A Non-invasive Model to Predict Antiviral Therapy in Gray Zone of Chronic Hepatitis B

September 10, 2023 updated by: Qilu Hospital of Shandong University

A Non-invasive Model to Predict Antiviral Therapy in Patients With Gray Zone of Chronic Hepatitis B: a Multi-center, Retrospective Study

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

Study Overview


Not yet recruiting

Intervention / Treatment

Detailed Description

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.

Study Type


Enrollment (Estimated)


Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers


Sampling Method

Non-Probability Sample

Study Population

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.


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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with the antiviral therapy as assessed by AASLD guideline
Time Frame: From Jan 1st,2010 to Aug 31,2023

The criteria of antiviral therapy:

  1. Immune-active CHB: an elevation of ALT≥2 the upper limit of normal (ULN)plus elevated HBV DNA above 2,000 IU/mL (HBeAg negative) or above 20,000 IU/mL (HBeAg positive).
  2. Immune-active CHB and cirrhosis if HBV DNA is >2,000 IU/mL.
  3. Immune-active CHB with ALT < 2 the ULN and HBV DNA below thresholds (less than 2,000 IU/mL if HBeAg negative or less than 20,000 IU/mL if HBeAg positive) are as follows: 1) Age: older age (>40 years). 2) Family history of cirrhosis or HCC. 3) Previous treatment history. 4) Presence of extrahepatic manifestations. 5) Presence of cirrhosis.
  4. Immune tolerance CHB with the moderate-to-severe necroinflammation or fibrosis on a liver biopsy specimen.
From Jan 1st,2010 to Aug 31,2023
Number of participants with significant liver histology as assessed by Metavia scoring system
Time Frame: From Jan 1st,2010 to Aug 31,2023

Significant liver histology showing significant hepatic inflammation ≥G2 and/or fibrosis ≥S2 as assessed by Metavir scoring system

The fibrosis score is used to describe the amount of inflammation (the intensity of inflammation/breakdown of tissue) in the liver:

F0: No fibrosis F1: Portal fibrosis without septa F2: Portal fibrosis with few septa F3: Numerous septa without cirrhosis F4: Cirrhosis

The activity score is a prediction about how rapidly the degree of fibrosis is progressing:

G0: No activity G1: Mild activity G2: Moderate activity G3: Severe activity

From Jan 1st,2010 to Aug 31,2023

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

October 1, 2023

Primary Completion (Estimated)

November 1, 2023

Study Completion (Estimated)

December 31, 2023

Study Registration Dates

First Submitted

September 3, 2023

First Submitted That Met QC Criteria

September 10, 2023

First Posted (Actual)

September 18, 2023

Study Record Updates

Last Update Posted (Actual)

September 18, 2023

Last Update Submitted That Met QC Criteria

September 10, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?


Drug and device information, study documents

Studies a U.S. FDA-regulated drug product


Studies a U.S. FDA-regulated device product


This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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