1. 1 Sponsored for Continuing Medical Education Credit by Rush University Medical Center Supported by an independent educational grant from Vertex Pharmaceuticals Incorporated Management Strategies to Raise Cure Rates in Patients With Genotype 1 HCV Infection

2. 2 Faculty: Content Development and Training David R. Nelson, MD Professor of Medicine Associate Dean, Clinical and Translational Research University of Florida Gainesville, Florida

3. 3 Disclosure Information: Content Faculty David R. Nelson, MD – Grants/Research Support Abbott, Bayer, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, Merck, Pharmasset, Vertex – Consultant Genentech, Pharmasset, Vertex – Speakers’ Bureau None – Stock Shareholder None – Other Financial or Material Support None

4. 4 Learning Objectives (CME/CNE) ●Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: – Prescribe anti-HCV regimens in my previously untreated, patients with chronic HCV genotype 1 infection who are candidates for therapy according to the AASLD recommendations – Utilize strategies to avoid potential resistance associated with antiviral therapy to optimize SVR rates in my previously untreated patients with chronic HCV genotype 1 infection – Prescribe management approaches for my HCV patients who develop complications associated with antiviral combination therapy

5. 5 Learning Objectives (CPE) ●Upon completion of this activity, the pharmacist should be able to: – Review anti-HCV regimens in my previously untreated, patients with chronic HCV genotype 1 infection who are candidates for therapy according to the AASLD recommendations – Utilize strategies to avoid potential resistance associated with antiviral therapy to optimize SVR rates in my previously untreated patients with chronic HCV genotype 1 infection – Describe management approaches for my HCV patients who develop complications associated with antiviral combination therapy

6. 6 Epidemiologic Trends and Milestones In Therapy for Chronic HCV Infection

7. 7 Prevalence of Blood-Borne Chronic Viral Infections in the US HCV Unaware of infection Aware of infection Prevalence (millions) 2,475,000 825,000 715,000 385,000 231,000 869,000 HBVHIV Institute of Medicine. Available at: http://www.nap.edu/catalog/12793.html. 75% Unaware 65% Unaware 21% Unaware

8. 8 Chronic HCV Infection in the United States >5.2 million living with chronic HCV in US – Prevalence: 2% Chronic HCV cases not included in NHANES estimate – Homeless (n=142,761-337,6100) – Incarcerated (n=372,754-664,826) – Veterans (n=1,237,461-2,452,006) – Active military (n=6805) – Healthcare workers (n=64,809-259,234) – Nursing home residents (n=63,609) – Chronic hemodialysis (n=20,578) – Hemophiliacs (n=12,971-17,000) Number of Cases (in millions) Estimated HCV Cases 1.9 3.2 Not Included in NHANES TotalNHANES 5.2 Conservative estimate Upper limit of estimate Chak E, et al. Liver Int. 2011; 31:1090-1101. http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm#section2. 7.1 3.8

9. 9 Epidemiologic Patterns of HCV Infection in the US Total HCV Infections (millions) Year Davis GL, et al. Gastroenterology. 2010;138:513-521. 1950 1960 1970 1980 1990 2000 2010 2020 2030 Ever infected Chronic HCV Acute HCV Cirrhosis Peak Cirrhosis

10. 10 Successful Treatment of HCV Is Associated With Improved Outcome Sustained viral response – Durable 99% stay HCV negative for >10 years – Leads to improved histology – Leads to clinical benefits – Decreased decompensation – Prevents de novo esophageal varices – Decreased hepatocellular carcinoma – Decreased mortality Bruno S, et al. Hepatology. 2010;51:2069-2076. Veldt BJ, et al. Ann Intern Med. 2007;147:677-684. Maylin S, et al. Gastroenterology. 2008;135:821-829.

11. 11 VA Cohort (2001-2008): Impact of SVR on Survival Clinical Case Registry (n=16,864) – HCV patients completing peginterferon + ribavirin – No HIV or HCC – High rates of comorbidities Diabetes mellitus, hypertension, alcohol abuse, coronary artery disease SVR rates by genotype – 1 (n=12,166): 35% – 2 (n=2904): 72% – 3 (n=1794): 62% Impact of SVR on All-Cause Mortality Adjusted for demographic, laboratory, comorbidity, and treatment variables. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.

12. 12 Chronic HCV Infection in the US 3.5 million chronically infected <25% have been identified <20% offered therapy 33% with cirrhosis at risk for complications Targeted national screening programs – Birth cohort screening for those born between 1945- 1965 Identify an additional 808,580 infected patients New therapies – Higher SVR rates – Shorter duration of therapy Challenges Opportunities Rein BD, et al. Ann Intern Med. 2012;156:263-270.

13. 13 Chronic HCV Therapy: Advances in Raising Cure Rates SVR (%) 6% 16% 6 Months 34% 55% >70% Jacobson IM. Clin Gastroenterol Hepatol. 2009;7:921-930. Ghany MG, et al. Hepatology. 2009;49:1335-1374. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 42% 39% IFN 12 Months6 Months IFN + RBV 12 Months PegIFN 12 Months DAA PegIFN + RBV PegIFN + RBV 1991 1998 2001 2011 Standard Interferon Ribavirin Peginterferon Direct Acting Antivirals

14. 14 Chronic HCV Infection: Potential Therapeutic Targets NS3 Protease Antiviral Agents Interferon Immuno- modulators Therapeutic Vaccines Host Targets Boceprevir Telaprevir IFN-α IFN-λ Replication and Assembly Entry NS5B Polymerase NS5A Replication Complex FDA Approved

15. 15 AASLD Recommendation: Treatment of Chronic HCV Genotype 1 The optimal therapy for genotype 1, chronic HCV infection – Boceprevir or telaprevir in combination with peginterferon alfa and ribavirin Boceprevir and telaprevir – Should not be used without peginterferon alfa and weight-based ribavirin – Not approved for use in patients with HIV coinfection, decompensated cirrhosis, and after liver transplantation Ghany MG, et al. Hepatology. 2011;54:1433-1444.

16. 16 Telaprevir and Boceprevir Full prescribing information for telaprevir and boceprevir.

17. 17 Telaprevir and Boceprevir in Treatment-Naïve Patients Full prescribing information for telaprevir and boceprevir. *Also for prior null responders to peginterferon + ribavirin therapy.

18. 18 Telaprevir: Recommended Treatment Duration (weeks) Treatment-Naïve or Prior Relapsers (non-cirrhotics) 0 4 12 24 Telaprevir + pegIFN + RBV 0 4 12 24 48 Telaprevir + pegIFN + RBV UndetectableUndetectable Detectable (<1000 IU/mL) Week 4 and/or 12 Treatment futility rules (all patients): HCV RNA >1000 IU/mL at week 4 or 12--discontinue all 3 drugs (telaprevir treatment complete at 12 weeks; HCV RNA >1000 IU/mL at week 24--discontinue pegIFN + RBV. Full prescribing information for telaprevir. Undetectable: COBAS TaqMan (HCV RNA <25 IU/mL)

19. 19 Telaprevir: Treatment Futility Rules (All Patients) HCV RNA >1000 IU/mL at week 4 or 12 – Discontinue all 3 drugs (telaprevir treatment complete at 12 weeks) Detectable HCV RNA at week 24 – Discontinue pegIFN + RBV Full prescribing information for telaprevir.

20. 20 Boceprevir: Recommended Treatment Duration (weeks) Previously Untreated (non-cirrhotics) Boceprevir + pegIFN + RBV pegIFN + RBV Full prescribing information for boceprevir. pegIFN + RBV pegIFN DetectableUndetectable Undetectable: COBAS TaqMan (HCV RNA <25 IU/mL) Treatment futility rules (all patients): HCV RNA >100 IU/mL at week 12 or detectable HCV RNA at week 24. UndetectableUndetectable 0 4 8 24 28 0 4 8 24 36 48

21. 21 Boceprevir: Treatment Futility Rules (All Patients) HCV RNA >100 IU/mL at week 12 or detectable HCV RNA at week 24 Full prescribing information for telaprevir and boceprevir.

22. 22 Cirrhosis: Telaprevir and Boceprevir Recommended Treatment Duration (weeks) Telaprevir Full prescribing information for telaprevir and boceprevir. Boceprevir Boceprevir + pegIFN + RBV pegIFN + RBV 0 4 12 24 48 Telaprevir + pegIFN + RBV 0 4 12 24 48

23. 23 Telaprevir and Boceprevir: Efficacy Considerations

24. 24 ADVANCE Study: Telaprevir + PegIFN Alfa-2a + RBV in Genotype 1 Phase 3 Treatment-naïve Genotype 1 HBsAg negative HIV negative No decompensated liver disease Week 0 8 12 24 48 72 PegIFN + RBV T12/ PR T8/ PR PR48 eRVR (extended rapid virologic response): HCV RNA <25 IU/mL and undetectable at week 4 and week 12. TVR: telaprevir; Pbo: placebo. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. TVR (750 mg q8h) PegIFN + RBV TVR + (750 mg q8h) PegIFN + RBV eRVR(-) PegIFN + RBV Follow-Up SVR eRVR(+) Follow-Up SVR Follow-Up PegIFN + RBV eRVR(-) PegIFN + RBV Follow-Up SVR eRVR(+) Follow-Up SVR Follow-Up Placebo + PegIFN + RBV SVR Follow-Up

25. 25 ADVANCE Study Outcomes: Telaprevir + PegIFN Alfa-2a + RBV Patients (%) T12/PR (n=363) Sustained Virologic Response 75%* 69%* 44% *P<0.0001 versus PR48. Overall relapse: patients with undetectable HCV RNA at the last dose of treatment. T8/PR (n=364) PR48 (n=361) Patients (%) Overall Relapse 9% 28% T12/PR (n=314) T8/PR (n=295) PR48 (n=220) Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

26. 26 ADVANCE Study Outcomes: SVR Rates by Predefined Subgroups Patients (%) Genotype 1a (n=213/208) HCV RNA (IU/mL) T12/PR PR48 1b (n=149/151) Patients (%) <800,000 (n=82/62) T12/PR PR48 >800,000 (n=281/279) 41% 71% 79% 48% 70% 78% 71% 36% Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

27. 27 ADVANCE Study Outcomes: SVR Rates by Predefined Subgroups Patients (%) Race White (n=325/318) Fibrosis T12/PR PR48 Black (n=26/28) Patients (%) F0-2 (n=290/288) T12/PR PR48 F3/4 (n=73/73) 46% 75% 62% 25% 46% 78% 62% 33% Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

28. 28 ADVANCE Study: Is IL28B Genotype Predictive of SVR for Telaprevir? CC (n=50/45/55) Telaprevir 12/PR Telaprevir 8/PR PR48 SVR (%) 90% 84% 64% 71% 57% 25% 73% 59% 23% CT (n=68/76/80) TT (n=50/45/55) Jacobson IM, et al. J Hepatol. 2011;54(suppl 1):S542-S543. Abstract 1369. U.S. Caucasians: 42% of study

29. 29 ILLUMINATE Study: 24 or 48 Weeks of PegIFN Alfa-2a + RBV After 12 Weeks of Telaprevir? Phase 3 Treatment-naïve Genotype 1 Week 0 12 20 24 48 72 T12/ PR eRVR (extended rapid virologic response): HCV RNA <25 IU/mL at weeks 4 and week 20. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024. Telaprevir (750 mg q8h) PegIFN + RBV SVR Follow-Up PegIFN + RBV SVR Follow-Up With eRVR SVR Follow-Up SVR Follow-Up PegIFN + RBV Without eRVR

30. 30 ILLUMINATE Study Outcomes Patients (%) Overall (n=540) Sustained Virologic Response 72% 92% 88% T12/PR24 (n=162) T12/PR48 (n=160) Patients (%) Overall Relapse 8% 6% 3% Difference 4.5% (95% CI -2.1%-11.1%) Overall (n=469) T12/PR24 (n=159) T12/PR48 (n=154) Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.

31. 31 Telaprevir Efficacy Summary: Treatment-Naïve HCV Patients Telaprevir + peginterferon + ribavirin for 12 weeks, then peginterferon + ribavirin for an additional 12 or 36 weeks Response-guided therapy is non-inferior to 48 weeks of treatment in patients with an eRVR (undetectable at week 4 and 24) – May be possible in up to two-thirds of treatment-naïve patients Sustained virologic responses – Significantly improved over standard of care for blacks, Latinos, and cirrhotic patients Improvement in SVR regardless of baseline genotype, HCV RNA level, IL28B Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024. Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S195. Abstract 477. Jacobson IM, et al. J Hepatol. 2011;54(suppl 1):S542-S543. Abstract 1369.

32. 32 SPRINT-2 Study: Boceprevir + PegIFN Alfa-2b + RBV in Chronic HCV Phase 3 Treatment-naïve Genotype 1 HBsAg negative HIV negative No decompensated liver disease (nonblack n=938; black n=159) Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Week 0 4 28 48 72 Placebo + PegIFN + RBV Follow-Up LI/ B24/ PR PR48 Weight-based ribavirin dosing (600-1400 mg/day). Boceprevir (800 mg tid) + PegIFN + RBV Follow-Up LI/ B44/ PR Boceprevir (800 mg tid) + PegIFN + RBV Lead in Lead in Lead in HCV RNA Detectable* PegIFN + RBV HCV RNA Undetectable* Follow-Up *During treatment week 8 to week 24.

33. 33 SPRINT-2 Study Outcomes: Boceprevir + PegIFN Alfa-2b + RBV Patients (%) Sustained Virologic Response 42% ‡ 68%* 67%* 40% *P<0.001, † P=0.004, and ‡ P=0.04 versus PR48. LI/B24/PR (n=316/52) LI/B44/PR (n=311/55) PR48 (n=311/52) Patients (%) Relapse 53% † 12% 9%* 17% 23% 8%* 23% Non-black patients Black patients Non-black patients Black patients LI/B24/PR (n=316/52) LI/B44/PR (n=311/55) PR48 (n=311/52) 14% Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

34. 34 SPRINT-2 Study: Advanced Liver Disease Subanalysis Patients (%) Sustained Virologic Response 52% 67% 38% 41% F0-2 (n=313/319/328) Relapse 67% 38% LI/B44/PR LI/B24/PR PR48 F3-4 (n=42/34/24) Patients (%) 12% 9% 22% 18% F0-2 (n=231/233/158) 9% 25% LI/B44/PR LI/B24/PR PR48 F3-4 (n=22/17/12) Bruno S, et al. J Hepatol. 2011;54(suppl 1):S4. Abstract 7.

35. 35 SPRINT-2 Subanalysis: Impact of Baseline HCV RNA on Outcomes Patients (%) Sustained Virologic Response 59% 83% 67% 41% <1 (n=122/62) Relapse 63% 65% Pooled boceprevir PR48 Patients (%) Gordon SC, et al. Hepatology. 2011;54(suppl):812A. Abstract 961. Baseline HCV RNA (million IU/mL) >2 to <5 (n=261/127) >5 to <10 (n=150/87) >10 (n=171/68) <1 (n=63/47) Baseline HCV RNA (million IU/mL) >2 to <5 (n=195/53) >5 to <10 (n=100/41) >10 (n=124/35) Pooled boceprevir PR48 32% 31% 12% 3% 11% 17% 10% 23% 40%

36. 36 Boceprevir Subanalysis: Is IL28B Genotype Predictive of SVR? Patients (%) SPRINT-2 80% 78% CC (n=55/77/64) RESPOND-2 82% LI/B44/PR LI/B24/PR PR48 TT (n=44/42/37) Patients (%) LI/B44/PR LI/B24/PR PR48 Poordad F, et al. J Hepatol. 2011;54(suppl 1):S6. Abstract 12. CT (n=115/103/116) 71% 28% 65% 59% 27% 55% CC (n=22/28/13) TT (n=18/11/10) CT (n=66/62/29) 77% 46% 79% 73% 61% 72% 55% 17% 50% Retrospective analysis.

37. 37 Boceprevir Efficacy Summary: Treatment-Naïve HCV Patients Boceprevir + peginterferon + ribavirin – Will require 4-week lead-in with peginterferon + ribavirin – Critical HCV RNA at treatment week 8 (after 4 weeks of boceprevir) Response-guided therapy – eRVR: total 28 weeks of therapy (eRVR: undetectable at weeks 8 to 24) 4-week LI, 24-weeks boceprevir + peginterferon + ribavirin – No eRVR: total 48 weeks of therapy 4-week LI, 24-weeks boceprevir + peginterferon + ribavirin, 20-weeks peginterferon + ribavirin Significantly improved over standard of care for black and cirrhotic patients – Improvement in SVR regardless of baseline genotype, HCV RNA level, IL28B Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Poordad F, et al. J Hepatol. 2011;54(suppl 1):S6. Abstract 12. Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S194-S195. Abstract 476.

38. 38 Telaprevir and Boceprevir: Resistance Considerations

39. 39 Different Virus Replication Strategies: Different Treatment Goals Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212. HCV (No Latent Reservoir) HCV RNA Definitive Viral Clearance: SVR Possible for HCV HBV (Latent Reservoir) Host DNA Host cell Nucleus cccDNA Long-Term Reduction of Viral Replication to Lowest Possible Level HIV (Latent Reservoir) Proviral DNA Lifelong Suppression of Viral Replication cccDNA = covalently closed circular DNA.

40. 40 Telaprevir Monotherapy and Development of Resistance Kieffer TL, et al. Hepatology. 2007;46:631-639. Sample Patient #1 HCV RNA (log 10 IU/mL) Wild type T54A V36A/M R155K/T 36/155 A156V/T 36/156 LOD LOD: sequencing limit of detection (100 IU/mL) 1 14 Telaprevir Monotherapy (day) Sample Patient #2 HCV RNA (log 10 IU/mL) Wild type T54A V36A/M R155K/T 36/155 A156V/T 36/156 LOD 1 14 Telaprevir Monotherapy (day)

41. 41 Telaprevir and Boceprevir Have Similar Resistant Variants Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212.

42. 42 ADVANCE and REALIZE Studies: Loss of Resistance by NS3 Position Sullivan JC, et al. J Hepatol. 2011;54(suppl 1):S4. Abstract 8. Population sequence analysis in patients not achieving a sustained virologic response with resistant variants at baseline. Hash marks indicate censored observations. Probability (%) 0 2 4 6 8 10 12 14 16 18 Time After Treatment Failure (months) Loss of Resistant Variant R155K V36M A156S/T T54A V36A Common genotype 1a variants Common genotype 1b variants

43. 43 Direct Acting Antiviral Agents: Considerations for Preventing Resistance Achieving a sustained virologic response – Best way to prevent resistance Patient education prior to treatment initiation Emphasize and take steps to maximize adherence to regimen Manage adverse events Closely monitor HCV RNA levels during therapy – Early stopping rule Further study is needed for combination regimens with agents that have complementary mechanisms of action and non-overlapping resistance Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411. Sarrazin C, et al. Gastroenterology. 2010;138:447-462.

44. 44 Telaprevir and Boceprevir: Safety Profiles and Drug Interactions

45. 45 Telaprevir: Adverse Events Most common – Itching, nausea, diarrhea, anal or rectal problems (hemorrhoids, discomfort/itching), dysgeusia, fatigue Most common serious adverse events – Rash – Anemia Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Full prescribing information for telaprevir.

46. 46 Telaprevir: Rash Overall incidence (56%) Mild-to-moderate rash – Mild: maculopapular – Moderate: some diffuse red spots Management (mild-to-moderate rash) – Monitor – Oral antihistamines or topical corticosteroids may provide relief, but unproven – Systemic corticosteroids are not recommended Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Lawitz EJ. Gastroenterol Hepatol. 2011;7:469-471. Full prescribing information for telaprevir. Mild Rash Moderate Rash

47. 47 Telaprevir: Severe Rash (Incidence 4%) Management – Discontinue telaprevir (continue peginterferon and ribavirin) – If after 7 days there is no improvement, consider sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa – Monitor patients until rash resolves – Telaprevir must not be restarted if discontinued due to rash Considerations – Oral antihistamines or topical corticosteroids may provide relief, but unproven – Systemic corticosteroids are not recommended (if used, discontinue HCV therapy) Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Lawitz EJ. Gastroenterol Hepatol. 2011;7:469-471. Full prescribing information for telaprevir. Severe Rash Maculopapular, confluence of red spots, eczematous, somewhat raised

48. 48 Telaprevir: Anemia Mainly grade 1-2 in severity – Overall incidence: 36% Discontinuation due to anemia – Telaprevir only: 4% – Telaprevir, peginterferon, ribavirin: 1% Management – Ribavirin dose reduction – Monitor hemoglobin every 4 weeks – If ribavirin dose reductions are inadequate Consider telaprevir discontinuation Telaprevir must not be restarted if discontinued due to anemia Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Full prescribing information for telaprevir.

49. 49 ADVANCE and ILLUMINATE Studies: SVR Rates by Anemia and Ribavirin Dosing Status Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S195. Abstract 477. Patients With SVR (%) Anemia (n=196/165/361/92) Anemia Status 76% 72% No Anemia (n=269/259/324/262) 74% 50% 77% 73% 41% T12/PR24 T12/PR48 T12/PR PR 70% Patients With SVR (%) Dose Reduction (n=172/148/320/89) Ribavirin Dose Reduction Status 78% 73% No Dose Reduction (n=293/272/565/285) 76% 54% 75% 72% 41% T12/PR24 T12/PR48 T12/PR PR 69% Retrospective pooled analysis.

50. 50 Boceprevir: Adverse Events Most common – Fatigue, anemia, nausea, headache, dysgeusia Most common serious adverse events – Anemia – Neutropenia Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Full prescribing information for boceprevir.

51. 51 Boceprevir: Anemia Overall incidence: 50% Anemia consequences (boceprevir versus controls) – Dose reduction: 21% versus 13% – Erythropoietin: 43% versus 24% – Transfusion: 3% versus 1% – Discontinuation: 2% versus 1% Management – Ribavirin dose reduction and or erythropoietin – If ribavirin dose reductions are inadequate Consider discontinuation of all 3 drugs in regimen Boceprevir must not be restarted if discontinued due to anemia Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Full prescribing information for boceprevir.

52. 52 Boceprevir Subanalysis: SVR Rates by Method of Anemia Management SPRINT-2 (Boceprevir Arms) Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S194-S195. Abstract 476. Retrospective analysis. Patients (%) 58% 74% No Anemia (n=363) 75% 71% 68% Erythropoietin (n=129) Ribavirin Dose Reduction (n=37) Both (n=153) Neither (n=44) No anemia Anemia

53. 53 Ribavirin Dose Reduction Versus Erythropoietin for Anemia Management Data from fixed-dose (n=111)* and response-guided boceprevir arms (n=576) combined – Hemoglobin (males 12-15 g/dL, females 13-15 g/dL) Patients randomly assigned when hemoglobin <10 g/dL (stratified by race and anemia onset) – Ribavirin dose reduction (200-400 mg/day) – Erythropoietin (40,000 IU/week) Secondary anemia management if hemoglobin <8.5 mg/dL Primary endpoint: SVR Poordad FF, et al. J Hepatol. 2012;56(suppl 2):S559. Abstract 1419. *Patients enrolled in fixed-dose arm (4-week lead-in then 48 weeks of boceprevir 800 mg tid + pegIFN + RBV) before protocol amendment allowed the response-guided paradigm. 0 4 12* 24* 28 48 72 Boceprevir (800 mg tid) + PegIFN + RBV Follow-Up Weight-based ribavirin dosing (600-1400 mg). Boceprevir (800 mg tid) + PegIFN + RBV Follow-Up Lead in Lead in *Stopping rules: HCV RNA detectable at week 12. HCV RNA Undetectable at Treatment Week 8-24 HCV RNA Detectable at Treatment Week 8-24 Response-Guided Therapy Weeks

54. 54 Ribavirin Dose Reduction Versus Erythropoietin for Anemia Management Both anemia management arms had similar end-of- treatment response, SVR, and relapse rates SVR rates were similar with ribavirin dose reduction and erythropoietin management regardless of race, sex, body weight, fibrosis score, and IL28B genotype Similar safety profiles Patients (%) EOT (n=249/251) EOT, SVR, and Relapse Rates 82% Poordad FF, et al. J Hepatol. 2012;56(suppl 2):S559. Abstract 1419. SVR (n=249/251) Relapse (n=196/197) 82% 71% 10% EOT: end-of-treatment. Ribavirin dose reduction Erythropoietin

55. 55 Boceprevir: Neutropenia Overall incidence*: – 7% compared with 4% in the pegIFN + RBV arms Management – Complete blood counts Prior to therapy and during treatment weeks 4, 8, and 12 Monitor closely at other time points, as clinically appropriate – May require dose reduction or discontinuation of peginterferon alfa and ribavirin Discontinue boceprevir if peginterferon and ribavirin are discontinued Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Full prescribing information for boceprevir. Neutropenia in phase 2 and 3 clinical trials (neutrophil counts <0.5 x 10 9 /L).

56. 56 Telaprevir and Boceprevir: Drug Interactions Telaprevir – Inhibitor of CYP3A and p-glycoprotein – Substrate for CYP3A and p-glycoprotein Boceprevir – Strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5 – Substrate for CYP3A and p-glycoprotein It is particularly important to review drug interaction information listed in the package insert for each of the drugs before starting Other helpful drug interaction resources – FDA Web site: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm – http//:222.drug-interactions.com – www.hep-druginteractions.org Ghany MG, et al. Hepatology. 2011;54:1433-1444. Full prescribing information for telaprevir and boceprevir.

57. 57 Raising Cure Rates in Chronic HCV Infection: Conclusions Boceprevir or telaprevir + pegIFN + RBV is the optimal therapy for genotype 1, chronic HCV infection – SVR rate: 65% to 75% of patients Interferon responsiveness, genotype subtype (1a versus 1b), and fibrosis impact SVR rate Response-guided therapy allows for shorter duration of therapy Need to identify infected HCV populations (birth- cohort screening)