The aim of current study is to investigate whether the HBsAg clearance rate can be improved if applying RGT((Response-Guided Therapy) strategy in HBeAg positive CHB(chronic hepatitis B) patients treated by nucleoside analogue(NUC) achieved HBVDNA<1000copies/ml，and HBsAg<5000IU/ml; &HBeAg<100PEIU/ml (or470s/co), combined with PEG-IFN a-2a for 24 weeks.

The current study is a prospective, randomized, open, multi-center investigation. The aim of current study is to investigate whether the HBsAg clearance rate can be improved if applying RGT strategy in HBeAg positive CHB patients treated by NUC achieved HBVDNA<1000copies/ml，and HBsAg<5000IU/ml; &HBeAg<100PEIU/ml (or470s/co), combined with PEG-IFN a-2a for 24 weeks. Then the subjects will be divided into three groups according to qHBsAg levels of week 24 (RGT). For the subjects who qHBsAg<200IU/ml of week 24, they are defined in Group A; the subjects in Group A will continue to be treated by NUC combined with PEG-IFN a-2a 180μg for another 24 weeks(total will be 48 weeks). If the qHBsAg at week 24 did not achieve minor 200IU/ml, the subjects will be randomized to 2 groups: Group B: the subjects will continue to be treated by NUC combined with PEG-IFN a-2a 180μg for another 24 weeks (total will be 48 weeks); Group C: the subjects will be treated by NUC until 48 weeks.

Inclusion Criteria:

1. Male and female patients with age ≥18 and ≤65 years;
2. There should be evidences that HBsAg and HBeAg have been positive for more than 6 months with HBsAb and HBeAb negative before treated with nucleoside analogue(NUC) (except of telbivudine);
3. Treated with NUC (except of telbivudine)for more than 24 weeks and achieve HBV DNA<1000copies/ml and HBsAg<5000IU/ml；&HBeAg<100PEIU/ml(470s/co);
4. Without contra-indications to Peginterferon alfa-2a therapy as detailed in the label;
5. Without co-infection with hepatitis C, hepatitis D and HIV;
6. Women without ongoing pregnancy or breast feeding and willing to take an effective contraceptive measure during the treatment
7. Agree to participate in the study and sign the patient informed consent form.

Exclusion criteria

1. Co-infection with active hepatitis A, hepatitis C, hepatitis D and/or human immunodeficiency virus (HIV)

2. AFP(alpha fetoprotein)>50ng/ml and/or evidence of hepatocellular carcinoma

3. Evidence of decompensated liver disease (Child-Pugh scores >5). Child-Pugh >5 means that, if one of the following 6 conditions is met, the patient has to be excluded:

   • Serum albumin <35 g/L
   • Prothrombin time prolonged≥ 4 seconds or PTA(prothrombin activity) < 60%
   • Serum bilirubin > 34 µmol/L
   • History of encephalopathy
   • Ascites

4. History or other evidence of a medical condition associated with chronic liver disease other than viral hepatitis (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures, thalassemia)

5. Pregnant or breast-feeding Women

6. ANC(absolute neutrophil count)<1.5x 10^9/L or PLT(platelet count)<90x 10^9/L

7. Consuming alcohol in excess of 20g/day for women and 30g/day for men within 6 months prior to enrollment

8. History of severe psychiatric disease, especially depression. Severe psychiatric disease is defined as major depression or psychosis that treated with antidepressant medication or a major tranquilizer at therapeutic doses respectively at any time prior to 3 months or any history of the following: a suicidal attempt hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease

9. History of immunologically mediated disease, (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, rheumatoid arthritis etc.)

10. History of esophageal varices bleeding or other evidence of esophageal varices bleeding or other symptoms consistent with decompensated liver disease

11. History of chronic pulmonary disease associated with functional limitation

12. History of severe cardiac disease (e.g., NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases)

13. Hemodialysis patients or patients with renal insufficiency

14. History of a severe seizure disorder or current anticonvulsant use

15. Major organ transplantation or other evidence of severe illness, malignancy, or any other conditions, which would make the patient, in the opinion of the investigator, unsuitable for the study

16. History of thyroid disease poorly controlled on prescribed medications

17. Evidence of severe retinopathy or clinically relevant ophthalmologic disorder

18. History of other severe disease or evidence of other severe disease or any other illness or conditions that the investigator believe that patients are not suitable to join in the study

19. Immunomodulatory treatment (including interferon) or LDT(telbivudine) within 1 year prior to the first dose of treatment

20. Patients included in another trial or having been given investigational drugs within 12 weeks prior to screening