Distribution and clinical characteristics of patients with chronic hepatitis B virus infection in the grey zone

Abstract

A substantial proportion of patients with chronic hepatitis B (CHB) who do not fit into any of the usual immune states are considered to be in the ‘grey zone (GZ)’. We aimed to investigate the distribution and characteristics of GZ in a large cohort of CHB patients. Four thousand seven hundred and fifty‐nine consecutive treatment‐naïve CHB patients were enrolled. The immune states were defined based on AASLD 2018 Hepatitis B Guidance. GZ CHB patients were classified into four groups: HBeAg positive, normal ALT levels and serum HBV DNA ≤106 IU/ml (GZ‐A); HBeAg positive, elevated ALT levels and serum HBV DNA ≤2 × 104 IU/ml (GZ‐B); HBeAg negative, normal ALT levels and serum HBV DNA ≥2 × 103 IU/ml (GZ‐C); HBeAg negative, elevated ALT levels and serum HBV DNA ≤2 × 103 IU/ml (GZ‐D). The distributions of different immune states were: 233 (4.90%) patients in immune‐tolerant phase, 941 (19.77%) patients in HBeAg‐positive immune active phase, 1,717 (36.08%) patients in inactive phase and 546 (11.47%) patients in HBeAg‐negative immune active phase. Of note, 1,322 (27.78%) patients did not fit into any of above phases and were defined as the GZ. A high proportion of patients in GZ‐B had advanced fibrosis (33.3%) or cirrhosis (25.8%). Older age, HBeAg‐positive status and higher ALT levels were independently risk factors of advanced disease in GZ CHB patients. Therefore, our results revealed that more than a quarter of CHB patients were classified into the GZ and a high proportion of patients in GZ‐B had advanced fibrosis or even cirrhosis.

KASL clinical practice guidelines for management of chronic hepatitis B

“…The natural course of CHB is divided into five phases with regard to clinical indicators such as ALT and HBV DNA – immune-tolerant, HBeAg-positive immune-active, immune-inactive, HBeAg-negative immune-active, and HBsAg loss. However, patients who do not fit into any of the usual clinical phases are considered to be in the “grey zone.” Approximately 30% of CHB patients are in the grey zone [ 50 - 52 ], and the prognosis and treatment of CHB patients in the grey zone are under study [ 52 - 57 ].…”

“…In this phase, long-term outcome without antiviral treatment is good for those without advanced fibrosis [ 68 ]. In contrast, risk of HCC is not low for these patients with high FIB-4 or APRI index suggesting advanced liver fibrosis [ 52 , 54 , 193 , 194 ]. The immune-inactive phase is a dynamic phase that can reactivate to an immune-active phase [ 14 ].…”

Expanding antiviral therapy indications for HBeAg-negative chronic hepatitis B patients with normal ALT and positive HBV DNA

“…According to the published literature, about 30%‒40% of patients may fall into this stage, and most are HBeAg-negative. 8 , 15 In a retrospective study by Yao et al, 24.73% (327/1322) of HBeAg-negative patients with normal ALT levels and serum HBV DNA ≥ 2 000 IU/mL were classified into the indeterminate phase based on the 2018-AASLD criteria. 15 …”

“… 8 , 15 In a retrospective study by Yao et al, 24.73% (327/1322) of HBeAg-negative patients with normal ALT levels and serum HBV DNA ≥ 2 000 IU/mL were classified into the indeterminate phase based on the 2018-AASLD criteria. 15 …”

HBeAg-negative Patients with Chronic Hepatitis B Virus Infection and Normal Alanine Aminotransferase: Wait or Treat?

“…Such patients are clinically defined as in the gray zone of the low or nonreplication phase. 2 Yao et al 3 conducted a retrospective study of 4759 untreated HBV-infected patients in China, of whom 21.4% were in the gray zone of the immune control period. Several studies have found that after 4-5 years of follow-up, 37-54.3% of HBeAg-negative patients with chronic HBV infection were still in the gray zone, 43.5-85% of whom transitioned to IHCs, and 2.2-15% of them to HBeAg-negative CHB.…”