Establishment and validation of the non-invasive model to predict antiviral therapy in the gray zone of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection continues to be a major public health problem worldwide today. According to statistics, the prevalence of chronic HBV infection assessed globally in 2016 was 3.5%, or 257 million people with chronic infection. In China, it is estimated that about 70 million people are chronically infected with HBV in 2019, including about 20-30 million people with chronic hepatitis B (CHB). CHB is a major risk factor for cirrhosis, and hepatocellular carcinoma (HCC). 12-20% of patients with chronic hepatitis B will develop cirrhosis, and of these, around 20% will further develop decompensated cirrhosis and 6-15% will develop HCC, with hepatitis B accounting for approximately 50% of HCC cases worldwide. Therefore, strongly and exact management of chronic hepatitis B is extremely important for the control of HBV progression. Current domestic and international clinical guidelines generally divide the natural history of chronic hepatitis B into four immune phases based on HBV DNA levels, liver injury, and HBeAg status: immune active, immune tolerant, inactive HBsAg carriers, and reactive stage. The guidelines of American Association for the Study of Liver Diseases (AASLD) recommend the use of antiviral therapy for patients in the immune active and reactive phases, and also provide a detailed follow-up plan for patients in other phases. However, a significant number of patients with chronic hepatitis B cannot be classified in any of these four phases, who falls into a gray area with uncertainty of formal management. According to the 2018 AASLD Hepatitis B Guidelines criteria for antiviral therapy, patients in the gray zone still do not have clarity on the need for antiviral therapy based only on clinical indicators. A recent study showed that nearly 40% of patients with chronic hepatitis B were in the indeterminate stage. At long-term follow-up assessment, half of these patients were still in the indeterminate phase and one-fifth had transitioned to the immune active phase. Patients in the indeterminate phase were 14 times more likely to develop HCC than those with inactive hepatitis B. Therefore, the management of antiviral therapy in patients with CHB in the "gray zone" is crucial and should be demonstrated. The aim of the investigators is to investigate the clinical characteristics of patients with uncertain treatment in the "gray zone" of CHB and to develop a non-invasive predictive model for the indication of antiviral therapy. This will provide guidance for the clinical management of patients in the "gray zone" of CHB, thereby reducing the incidence of cirrhosis and liver cancer and improving their quality of life.

Inclusion Criteria:

• HBeAg positive, normal serum alanine aminotransferase(ALT) level，HBVDNA≤10^6 IU/ml
• HBeAg positive, elevated serum ALT, HBVDNA≤2*10^4 IU/ml
• HBeAg negative, elevated serum ALT, HBVDNA≤2*10^3 IU/ml
• HBeAg negative, normal serum ALT, HBVDNA≥2*10^3 IU/ml

Normal upper limit of ALT is 35 U/L for male and 25 U/L for female.

Exclusion Criteria:

• Concurrent with other liver diseases such as autoimmune hepatitis, Hepatitis C virus infectious, liver cirrhosis, HCC, or unexplained liver function abnormalities
• Patients with incomplete clinical data

The minimum sample size required for the study was calculated to be 417, and it was estimated that almost 1000 patients with chronic hepatitis B underwent hepatic puncture biopsy in the seven hospitals from 2010 to 2022, and all patients will be included in the study.