This study evaluates whether Peg-IFN alfa-2a can reduce the recurrence rate of hepatitis B in 96 weeks after nucleoside analogue (NUC) withdrawal.

The HBV HBeAg-Negative patients who received NUC anti-virus treatment for 2.5 years and reached stopping rule in 《Chinese chronic hepatitis B prevention and treatment guidelines》(2010) were randomly assigned into three groups: One group discontinue the NUC treatment and follow up for 96 weeks,One discontinue the NUC treatment ,receive Peg-IFN alfa-2a 180 μg by week for 24 weeks and follow up for 72 weeks,The other discontinue the NUC treatment ,receive Peg-IFN alfa-2a 180 μg by week for 48 weeks and follow up for 48 weeks.

NUC is a potent inhibitor of hepatitis B viral(HBV) replication, but long-term therapy may be required. Therefore, NUC resistance is an important clinical risk resulting from long-term therapy in chronic hepatitis B (CHB) management. Discontinuation of NUC is a feasible strategy to reduce resistance. However, the high rate of relapse after cessation of NUC treatment in CHB patients remains a big problem. NUC treatment of how to safely stop drug needs to be solved.

Peg-IFN can clear HBV by direct anti-viral and immune regulation mechanisms including enhancing natural killer cell response, increased cluster of differentiation 8(CD8 +) T lymphocytes and other mechanisms to restore and enhance the immune response in patients with CHB. Response to PEG-IFN is frequently sustained after a finite treatment course due to its immune modulating capacity.

Inclusion Criteria:

1. HBeAg-Negative Chronic Hepatitis B Patients：HBsAg-Positive,HBsAb-Negative,HBeAg-Negative,HBeAb-Positive during screening period and before NA treatment
2. NUC monotherapy (including adefovir and entecavir) for more than 2.5 years,and reached stopping rule in 《Chinese chronic hepatitis B prevention and treatment guidelines》(2010):the patients who achieved undetectable HBV DNA (<300 copies/mL) with normal alanine aminotransferase (ALT) and the consolidation therapy reached 1.5 years ,total course of the treatment reached 2.5 years can stop NUC therapy
3. Willing to stop the drug, and signed a written informed consent

Exclusion Criteria:

1. HBsAb positive in screening period
2. Compensated or Decompensated liver cirrhosis:with history of cirrhosis before NUC treatment or Child-Pugh score ≥ 5 or Complications of liver cirrhosis such as ascites, hepatic encephalopathy, esophageal gastric varices bleeding
3. Hypersensitivity to interferon(IFN) or its active substance, and ineligible to IFN
4. A history of immunoregulation drug therapy within one year before entry including IFN and so on.
5. Coinfection with HAV、HCV、HDV、HEV 、HIV or with Other chronic liver diseases such as Alcoholic Liver Disease,Inherited Metabolic Liver Disease,Drug induced Liver Disease and nonalcoholic fatty liver
6. Autoimmune disease including Autoimmune hepatitis and Psoriasis and so on.
7. Hepatocellular carcinoma(HCC) or alpha feto protein(AFP) levels more than 100 ng/ml and Hepatic malignant potential of Imaging examination or AFP levels more than 100 ng/ml for 3 months
8. A neutrophil count of less than 1500 per cubic millimeter or a platelet count of less than 90,000 per cubic millimeter
9. A serum creatinine level that was more than 1.5 times the upper limit of the normal range
10. With other malignant tumors(exclude the cured ones)
11. Severe organ dysfunction
12. With severe psychiatric condition or nervous disease such as epilepsy, depression, mania, epilepsy, schizophrenia and so on
13. Uncontrolled diabetes, hypertension or thyroid disease
14. Pregnant women and lactating women or patients with pregnancy plans and not willing to use contraception during the study period
15. Participate in other clinical studies at the same time
16. Patients unsuitable for the research