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Sponsored for Continuing Medical Education Credit by Rush University Medical Center

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.

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Sponsored for Continuing Medical Education Credit by Rush University Medical Center

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  1. Sponsored for Continuing Medical EducationCredit 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. Faculty:Content Development and Training David R. Nelson, MD Professor of Medicine Associate Dean, Clinical and Translational Research University of Florida Gainesville, Florida

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

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

  8. Chronic HCV Infectionin 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) Estimated HCV Cases Conservative estimate Upper limit of estimate 7.1 5.2 3.8 Number of Cases (in millions) 3.2 1.9 Total NHANES Not Included in NHANES Chak E, et al. Liver Int. 2011; 31:1090-1101. http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm#section2.

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

  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. 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. 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. Chronic HCV Therapy:Advances in Raising Cure Rates Direct Acting Antivirals 2011 Peginterferon 2001 >70% Ribavirin Standard Interferon 1998 55% SVR (%) 1991 42% 39% 34% 16% 6% DAA PegIFN + RBV 12 Months 12 Months 12 Months 6 Months 12 Months 6 Months IFN + RBV PegIFN PegIFN + RBV IFN 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.

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

  15. AASLD Recommendation: Treatmentof 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. Telaprevir and Boceprevir Full prescribing information for telaprevir and boceprevir.

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

  18. Telaprevir: RecommendedTreatment Duration (weeks) Treatment-Naïve or Prior Relapsers (non-cirrhotics) Undetectable: COBAS TaqMan (HCV RNA <25 IU/mL) Telaprevir + pegIFN + RBV pegIFN + RBV 0 4 12 24 Undetectable Undetectable Telaprevir + pegIFN + RBV pegIFN + RBV 0 4 12 24 48 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.

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

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

  23. Telaprevir and Boceprevir: Efficacy Considerations

  24. ADVANCE Study: Telaprevir +PegIFN Alfa-2a + RBV in Genotype 1 eRVR(+) Follow-Up SVR Follow-Up TVR + (750 mg q8h) PegIFN + RBV PegIFN + RBV T12/ PR SVR Follow-Up eRVR(-) PegIFN + RBV Phase 3 Treatment-naïve Genotype 1 HBsAg negative HIV negative No decompensated liver disease eRVR(+) Follow-Up SVR TVR (750 mg q8h) PegIFN + RBV Follow-Up PegIFN + RBV T8/ PR SVR Follow-Up eRVR(-) PegIFN + RBV SVR Placebo + PegIFN + RBV Follow-Up PR48 PegIFN + RBV Week 0 8 12 24 48 72 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.

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

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

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

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

  29. ILLUMINATE Study: 24 or 48 Weeks of PegIFN Alfa-2a + RBV After 12 Weeks of Telaprevir? SVR SVR Follow-Up Follow-Up PegIFN + RBV Telaprevir (750 mg q8h) PegIFN + RBV Phase 3 Treatment-naïve Genotype 1 PegIFN + RBV T12/ PR With eRVR SVR Follow-Up PegIFN + RBV SVR Without eRVR Follow-Up PegIFN + RBV Week 0 12 20 24 48 72 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.

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

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

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

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

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

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

  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. Telaprevir and Boceprevir: Resistance Considerations

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

  40. Telaprevir Monotherapy and Development of Resistance Sample Patient #2 Sample Patient #1 Wild type T54A V36A/M R155K/T Wild type T54A V36A/M R155K/T 36/155 A156V/T 36/156 36/155 A156V/T 36/156 HCV RNA (log10 IU/mL) HCV RNA (log10 IU/mL) LOD LOD 1 14 1 14 Telaprevir Monotherapy (day) Telaprevir Monotherapy (day) LOD: sequencing limit of detection (100 IU/mL) Kieffer TL, et al. Hepatology. 2007;46:631-639.

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

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

  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. Telaprevir and Boceprevir: Safety Profiles and Drug Interactions

  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. 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 Moderate Rash Mild Rash 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.

  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) Severe Rash Maculopapular, confluence of red spots, eczematous, somewhat raised 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.

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

  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.

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