1. Debate: What Is the Best Rescue Strategy for the Management of Primary Nonresponse: Switch or Add? Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Supported by an unrestricted educational grant from

2. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B About These Slides Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.  These slides accompany CCO’s online Treatment Update on Case Debates With the Experts: Applying the Updated Practice Guidelines to the Management of Hepatitis B  The full program is available on the Clinical Care Options Hepatitis Web site: clinicaloptions.com/HBVguidelines  We are grateful to Nezam H. Afdhal, MD, FRCPI, Robert G. Gish, MD, and Norah Terrault, MD, MPH for their contributions to this program  Users are encouraged to use these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options

3. Nezam H. Afdhal, MD, FRCPI Associate Professor of Medicine Harvard Medical School Chief of Hepatology Beth Israel Deaconess Medical Center Boston, Massachusetts Add as Rescue Strategy for the Management of Primary Nonresponse

4. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Definitions of Primary Nonresponse With Oral Therapies  AASLD [1] : Decrease in serum HBV DNA by < 2 log 10 IU/mL after at least 24 weeks of therapy  Other definitions –NIH HBV Workshop [2] : Inability of nucleoside/tide analogue treatment to reduce serum HBV DNA by ≥ 1 log 10 IU/mL after the first 6 months of treatment –Keeffe roadmap [3] : Failure to reduce HBV DNA by 1 log 10 IU/mL or more at Week 12 1. Lok AS, et al. Hepatology. 2007;45:507-539. 2. Lok AS, et al. Hepatology. 2007;46:254-265. 3. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.

5. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Definitions of Antiviral Resistance  Virologic breakthrough –> 1 log 10 increase in HBV DNA above nadir on continued treatment after achieving virologic response  Biochemical breakthrough –Increase in ALT on continued treatment after achieving normalization  Genotypic resistance –Detection of HBV polymerase substitutions known to decrease antiviral susceptibility  Phenotypic resistance –In vitro confirmation of decreased antiviral susceptibility with acquisition of HBV polymerase substitutions Lok AS, et al. Hepatology. 2007;45:507-539.

6. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Potential Consequences of Mutations on Viral Replication and Persistence Locarnini S, et al. J Gastroenterol Hepatol. 2004;19:S322-S328. Locarnini S, et al. Antivir Ther. 2004;9:679-693. Compromises replication (reduced fitness) Enhances replication No effect Wild type Mutation

7. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Factors Affecting Probability of Drug Resistance Development Drug Factors  Antiviral activity  Level of exposure to drug  Chemical structure  Number of mutations needed to overcome drug suppression Viral Factors  Viral replication?  Replication fidelity?  Preexisting mutations  Impact of mutations on viral fitness Patient Factors  Poor antiviral exposure  Adherence  Immune status  Long-term persistence of infected cells containing archived mutations  Metabolism  Body mass Zoulim F. Antiviral Res. 2004;64:1-15. Fung SK, et al. Antivir Ther. 2004;9:1013-1026. Locarnini S, et al. Antivir Ther. 2004;9:679-693.

8. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Managing Suboptimal Responses in the Treatment of Chronic Hepatitis B Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897. Week 12 Assess for primary nonresponse Week 24 Assess early predictors of efficacy Complete response HBV DNA negative by PCR Partial response HBV DNA 60 to < 2000 IU/mL Inadequate response HBV DNA ≥ 2000 IU/mL Continue Monitor every 6 months Add another drug without cross-resistance or continue Monitor every 3 months Add a more potent drug Monitor every 3 months

9. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Early, Profound Suppression Correlates With Greater Sustained Response PegIFN alfa-2a at Week 72 HBeAg- Patients LAM at Week 52 HBeAg+ Patients ETV at Week 52 HBeAg+ Patients LdT at Week 52 HBeAg+ Patients HBV DNA at Week 24HBV DNA at Week 12 Zeuzem S. EASL 2006. Abstract 51. Farci P, et al. J Hepatol. 2005; 42(suppl 2):175. Yurdaydin C, et al. EASL 2006. BMS symposium. Patients PCR Negative at Follow-up (%) < 400 c/mL ≥ 400 c/mL n = < QL ≥ QL 61 31 84 20 96 50 95 33 0 20 40 60 80 100 70106146317255153160203

10. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Less Resistance With Early HBV DNA Suppression Patients (%) Month 6 HBV DNA (copies/mL) 0 20 40 60 80 100 8 13 32 64 Serum DNA at Month 6 vs Lamivudine Resistance by Month 61 < 200 (n = 12) < 3 log 10 (n = 23) < 4 log 10 (n = 41) > 4 log 10 (n = 118) Serum HBV DNA at Week 48 vs Adefovir Resistance by Week 144 Yuen M, et al. Hepatology. 2001; 34(4):785-791. Locarnini S, et al. J. Hepatology 2005;42(suppl 2):17. 67 26 4 < 3 log 10 (n = 80) 3-6 log 10 (n = 31) > 6 log 10 (n = 3) Week 48 HBV DNA (copies/mL)

11. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Adefovir Resistance Not Observed With Lamivudine Combination Therapy *2 patients enrolled in Study 435, initially on combination therapy with adefovir + lamivudine, and subsequently selected adefovir resistance mutation N236T. However, they were on adefovir monotherapy when adefovir resistance mutation was detected. Incidence of Resistance (%) 0 0 3 0 11 0 19 30 0 20 40 60 Year 1Year 2Year 3Year 4Year 5 Adefovir monotherapy (Study 438) Adefovir + lamivudine (lamivudine resistance Studies 435 and 460i)* Study 435: pre- and post-OLT Study 460i: HIV/HBV 0 Lee YS, et al. Hepatology. 2006;43:1385-1391. Lampertico P, et al. AASLD 2006. Abstract LB5. Schiff E, et al. Liver Transpl. 2007;13:349-360. Hepsera [package insert]. Foster City, Calif: Gilead Sciences; 2006.

12. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Preventing Lamivudine Resistance With de Novo Combination Therapy 1. Sung J, et al. J Hepatol. 2003;38(suppl 2):25-26. 2. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217. 3. Lau G, et al. Hepatology. 2004;40:171A. 4. Lai C, et al. Hepatology. 2003;38:262A. 20 18 34 21 2 1 11 12 0 20 40 60 80 100 Sung [1] Marcellin [2] Lau [3] Lai [4] LAM LAM + ADV LAM + LdT Incidence of Resistance After 1 Year of Therapy LAM + PegIFN LAMLAM + PegIFN Patients (%)

13. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Summary  Primary nonresponse is associated with treatment failure and increased risk of resistance  Sequential therapies further increase the risk of resistance  Resistance less common with combination therapy and support need for additional studies in the setting of primary nonresponse

14. Robert G. Gish, MD Medical Director Liver Transplant Program California Pacific Medical Center San Francisco, California Switch as Rescue Strategy for the Management of Primary Nonresponse

15. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Primary Nonresponse  AASLD definition –When oral therapy is incapable of reducing serum HBV DNA ≥ 2 log 10 IU/mL within the first 24 weeks of therapy  Impact –Persistently elevated levels of HBV DNA –Increased risk of antiviral resistance –Less likely to achieve other treatment outcomes, including ALT normalization and HBeAg seroconversion –AASLD advice: alternative treatment should be considered Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2007;46:254-265.

16. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Why Change if Primary Suboptimal Response?  HBV DNA negativity associated with improved outcomes –Combined analysis of 26 prospective studies [1] showed that reduced HBV DNA levels significantly associated with –HBeAg seroconversion (P <.0002) –Improved ALT levels (P =.0004) –Improved histologic activity index grading (P =.003) –HBV DNA reductions on lamivudine, [2] adefovir, [3] and entecavir [4] associated with histologic improvements according to Knodell score 1. Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319. 2. Dienstag J, et al. Gastroenterology. 2003;124:105-117. 3. Hadziyannis S, et al. N Engl J Med. 2005;352:2673-2681. 4. Lai CL, et al. N Engl J Med. 2006;354:1011-1020.

17. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Managing Suboptimal Responses in the Treatment of Chronic Hepatitis B Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897. Week 12 Assess for primary nonresponse Week 24 Assess early predictors of efficacy Complete response HBV DNA negative by PCR Partial response HBV DNA 60 to < 2000 IU/mL Inadequate response HBV DNA ≥ 2000 IU/mL Continue Monitor every 6 months Add another drug without cross-resistance or continue Monitor every 3 months Add a more potent drug Monitor every 3 months

18. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Switch vs Add in Primary Nonresponse  2007 AASLD guidelines can be interpreted to show a recommendation for switching in case of a primary nonresponse –“Patients who failed to achieve primary response as evidenced by < 2 log decrease in serum HBV DNA level after at least 6 months of NA therapy should be switched to an alternative treatment”  No data show that using 2 nucleos(t)ide analogues results in deeper viral suppression vs single agent –Level of suppression equal to most potent agent in regimen Lok AS, et al. Hepatology. 2007;45:507-539.

19. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Outcomes After Switching: Adefovir to Telbivudine Bzowej N, et al. AASLD 2006. Abstract 1005. HBV DNA Undetectable at Week 52 Adefovir: 39% (P =.07 vs telbivudine) Telbivudine: 58% Adefovir → telbivudine: 54% Adefovir (n = 44) Telbivudine (n = 45) Week QL = 300 copies/mL 2 3 4 5 6 7 8 9 10 3.02 log 10 4.26 log 10 P <.01 0481216202428323640444852 Serum HBV DNA (log 10 copies/mL ± SE) HBV DNA at Week 52 3.02 log 10 Adefovir → telbivudine* (n = 46) *Switch at Week 24

20. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Outcomes After Switching: Adefovir to Telbivudine Week 52 OutcomesTelbivudine (n = 45) Adefovir → Telbivudine (n = 46) Adefovir (n = 44) ALT normalization, %778581 HBeAg loss, %312620 HBeAg seroconversion, %272418 Virologic breakthrough, n201 Primary treatment failure (HBV DNA > 5 log 10 copies/mL at Wk 52), % 2*11 † 32 Virologic breakthrough, increase of HBV DNA to ≥ 5 log 10 copies/mL on 2 occasions after suppression. *P <.01 for telbivudine vs adefovir. † P =.02 for adefovir to telbivudine switch vs continued adefovir. Bzowej N, et al. AASLD 2006. Abstract 1005.

21. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Delayed Disease Progression With Continued Suppression: Noncirrhotics  76.3% of lamivudine-treated patients had YMDD mutations at Year 6 –Benefits of treatment reduced for those with YMDD mutations Yuen MF, et al. AASLD 2005. Abstract 985. P =.024 P =.390 P =.005 Lamivudine (YMDD) Patients With Cirrhosis/HCC (%) ControlsLamivudine (WT) 0 2 4 6 8 10 12 14

22. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B TherapyPredictorPatients Developing Resistance, % Lamivudine [1] HBV DNA levels ≤ 10 3 copies/mL at Week 2413 (Week 120) HBV DNA levels > 10 3 copies/mL at Week 2463 (Week 120) Telbivudine [2] HBV DNA below detection limit at Week 242-4 (Week 104) HBV DNA levels > 10 3 copies/mL at Week 2430-60 (Week 104) Adefovir [3] HBV DNA < 3 log 10 copies/mL at Week 484 (Week 144) HBV DNA > 6 log 10 copies/mL at Week 4867 (Week 144) Predicting Resistance Based on Level of HBV DNA Suppression 1. Yuen Y, et al. Hepatology. 2001;34:785-791. 2. Di Bisceglie A, et al. AASLD 2006. Abstract 112. 3. Locarnini S, et al. EASL 2005. Abstract 36.

23. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Standard Interferon and Lamivudine Nonresponders Switch to Peginterferon  Interferon and lamivudine HBeAg-positive nonresponders (N = 76) treated with peginterferon alfa-2b ± lamivudine for 52 weeks Outcomes in Patients Receiving Peginterferon Outcome, % Treatment Naive Interferon NR (n = 37) Lamivudine NR (n = 17) Interferon/ Lamivudine NR (n = 22) HBeAg loss39352918 HBeAg seroconversion31302918 ALT normalization37244114 HBV DNA < 400 copies/mL 9560 Fink H, et al. Am J Gastroenterol. 2006;101:2523-2529.

24. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Use of Potent Therapies Can Avoid Suboptimal Response Colonno R, et al. EASL 2006. Abstract 490.  Analysis of efficacy of entecavir treatment through Week 96 showed efficacy in patients regardless of viral load at baseline  94% of 369 patients with baseline HBV DNA < 10 9 copies/mL (and a Week 48 PCR measurement) achieved < 300 copies/mL  77% of 141 patients with baseline HBV DNA ≥ 10 9 copies/mL (and a Week 96 PCR measurement) achieved < 300 copies/mL

25. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Long-term Treatment With Potent Agent: ETV in Naive Patients  Pooled data from phase III studies of nucleos(t)ide-naive patients Response, % Year 1 (n = 663) Year 2 (n = 278) Year 3 (n = 149) Year 4 (n = 120) HBV DNA < 300 copies/mL81848991 Resistance< 1 Colonno R, et al. EASL 2007. Abstract 781.

26. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B Conclusions  If a primary nonresponse is identified –Switch therapy –Early –Before resistance develops  Avoid primary nonresponse –Start with potent monotherapy associated with low rate of viral resistance  No known advantage of combination therapy (add) vs switch to potent antiviral in patients with suboptimal response in terms of depth of viral suppression

27. clinicaloptions.com/hep Applying the Updated Practice Guidelines to the Management of Hepatitis B For a detailed overview of this topic, visit clinicaloptions.com/HBVguidelines  Free, online CME credit for Interactive Case Challenges written by our expert faculty: Nezam H. Afdhal, MD, FRCPI; Jules L. Dienstag, MD; and Emmet B. Keeffe, MD, MACP –Selecting First-line Therapy in Hepatitis B –Choosing Appropriate Rescue Therapy for Primary Nonresponse –Management of Lamivudine Resistance in Hepatitis B  Downloadable slides are also available covering each of these important topics!