A clinical trial is being conducted at West China Hospital of Sichuan University to evaluate the effectiveness of nucleos(t)ide analogs (NAs) in treating patients with positive hepatitis B virus (HBV) DNA, despite having normal alanine transaminase (ALT) levels and being hepatitis B e antigen (HBeAg)-negative. This randomized controlled trial aims to determine if antiviral treatment can improve virological response, quality of life, and liver-related outcomes in this specific patient population.
Study Design and Patient Population
The trial will enroll 300 patients who meet the following criteria: positive hepatitis B surface antigen (HBsAg) for at least 24 weeks, negative HBeAg with positive hepatitis B e antibody (HBeAb), at least three instances of ALT below the upper limit of normal (ULN) in the past year, detectable serum HBV DNA (≥ 20 IU/ml), and no signs of cirrhosis or liver nodules. Participants must be HBV treatment-naïve. Exclusion criteria include age < 18 years, pregnancy, coinfection with HIV, HCV, or HDV, and confirmed liver cirrhosis, HCC, or other liver diseases.
Intervention
Patients in the treatment group will receive oral NAs, including entecavir (ETV) 0.5 mg, tenofovir disoproxil fumarate (TDF) 300 mg, tenofovir alafenamide (TAF) 25 mg, or tenofovir amibufenamide (TMF) 25mg per day for 96 weeks. The choice of antiviral drug will be based on the patient's age, gender, economic conditions, and medication habits, with the final decision made by the participant. The control group will undergo regular disease assessment without antiviral treatment. Treatment adjustments will be made if HBV DNA remains positive or if patients experience intermittent hypoviremia or intolerable adverse reactions.
Outcomes and Assessments
The primary outcomes of the study include rates of virological response, changes in serum HBV pgRNA levels, and scores on the Hepatitis B Quality of Life Instrument, Version 1.0 (HBQOL V1.0). Secondary outcomes include rates of serum HBsAg loss, changes in serum HBsAg levels, noninvasive liver fibrosis scores (APRI and FIB-4), liver stiffness measurement (LSM), and the incidence of liver nodules, liver cirrhosis, and HCC. Assessments, including abdominal ultrasonography, transient elastography, and blood tests, will be conducted at baseline and every 3 to 6 months.
Sample Size and Statistical Analysis
The sample size calculation is based on the incidence of liver cirrhosis, with an estimated 1.1% incidence in the treatment group and 10.4% in the untreated group over 5 years. With a statistical power of 90% and a significance level of 0.05, 150 cases will be enrolled in each group. Statistical analysis will be performed on both the modified intention-to-treat (mITT) and per-protocol populations, with multiple imputation used for missing data. Subgroup analyses will be conducted based on HBV DNA levels (< 2000 vs. ≥ 2000 IU/ml) and age (< 30 vs. ≥ 30 years).
Potential Impact
This trial is expected to provide valuable insights into the management of HBeAg-negative patients with normal ALT and detectable HBV DNA. The results could influence clinical guidelines and improve patient outcomes by clarifying the role of antiviral therapy in this population.
