Sequential PEG-IFN for HBV After Ending RNA-targeted Regimens

The goal of this clinical trial is to compare sequential PEG-IFNα therapy strategies in chronic hepatitis B (CHB) patients previously treated with ASO/siRNA. The main questions it aims to answer are: 1. Does sequential PEG-IFNα therapy (vs. deferred/no treatment) improve HBsAg clearance rates? 2. What are the HBsAg clearance and relapse rates after 24 weeks of PEG-IFNα therapy? 3. Is intermittent PEG-IFNα therapy as effective and safe as continuous therapy? Researchers will compare: • Group A (immediate 24-week PEG-IFNα + 24-week follow-up) vs. Group B (24-week observation + 24-week PEG-IFNα) in Phase 1 to see if sequential PEG-IFNα therapy will improve HBsAg loss rate . Researchers will describe: * The response rate of IFN treatment in non-responders (HBsAg-positive) in Phase 2. * The relaspe rate of responders (HBsAg-negative). Participants will: Phase 1 (0-48 weeks): * Group A: Receive PEG-IFNα for 24 weeks, followed by 24-week treatment-free follow-up. * Group B: Undergo 24-week observation, then receive PEG-IFNα for 24 weeks. Phase 2 (48-96 weeks): * HBsAg-positive at week 48 patients either from group A or group B : Receive 24-week PEG-IFNα therapy, followed by 24-week follow-up. * HBsAg-negative at week 48 patients either from group A or group B: Enter 24-week follow-up without treatment. All participants will undergo: • HBsAg quantification, HBV DNA, liver function, and safety monitoring (every 12 weeks).

Inclusion Criteria: * Age ≥18 years. * Chronic HBV infection (documented HBsAg positivity for \>6 months). * Prior participation in ASO or siRNA clinical trials: * Received ≥1 dose of ASO/siRNA (or matched placebo, if applicable). * Achieved ≥1 log10 IU/mL HBsAg decline from baseline during prior therapy. * Discontinued ASO/siRNA therapy before screening. * Screening HBsAg: 1-500 IU/mL. * No prior interferon (IFN) therapy within 6 months before enrollment. * Willingness to comply with study-related treatments, tests, and procedures. * Commitment to contraception during the study. * Voluntary participation with signed informed consent. Exclusion Criteria: * Decompensated cirrhosis or hepatic malignancy (evidenced by imaging or histology within 6 months before/during screening). * Elevated AFP: Screening AFP \>100 ng/mL; AFP 20-100 ng/mL with imaging-confirmed hepatocellular carcinoma (ultrasound/CT/MRI). * Coinfection with hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), or human immunodeficiency virus (HIV). * Recent immunomodulatory therapy: Systemic corticosteroids, thymosin, or other potent immunomodulators for \>2 weeks within 6 months before enrollment. * Pregnancy, lactation, or plans for pregnancy during the study. * Autoimmune hepatitis. * Active autoimmune diseases (e.g., psoriasis, systemic lupus erythematosus). * Uncontrolled cardiovascular disease (e.g., unstable angina, myocardial infarction within 6 months). * Poorly controlled endocrine disorders (e.g., diabetes mellitus, thyroid dysfunction). * Severe psychiatric disorders: History of depression, anxiety, bipolar disorder, schizophrenia, or family history of psychiatric conditions (especially depression). * Substance abuse: Alcohol (\>40 g/day for males; \>20 g/day for females) or Illicit drug use. * Severe retinopathy or ophthalmologic disorders. * Renal diseases: Chronic nephritis, renal insufficiency, nephrotic syndrome. * Major organ dysfunction (e.g., heart, lung, pancreas). * Organ transplant recipients or candidates. * Hypersensitivity to interferon or excipients. * Concurrent participation in other HBV-related interventional trials. * Other conditions deemed unsuitable by investigators (e.g., non-compliance risk).