1. Milan J. Sonneveld,1 Bettina E. Hansen, Teerha Piratvisuth, Ji-Dong Jia, Stefan Zeuzem, Edward Gane, Yun-Fan Liaw, Qing Xie, E. Jenny Heathcote, Henry L.-Y. Chan, Harry L.A. Janssen Response-Guided Peginterferon Therapy in Hepatitis B e Antigen-Positive Chronic Hepatitis B Using Serum Hepatitis B Surface Antigen Levels 2013-10-07 R1. 박은지 / Pf. 심재준 Hepatology 2013;58:872-880

2. Introduction Chronic hepatitis B (CHB) ; One of the leading causes of cirrhosis and hepatocellular carcinoma Peginterferon-alfa (PEG-IFN) ; Suppression of HBV DNA, HBeAg loss, HBsAg clearance → HCC ↓ (BUT) Limited response rates → Clinical application is compromised → Careful selection of patients ; Genotype A or B > C or D Higher ALT Lower HBV DNA HBsAg may predict response to PEG-IFN therapy in CHB → Limited prediction role ~!

3. Patients - HBeAg-positive CHB patients who were previously enrolled in three separate randomized controlled trials on PEG-IFN therapy (Total N=899) Methods (1) 1. PEG-IFN alfa-2a Phase 3 study (N=542) 2. HBV 99-01 study (N=221) 3. Neptune study (N=136) PEG-IFN(P) : Lamivudine(L) : PEG-INF + Lamivudine(P+L) 48 wks Respose : 6mo (post Tx) P : P + L 52wks Respose : 6mo P (full dose;180ug/wk) : P (half dose;90ug/wk) 24wk or 48wks Respose : 6mo Inclusion (N=803)Exclusion (N=96) - HBsAg positive for at least 6 mo - HBeAg positive - Elevated ALT X1~10 ULN - HBV DNA levels > 1.0 X 10 5 copies/mL - Coinfection (HCV, hepatitis delta virus, HIV) - Decompensated liver disease - Previous antiviral therapy within 6 mo - Neutropenia - Thrombocytopenia.

4. Lab measurements : serum HBsAg, HBV DNA, ALT, HBV genotype → Baseline ~ during the treatment (End of Tx) ~ follow-up (6mo post Tx) Response to treatment : HBeAg loss + HBV DNA level <2,000 IU/mL or HBsAg loss Methods (2)

5. Results (1) Table 1. Characteristics of the Study Cohort Total N=803

6. Results (2) Fig. 1. Change in serum HBsAg from baseline during treatment and 6 months of off-treatment follow-up across HBV genotypes A through D 1.60 0.96 0.46 0.39 P < 0.001

7. Results (3) Fig. 2. Mean change in serum HBsAg from baseline in patients with a response by HBV genotype A through D 1.98 2.39 0.73 0.34 P < 0.001 Overall D C B A

8. Results (4) Fig. 3. Application of the prediction rules based on HBsAg levels at week 12 (A) and 24 (B) and HBsAg declines at weeks 12 (C) and 24 (D) 12 wks HBsAg level 12 wks HBsAg declines 24wks HBsAg declinesHBsAg level

9. Results (5) Table 2. Observed Response Rates According to HBsAg Level at Week 12 Stratified by HBV Genotype Table 3. According to HBsAg Decline at Week 12

10. Results (7) Table 4. Performance of Proposed Stopping-Rules at Week 12 And 24 for Response Across the HBV Genotypes in Patients Treated With Peginterferon Monotherapy for 1 Year

11. Results (8) Fig. 4. Relationship between HBsAg level (in IU/mL) at week 24 of treatment and response 6 months off-treatment.

12. Conclusion HBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB HBV genotype-specific stopping-rules may be considered at week 12 But treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype

13. Thank you !