2. 3rd Paris Hepatitis Conference: Morning Session on HBeAg-Neg CHB WHY DO I TREAT MY PATIENTS WITH PEGYLATED INTERFERON? PEGYLATED INTERFERON?

3. Problems Confronting Clinician with HBeAg Negative Hepatitis B High rate of relapse to conventional strategies Diagnosis can be a bit challenging Patients tend to be older group than HBeAg (+) with more severe disease Not much known about predictors of sustained virologic response to IFN

4. Recent PEG IFN Developments that Impact on Care of Patients with HBeAg (-) CHB  Long-term follow up Durability HBsAg clearance  On treatment prediction of SVR HBV DNA response HBsAg response  Clarification of importance of genotype  Better understanding of tolerability

5. Antiviral Therapy: A Matter of Choice Case Features Should Determine Approach Poor tolerability in elderly and those with comorbid illness Any age, minimal adverse events Less effective for high level viremia Baseline viremia generally not an issue Chance for SVR determined by baseline ALT ALT elevation not required for viral suppression Response genotype dependent Viral suppression independent of genotype Contraindicated with decompensated disease Can be used safely in decom- pensated disease Limited usefulness in special populations Appropriate in certain settings Peginterferon Nucleoside Analog

6. Finite treatment * Diminished infectivity Potential for long term benefit (HBsAg loss)* Durability off treatment Drug cost /cost of care Indirect costs * Tolerability * Convenience * Need for monitoring * Many Other Factors Go Into a Treatment Decision Modified from Perrillo, Hepatology, 2006

7. Initial and Long Term Follow Up from PEG IFN alfa-2a Study in HBeAg-Neg CHB 0 10 20 30 40 50 60 70 60% 19% 27% 17% ALT HBV DNA ALT HBV DNA normal <20,000 < 400 normal < 20,000 < 400 Initial study Follow-up study 6 mos after EOT 4years after EOT n= 356 * n = 230 * * w/wo LAM Marcellin, EASL, 2008 Marcellin, NEJM 2005 43% 24%

8. Follow up Data in PEG IFN-Treated HBeAg-Neg CHB ALT normal HBV DNA < 400 copies HBsAg clearance Initial study 6 months after EOT n =356 Follow-up study 4 years after EOT n = 230 0 10 20 30 40 50 60 70 3% 11% ~ 3% increase annually in responders Marcellin, 2005, 2008 2 % with lamivudine

9. 0- 2 4 6 8 10 12 14 16 18 Virologic relapse 0.2 0.4 0.6 0.8 Fung, 2004 Months to Relapse 50 Chinese patients treated with LAM 37 treated for 2 yrs 27 neg. by PCR for ≥ 9 mos meet criteria for treatment withdrawal Prolonged PCR Negativity Does not Allay Concerns About Relapse Clinical relapse

10. Long Term Response in Adefovir-Treated Cohort Negative for HBV DNA x 4-5 Years 33 patients neg for HBV DNA x 4-5 yrs on adefovir33 patients neg for HBV DNA x 4-5 yrs on adefovir Followed for median duration 18 mos off treatmentFollowed for median duration 18 mos off treatment 67% continue with ALT NL67% continue with ALT NL HBV DNA becomes detectable in all (“low,” varying from BDL to 5 x 10 4 copies)HBV DNA becomes detectable in all (“low,” varying from BDL to 5 x 10 4 copies) HBV DNA declines with further ollow upHBV DNA declines with further ollow up Hadziyannis et al, AASLD, 2006 Hadziyannis et al, AASLD, 2006

11. Worldwide Distribution of HBV Genotypes Genotype A Genotype B Genotype C Genotype D Genotype E Genotype F Genotype G 1 Westland, Gastroenterology 2003; 2 Chu, Gastroenterology 2003 Asia 1 Europe 1 USA 2 Mediterranean 1 42% 46% 9% 83% 14% 35% 40% 15% 22% 35% 31% 10%

12. Genotype A n=174 Genotype B n=245 Genotype C n=464 Genotype D n=346 HBeAg (+) n=703 36.3%21.1%18.5%14.6% HBeAg (-) n=526 34.0%32%50.4%21.4% Genotype and Virologic Response to IFN According to HBeAg Status in 1229 Patients Erhardt, AASLD 2008, Absract 883 Standard =298l PEG = 491; with LAM 440

13. 0 5 10 15 20 25 ALL PATIENTS ASIANS CAUCASIANS Chronic hep B studies Chronic hep C studies Events (%) Frequency of Depression-Related Events During Treatment with PEG IFN alfa-2a Marcellin et al, Liver International, 2007 4% 22% 2% 9% 10% 23% P < 0.001 P = 0.003 P = 0.027     Depression events 4% (B) vs 22% (C)

14. Side Effects: HBeAg (-) CHB (n = 177) vs CHC (n = 791) Drug Discon- tinuations B, C % Discontinua- tion for Safety, B, C % 1 or More Serious Adverse Events B, C% Most Common Serious Event B, C% 8, 17-33 7, 7-22 5 (n =9), 7-16 Infection (6), psychiatric

15. Patients with Cirrhosis Respond Just as Well to IFN As Those Without modified after Chu and Liaw Sem Liver Dis 2006 Niederau + 63% 47%ns D Lau + 59% 24%0.01 van Zonneveld + 50% 29%0.034 Lin + 39% 35%ns Cooksley Peg IFN  2a + 48% 35%ns Buster Peg IFN  2b + 33% 14%0.02 * Papatheodoridis - 28% 27%ns Brunetto - 26% 18%ns Cooksley Peg IFN  2a - 40% 45%ns CirrhosisNon-CirrhosisHBeAgP Value Response rates * Dose reduction, early discontinuation, and SAEs comparable for both groups (33% vs 34%, 11% vs 8%, 4% vs 5%)

16. Peginterferon for Delta Hepatitis Patients often HBeAg-negative Interferon only effective treatment Treatment required long-term –Where possible, continue until loss of HBsAg (Farci, J Viral Hep 2007; 14:S58-63)

17. 3rd Paris Hepatitis Conference: Session on HBeAg-Neg CHB HBsAg Loss, HBsAg Monitoring, and Relationship of Treatment- Induced Changes in HBsAg Concentration to Virologic Response

18. Why Is HBsAg Clearance So Important?

19. Qualitative Differences Between HBsAg and Prolonged Viral Suppression Durability of virologic response Significantly lower levels of intracellular genomic template (cccDNA ) Better long-term prognosis –Lower rate of HCC –Lower rate of progression to cirrhosis Less chance of viral reactivation –Spontaneous –Immune suppression

20. HBsAg Levels with Peg IFN Alfa -2a and Lamivudine in HBeAg (-) CHB 63 patients (42 IFN, 21 LAM) analyzed for HBsAg by ADVIA Centaur [Bayer]; (92% geno D) Low BSL HBsAg level predictive of HBsAg clearance HBsAg decreased in both treatment groups - Sharp drop in most IFN treated patients; sustained in VR - More gradual slope for LAM: ETU of HBsAg is median of 10.6 yrs of treatment vs 5.4 yrs with IFN Manensis et al, Anitiviral Ther, 2007

21. HBsAg ng/mL BaselineTreatment Week 12 Week 12 Treatment Treatment Week 60 Week 60 Follow up Week 12 Week 12 Follow up Week 24 Resp 1* 6,515 6,515 7,257 19 77 0 Resp 2 >7692 >7692 >7692 273 446 205 Resp 3 1,619 1,619 566 9 20 61 Resp 4 >7,692 >7,692 196 38 27 19 NR 1 NR 1 1,212 1,056 NA 1,910 1,473 NR 2 6,881 >7,692 6,088 6,823 5,219 NR 3 368 392 304 NA 189 NR 4 5,019 6,030 7,584 6,161 7,715 Measuring HBsAg in HBeAg (-) CHB: with 60 Week Extended Course of Peg IFN Alfa -2a Gish, Lau, Schmid, Perrillo Am J Gastro 2007 * Response = PCR negative at FU week 24

22. HBV DNA SVRs vs Non-responders Log copies/mL TreatmentFUP SVRs (n=12) NRs (n=18) Moucari et al, Hepatology, in press

23. HBsAg Level SVRs vs Non-Responders Log IU/mL FUPTreatment SVRs (n=12) NRs (n=18) Moucari et al, Hepatology, in press

24. HBsAg: Predictive Value for SVR by Wk 24 Decline (1 Log IU/mL) 48 Patients n = 12 n = 36 n = 1 n = 35 n = 1 n = 11 PPV = 92 % NPV = 97 % Week 24 ↓ HBsAg ≥ 1 Log IU/mL Week 24 ↓ HBsAg < 1 Log IU/mL SVR (+) SVR (-) SVR (+) SVR (-)

25. Predictive Value of qHBsAg Predictive Value of qHBsAg at Wk 48 for Outcome: at Wk 48 for Outcome: NPV NPV PPV PPV Spec SpecSens Sustained HBsAg Clearance at Yr 3 HBsAg < 380 IU/mL at wk 48 100 25 100 74 HBsAg reduction > 1.9 log 10 at wk 48 98 44 92 75 HBV DNA ≤ 400 copies at 3 Yrs HBsAg < 19 IU/mL at wk 48 98 44 75 92 HBsAg reduction > 0.46 log 10 IU/mL at wk 48 95 30 66 81 HBsAg Decline at Wk 48 Predicts Outcomes at Year 3 After End of Rx* Brunettto et al, Hepatology, in press * Based on subset of 198 patients In initial treatment cohort; HBsAg (-) in 16 (8%)

26. WhyPEG IFN First for HBeAg-Negative CHB? SUMMARY Why PEG IFN First for HBeAg-Negative CHB? Useful as first line therapy in selected patients: Age, comorbid illnesses, compensated liver disease Test for genotype (non geno D) Better tolerated than in hepatitis C Patients with stable cirrhosis can be treated safely Specific advantages: –Discrete interval of treatment –Responses can be durable –HBsAg loss –Possibility of response directed therapy

27. Summary: Why PEG IFN FIrst? (2) Responses can be durable If treatment fails, no impact on success with NA or requirement for more complex therapy

29. Managing Patients with Limited Access to Care I dentify those chronically infected Government or privately sponsored screening programs D etermine ease of, and need for treatment Liver biopsy may be optional: High likelihood of response Obvious features of cirrhosis Treatment to prevent HCC?**** I nvestigate treatment possibilities Government health care programs Pharmaceutical free/discounted drug O nly monitor what and when it is necessary More dependence on ALT Minimize HBV DNA testing intervals Monitor compliance Annual HBeAg assessment M anage patient education Native language; encourage family participation; reasonable insight S urvey for confounding factors Social circumstances, HIV/HCV/delta, Compliance history Potential Problem Addressment