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Sponsored for CME credit by Rush University Medical Center

Post Conference Update 48 th Annual Meeting of the European Association for the Study of the Liver. Sponsored for CME credit by Rush University Medical Center. Supported by an independent educational grant from Gilead Sciences Medical Affairs. Content Development & Training Faculty.

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Sponsored for CME credit by Rush University Medical Center

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  1. Post Conference Update48th Annual Meeting of the EuropeanAssociation for the Study of the Liver Sponsored for CME credit by Rush University Medical Center Supported by an independent educational grant from Gilead Sciences Medical Affairs

  2. Content Development & Training Faculty Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine and Surgery Chief, Center for Liver Disease and Transplantation Columbia University College of Physicians and Surgeons NewYork-Presbyterian Hospital New York, New York • Disclosures • Grants/Research Support: Gilead Sciences, Jannsen, Merck Vertex • Consultant: Gilead Sciences, Vertex • Speakers’ Bureau: Genentech, Gilead Sciences, Merck, Vertex • Stock Shareholder: None • Other Financial or Material Support: None

  3. Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: Screen and test for hepatitis B and C virus (HBV, HCV) infection in my patients according to the recommendations from the American Association for the Study of Liver Diseases (AASLD) and the Centers for Disease Control and Prevention (CDC) Appropriately select antiviral HBV and HCV treatment strategies for my patients with HBV and HCV infection Manage safety and tolerability problems with antiviral HBV and HCV agents, including side effect, drug-drug interactions, and resistance Evaluate new agents being investigated for HBV and HCV therapy with patients in order to optimize information-based decision making about therapy Learning Objectives(CME/CNE and CPE) We Are Eliminating Hard Copy Evaluations! CPE CME/CNE • Upon completion of this activity, the pharmacist should be able to: • Review the screening and testing process for hepatitis B and C virus (HBV, HCV) infection in my patients according to the recommendations from the American Association for the Study of Liver Diseases (AASLD) and the Centers for Disease Control and Prevention (CDC) • Discuss antiviral HBV and HCV treatment strategies in patients with HBV and HCV infection • Review safety and tolerability problems with antiviral HBV and HCV agents, including side effect, drug-drug interactions, and resistance • Evaluate new agents being investigated for HBV and HCV therapy with patients

  4. Program Overview • HCV and HBV: epidemiology and public health considerations • Chronic HCV infection • New and emerging HCV regimens • Interferon-free regimens • DAA + PR • Clinical considerations with telaprevir-based regimens • Liver transplantation and triple therapy • Chronic HBV infection

  5. ANRS CO12 CirVir: HCC in HCV- andHBV-Related Compensated Cirrhosis • Prospective cohort (2006-2012) • 35 French centers, consecutive enrollment • Biopsy proven Child-Pugh A cirrhosis related to chronic HCV or HBV infection • Absence of previous decompensation • 6 month visits (HCC screening) • Median follow-up: 33.9 months • Receiving treatment • HCV: 93.4% • HBV: 92.4% Baseline Characteristics TrinchetJC, et al. J Hepatol. 2013;58(suppl 1):S50. Abstract 112.

  6. ANRS CO12 CirVir:Outcomes • Comorbidities and the absence of viral control were more frequent in the HCV arm • HCC incidence was higher in the HCV arm • Only 48% of detected hepatic nodules were confirmed as primary liver cancer • Complications and death were more frequent in the HCV arm • Non-liver mortality accounts for half of deaths after 3 years Outcomes *P=0.0002 log-rank versus HBV arm. TrinchetJC, et al. J Hepatol. 2013;58(suppl 1):S50. Abstract 112.

  7. HCV Treatment Rate in Select European Countries (2010) • Approximately 6.7 million persons were HCV viremic in 22 European countries • Russia (2.1 million) and Italy (1.5 million) comprised 55% of HCV prevalence • Since 2008, there are signs of patients being warehoused in Western European countries • Highest treatment rates were in Western Europe relative to Eastern Europe • France has the highest treatment rate in Europe (and globally) Treatment Rates in Select Countries (2010) 6.7% 4.3% 4.3% Treatment Rate (%) 3.4% 3.0% 0.8% 0.3% Russia UK Austria Italy Sweden Germany France Razavi H, et al. J Hepatol. 2013;58(suppl 1):S22-S23. Abstract 51.

  8. Predictors of Mortality Among US Veterans With Chronic HCV Infection • Retrospective cohort study of US Veterans using ERCHIVES • HCV positive (n=195,585) • HCV negative (n=202,739) • All-cause mortality for HCV infected and non-infected • 43.9 and 24.0 per 1000 person-years, respectively • Strongest predictors of mortality among HCV infected • Decompensated liver disease, anemia, cancer, chronic kidney disease, and COPD • HCV treatment was associated with a lower risk of mortality (HR: 0.43) Predictors of Mortality (Adjusted Hazard Ratios) ERCHIVES: Electronically retrieved cohort of HCV Infected Veterans. Erqou S, et al. J Hepatol. 2013;58(suppl 1):S185. Abstract 453.

  9. Program Overview • HCV and HBV: epidemiology and public health considerations • Chronic HCV infection • New and emerging HCV regimens • Interferon-free regimens • DAA + PR • Clinical considerations with telaprevir-based regimens • Liver transplantation and triple therapy • Chronic HBV infection

  10. FISSION Trial: Sofosbuvir + RBV in Treatment-Naïve, HCV Genotype 2 or 3 Phase 3 Open-label Treatment-Naïve Genotype 2 or 3 Sofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=256) Follow-Up Follow-Up PegIFN + RBV (800 mg/day) (n=243) Week 0 12 24 36 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelet >75,000/mm3 (cirrhotic: 20% maximum). Stratified by genotype, HCV RNA, and cirrhosis. Primary efficacy endpoint: SVR12 (non-inferiority margin: 15%). Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  11. FISSION Trial: SVR12 Ratesby Prespecified Subgroups Sofosbuvir + RBV PR 97% 79% 78% 76% 75% 74% 72% 67% 67% 67% 66% 63% 62% 62% 61% 56% Patients (%) 47% 38% 3 (n=183/176) <6 (n=107/106) No (n=204/193) Overall* (n=253/243) Yes (n=49/50) Male (n=168/156) 2 (n=70/67) >6 (n=146/137) Female (n=85/87) Genotype Baseline HCV RNA (log) Cirrhosis Gender *Non-inferiority criteria met. Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  12. FISSION Trial: SVR12 Ratesby Genotype and Cirrhosis Genotype 2 Genotype 3 Sofosbuvir + RBV PR Sofosbuvir + RBV PR 98% 91% 82% 71% 62% 61% Patients (%) Patients (%) 34% 30% Cirrhosis (n=11/13) No Cirrhosis (n=59/54) Cirrhosis (n=38/37) No Cirrhosis (n=145/139) Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  13. FISSION Trial:Resistance and Safety • No resistance detected in sofosbuvir + RBV virologic failures • Relapse accounted for all but 1 virologic failure (nonadherence) • Safety of sofosbuvir + RBV • Well tolerated and few adverse events • Most common adverse events • Fatigue (36%), headache (25%), nausea (18%), insomnia (12%) • Safety profile consistent with ribavirin Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  14. FUSION Trial: Sofosbuvir + RBV for 12 Versus 16 Weeks inHCV Genotype 2/3, Previously Failed PR Therapy Phase 3 Double-blind Failed Prior PegIFN-Based Therapy Genotype 2 or 3 Sofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=103) Follow-Up Placebo Sofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=98) Follow-Up Week 0 12 16 24 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelet >50,000/mm3, no neutrophil minimum. Cirrhosis at baseline (34%). Prior relapsers (76%). Stratified by genotype and cirrhosis. Primary efficacy endpoint: SVR12. Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  15. FUSION Trial: SVR12 Ratesby Prespecified Subgroups Sofosbuvir + RBV 12 weeks 16 weeks 94% 87% 86% 77% 76% 73%* 69% 66% 66% 62%* 62% 61% 50% 50% 50% Patients (%) 42% 31% 30% 3 (n=64/63) <6 (n=26/29) No (n=64/63) Overall (n=100/95) Yes (n=36/32) Male (n=71/64) 2 (n=36/32) >6 (n=74/66) Female (n=29/31) Genotype Baseline HCV RNA (log) Cirrhosis Gender *P<0.001 versus 12 weeks of active therapy. Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  16. FUSION Trial: SVR12 Ratesby Genotype and Cirrhosis Genotype 2 Genotype 3 Sofosbuvir + RBV 12 weeks 16 weeks Sofosbuvir + RBV 12 weeks 16 weeks 100% 96% 78% 63% 61% 60% Patients (%) Patients (%) 37% 19% Cirrhosis (n=10/9) No Cirrhosis (n=26/23) Cirrhosis (n=26/23) No Cirrhosis (n=38/40) Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  17. FUSION Trial:Resistance and Safety • No resistance detected in sofosbuvir + RBV virologic failures • Safety of sofosbuvir + RBV • Well tolerated and few adverse events • No discontinuations due to adverse events • Most common adverse events • Fatigue (46%), headache (27%), nausea (21%), insomnia (24%) • Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 7.5% • Hemoglobin <8.5 g/dL: 1% Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  18. POSITRON Trial: Sofosbuvir + RBV in HCV Genotype 2 or 3 With Limited Options Phase 3 Double-blind, placebo-controlledInterferon-Ineligible, Intolerant, or unwilling Genotype 2 or 3 Sofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=207) Follow-Up Follow-Up Placebo (n=71) Week 0 12 24 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. No lower limit to platelet or neutrophil count. Cirrhosis at baseline (16%). Prior relapsers (76%). Stratified by presence or absence of cirrhosis. Primary efficacy endpoint: SVR12. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  19. POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Prespecified Subgroups 93% 84% 81% 79% 78% 76% 73% 61% 61% Patients (%) 3 (n=98) <6 (n=67) No (n=176) Overall (n=207) Yes (n=31) Male (n=117) 2 (n=109) >6 (n=140) Female (n=90) Genotype Baseline HCV RNA (log) Cirrhosis Gender SVR12 rate was 0% in the placebo arm. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  20. POSITRON Trial: SVR12 Rates WithSofosbuvir + RBV by Genotype and Cirrhosis Genotype 2 Genotype 3 94% 92% 68% Patients (%) Patients (%) 21% Cirrhosis (n=17) No Cirrhosis (n=92) Cirrhosis (n=14) No Cirrhosis (n=84) SVR12 rate was 0% in the placebo arm. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  21. POSITRON Trial:Resistance and Safety • No resistance detected in sofosbuvir + RBV virologic failures • Safety of sofosbuvir + RBV • Well tolerated and few adverse events • Treatment discontinuations due to adverse events: 2% • Most common adverse events • Fatigue (44%), headache (21%), nausea (22%), insomnia (19%) • Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 7% • Hemoglobin <8.5 g/dL: 1% Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  22. Study 040: Sofosbuvir + Daclatasvir + RBV in Previous Telaprevir or Boceprevir Failures Phase 2a Prior Nonresponse, Relapse, or Breakthrough with Telaprevir or Boceprevir With PR Genotype 1 Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=21) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=20) Week 0 12 24 48 Sofosbuvir (nucleotide NS5B polymerase inhibitor). Daclatasvir (NS5A replication complex inhibitor). HCV RNA >105 IU/mL. No upper limit to age or BMI. METAVIR score: F0-F1 (12%), >F2 (88%). NS3 polymorphisms conferring resistance to boceprevir or telaprevir as baseline: 46% NS5A polymorphisms conferring resistance to daclatasvir: 7% Excluded: patients who discontinued telaprevir or boceprevir due to an adverse event. Primary efficacy endpoint: SVR12. Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417.

  23. Study 040 (24-Week Treatment):SVR4 and SVR12 Rates • No virologic failures • Neither baseline NS3 PI resistance nor use of RBV influenced response • Sofosbuvir + daclatasvir + RBV was well tolerated • No discontinuations due to adverse events • Most common adverse events (without RBV) • Fatigue (29%), headache (33%), arthralgia (14%) • No grade 3/4 elevations in ALT, AST, or total bilirubin • Anemia (hemoglobin <9 g/dL): 0% Genotype 1 SVR4 SVR12 100% 100% 100% 95%* Patients (%) Sofosbuvir + Daclatasvir (n=21) Sofosbuvir + Daclatasvir + RBV (n=20) *1 patient missing at post-treatment 12 weeks, HCV RNA undetectable at post-treatment week 24 (preliminary). Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417.

  24. ELECTRON Study: Sofosbuvir + RBV + Either Ledipasvir (NS5A Inhibitor) or GS-9669 (NS5B Non-Nucleoside Inhibitor) Phase 2b Genotype 1 Follow-Up Treatment-Naïve (n=25) Sofosbuvir 400 mg qd + RBV Null Responders (n=10) Follow-Up Sofosbuvir 400 mg qd + RBV Follow-Up Sofosbuvir 400 mg qd + Ledipasvir + RBV Treatment-Naïve (n=25) Sofosbuvir 400 mg qd + Ledipasvir + RBV Follow-Up Null Responders (n=9) Follow-Up Sofosbuvir 400 mg qd + GS-9669 + RBV Treatment-Naïve (n=25) Sofosbuvir 400 mg qd + GS-9669 + RBV Follow-Up Null Responders (n=9) Week 0 4 8 12 24 Sofosbuvir (nucleotide NS5B polymerase Inhibitor). No cirrhosis. Weight-based ribavirin dosing (1000-1200 mg). Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.

  25. ELECTRON Study (Genotype 1 Cohort):Interim Analysis of SVR12 Rates Treatment-Naive Null Responders 100% 100% 100% 92% 84% Patients (%) Patients (%) 10% Sofosbuvir + RBV (n=25) Sofosbuvir + GS-9669 + RBV (n=25) Sofosbuvir + Ledipasvir + RBV (n=25) Sofosbuvir + RBV (n=10) Sofosbuvir + GS-9669 + RBV (n=3) Sofosbuvir + Ledipasvir + RBV (n=9) Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.

  26. ELECTRON Study(Genotype 1 Cohort): Safety • Adding ledipasvir to sofosbuvir + RBV • No additional safety or tolerability issues • Adding GS-9669 to sofosbuvir + RBV • No additional safety or tolerability issues • Fix-dose combination of sofosbuvir/ledipasvir • Undergoing phase 3 trial in patients with and without cirrhosis • Additional studies exploring shorter duration of therapy Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.

  27. AVIATOR Study: ABT-450/r-Based Therapy (Treatment-Naïve Cohort) Phase 2 Treatment-naïve Genotype 1 Follow-Up ABT-450/r 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80) Follow-Up ABT-450/r 150/100 mg qd + ABT-333 + RBV (n=41) Follow-Up ABT-450/r 100/100 or 200/100 mg qd + ABT-267 + RBV (n=79) Follow-Up ABT-450/r 150/100 mg qd + ABT-267 + ABT-333 (n=79) Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=79) ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80) Week 0 8 12 24 ABT-450 (NS3/4A protease inhibitor); ABT-267 (NS5A replication complex inhibitor); ABT-333 (non-nucleoside NS5B polymerase inhibitor). HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV. ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid. Primary outcome: SVR24. Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

  28. AVIATOR Study (ITT): OverallSVR Rates (Treatment-Naïve Cohort) SVR12 SVR24 99% 96% 93% 91% 90% 90% 89% 89% 88% 87% 85% 83% Patients (%) ABT-450/r ABT-267 ABT-333 RBV (n=80) ABT-450/r ABT-267 ABT-333 RBV (n=80) ABT-450/r ABT-267 ABT-333 RBV (n=79) ABT-450/r ABT-267 ABT-333 -- (n=79) ABT-450/r -- ABT-333 RBV (n=41) ABT-450/r ABT-267 -- RBV (n=79) 24 Weeks 12 Weeks 8 Weeks Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

  29. AVIATOR Study: SVR24 by Baseline Subgroups (Treatment-Naïve Cohort) ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined) 98% 95% 94% 94% 94% 92% 91% 91% 89% 89% Patients (%) CC (n=44) 1b (n=50) F2-F3 (n=42) Non-CC (n=115) 1a (n=108) F0-F1 (n=113) <7 (n=124) Male (n=78) Female (n=81) >7 (n=35) Genotype HCV RNA (log) Fibrosis Stage IL28B Genotype Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

  30. AVIATOR Study: ABT-450/r-Based Therapy (Null Responders Cohort) Phase 2 Null Responders Genotype 1 Follow-Up ABT-450/r 100/100 or 200/100 mg qd + ABT-267 + RBV (n=45) Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=45) ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=43) Week 0 8 12 24 Received at least 12 weeks of pegIFN + RBV and failed to achieve >2 log10 IU/mL HCV RNA decrease. HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV. IL28B CC genotype (~3%). ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid. Primary outcome: SVR24. Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

  31. AVIATOR Study (ITT): OverallSVR Rates (Null Responders Cohort) SVR12 SVR24 98% 95% 93% 93% 89% 89% Patients (%) ABT-450/r ABT-267 ABT-333 RBV (n=43) ABT-450/r ABT-267 ABT-333 RBV (n=45) ABT-450/r ABT-267 -- RBV (n=45) 24 Weeks 12 Weeks Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

  32. AVIATOR Study: SVR24 by Baseline Subgroups (Null Responders Cohort) ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined) 100% 97% 97% 96% 95% 94% 93% 93% 93% 91% Patients (%) 1b (n=33) Non-CC (n=85) CC (n=3) 1a (n=55) F0-F1 (n=41) F2-F3 (n=45) <7 (n=66) Male (n=55) Female (n=53) >7 (n=22) Genotype HCV RNA (log) Fibrosis Stage IL28B Genotype Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

  33. AVIATOR Study:Virologic Relapse and Safety • Virologic relapse in prior null responders • 8-, 12-, and 24-week arms: 12.5%, 6.3%, 2.5% • Discontinuations due to adverse events in the 12- and 24-week arms: 2.4% • Considered related to treatment (n=4/6): hepatitis cholestatic, feeling jittery, homicidal ideation, decreased creatinine clearance • Most common adverse events • Headache (31%), fatigue (30%), nausea (23%), insomnia (20%), diarrhea (15%) • Bilirubin increase: 2.4% • Anemia (hemoglobin 6.5 to <8 g/dL): 2.4% Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

  34. Program Overview • HCV and HBV: epidemiology and public health considerations • Chronic HCV infection • New and emerging HCV regimens • Interferon-free regimens • DAA + PR • Clinical considerations with telaprevir-based regimens • Liver transplantation and triple therapy • Chronic HBV infection

  35. NEUTRINO Study: Sofosbuvir + PR in Treatment-Naïve, HCV Genotype 1, 4, 5, and 6 Phase 3 Open-label Treatment-Naïve Genotype 1, 4, 5, and 6 Sofosbuvir 400 mg qd + PR (n=327) Follow-Up Week 0 12 24 36 Sofosbuvir (nucleotide NS5B polymerase Inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelets >90,000/mm3, neutrophils >1500/mm3 or 1000/mm3 (blacks). Cirrhosis permitted (17% enrolled). Primary efficacy endpoint: SVR12. Prespecified comparison to historical SVR control rate of 60%. Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  36. NEUTRINO Study: SVR12 Ratesby Prespecified Subgroups Sofosbuvir 400 mg qd + PR (12 weeks) 100% 98% 96% 96% 92% 92% 90%* 89% 87% 82% 80% Patients (%) 4 (n=28) 5/6 (n=7) 1b (n=66) <6 (n=71) No (n=273) Overall (n=327) Yes (n=54) CC (n=98) 1a (n=225) >6 (n=256) Non-CC (n=232) Genotype Baseline HCV RNA (log) Cirrhosis IL28B *P<0.001 versus historical SVR rate of 60%. Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  37. NEUTRINO Study:Resistance and Safety • No resistance detected in sofosbuvir + PR virologic failures and 1 relapse patient who discontinued therapy (HCV RNA >1000 IU/mL) • Safety of sofosbuvir + PR • Well tolerated and no additive effects of the addition of sofosbuvir to PR • Discontinuations due to adverse events: 2% • Most common adverse events • Fatigue (59%), headache (36%), nausea (34%), insomnia (25%), anemia (21%), rash (18%) • Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 23% • Hemoglobin <8.5 g/dL: 2% Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  38. QUEST-2 Trial: Simeprevir + PR in Treatment-Naïve, HCV Genotype 1 Phase 3 Treatment-naïve Genotype 1 Follow-Up Simeprevir 150 mg qd + PR (n=257) PR PR Follow-Up Follow-Up PR (n=134) Week 0 12 24 48 72 Simeprevir (NS3/4A protease inhibitor). HCV RNA >10,000 IU/mL. PR: pegIFN (alpha 2a or 2b) + RBV (weight-based dosing: 1000-1200 mg). Patients stratified by HCV subtype and IL28B genotype. Response-guided therapy criteria: HCV RNA <25 IU/mL at week 4 and undetectable at week 12. METAVIR score: F0-F1 (50%); >F2 (50%). Primary efficacy endpoint: SVR12. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.

  39. QUEST-2 Trial: SVR12 Ratesby Prespecified Subgroups Simeprevir + PR PR 96%* 85%* 82%* 81% 81%* 80%* 80%* 67%* 65%* 58%* 53% 53% 51% 50% Patients (%) 46% 41% 40% 19% 1b (n=150/77) CC (n=75/42) TT (n=40/21) Overall (n=257/134) F0-F2 (n=195/102) F3 (n=37/17) 1a (n=107/57) CT (n=142/71) F4 (n=17/15) Genotype IL28B Genotype METAVIR Score *P<0.01 versus PR. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.

  40. QUEST-2 Trial:Resistance and Safety • NS3 PI mutations were detected in the time of failure 98% of simeprevir-treated patients not achieving an SVR • Genotype 1: mainly R155 alone • Genotype 1b: mainly D168V or Q80R + D168E • Simeprevir + PR was well tolerated • Simeprevir treatment discontinuations due to adverse events: 1.6% • Adverse event profile of simeprevir + PR was similar to the PR arm • Headache, pyrexia, fatigue, influenza-like illness, rash, anemia, pruritus Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.

  41. STARTVerso1 Trial: Faldaprevir + PRin Treatment-Naïve, Genotype 1 Phase 3 Treatment-Naïve Genotype 1 ETS, Follow-Up PR Faldaprevir 120 mg qd + PR (n=261) Follow-Up Faldaprevir + PR PR No ETS ETS, Follow-Up Faldaprevir 240 mg qd + PR (n=262) Follow-Up PR PR No ETS Follow-Up PR Week 0 12 24 48 72 Faldaprevir (NS3/4A protease inhibitor). Platelets >90,000 cells/mm3. No HBV or HIV coinfection. Fibrosis stage >F3: 17% ETS: early treatment success (HCV RNA <25 IU/mL at week 4 and undetectable at week 8. Primary efficacy endpoint: SVR12 Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.

  42. STARTVerso1 Trial: SVR12 Ratesby Prespecified Subgroups Faldaprevir 120 mg qd + PR Faldaprevir 240 mg qd + PR PR 95% 90% 89% 86% 84% 83% 80%* 79% 79%* 76% 76% 70% 69% 69% 63% 60% 52% 51% Patients (%) 36% 28% 1b (171/171/86) 1a (n=87/90/45) CC (n=75/42) TT (n=40/21) Overall (n=259/261/132) ETS Patients (n=225/232) CT (n=142/71) Genotype IL28B Genotype *P<0.0001 versus PR. Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.

  43. STARTVerso1 Trial:Resistance and Safety • No significant effect of Q80K on SVR12 in genotype 1a patients • Faldaprevir + PR was well tolerated • Discontinuations due to adverse events: 4% • Adverse event profile of faldaprevir + PR was similar to the PR arm • Most common adverse events of at least moderate severity • Rash (8%), anemia (12%) • Total bilirubin elevations >2.6 x ULN with faldaprevir + PR were benign and transient • 120 mg qd: 12% • 240 mg qd: 53% The Q80K mutation is associated with a decreased susceptibility to some NS3/4A protease inhibitors. Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.

  44. Program Overview • HCV and HBV: epidemiology and public health considerations • Chronic HCV infection • New and emerging HCV regimens • Interferon-free regimens • DAA + PR • Clinical considerations with telaprevir-based regimens • Liver transplantation and triple therapy • Chronic HBV infection

  45. HEP3002 Study: Impact of Anemia inSevere Fibrosis and Compensated Cirrhosis • International telaprevir early access program • Open-label, genotype 1 • No HIV or HBV coinfection • No history of decompensated liver disease • Telaprevir + PR • Severe fibrosis (F3) • Compensated cirrhosis (F4) • Interim analysis of the first 609 patients with data to week 16 Baseline Characteristics Colombo M, et al. J Hepatol. 2013;58(suppl 1):S329-S330. Abstract 806.

  46. HEP3002 Study: Impact of Anemia inSevere Fibrosis and Compensated Cirrhosis • Incidence of grade 3 or 4 amenia: 31% • More common in patients with F4 stage disease at baseline • Discontinuations due to anemia: 3% • Anemia management • Dose-reduced RBV: 34% • Erythropoietin: 24% • Transfusion: 11% • Iron-based therapy: 1% Discontinuations due to Adverse Events (%) Colombo M, et al. J Hepatol. 2013;58(suppl 1):S329-S330. Abstract 806.

  47. C219 Rollover Study: Telaprevir + PR in PR Failures From the REALIZE Study • Phase 3b, single-arm, open-label study • Patients not achieving SVR with PR in REALIZE study (n=81) • Telaprevir + PR for 12 weeks followed by an addition 36 weeks of PR • Baseline sequencing revealed V36L in one patient Baseline Characteristics Mathurin P, et al. J Hepatol. 2013;58(suppl 1):S356-S357. Abstract 868.

  48. C219 Rollover Study: Telaprevir + PR in PR Failures From the REALIZE Study • Overall SVR rate: 60% • Higher rates in prior relapsers and prior partial responders • NS3 variants among those not achieving SVR • Consistent with previously described mutations that confer decreased susceptibility to telaprevir • Safety profile was similar to previous studies SVR24 Rates 81% 73% 60% Patients (%) 34% Prior Partial Responders (n=22) Prior Null Responders (n=32) Prior Relapsers (n=27) Overall (n=81) Mathurin P, et al. J Hepatol. 2013;58(suppl 1):S356-S357. Abstract 868.

  49. Program Overview • HCV and HBV: epidemiology and public health considerations • Chronic HCV infection • New and emerging HCV regimens • Interferon-free regimens • DAA + PR • Clinical considerations with telaprevir-based regimens • Liver transplantation and triple therapy • Chronic HBV infection

  50. CRUSH-C: Triple Therapy inHCV-Infected Transplant Recipients • Multicenter, retrospective, cohort study of consecutive HCV-infected, genotype 1 liver transplant recipients (n=112) • 6 US transplantation centers • Protease inhibitor • Telaprevir: 90% • Boceprevir: 10% • Median time from liver transplant to triple therapy: 3.7 years • Median days of LI and total treatment • LI <90 arm (n=97): 30 and 282 days • LI >90 arm (n=15): 182 and 370 days Baseline Characteristics LI: lead-in period with only PR therapy. Verna EC, et al. J Hepatol. 2013;58(suppl 1):S10-S11. Abstract 23.

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