The investigators' research is aimed at developing more effective, finite approaches for managing individual patients with chronic hepatitis B (CHB). This prospective clinical and basic scientific study exclusively focuses on patients with the early antigen negative form of disease, which in developed countries is treated indefinitely with antiviral drugs. The investigators' study "BeNEG-DO," directly offers patients who are already taking standard oral Hepatitis B Virus (HBV) antiviral therapy for at least 192 weeks the option to stop or continue treatment. Drawing on data from pilot studies, including the investigators' own University of California, San Francisco and Sutter Institutional Review Board-approved study, the investigators will examine a finite HBV treatment strategy on clinical outcome and safety. In conjunction, the investigators will study immunologic mechanisms and gene expression profiles that correlate with and predict the post-treatment clinical course. The BeNEG-DO study could seriously question, and potentially change, the current treatment paradigm for millions of patients with CHB and also lead to new disease-terminating antiviral therapeutics.

A prospective case-control study of safety and clinical outcomes, and of innate and adaptive immune responses and their genetic predictors, in adult human subjects with HBeAg-CHB who either continue or stop nucleoside or nucleotide analog (NA) antiviral therapy. Immune responses will be studied using liver tissue and serial peripheral blood samples. The immunological factors selected have been chosen based on preliminary and inferential evidence. Immunologic findings will be correlated with different serologic, virologic and biochemical outcomes. Genetic predictors of the type of response and respective clinical outcomes will also be sought.

Inclusion Criteria:

1. HBeAg-CHB with at least 192 weeks (3.7 years) of complete viral suppression (serum HBV DNA <50 IU/ml) on NA therapy
2. No bridging fibrosis (≥ Metavir stage 3)
3. Normal liver tests and platelet count
4. Age 18-67
5. Otherwise healthy with no serious co-morbidities
6. Patients who are willing, prepared, and able to immediately resume antiviral treatment upon medical instruction and on satisfying study re-treatment criteria.

Exclusion Criteria:

1. HBeAg-CHB with virologic breakthrough while on NA therapy during the prior 192 weeks (3.7 years)

2. Age <18 or >67 years

3. Significant co-morbidities including co-infection and significant co-existing liver disease or anemia. Mild Non-Alcoholic Fatty Liver Disease (NAFLD) without Non-Alcoholic Steatohepatitis (NASH) or associated liver enzyme elevation will be allowed.

4. Bridging hepatic fibrosis (≥ Metavir stage 3) at the time of potential study entry

   a. Control Group: Determination will be based on historical biopsy data, imaging studies, Platelet count (<150,000), Aspartate aminotransferase to Platelet Ratio Index (APRI) <1.5) and Red Cell Distribution Width-to-Platelet Ratio (RPR) (<0.16) scores, and clinical assessment

5. Alanine Aminotransferase (ALT) above the quoted normal range

6. Clinical, serologic, radiological or biochemical suspicion for cirrhosis

7. Prior liver transplantation

8. A documented history of extrahepatic manifestations of hepatitis B, including renal disease and/or vasculitis

9. Cases: A family history of hepatocellular carcinoma due to hepatitis B virus in a first degree family member

10. On Prednisone or other immunosuppressive or immune-modulating therapy during the 6 months before study entry

11. Pregnancy

12. Patients who are not willing, prepared, and able to immediately resume antiviral treatment upon medical instruction and on satisfying re-treatment criteria

No one will be excluded on the basis of race, gender, religion, sexual orientation, or any cultural factor. An Institutional Review Board (IRB)-approved, translated consent will be used for patients that do not speak English