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 Sustained remission = Maintained remission = Low viraemia + Low viraemia + ALT normalisation Immune control, no antiviral drugs Long term viral suppression antiviral drugs

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

4. Immune Response to HBV Infection DC maturation NK Cell Activation Innate Response Type 1 IFN  production B cell Blocking viral spread with Ab production CTL Direct recognition of infected cells Th1 Th2 T helper cells Expansion of Immune response Y Y Y Y Adaptive Response

5. Ganem, D. et al. N Engl J Med 2004;350:1118-1129 Cellular Immune Responses is important to HBV Clearance 1.HBsAg particles and virions recognized by APC 2.Processed antigen recognized by CD4+ and CD8+ cells 3.Virus specific CD8+ cells (with help from CD4+) recognize MHC class I chain on infected hepatocytes 4.Direct lysis of infected hepatocytes or relatease of IFN  and TNFa

6. HBsAg Seroconversion: The ‘Ultimate’ Goal of Therapy in CHB HBsAg seroconversion 1 –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. Fattovich G et al. Am J Gastroenterol 1998 HBsAg Seroconversion: A Potent Marker of Sustained Remission Retrospective study of 309 patients over mean follow-up of 5.7 years Survival Probability (%) WITH HBsAg seroconversion WITHOUT HBsAg seroconversion Proportion of patients surviving Months 100 80 60 40 20 48729612014416824 P<0.001

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. 84 Niederau NEJM 1996 Proportion of patients surviving Proportion free of hepatic complications Months 1.0 0.8 0.6 0.4 0.2 243636486060728412243648607212 IFN  -treated WITH HBeAg loss 1.0 0.8 0.6 0.4 0.2 IFN  -treated WITHOUT HBeAg loss P=0.004*P=0.018* *According to the proportional hazards model HBeAg Loss Following IFN  Treatment Results in Increased Survival

10. From CHB to Liver Cirrhosis: Cirrhosis Number %/year 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 HBeAg (+) 1 509 3 35 2.4 (+)  (+) 2 134 6.8 3.5 (+)  (-) 2 74 6.8 1.5 HBeAg seroconversion 3 269 8.6 21 0.9 HBsAg seroclearance 4 189 5.3 0 Status Number F/U (year)

11. van Zonneveld. Hepatology 2004 Time from start of therapy (years) 4681012142 1.0 0.8 0.6 0.4 0.2 0 HBeAg response * No HBeAg response Proportion of patients with HBsAg loss * Response defined as HBeAg loss within12 months of treatment 50% HBsAg Response After HBeAg Clearance in HBeAg-positive CHB Long-term outcome following IFN  treatment

12. Nucleosideanalogues THTHTHTH TSTSTSTS Immunostimulants Immunosuppressives NK CTL + + + - - - Lamivudine Prednisone Levamisole, Thymosin Treatment Options for Chronic HBV Adevofir Entecavir LdT Interferon + + + - pIFN

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

14. Mean HBV DNA (log 10 copies/mL) * log 10 reduction from baseline HBV DNA Reduction On-treatment HBeAg Seroconversion 24 Weeks Post-treatment PEGASYSLAM 32% P<0.01 2 4 6 8 10 12 06 182430364248 -4.5* PEGASYS -5.8* LAM 19% 0 10 20 30 40 50 Fried et al EASL 2005 PEGASYS vs LAM in HBeAg Positive Despite a More Profound Viral Reduction with LAM, Sustained HBeAg Response at Week 72 was Higher with PEGASYS

15. -4.1* -4.2* Mean HBV DNA (log 10 copies/mL) 2 3 4 5 6 7 8 012243648 PEGASYS LAM HBV DNA Reduction On-treatment Sustained Responses 24 Weeks Post-treatment Lai et al APASL 2004 and Roche data on file PEGASYS vs LAM in HBeAg Negative Despite a More Rapid Viral Reduction with LAM, Sustained Response at Week 72 was Higher with PEGASYS PEGASYSLAM 59% 44% 43% 29% ALT normalisation HBV DNA <20,000 cp/mL P<0.01 * log 10 reduction from baseline

20. Antiviral Potency and HBeAg Seroconversion HBV DNA change from baseline 1 year post treatment (log 10 ) HBeAg seroconversion (%) Adefovir (antiviral) Lamivudine* (antiviral) Entecavir (antiviral) Pegasys* (antiviral + immun.) * Study WV16240 Pegasys*+Lamivudine (antiviral + immun.) Interferon (antiviral + immun.)

21. Favorable Outcome of HBV Treatment 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 HBeAg seroconversion HBsAg loss/seroconversion Prevention of HCC Improved survival HBeAg loss Normal ALT, Reduced HBV DNA

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