk ratio.

Table 2 Conventional international guideline approaches to grey zone hepatitis B: Recommendations and limitations

Guideline	Recommendation for GZ	Limitations
Asian Pacific Association for the Study of the Liver (2016, updated 2021)	Therapy if HBV DNA > 2000 IU/mL and histological evidence of damage; normal ALT often delays treatment	Requires invasive biopsy; limited access to advanced diagnostics in low-resource settings; no clear GZ protocol
American Association for the Study of Liver Diseases (2018)	Antiviral therapy if HBV DNA > 2000 IU/mL, ALT > 2 × upper limit of normal, or fibrosis ≥ F2. GZ patients often excluded unless biopsy-confirmed damage	Heavy reliance on ALT thresholds; no specific GZ criteria; limited guidance for normal ALT with high HBV DNA
European Association for the Study of the Liver (2017, updated 2022)	Therapy considered for HBV DNA > 2000 IU/mL, age > 30, or family history of hepatocellular carcinoma, even with normal ALT	Inconsistent ALT thresholds; lack of GZ-specific trial data; variable adoption across regions

ALT: Alanine aminotransferase; GZ: Grey zone; HBV: Hepatitis B virus.