1. The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based Therapy This program is supported by an educational grant from

2. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy About These Slides  Users are encouraged to use these slides in their own noncommercial 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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.

3. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Program Faculty Program Director: Fred Poordad, MD Chief of Hepatology Cedars-Sinai Medical Center Associate Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California Faculty: Bruce R. Bacon, MD James F. King, MD, Endowed Chair in Gastroenterology Professor of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University Liver Center Saint Louis University School of Medicine St Louis, Missouri Graham R. Foster, FRCP, PhD Professor of Hepatology The Liver Unit Consultant Hepatologist Queen Mary, University of London London, United Kingdom Paul Y. Kwo, MD Professor of Medicine Medical Director of Transplantation Division of Medicine/Gastroenterology/ Hepatology Indiana University School of Medicine Indianapolis, Indiana

4. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Faculty Disclosures Bruce R. Bacon, MD, has disclosed that he has received grants for research support from Bristol- Myers Squibb, Gilead Sciences, Merck, Roche, Romark, Three Rivers, Vertex, and Wyeth; has received consulting fees from Merck and Romark; has served on speaker bureaus for Gilead Sciences, Merck, and Three Rivers; has served on advisory boards for Gilead Sciences, Three Rivers, Vertex; and has served as a data and safety monitoring board member for Gilead Sciences, ISIS, and Vertex. Fred Poordad, MD, has disclosed that he has received grants for research support from Abbott, Anadys, Achillion, Bristol-Myers Squibb, Gilead Sciences, Genentech, Merck, and Vertex and has received consulting fees from Abbott, Anadys, Achillion, Bristol-Myers Squibb, Gilead Sciences, Genentech, Idenix, Merck, Pharmasset, and Vertex. Graham R. Foster, FRCP, PhD, has disclosed that he has received grants for research support from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Roche; has received consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, Pharmasset, and Roche; and has received fees for non-CME services from Gilead Sciences, Janssen, Merck, and Roche. Paul Y. Kwo, MD, has disclosed that he has received research support from Abbott, Anadys, Bayer, Bristol-Myers Squibb, Conatus, GlaxoSmithKline, Gilead Sciences, Merck, Novartis, Roche, and Vertex; has received consulting fees from Abbott, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Johnson & Johnson, Merck, Novartis, and Vertex; and has received fees for non-CME services from Bristol-Myers Squibb, Gilead Sciences, Merck, and Roche.

5. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy The Hepatitis C Epidemic  Worldwide prevalence of chronic hepatitis C: 170 million [1]  US prevalence of chronic hepatitis C [2,3] –5.0 million exposed –3.5 million with chronic viremia  Most patients with hepatitis C asymptomatic until irreversible liver damage occurs [4]  Diagnosis depends on high index of suspicion and proper screening  Forthcoming guidelines from CDC for screening (birth cohort) 1. World Health Organization hepatitis C fact sheet 2011. 2. Chak E, et al. Liver Int. 2011;31:1090-1101. 3. Armstrong GL, et al. Ann Intern Med. 2006;144:705-714. 4. Ghany MG, et al. Hepatology. 2009;49:1- 40.

6. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy SVR Equivalent to Viral Cure 1. Swain MG, et al. Gastroenterology. 2010;139:1593-1601. 2. Giannini EG, et al. Aliment Pharmacol Ther. 2010;31:502-508. 3. Maylin S, et al. Gastroenterology. 2008;135:821-829. 4. George SL, et al. Hepatology. 2009;49:729-738. 0 20 40 60 80 100 Duration of Follow-up Patients With SVR (%) 3.9 yrs (mean) 3.4 yrs (median) 3.3 yrs (median) 5.4 yrs (median) 99 [1] 99 [2] 100 [3] 100 [4]  Nearly 100% of patients who achieve SVR remain undetectable during long-term follow-up [1-4]

7. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Treatment of Chronic Hepatitis C 0 20 40 60 80 100 8-12 SVR (%) 15-20 38-43 25-30 50-60 Standard interferon (6 mos) [1] Standard interferon (12-18 mos) [2,3] Interferon/ ribavirin (6-12 mos) [3,4] PegIFN monotherapy (6-12 mos) [5,6] PegIFN/ ribavirin (6-12 mos) [6,7] 1. Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965. 1991 200119951998

8. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy PegIFN alfa-2b 1.0 µg/kg/wk + RBV 800-1400 mg/day PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day Intent-to-Treat Analysis (N = 3070) IDEAL Study: PegIFN alfa-2a vs alfa-2b in Treatment-Naive Genotype 1 HCV Patients 40 38 41 0 20 40 PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day SVR (%) 60 80 100 McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

9. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Protease InhibitorAdditional Regimen Components Considerations Boceprevir 800 mg TID (q7-9hrs) [1,2] PegIFN alfa + weight-based RBV  Naive to previous therapy  Previous treatment failure  Compensated cirrhosis  RGT  Take with food Telaprevir 750 mg TID (q7-9hrs) [2,3] PegIFN alfa + weight-based RBV  Naive to previous therapy  Previous treatment failure  Compensated cirrhosis  RGT  Take with food (not low fat) 2 Protease Inhibitors Approved for Genotype 1 HCV Infection 1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. 2011. For patients with genotype 2/3 infection, HCV therapy with pegIFN/RBV remains the standard of care

10. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Phase III Protease Inhibitor Studies  Telaprevir –Treatment-naive –ADVANCE [1] –ILLUMINATE [2] –Treatment-experienced –REALIZE [3]  Boceprevir –Treatment-naive –SPRINT-2 [4] –Treatment-experienced –RESPOND-2 [5] 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024. 3. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

11. Clinical Care Options, LLC in Partnership with Oncology Today Treatment-Naive Patients

12. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy New Standard of Care for Genotype 1 Treatment-Naive Patients BOC + PegIFN +  RBV 48028124 PegIFN + RBV 836 BOC + PegIFN +  RBV 24 Early response*; stop at Wk 28; f/u 24 wks F/u 24 wks Boceprevir [1,2] TVR + PegIFN + RBV 48024124 eRVR † ; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u 24 wks Telaprevir [2,3] 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.  Recommendation: Optimal treatment for all genotype 1 treatment-naive patients is BOC or TVR + pegIFN/RBV –BOC and TVR should not be used without pegIFN/RBV *Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy). † Undetectable HCV RNA at Wks 4 and 12 of triple therapy. No eRVR; PegIFN + RBV

13. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy SVR Rates With BOC + PegIFN/RBV in Genotype 1 Treatment-Naive Patients P <.001 Nonblack Patients P =.04 P =.004 Black Patients 125/ 311 211/ 316 213/ 311 12/ 52 22/ 52 29/ 55 Patients (%) PR 48 BOC RGT 100 80 60 40 20 0 BOC/PR48 40 67 68 Patients (%) PR 48 BOC RGT 100 80 60 40 20 0 BOC/PR48 23 42 53 n/ N= Poordad F, et al. N Engl J Med. 2011;364:1195-1206. SPRINT-2

14. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy SVR Rates With TVR + PegIFN/RBV in Genotype 1 Treatment-Naive Patients P <.001 SVR (%) 0 20 40 60 80 100 PRT12PR 75 271/ 363 44 158/ 361 n/ N = 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Dusheiko GM, et al. EASL 2011. Abstract 1788. Pooled Analysis From ADVANCE and ILLUMINATE [2] ADVANCE [1] SVR (%) 0 20 40 60 80 100 PRT12PR n/ N = Nonblack Black 75 599/ 804 61 60/ 99 45 151/ 333 25 7/ 28

15. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. BOC + PegIFN +  RBV 48 0 28124 PegIFN + RBV 8 36 24 Early response; stop at Wk 28; f/u 24 wks HCV RNA Undetectable Undetectable 48028124 PegIFN + RBV 8 36 BOC + PegIFN +  RBV 24 HCV RNA Detectable Undetectable Slow response; extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks  Recommendation: Noncirrhotic patients can be considered for response-guided therapy with BOC < 100 IU/mL

16. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Impact of Early Response to Boceprevir- based Therapy HCV RNA undetectable at Weeks 8 and 24 HCV RNA detectable at Week 8, undetectable at Week 24 Poordad F, et al. N Engl J Med. 2011;364:1195-1206. SPRINT-2: BOC + PegIFN/RBV in GT1 Treatment-Naive Patients Nonblacks 0 20 40 60 80 100 PR48BOC/PR RGT BOC/PR 48 Wks 93 66 97 74 96 74 37/ 40 78/ 118 143/ 147 52/ 70 137/ 142 48/ 65 95 88 Blacks SVR (%) 0 20 40 60 80 100 PR48BOC/PR RGT BOC/PR 48 Wks 100 62 87 58 n/ N = 3/ 3 8/ 13 13/ 15 7/ 12 18/ 19 7/ 8  57% of patients eligible for shorter therapy

17. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Response-Guided Therapy Paradigm With TVR + PegIFN/RBV in Tx-Naive Patients Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.  Recommendation: Noncirrhotic patients can be considered for response-guided therapy with TVR TVR + PegIFN + RBV 48024124 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV TVR + PegIFN + RBV 48024124 PegIFN + RBV HCV RNA Undetectable Detectable (≤ 1000 IU/mL) Undetectable or detectable (≤ 1000 IU/mL) No eRVR; extend pegIFN + RBV to Wk 48; f/u 24 wks HCV RNA

18. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Response-Guided Approach With TVR in Tx-Naive Patients Supported by 2 Studies  65% of patients eligible for shortened therapy [1] 92 88 ILLUMINATE: Response-Guided TVR + PegIFN/RBV in Treatment-Naive Genotype 1 T12PR24T12PR48 SVR in Pts Achieving eRVR (%) 100 80 60 40 20 0 149/ 162 140/ 160 n/ N= 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024. ADVANCE: TVR + PegIFN/RBV in Treatment-Naive Genotype 1  58% of patients eligible for shortened therapy [2] 89 97 T12PR24PR SVR in Pts Achieving eRVR (%) 100 80 60 40 20 0 189/ 212 28/ 29 n/ N=

19. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive Patients 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.  Recommendation: All therapy should be discontinued in patients with the following: Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL. BOC [1,2] Time PointCriteriaAction Wk 12HCV RNA ≥ 100 IU/mLDiscontinue all therapy Wk 24HCV RNA detectableDiscontinue all therapy TVR [1,3] Time PointCriteriaAction Wk 4 or 12HCV RNA > 1000 IU/mLDiscontinue all therapy Wk 24HCV RNA detectableDiscontinue pegIFN/RBV

20. Clinical Care Options, LLC in Partnership with Oncology Today Treatment-Experienced Patients

21. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Retreatment With BOC + PegIFN/RBV in Treatment-Experienced Patients 1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.  Recommendation: BOC approved for previous relapsers, partial, and null responders [1] –AASLD guidelines say BOC “recommended” for previous relapsers and partial responders; advise caution in null responders given lack of definitive information from phase III studies [2] Previous relapse 0 20 40 60 80 100 40 69 BOC RGT 52 75 BOC/PR48 7 29 PR48 n/N = 2/29 15/51 23/57 72/105 30/58 77/103 SVR (%) [3] Previous partial response F/u 24 wks BOC + PegIFN + RBV 48028124 PegIFN + RBV 836 BOC + PegIFN + RBV 24 Early response; stop at Wk 36; f/u 24 wks

22. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy SVR in Poorly IFN-Responsive Patients by Wk 4 PR Lead-in Response 0/ 12 15/ 46 15/ 44 SVR (%) PR48 100 80 60 40 20 0 0 33 34 BOC RGTBOC/PR48 17/ 67 80/ 110 90/ 114 SVR (%) PR48 100 80 60 40 20 0 25 73 79 BOC RGTBOC/PR48 RESPOND-2: BOC + PegIFN/RBV in GT 1 Treatment-Experienced Patients n/N = Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Poorly Responsive to IFN: < 1 log 10 HCV RNA decline at Wk 4 Responsive to IFN: ≥ 1 log 10 HCV RNA decline at Wk 4

23. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Retreatment With TVR + PegIFN/RBV in Treatment-Experienced Patients 1. Telaprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. F/u 24 wks TVR + PegIFN + RBV 48024124 PegIFN + RBV No eRVR; PegIFN + RBV TVR + PegIFN + RBV 48024124 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u 24 wks Previous relapsers* [1,2] (same as naives) Previous partial responders † and null responders [1,2] *Response-guided therapy not studied in relapsers in registration trials. † AASLD guidelines say RGT “may be considered” for prior partial responders [2] but package insert recommends 48 weeks of therapy [1]  Recommendation: TVR approved for previous relapsers, partial, and null responders [1] –AASLD guidelines say TVR “recommended” for previous relapsers and partial responders; “may be considered” for previous null responders [2]

24. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy 100 0 60 SVR (%) 80 40 SVR in Previous Relapsers, Partial Responders, Null Responders Lead-in examined but found not to influence response and not included in TVR label Previous RelapsersPrevious Partial Responders n/N= Previous Null Responders *P <.001 vs PR48. REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders 20 121/145124/141 83* 88* 16/68 24 29/4926/48 59* 54* 4/27 15 21/7225/75 29* 33* 2/37 5 T12/PR48PR48LI T12/PR48 Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

25. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.  Recommendation: Response-guided therapy can be considered for previous relapsers, may be considered for previous partial responders, but not for previous null responders BOC + PegIFN +  RBV 48 0 28124 PegIFN + RBV 8 36 24 Early response; stop at Wk 36; f/u 24 wks HCV RNA Undetectable Undetectable 48 0 28124 PegIFN + RBV 8 36 BOC + PegIFN +  RBV 24 HCV RNA Detectable Undetectable Slow response; PR to Wk 48; f/u 24 wks < 100 IU/mL

26. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Response-Guided Therapy Paradigm With TVR + PegIFN/RBV in Tx-Exp Patients 1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.  Recommendation: Response-guided therapy recommended for previous relapsers, but not for previous partial or null responders* [1] *AASLD guidelines say RGT “may be considered” for previous partial responders [2] but package insert recommends 48 wks of therapy. [1] TVR + PegIFN + RBV 48024124 eRVR; stop at Wk 24, f/u 24 wks PegIFN + RBV TVR + PegIFN + RBV 48024124 PegIFN + RBV HCV RNA Undetectable Detectable (≤ 1000 IU/mL) Undetectable/detectable (≤ 1000 IU/mL) No eRVR; extend pegIFN + RBV to Week 48; f/u 24 wks HCV RNA

27. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Exp Patients 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.  Recommendation: All therapy should be discontinued in patients with the following: Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL. BOC [1,2] Time PointCriteriaAction Wk 12HCV RNA ≥ 100 IU/mLDiscontinue all therapy Wk 24HCV RNA detectableDiscontinue all therapy TVR [1,3] Time PointCriteriaAction Wk 4 or 12HCV RNA > 1000 IU/mLDiscontinue all therapy Wk 24HCV RNA detectableDiscontinue pegIFN/RBV

28. Clinical Care Options, LLC in Partnership with Oncology Today Other Management Considerations

29. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving BOC + PegIFN/RBV  Recommendation: All cirrhotic patients receiving BOC + PR should receive 48 weeks of therapy [1,2] Subgroup Analysis of SPRINT-2 [3] PR48 BOC RGT BOC/PR48 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Poordad F, et al. NEJM. 2011;364:1195-1206. 4. Bacon BR, et al. NEJM. 2011;364:1207-1217. F3/4 100 80 60 40 20 0 SVR (%) F0/1/2 38 67 213/ 319 n/ N= 38 9/ 24 52 22/ 42 41 14/ 34 211/ 313 67 F3/4 100 80 60 40 20 0 SVR (%)F0/1/2 23 66 77/ 117 13 2/ 15 68 21/ 31 44 14/ 32 81/ 119 68 Subgroup Analysis of RESPOND-2 [4] 123/ 328 n/ N= 14/ 61

30. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy PR48 T12PR T8PR SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving TVR + PegIFN/RBV  Recommendation: All cirrhotic patients receiving TVR + PR may benefit from 48 weeks of therapy [1,2] 1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Jacobson IM, et al. NEJM. 2011;364:2405-2416. 78 62 73 53 47 33 0 20 40 60 80 100 No, Minimal, or Portal FibrosisBridging Fibrosis or Cirrhosis SVR (%) [3,4] 134/ 288 n/ N = 226/ 290 205/ 279 24/ 73 45/ 73 45/ 85

31. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy IL28B Genotype Predicts Likelihood of Achieving SVR  Recommendation: IL28B genotype testing may be considered prior to therapy if more information about probability of response or treatment duration desired 1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369. SPRINT-2: BOC + PR48 [1] SVR (%) 44/ 55 82/ 115 26/ 44 CC CT TT 80 100 80 60 40 20 0 71 59 n/ N = ADVANCE: T12PR48* [2] SVR (%) 45/ 50 48/ 68 16/ 22 CC CT TT 90 100 80 60 40 20 0 71 73 n/ N = IL28B Genotype Predicts Likelihood of SVR With Triple Therapy *IL28B testing in ADVANCE was in whites only.

32. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy IL28B Genotype Predicts Likelihood of Eligibility for Shortened Therapy  Recommendation: IL28B genotype testing may be considered prior to therapy if more information about probability of response or treatment duration desired 1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369. SPRINT-2: BOC + PR [1] Eligibility for RGT (%) 118/ 132 158/ 304 CC CT/TT 89 100 80 60 40 20 0 52 ADVANCE: T12PR* [2] Eligibility for RGT (%) 39/ 50 39/ 68 10/ 22 78 100 80 60 40 20 0 57 45 n/ N = IL28B Genotype Predicts Likelihood of Short-Duration Therapy *IL28B testing in ADVANCE was in whites only. CC CT TT n/ N =

33. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy IL28B Genotype Should Not Be Used to Exclude Patients From Therapy  If patients have favorable CC genotype –Likelihood of SVR is high with PR alone, but triple therapy may allow shorter therapy and, in one TVR study, higher SVR rates [1]  If patients have unfavorable CT/TT genotype –Likelihood of SVR is higher with triple therapy than with PR –59% to 71% in SPRINT-2 [2] –71% to 73% in ADVANCE* [1]  Limited value of IL28B genotyping in treatment-experienced patients –Most have unfavorable TT or CT genotype 1. Jacobson IM, et al. EASL 2011. Abstract 1369. 2. Poordad F, et al. EASL 2011. Abstract 12. *IL28B testing in ADVANCE was in white Americans only.

34. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy 152/ 213 118/ 149 100 0 50 1b 1a Genotype 79 71 < 800,000 ≥ 800,000 HCV RNA (IU/mL) 78 74 F0-2 F3-F4 Fibrosis 62 78 SVR (%) 75 25 ADVANCE: Influence of Baseline Patient and Virus Factors on SVR  Data from T12PR arm only 207/ 281 64/ 82 45/ 73 226/ 290 Marcellin P, et al. EASL 2011. Abstract 451. n/ N =

35. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy 93/ 133 89/ 134 100 0 50 1b 1a Genotype 70 66 ≤ 800,000 > 800,000 HCV RNA (IU/mL) 85 76 F0-2 F3-F4 Fibrosis 67 SVR (%) 75 25 SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR 41/ 54 45/ 53 213/ 319 211/ 313 n/ N = BOC/PR RGT BOC/PR48 63 59 63 61 41 52 Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Reddy KR, et al. EASL 2011. Abstract 466. 118/ 187 106/ 179 14/ 34 22/ 42 192/ 314 197/ 313

36. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Predictive Value of Response to Lead-in in Treatment-Experienced Patients *Pooled data from RGT and BOC/PR48. 1. Foster G, et al. EASL 2011. Abstract 6. 2. Vierling JM, et al. EASL 2011. Abstract 481. 0 20 40 60 80 100 SVR (%) 33 REALIZE (TVR) [1] 82 ≥ 1 log decline < 1 log decline 0 20 40 60 80 100 SVR (%) 33 RESPOND-2* (BOC) [2] 76

37. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts 0/ 2 2/ 3 2/ 4 56/ 75 83/ 102 58/ 72 1/ 27 19/ 51 20/ 45 37/ 117 83/ 111 109/ 133 1/ 20 6/ 25 10/ 25 13/ 26 23/ 28 26/ 34 CCCTTT ≥ 1 log SVR (%) SPRINT-2 and RESPOND-2 Combined 100 80 60 40 20 0 67 50 75 81 4 37 44 32 75 82 5 24 40 50 82 76 PR48 BOC RGT BOC/PR48 < 1 log n/N= Poordad F, et al. EASL 2011. Abstract 12.

38. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy REALIZE: SVR by Response at Wk 4 in Lead-in Arm 62 94 56 59 15 54 Foster GR, et al. EASL 2011. Abstract 6. 0 20 40 60 80 100 SVR (%) < 1 log≥ 1 log Partial responder Relapsers Null responder

39. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Boceprevir + PR: Adverse Events  Significantly higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs control Adverse Event, %PR48 (n = 467) BOC + PR RGT/48 (n = 1225) Anemia*3050 Neutropenia1925 Dysgeusia1635 *Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR). Boceprevir [package insert]. May 2011.

40. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Telaprevir + PR: Adverse Events  Higher rates of rash, anemia, and anorectal signs/symptoms in TVR arms vs control Adverse Event, %PR48 (n = 493) TVR + PR RGT/48* (n = 1797) Rash3456 Anemia † 1736 Anorectal events7 29 *Pooled results from TVR arms. † Anemia was managed with RBV dose modification; epoetin alfa was not permitted. Telaprevir [package insert]. May 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf  In most subjects, rash was mild to moderate –Severe rash in 4%; discontinuation due to rash in 6% of subjects –Occurred early, usually first 4 wks, but can occur at any time during TVR exposure –< 1% had SJS or DRESS (11 cases DRESS and 3 cases SJS)

41. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Adverse Effect Management: Anemia  Recommendation: Anemia should be managed initially by reducing the RBV dose [1]  Dose reduction of RBV is acceptable  Dose reduction of DAA is not acceptable  Do not discontinue pegIFN/RBV and continue DAA  DAA should not be stopped and then restarted  Monitor closely if Hb falls < 10 g/dL  ESA agents are unlabeled for HCV anemia and should not be used if Hb > 12 g/dL 1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

42. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Predictive Value of Anemia for SVR With BOC or TVR 58 72 73 74 SVR (%) SPRINT-2* [1] Hb ≥ 10 g/dL Hb < 10 g/dL n/N = 0 20 40 60 80 100 1. Sulkowski M, et al. EASL 2011. Abstract 476. 2. Poordad F, et al. DDW 2011. Abstract 626. 212/363263/363 n/N = 0 20 40 60 80 100 267/361384/524 ADVANCE and ILLUMINATE †[2] † Data from T12/PR arm only.*Data from BOC/48 and BOC RGT arms.

43. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Predictive Value of Hb Decline > and < 3 g/dL From Baseline for SVR With TVR 55 76 < 3 g/dL n/N = 0 20 40 60 80 100 590/77461/111 *Data from T12/PR arm only. Poordad F, et al. DDW 2011. Abstract 626. SVR (%) Hb Decline ≥ 3 g/dL ADVANCE and ILLUMINATE*

44. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Telaprevir: SVR Rates by RBV Dose Reduction in ADVANCE and ILLUMINATE 76 54 72 41 SVR (%) RBV Dose ReductionNo RBV Dose Reduction T12PR PR n/N = 0 20 40 60 80 100 Poordad F, et al. DDW 2011. Abstract 626. 243/32037/69117/285408/565

45. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Boceprevir: SVR in Pts With Hb < 10 g/dL by EPO and/or RBV Dose Reduction 73 80 83 72 SPRINT-2 (BOC Arms Only)RESPOND-2 (BOC Arms Only) BothRBV Dose Reduction EPONeitherBothEPONeither 6874 78 71 0 20 40 60 80 100 SVR (%) RBV Dose Reduction Sulkowski M, et al. DDW 2011. Abstract 1865. 109/15329/3795/12930/44 48/675/647/5919/26 n/N = 100 80 0 20 40 60

46. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Adverse Effect Management: Rash and Anorectal Symptoms  Rash management –Mild to moderate rash can be treated with oral antihistamines, topical steroids –Systemic steroids are not recommended –Stop all 3 drugs for severe rash, DRESS, or SJS –Important to have “go-to” dermatologist; vigilance with rash is key  Anorectal symptom management –Fiber, loperamide, hydrocortisone, and pramoxine topical cream Telaprevir [package insert]. May 2011.

47. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Resistance-Associated Variants Develop When SVR Not Achieved  Recommendation: Patients with virologic failure on one PI should not be retreated with the other  Similar mutations selected in resistance-associated variants detectable in patients failing BOC or TVR  Clinical significance of resistance-associated variants unknown  Predominant strain returns to wild type in majority within 2 yrs –Slower process in subtype 1a  Recommendation: Follow stopping rules strictly to minimize selection of resistance-associated variants Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

48. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Loss of Detectable Resistance in Patients Stopping BOC + PegIFN/RBV Vierling JM, et al. EASL 2010. Abstract 2016. *Data from phase II studies. Cumulative Rate of Wild-Type Variant (%)* Mos After End of Therapy 100 80 60 40 20 0 061218 V36M T54A R155K Any mutation

49. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Loss of Detectable Resistance in Patients Stopping TVR + PegIFN/RBV Sullivan J, et al. EASL 2011. Abstract 8. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Probability Time After Treatment Failure (months) 180246810121614 Common 1a variants Common 1b variants median R155K V36M A156S/T T54A V36A

50. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Contraindications and Cautions for Use of HCV Protease Inhibitors  Contraindications for BOC and TVR therapy –Patients with previous SAEs leading to premature pegIFN/RBV discontinuation –Pregnant women or men whose female partners are pregnant –Coadministration with other drugs highly dependent on CYP3A4/5 for clearance –Coadministration with potent CYP3A4/5 inducers that may significantly reduce BOC or TVR plasma concentrations, leading to reduced efficacy  Safety and pharmacokinetics have not been studied in patients with decompensated cirrhosis or in liver transplant recipients, patients coinfected with HBV or HIV, or persons younger than 18 yrs of age  Assess carefully for all drug-drug interactions prior to commencing therapy Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

51. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Drug-Drug Interactions With PIs  HCV PIs are CYP3A4 inhibitors –~ One half of FDA-approved drugs are metabolized by CYP3A4  Until the drug is specifically studied, magnitude of the impact of PI on its level is not known  HCV PI metabolism differs –Boceprevir : primarily aldo-ketoreductase and partially CYP3A4/5 –Telaprevir : CYP3A4  Exercise caution with ALL coadministered medications

52. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Contraindications to BOC and TVR as Listed in Prescribing Information* 1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. Drug ClassContraindicated With BOC [1] Contraindicated With TVR [2] Alpha 1-adrenoreceptor antagonist Alfuzosin AnticonvulsantsCarbamazepine, phenobarbital, phenytoin N/A AntimycobacterialsRifampin Ergot derivativesDihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agentsCisapride Herbal productsHypericum perforatum (St John’s wort)Hypericum perforatum HMG CoA reductase inhibitors Lovastatin, simvastatinAtorvastatin, lovastatin, simvastatin Oral contraceptivesDrospirenoneN/A NeurolepticPimozide PDE5 inhibitorSildenafil or tadalafil when used for tx of pulmonary arterial hypertension Sedatives/hypnoticsTriazolam; orally administered midazolam Orally administered midazolam, triazolam *Studies of drug-drug interactions incomplete.

53. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Summary: Updated AASLD Guidelines on Treatment of HCV Genotype 1 Infection  Optimal treatment is BOC or TVR, each in combination with pegIFN/RBV –All treatment-naive and -experienced patients can be considered for treatment with BOC and TVR –Caution is advised when using BOC in null responders given lack of definitive information from phase III studies* –All patients can be considered for shortened duration of therapy except patients with cirrhosis and null responders (who should receive 48 wks of therapy) † –Stopping rules outlined in package inserts should be strictly adhered to in order to avoid antiviral resistance  Anemia should be managed with RBV dose reductions  Patients failing one PI should not be retreated with the other  IL28B genotype testing may be considered prior to therapy if more information about probability of response or treatment duration desired Ghany MG, et al. Hepatology. 2011;54:1433-1444. *Package insert says if BOC tx of previous null responders is considered, it should be 48 wks of therapy. † Package insert recommends 48 wks of therapy with TVR for previous partial responders.

54. Clinical Care Options, LLC in Partnership with Oncology Today The New Elements of HCV Care: Practical Skills to Optimize HCV Protease Inhibitor–Based Therapy Treatment of Chronic Hepatitis C 1991 2001 0 20 40 60 80 100 8-12 SVR (%) 15-20 38-43 25-30 50-60 19951998 Standard interferon (6 mos) [1] Standard interferon (12-18 mos) [2,3] Interferon/ ribavirin (6-12 mos) [3,4] PegIFN monotherapy (6-12 mos) [5,6] PegIFN/ribavirin (6-12 mos) [6,7] 2011 70-75 PI + PegIFN/RBV (6-12 mos) [8-10] 1. Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666- 1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965. 8. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 9. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 10. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.

55. Go Online for More Educational Programming on the New HCV Protease Inhibitors! Case vignettes highlighting important management decisions for HCV- infected patients with the new protease inhibitors. clinicaloptions.com/elements