Joseph Sung MD , PhD Department of Medicine and Therapeutics Institute of Digestive Diseases

1. Treating HBV Infection: Sustained Remission with Immune control Joseph Sung MD , PhD Department of Medicine and Therapeutics Institute of Digestive Diseases The Chinese University of Hong Kong

2. Treatment Goals in CHB

3. 3. Prevention of infecting uninfected hepatocytes 4. Prevention of reinfecting infected hepatocytes 2. Inhibit new virus production 1. Clearance of circulating virus 5. Elimination of cccDNA from infected cells Why is HBV so difficult to clear? 6. Elimination of extrahepatic reservior Ganem, D. et al. N Engl J Med 2004;350:1118-1129

4. Type 1 IFN (a-b) production CTL Direct recognition of infected cells NK Cell Activation Th1 T helper cells Expansion of Immune response Th2 DC maturation Y B cell Blocking viral spread with Ab production Y Y Y Adaptive Response Innate Response Immune Response to HBV Infection

5. Cellular Immune Responses is important to HBV Clearance • HBsAg particles and virions recognized by APC • Processed antigen recognized by CD4+ and CD8+ cells • Virus specific CD8+ cells (with help from CD4+) recognize MHC class I chain on infected hepatocytes • Direct lysis of infected hepatocytes or relatease of IFNg and TNFa Ganem, D. et al. N Engl J Med 2004;350:1118-1129

6. HBsAg Seroconversion: The ‘Ultimate’ Goal of Therapy in CHB • HBsAg seroconversion1 • Represents an identical state to that achieved in patients who effectively control HBV following acute infection • Reliable marker for the resolution of CHB, both HBeAg-positive and HBeAg-negative • Constitutes the outcome closest to a ‘cure’ of CHB in clinical practice • Stringent criterion, rarely achieved with current treatments within a short time frame 1. Ganem and Prince. NEJM 2004

7. HBsAg Seroconversion: A Potent Marker of Sustained Remission Retrospective study of 309 patients over mean follow-up of 5.7 years Proportion of patients surviving 100 80 P<0.001 60 Survival Probability (%) 40 20 24 48 72 96 120 144 168 Months WITH HBsAg seroconversion WITHOUT HBsAg seroconversion Fattovich G et al. Am J Gastroenterol 1998

8. Treatment Endpoint for HBeAg-positive • During CHB infection, presence of HBeAg is associated with active and progressive liver disease • HBeAg loss/seroconversion is the strongest indicator of lasting remission in HBeAg-positive CHB Lok and McMahon. Hepatology 2004

9. HBeAg Loss Following IFN Treatment Results in Increased Survival Proportion free of hepatic complications Proportion of patients surviving 1.0 1.0 P=0.004* P=0.018* 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 84 12 24 36 48 60 72 84 12 24 36 48 60 72 Months Months IFN-treated WITH HBeAg loss IFN-treated WITHOUT HBeAg loss Niederau NEJM 1996 *According to the proportional hazards model

10. From CHB to Liver Cirrhosis: Cirrhosis Status F/U (year) Number %/year Number HBeAg (+)1 509 3 35 2.4 (+)  (+)2134 6.8 3.5 (+)  (-)274 6.8 1.5 HBeAg seroconversion3269 8.6 21 0.9 HBsAg seroclearance4189 5.3 0 1. Liaw YF et al. Hepatology 1988; 2. Liaw YF et al. 2005; 3. Hsu et al. Hepatology 2002; 4. Chen et al. Gastroenterology 2002

11. 1.0 0.8 HBeAg response * 0.6 0.4 No HBeAg response 0.2 0 2 4 6 8 10 12 14 HBsAg Response After HBeAg Clearance in HBeAg-positive CHB Long-term outcome following IFN treatment Proportion of patients with HBsAg loss 50% Time from start of therapy (years) * Response defined as HBeAg loss within12 months of treatment van Zonneveld. Hepatology 2004

12. + + + - Interferon pIFN Treatment Options for Chronic HBV Levamisole, Thymosin Immunostimulants + TH + TS + - Prednisone CTL - NK Immunosuppressives - Lamivudine Nucleoside analogues Adevofir Entecavir LdT

13. NA PIFN IFN Th APC CTL Lymphocyte B cell NK Approach to Sustained Remission Immune control 100% HBV DNA Suppress viral replication Induction phase Clear infected hepatocyte Sustained phase Assay limit 0% Immuno-modulation Direct viral suppression About 14.5 years to deplete replication template with single NA

14. PEGASYS vs LAM in HBeAg PositiveDespite a More Profound Viral Reduction with LAM, Sustained HBeAg Response at Week 72 was Higher with PEGASYS -4.5* HBV DNA Reduction On-treatment HBeAg Seroconversion 24 Weeks Post-treatment 12 50 P<0.01 40 32% 10 30 19% Mean HBV DNA (log10 copies/mL) 8 20 PEGASYS 10 6 0 PEGASYS LAM LAM 4 -5.8* 2 *log10 reduction from baseline 0 6 12 18 24 30 36 42 48 Fried et al EASL 2005

15. PEGASYS vs LAM in HBeAg NegativeDespite a More Rapid Viral Reduction with LAM, Sustained Response at Week 72 was Higher with PEGASYS HBV DNA Reduction On-treatment Sustained Responses 24 Weeks Post-treatment 8 ALT normalisation HBV DNA <20,000 cp/mL 7 59% P<0.01 6 44% 43% 29% Mean HBV DNA (log10 copies/mL) 5 PEGASYS 4 PEGASYS LAM -4.1* 3 -4.2* LAM 2 0 12 24 36 48 *log10 reduction from baseline Lai et al APASL 2004 and Roche data on file

20. Antiviral Potency and HBeAg Seroconversion Pegasys* (antiviral + immun.) HBeAg seroconversion (%) Pegasys*+Lamivudine (antiviral + immun.) Interferon (antiviral + immun.) Entecavir (antiviral) Lamivudine*(antiviral) Adefovir(antiviral) HBV DNA change from baseline 1 year post treatment (log10) * Study WV16240

21. Favorable Outcome of HBV Treatment Normal ALT, Reduced HBV DNA HBeAg loss HBeAg seroconversion HBsAg loss/seroconversion Prevention of HCC Improved survival Hoofnagle et al. Ann Intern Med 1981; Fattovich et al. Hepatology 1986; Di Bisceglie et al. Gastroenterology 1987; Niederau et al. NEJM 1996; Chu et al. Gastroenterology 2002; van Zonneveld et al. Hepatology 2004

22. Developments in Therapeutic Approaches: Treatment Strategies Survival yes Sustainedresponse 2nd choice therapy Maintenance therapy eg nucleoside/tide analogues no* 1st choicetherapy Finite therapy course with highest chance of sustained response (remission) eg peginterferon alfa-2a or IFN *or IFN contraindicated / not tolerated