Chronic infection with hepatitis B virus (HBV) afflicts ~400 million people worldwide, including 1.5-2 million in the U.S.A. Chronic hepatitis B (CHB) leads to early death from cirrhosis, liver failure and primary liver cancer (HCC) in at least 1 million people annually. Current antiviral therapies (AVT) can suppress but rarely cure infection, emphasizing need for fresh approaches. We propose one here. Most CHB patients receiving AVT in the West have “early antigen negative (HBeAg-)” disease, caused by a futile host immune response against a mutated form of HBV. The current standard-of-care is lifelong AVT which can prevent disease advancement and likely lower HCC risk. However, indefinite AVT incurs financial burden to healthcare systems and patients, raises safety concerns and carries drug resistance risk. New data from 33 HBeAg–CHB patients in Greece, supported by our pilot study, suggest that AVT withdrawal after ≥3.7 years (192 weeks) of viral suppression can be safe, benefit many and even stimulate protective immunity. During follow-up, 18 (55%) achieved sustained viral and biochemical responses. Of these, 13 (39% of the original cohort) went on to clear HBV by generating neutralizing surface antibody (HBsAb). This seismic result indicated that in HBeAg-CHB, AVT withdrawal is likely safe and can effect “close to cure” of what would otherwise be a lifelong, life-threatening and indefinitely treated infection. Seminally, it also opens a new door for understanding how to tilt a curative host immune response in CHB, which we already study. In this grant, we propose testing the findings of the Greek study in a larger, ethnically diverse San Francisco population that is naturally enriched for Asians who comprise the world’s greatest HBV reservoir. In parallel, we will use cellular and molecular studies on liver and blood from the patients to dissect immunological mechanisms of seroclearance versus persistence of HBV and its antigens. The translational scientific component will in part be driven by hypotheses based on our published and unpublished data;; and it will also contain a host genetic prospecting arm that will seek evidence for signature gene expression patterns that both predict outcome and could point to unsuspected mechanisms of immunity. A key objective will be to attempt to distinguish patients who are most or least likely to benefit from the treatment withdrawal intervention. METHODS: An IRB-approved, 2-center (CPMC & UCSF) multidisciplinary prospective study of clinical outcomes, genetic profiles and immune responses in 80 adult human patients with HBeAg-CHB, during and after oral AVT, using serial blood samples and liver biopsy tissue. 30 adult HBeAg- controls will also be studied. PATIENT OUTCOMES (PROJECTED) 31 patients are predicted to HBsAb seroconvert and clear circulating HBV DNA and antigens;; 49 ar...