Currently, there is limited research on the natural history of disease in patients with chronic hepatitis B in the "gray zone," and there is still debate about the necessity of initiating antiviral treatment. At the 58th Annual Meeting of the European Association for the Study of the Liver (EASL 2023) and the 2023 EASL Congress, Dr. Peng Hu's team from the Second Affiliated Hospital of Chongqing Medical University (with Dr. Yunling Xue as the first author) presented their latest research findings on the natural history and prognosis of HBeAg-negative patients and those in the "gray zone" with chronic hepatitis B: patients in the "gray zone" with chronic hepatitis B have a higher risk of disease progression than HBeAg-negative HBV-infected individuals.
Chronic hepatitis B (CHB) remains a global medical burden. According to the guidelines released by the European Association for the Study of the Liver (EASL) in 2017, the natural history of chronic HBV infection is divided into four stages: HBeAg-positive HBV infection, HBeAg-positive chronic hepatitis B, HBeAg-negative HBV infection, and HBeAg-negative chronic hepatitis B. Among these, HBeAg-negative HBV infection is the most common stage. However, in HBeAg-negative patients, some individuals have normal alanine aminotransferase (ALT) levels and do not fit into any defined immunological category, referred to as the “gray zone” (GZ). Currently, there is limited research on the natural history of disease in “gray zone” patients, and there is also debate about the necessity of initiating antiviral treatment in this group. Therefore, this study mainly compared the natural history and prognosis of HBeAg-negative HBV infection and “gray zone” patients.
This retrospective study recruited 321 patients who were HBeAg-negative, had normal ALT levels (<40 U/L), had not received antiviral treatment, and had not been diagnosed with cirrhosis or liver cancer. According to the EASL guidelines, patients who met the following criteria were defined as having HBeAg-negative HBV infection: ① Normal ALT, HBeAg-negative, and DNA <2000 IU/ml; ② No obvious liver fibrosis: B-mode ultrasound did not indicate liver fibrosis, GPR <0.32, APRI <1.5, FIB-4 <3.25. Patients who did not meet these criteria were defined as being in the “gray zone.” The natural history changes in both groups of patients were explored and compared.
At baseline, among the 321 patients, 211 (65.73%) were defined as having HBeAg-negative HBV infection, and 110 (34.27%) were defined as “gray zone” patients. During follow-up, 7 (3.32%) of the 211 HBeAg-negative HBV-infected patients and 27 (24.5%) of the 110 “gray zone” patients transitioned to HBeAg-negative chronic hepatitis B and their corresponding “gray zone.” The cumulative incidence of “gray zone” patients transitioning to HBeAg-negative chronic hepatitis B and their corresponding “gray zone” was significantly higher than that of HBeAg-negative HBV infection (P < 0.0001) .
Terminal liver disease was defined as indicated by ultrasound findings of cirrhosis and/or liver cancer. In the study population, 9 patients (2.8%) experienced terminal liver disease events, of which 7 (77.78%) were in the “gray zone” and 2 (22.22%) were HBeAg-negative HBV-infected patients. Both patients with liver cancer at baseline were in the “gray zone,” and the cumulative incidence of terminal liver disease in “gray zone” patients was significantly higher than that in HBeAg-negative HBV-infected patients (P=0.0018) .The study also investigated ALT elevation and antiviral treatment initiation in patients. ALT elevation occurred in 46 cases (54.8%) of “gray zone” patients and 38 cases (45.2%) of HBeAg-negative HBV-infected patients. Antiviral treatment was initiated in 22 cases (77.3%) of “gray zone” patients and 8 cases (22.7%) of HBeAg-negative HBV-infected patients.Cumulative incidence rates for both outcome events were found to be higher in “gray zone” patients than in HBeAg-negative HBV-infected patients (P < 0.001, P < 0.001).
Figure 1. Comparison of Cumulative Incidence Rates of Relevant Outcome Events in HBeAg-Negative HBV-Infected Patients (A) and “Gray Zone” Patients (B)
(a) Outcome event: Transition to HBeAg-Negative Chronic Hepatitis B and its “Gray Zone.”
(b) Outcome event: Occurrence of Terminal Liver Disease Events.
(c) Outcome event: ALT Elevation.
(d) Outcome event: Initiation of Antiviral Treatment.
Conclusion
The above study suggests that more than one-third of patients were in the “gray zone” at baseline. The cumulative incidence rates of “gray zone” patients transitioning to HBeAg-negative chronic hepatitis B and their corresponding “gray zone,” terminal liver disease, ALT elevation, and initiation of antiviral treatment were all significantly higher than those of HBeAg-negative HBV infection. Therefore, close follow-up and timely initiation of antiviral treatment should be considered for “gray zone” patients to achieve a favorable prognosis.
TAG: EASL2023;Vioce of China;CHB;HBV
