Shaping the Future.Clinicians and Faculty Define: Strategies for the Next Era of HCV Therapy.2014

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  • GT, genotype; HCV, hepatitis C virus; P/R, peginterferon/ribavirin.
  • GT, genotype; P/R, peginterferon/ribavirin; SVR12, sustained virologic response at 12 weeks posttreatment.
  • GT, genotype; P/R, peginterferon/ribavirin; SOF, sofosbuvir; SVR, sustained virologic response.
  • BID, twice daily; EOT, end of treatment; HCV, hepatitis C virus; NNI, nonnucleoside inhibitor; PI, protease inhibitor; QD, once daily; RBV, ribavirin; SVR12, sustained virologic response at 12 weeks posttreatment.
  • GT, genotype; ITT, intent to treat; NNI, nonnucleoside inhibitor; NS5A, nonstructural protein 5A; PI, protease inhibitor; RBV, ribavirin; RTV, ritonavir; SVR12, sustained virologic response at 12 weeks posttreatment.
  • NI, nucleos(t)ide inhibitor; NNI, nonnucleoside inhibitor; NS5A, nonstructural protein 5A; PI, protease inhibitor.
  • DAA, direct-acting antiviral; LDV, lepidasvir; PI, protease inhibitor; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response at 12 weeks posttreatment.
  • ECHO, Extension for Community Healthcare Outcomes.
  • GT, genotype; HCV, hepatitis C virus; IFN, interferon.
  • ALT, alanine aminotransferase; GT, genotype; HCV, hepatitis C virus; tx, treatment.
  • GT, genotype; pegIFN, peginterferon; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response at 12 weeks posttreatment.
  • RBV, ribavirin; SVR12, sustained virologic response at 12 weeks posttreatment.
  • GT, genotype; RBV, ribavirin; SOF, sofosbuvir; SVR4, sustained virologic response at 4 weeks posttreatment; SVR12, sustained virologic response at 12 weeks posttreatment; SVR24, sustained virologic response at 24 weeks posttreatment; Tx, treatment.
  • GT, genotype; RBV, ribavirin; SOF, sofosbuvir; SVR4, sustained virologic response at 4 weeks posttreatment; SVR12, sustained virologic response at 12 weeks posttreatment; TE, treatment experienced; TN, treatment naive.
  • GT, genotype; pegINF, peginterferon; RBV, ribavirin; SOF, sofosbuvir.
  • HCV, hepatitis C virus.
  • CC, CC IL28B genotype; F, fibrosis stage; SVR4, sustained virologic response at 4 weeks posttreatment. 
  • ASV, asunaprevir; DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; IFN, interferon; LDV, ledipasvir; NS5A, nonstructural protein 5A; NS5B, nonstructural protein 5B; PI, protease inhibitor; SOF, sofosbuvir; RBV, ribavirin; SVR4, sustained virologic response at 4 weeks posttreatment; SVR12, sustained virologic response at 12 weeks posttreatment; SVR24, sustained virologic response at 24 weeks posttreatment; Tx, treatment.
  • FDC, fixed-dose combination; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; Nuc, nucleotide polymerase inhibitor; NS5A, nonstructural protein 5A; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks posttreatment; Tx, treatment.
  • F, fibrosis stage; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir; SVR4, sustained virologic response at 4 wks posttreatment; SVR12, sustained virologic response at 12 weeks posttreatment.
  • DAA, direct-acting antiviral; FDC, fixed-dose combination; GT, genotype; PI, protease inhibitor; RBV, ribavirin; RTV, ritonavir; SVR12, sustained virologic response 12 weeks posttreatment; Tx, treatment.
  • DAA, direct-acting antiviral; GT, genotype; IFN, interferon; LDV, ledipasvir; PI, protease inhibitor; RBV, ribavirin; SOF, sofosbuvir; SVR4, sustained virologic response 4 weeks posttreatment; SVR12, sustained virologic response 12 weeks posttreatment; TE, treatment exposed.
  • FDC, fixed-dose combination; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; Nuc, nucleotide polymerase inhibitor; NS5A, nonstructural protein 5A; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks posttreatment.
  • DAA, direct-acting antiviral; HCV, hepatitis C virus.
  • HCV, hepatitis C virus.
  • DAA, direct-acting antiviral; HBV, hepatitis B virus; HCV, hepatitis C virus.
  • GT, genotype; HCV, hepatitis C virus; PI, protease inhibitor; RBV, ribavirin; SVR4, sustained virologic response rate at 4 weeks posttreatment; SVR12, sustained virologic response rate at 12 weeks posttreatment.
    For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Amsterdam%202013/Viral%20Hepatitis/Capsules/1417.aspx.
  • FDC, fixed-dose combination; GT, genotype; PI, protease inhibitor; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR12, sustained virologic response rate at 12 weeks posttreatment.
  • NS5A, nonstructural protein 5A; RIG-I, retinoic acid inducible gene I.
  • GT, genotype; NRs, null responders; P/R, peginterferon/ribavirin; PRs, partial responders; SVR12, sustained virologic response at 12 weeks posttreatment.
  • F, fibrosis stage; GT, genotype; PI, protease inhibitor; P/R, peginterferon/ribavirin; SVR12, sustained virologic response at 12 weeks posttreatment.
  • GT, genotype; P/R, peginterferon/ribavirin; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response at 12 weeks posttreatment; Tx, treatment.
  • GT, genotype; pegIFN/RBV, peginterferon/ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response at 12 weeks posttreatment; Tx, treatment.
  • DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; IFN, interferon; PI, protease inhibitor; RBV, ribavirin; SVR4, sustained virologic response at 4 weeks posttreatment; SVR12, sustained virologic response at 12 weeks posttreatment; Tx, treatment.
  • DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; RBV, ribavirin; SOF, sofosbuvir.
  • HCV, hepatitis C virus.
  • HCV, hepatitis C virus.
  • GT, genotype; HCV, hepatitis C virus; LT, liver transplantation; pegIFN, peginterferon; RBV, ribavirin.
  • CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; RBV, ribavirin; SOF, sofosbuvir.
    For more information about this study, please see the CCO Capsule Summary at:
    http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202013/Other%20Highlights/Capsules/213.aspx
  • HCV, hepatitis C virus; LT, liver transplantation; TND, target not detected.
    For more information about this study, please see the CCO Capsule Summary at:
    http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202013/Other%20Highlights/Capsules/213.aspx
  • AE, adverse effect; BOC, boceprevir; Cr, creatine; d/c, discontinuation; EOTR, end-of-treatment response; eRVR, extended rapid virologic response; F, fibrosis score; FCH, fibrosing cholestatic hepatitis; G-CSF, granulocyte-colony stimulating factor; LOD, limit of detection; peg-IFN, peginterferon; PI, protease inhibitors; P/R, peginterferon/ribavirin; RBV, ribavirin; SVR4, sustained virologic response at 4 weeks posttreatment; TT, triple therapy; TVR, telaprevir.
  • Alk Phos, alkaline phosphatase; ALT, alanine transaminase; HCV, hepatitis C virus; LT, liver transplantation.
  • CTP, Child-Turcotte-Pugh; EOT, end of treatment; GT, genotype; HCV, hepatitis C virus; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; RBV, ribavirin; SOF, sofosbuvir; SVR4, sustained virologic response at 4 weeks posttreatment.
  • FDC, fixed-dose combination; RBV, ribavirin; RTV, ritonavir.
  • HCV, hepatitis C virus; LT, liver transplantation.
  • Shaping the Future.Clinicians and Faculty Define: Strategies for the Next Era of HCV Therapy.2014

    1. 1. Shaping the Future: Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy This program is supported by educational grants from
    2. 2. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Program Director Mark S. Sulkowski, MD Professor of Medicine Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology Johns Hopkins University School of Medicine Baltimore, Maryland
    3. 3. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Faculty Jordan J. Feld, MD, MPH Assistant Professor of Medicine University of Toronto Hepatologist Toronto Western Hospital Liver Centre McLaughlin-Rotman Centre for Global Health Toronto, Ontario, Canada Graham R. Foster, FRCP, PhD Professor of Hepatology The Liver Unit Consultant Hepatologist Queen Marys University of London London, United Kingdom Michael W. Fried, MD Professor of Medicine Director, UNC Liver Center University of North Carolina at Chapel Hill Chapel Hill, North Carolina Alessandra Mangia, MD Liver Unit Hospital ‘Casa Sollievo della Sofferenza’ Istituto di Ricovero e Cura a Carattere Scientifico San Giovanni Rotondo, Italy Fred Poordad, MD Vice President, Academic and Clinical Affairs The Texas Liver Institute Professor of Medicine University of Texas Health Science Center San Antonio, Texas Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine I JW Goethe University Hospital Frankfurt, Germany
    4. 4. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy New Standard of Care for HCV in 2013/2014 Standard Interferon Interferon + Ribavirin Peginterferon/ Ribavirin 1991 1998 2001 2005 Boceprevir or Telaprevir + P/R GT1 GT2/3 2011 2013 2013 Simeprevir or Sofosbuvir + P/R Sofosbuvir + Ribavirin
    5. 5. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Key Questions That Define the Future of Hepatitis C Virus Therapy  How do we determine the best regimen for genotype 1 going forward? Jordan J. Feld, MD, MPH  Why does genotype 3 do poorly and how can we do better? Stefan Zeuzem, MD  Is one-size-fits-all treatment a possibility and how would that change management? Alessandra Mangia, MD  How will we manage patients who fail direct-acting antiviral therapies? Graham R. Foster, FRCP, PhD  Why do cirrhotics do poorly and how can we do better? Fred Poordad, MD  How will high-risk patients be managed going forward? Michael W. Fried, MD
    6. 6. Jordan J. Feld, MD, MPH Assistant Professor of Medicine University of Toronto Hepatologist Toronto Western Hospital Liver Centre McLaughlin-Rotman Centre for Global Health Toronto, Ontario, Canada How Do We Determine the Best Regimen for Genotype 1 Going Forward?
    7. 7. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Summary of New Agents for GT1 in 2013  Sofosbuvir + P/R – Sofosbuvir is oral, once daily – 12 wks with P/R – SVR rate 89% in naives – Low impact of baseline factors  Simeprevir + P/R – Simeprevir is oral, once daily – 12 wks with P/R + 12-36 wks with P/R – SVR rate 80% in naives – Q80K testing will be needed in GT 1a Baseline Factor SVR12, % (n/N) Black Non-Black 86 (43/50) 90 (218/242) Genotype 1a Genotype 1b 92 (206/225) 82 (54/66) Cirrhosis* No cirrhosis* 80 (43/54) 92 (252/273) *Represents GT 1/4/5/6. Sofosbuvir FDA hearing. October 25, 2013. Simeprevir FDA hearing. October 24, 2013. Baseline Factor SVR12, % (n/N) Black Non-Black 67 (29/43) 81 (378/464) GT1a with Q80K GT 1a, no Q80K GT 1b 58 (49/84) 84 (138/165) 85 (228/267) F3-F4* F0-F2* 68 (89/130) 84 (317/378)
    8. 8. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Priorities  SVR trumps all  But SVR is a necessity—assuming SVR > 90%, what is next?  Considerations – Several new P/R-based regimens completing phase III – Faldaprevir + P/R – Daclatasvir + P/R – But with 89% SVR with 12-wk SOF + P/R, will there be a clinical role for longer-duration P/R-based regimens? – An all-oral future for GT1: multiple studies of 12- to 16-wk regimens
    9. 9. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Over- treatment of some Tailored regimen for each population Priorities Cost Fewest drugs Shortest duration Simplicity One size fits all
    10. 10. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy 2/12 One Size Fits All or Simpler Regimen for Genotype 1b Only?  Genotype 1, naive  10% had cirrhosis Dufour J-F, et al. AASLD 2013. Abstract 1102. 16-Wk Regimen: Faldaprevir (PI) 120 mg QD + Deleobuvir (NNI) 600 mg BID + RBV (N = 32) Simple regimen for genotype 1b only? What if it were very cheap? EOT SVR12 UndetectableHCV RNA(IU/mL) 100 80 60 40 20 0 58 100 17 95 7/12 20/20 19/20 Genotype 1a, IL28B CC Genotype 1b
    11. 11. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy One Size Fits All or Simpler Regimen for GT1b? Various Ways to Look at the Same Data 82 0 20 40 60 80 100 SVR12(%) 100 100 100 100 100 79 100 29 12 85 100 52 27 83 96 52 25 96 100 54 25 81 100 26 18 89 100 28 17 Observed data (above bar) ITT (within bar) n = 81 98 8888 100 89 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV Treatment-Naive Patients Null Responders Kowdley KV, et al. AASLD 2012. Abstract LB-1. ABT-450/RTV (PI) ± ABT-333 (NNI) + ABT-267 (NS5A) ± RBV x 12 Wks One size fits all OR “simpler regimen” for GT1b?
    12. 12. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy What Is the Role of Ribavirin for Genotype 1 Going Forward?  Still an enigma  Prevents/delays resistance – Important for genotype 1a – Important with NNI, PI, and NS5A – Not relevant with NI-based combination  Reduces relapse – May be relevant with shorter durations – Limited data to date but does not look critical for most NI-based combination regimens
    13. 13. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Same Duration for All or Shorter for Naive, Longer for Previous Failures? 12 wks for all or 8 for naive and 12 for failures? What about RBV? A third DAA for 6 wks? SVR12(%) 0 20 40 60 80 100 19/ 20 SOF LDV SOF LDV RBV SOF LDV 95 100 21/ 21 95 18/ 19 95 SOF LDV 100 18/ 19 21/ 21 8 Wks 12 Wks 12 Wks SOF LDV RBV Naive PI failure n/N = Lawitz E, et al. AASLD 2013. Abstract 215.
    14. 14. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Are We Moving to Primary Care? Project ECHO One size fits all may be critical Project ECHO Web site.
    15. 15. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Conclusions  Research continues for GT1 HCV – More tailored approach in the near future – Longer duration or additional agents for difficult-to-treat populations?  One-size-fits-all approach ideal for inexperienced providers  Rising demand for treatment anticipated – Increased screening – Availability of IFN-free regimens
    16. 16. Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine JW Goethe University Hospital Frankfurt, Germany Why Does Genotype 3 Do Poorly and How Can We Do Better?
    17. 17. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Standard Treatment for GT2/3 HCV Before treatment (HCV RNA quantification) 16 wks therapy HCV RNA < 12-15 IU/mL Pre-tx < 8 x 105 IU/mL* 48 wks therapy‡ HCV RNA ≥ 2 log decline† Wk 4 HCV RNA quantification Wk 12 HCV RNA quantification 24 wks therapy HCV RNA < 12-15 IU/mL *No treatment shortening in patients with advanced fibrosis, cirrhosis, metabolic syndrome, insulin resistance, HIV/HCV coinfection, etc. No data for patients with persistently normal ALT levels. † Detectable HCV RNA at Wk 24: discontinuation of treatment.‡ Treatment duration of 36, 48, 72 wks in slow responders is currently investigated in prospective trials. Tx discontinued < 2 log decline EASL Practice Guidelines.
    18. 18. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy FISSION: Poorer Response to SOF/RBV in GT3 vs GT2 Naives, Especially Cirrhotics Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. SVR12(%) All Patients Patients With Cirrhosis n/N = 10/ 11 13/ 38 8/ 13 11/ 37 100 80 60 40 20 0 97 56 78 63 91 34 62 30 68/ 70 52/ 67 102/ 183 110/ 176 GT2 GT3 SOF/RBV 12 Wks PegIFN/RBV 24 Wks GT2 GT3
    19. 19. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy FUSION: Impact of Cirrhosis and Duration on SVR Rates Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. 6/10 5/26 SVR12(%) 25/26 7/923/23 14/38 14/2325/40 No Cirrhosis Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks No CirrhosisCirrhosis Cirrhosis Genotype 2 Genotype 3 19 6163 37 n/N = 100 80 60 40 20 0 96 100 60 78 100 80 60 40 20 0 SVR12(%) n/N =
    20. 20. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Wk 0 Wk 24 SVR4, SVR12, SVR24 Placebo* (n = 85) Sofosbuvir + Ribavirin (n = 84)* *Protocol amended to eliminate placebo arm. 12-wk arm predominantly GT2 patients (N = 73); 11 GT3 patients completed 12 wks of SOF + RBV prior to amendment to extend treatment duration. Zeuzem S, et al. AASLD 2013. Abstract 1085. VALENCE: Evaluating Impact of Duration on SVR With SOF/RBV Wk 12 Tx-naive or -experienced GT2 or GT3 pts
    21. 21. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Overall Treatment Naive Treatment Experienced SVR4(%) n/N = 2/ 2 30/ 33 12/ 13 87/ 100 100 80 60 40 20 0 93 97 85 94 100 9192 87 68/ 73 212/ 250 29/ 30 86/ 92 No Cirrhosis Cirrhosis 7/ 8 27/ 45 88 60 No Cirrhosis CirrhosisOverall 12 wks of SOF + RBV in GT2 24 wks of SOF + RBV in GT3 Zeuzem S, et al. AASLD 2013. Abstract 1085. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. VALENCE Efficacy Summary: SVR12  Phase III GT3 SVR12 data summary: – TN noncirrhotics, 12 wks: 61% (FISSION) – TN cirrhotics, 12 wks: 34% (FISSION) – TE noncirrhotics, 16 wks: 63% (FUSION) – TE cirrhotics, 16 wks: 61% (FUSION)
    22. 22. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Conclusions  Most GT3 patients will be able to be treated with 24 wks of SOF/RBV  GT3, treatment-experienced, cirrhotic patients most challenging group to treat with all-oral regimens – Experts recommend 12 wks of SOF + pegIFN/RBV in short term
    23. 23. Alessandra Mangia, MD Liver Unit Hospital 'Casa Sollievo della Sofferenza' Istituto di Ricovero e Cura a Carattere Scientifico San Giovanni Rotondo, Italy Is One-Size-Fits-All Treatment a Possibility and How Would That Change Management?
    24. 24. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy How Far Are We? One Size . . . . . . Fits All? Same treatment regardless of fibrosis level, previous treatment experience, or HCV genotype?
    25. 25. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy AVIATOR: Less Impact of Traditional Negative Predictors on SVR Rates  Comparable high SVR rates among 247 patients administered 12 or 24 wks of treatment  All enrolled patients were noncirrhotic Kowdley KV, et al. EASL 2013. Abstract 3. Treatment Naive Null Responders 100 80 60 40 20 0 M aleFem ale 1a 1b ≥ 7log F0-F1 < 7 log F2-F3Non-CC CC SVR24(%) SVR24(%) n = 92 94 91 98 89 94 94 91 95 89 78 81 108 50 35 124 113 42 115 44 100 80 60 40 20 0 M aleFem ale 1a 1b ≥ 7 log F0-F1 < 7 log F2-F3Non-CC CC n = 93 97 93 97 91 96 95 93 94 100 55 33 55 33 22 66 41 45 85 3
    26. 26. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy GT1 HCV Tx Naive: SVR Rates With 12 Wks of IFN-Free Tx in Phase II Studies  Few or no cirrhotic patients included in above studies  Corresponding rates for 24-wk regimens showed SVR12/24 of 52% (QUANTUM[1] ), 95% to 100% (AI-444040[6] ), 93% (AVIATOR[5] ), 94% (A1443-014[8] ) 1. Lalezari LP, et al. EASL 2013. Abstract 845. 2. Gane E, et al. EASL 2013. Abstract 14. 3. Lawitz E, et al. AASLD 2013. Abstract 215. 4. Sulkowski MS, et al. AASLD 2012. Abstract LB-2. 5. Kowdley K, et al. EASL 2013. Abstract 3. 6. Everson G, et al. AASLD 2013. Abstract LB-1. 7. Lawitz E, et al. AASLD 2013. Abstract 76. 8. Sulkowski M, et al. EASL 2013. Abstract 1423. Regimen N Study SVR 4/12, % SOF (NS5B) + RBV 25 QUANTUM[1] 56 SOF (NS5B) + RBV 25 ELECTRON[2] 84 SOF (NS5B) + LDV (NS5A) 19 LONESTAR[3] 95 SOF (NS5B) + DCV (NS5A) ± RBV 82 AI-444040[4] 98-100 ABT-450 (PI) + ABT-267 (NS5A) + ABT-333 (NS5B) ± RBV 158 AVIATOR[5] 94 DCV (NS5A) + ASV (PI) + BMS-791325 (NS5B) 161 A1443-014[6] 92 MK-5172 (PI) + MK-8742 (NS5A) ± RBV 65 C-WORTHY[7] 96-100
    27. 27. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Phase III Studies of Sofosbuvir (Nuc) + Ledipasvir (NS5A) ± RBV in GT1 HCV ION-1*: GT1 Tx-Naive Pts (16% Cirrhotic): SOF/LDV FDC ± RBV for 12 Wks Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data. *24-wk arms not yet reported. ION-3: GT1 Tx-Naive Pts: SOF/LDV FDC ± RBV for 8 or 12 Wks SOF/LDV FDC SOF/LDV FDC + RBV n/N = 209/ 214 211/ 217 SVR12(%) 12 Wks 98 97100 90 60 40 20 0 8 Wks 12 Wks 202/ 215 206/ 216 201/ 216 94 93 95
    28. 28. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy 12-Wk Treatment in Previous Null Responders? ABT-450/RTV + ABT-267 + ABT-333 + RBV 12 Wks SVR12(%) Naive n/N = 42/ 45 F0-F2 fibrosis SVR4/12(%) n/N = SMV + SOF + RBV 12 Wks SMV + SOF 12 Wks *No F4 COSMOS[1,2] Caveat: small numbers, few patients with cirrhosis 1. Jacobson IM, et al. AASLD 2013. Abstract LB-3. 2. Lawitz E, et al. CROI 2013. Abstract 155LB. 3. Kowdley K, et al. EASL 2013. Abstract 3. 26/ 27 13/ 14 96 93 76/ 79 14/ 15 7/ 7 93 100 F3/4 fibrosis 96 93 AVIATOR[3] 100 80 60 40 20 0 Null* 100 80 60 40 20 0
    29. 29. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy SAPPHIRE Phase III Studies: PI Backbone + 2 Other DAAs SAPPHIRE-1: GT1 Tx-Naive Noncirrhotic Pts: ABT-450/RTV/ABT-267 FDC + ABT-333 + RBV for 12 Wks Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data. n/N = 455/ 473 307/ 322 148/ 151 SAPPHIRE-2: GT1 Tx-Experienced Noncirrhotic Pts (49% Null Responders): ABT-450/RTV/ABT-267 FDC + ABT-333 + RBV for 12 Wks 100 80 60 40 20 0 SVR12(%) 96 95 98 Overall GT1a GT1b n/N = 286/ 297 166/ 173 119/ 123 100 80 60 40 20 0 SVR12(%) 96 96 97 Overall GT1a GT1b
    30. 30. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy SOF-Based IFN-Free DAA Treatment in GT1 Treatment-Experienced Patients SOF + LDV + RBV x 12 wks (prior null, noncirrhotic) 100 80 60 40 20 0 SVR4/12(%) 100[1] 2 DAAs + RBV SOF + LDV x 12 wks (prior PI failures, 50% cirrhotic) 2 DAAs, No RBV 7/10 70[2] 9/9 100[2] SOF + LDV + RBV x 12 wks (TE with cirrhosis) SOF + LDV x 12 wks (TE with cirrhosis) 95[3] 1. Gane EJ, et al. CROI 2013. Abstract 41LB. 2. Gane EJ, et al. AASLD 2013. Abstract 73. 3. Lawitz E, et al. AASLD 2013. Abstract 215. 18/199/9n/N =
    31. 31. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Phase III Studies of Sofosbuvir (Nuc) + Ledipasvir (NS5A) ± RBV in GT1 HCV Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data. SOF/LDV FDC SOF/LDV FDC + RBV ION-2: GT1 Treatment-Experienced Pts (20% Cirrhotic): SOF/LDV FDC ± RBV for 12 or 24 Wks n/N = SVR12(%) 100 90 60 40 20 0 12 Wks 24 Wks 102/ 109 107/ 111 108/ 109 110/ 111 94 96 99 99
    32. 32. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Challenging Patient Groups  Patients with cirrhosis  HCV genotype 3 infection  Patients nonresponsive to DAA regimens  HIV coinfection
    33. 33. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Conclusions  Future role for specialists in HCV – Treating more complex cases – Determining indication for starting treatment – Surveillance of cirrhotic patients following successful therapy
    34. 34. Graham R. Foster, FRCP, PhD Professor of Hepatology The Liver Unit Consultant Hepatologist Queen Marys University of London London, United Kingdom How Will We Manage Patients Who Fail Direct-Acting Antiviral Therapies?
    35. 35. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy DAA Failures: The Principles  In other viral infections, “failure” can be resolved by complementary drugs – eg, in HBV, lamivudine failures respond to adefovir or tenofovir  Will the same hold true for HCV?
    36. 36. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy High SVR Rates With 24 Wks of All-Oral Therapy in GT1 Patients With PI Failure Sulkowski MS, et al. EASL 2013. Abstract 1417. *1 patient in daclatasvir/sofosbuvir/RBV arm had missing data at Wk 12 posttreatment; this patient had undetectable HCV RNA at Wk 4 and Wk 24 posttreatment. SVR4 SVR12 24 wks of daclatasvir + sofosbuvir 24 wks of daclatasvir + sofosbuvir + RBV 100 100 100 95*100 80 60 40 20 0 Patients(%) n/N = 21/ 21 20/ 20 21/ 21 19/ 20
    37. 37. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy LONESTAR: High SVR Rates With 12 Wks of Therapy in GT1 Patients With PI Failure Lawitz E, et al. AASLD 2013. Abstract 215. 12 wks of SOF/LDV FDC 12 wks of SOF/LDV FDC + RBV 95 100 100 80 60 40 20 0 SVR12(%) n/N = 18/ 19 21/ 21
    38. 38. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Complementary Regimens: Drug Classes for the Future  Nucleotide polymerase inhibitors (eg, sofosbuvir)  NS5A inhibitors (eg, daclatasvir, ledipasvir)  Protease inhibitors (eg, simeprevir, faldaprevir)  Non-nucleotide polymerase inhibitors (3 different classes)  Host-targeting drugs (cyclophilins, microRNAs RIG-I activators)  Which will work best together?
    39. 39. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Conclusions  Second-line therapy and beyond – New challenges with increased treatment options – Continued treatment failures anticipated with more difficult- to-treat populations  Managing treatment failures – Determine cause – Risk factors – modifiable? – Adherence with all-oral regimens – Patient education and adherence management key
    40. 40. Fred Poordad, MD Vice President Academic and Clinical Affairs The Texas Liver Institute Professor of Medicine University of Texas Health Science Center San Antonio, Texas Why Do Cirrhotics Do Poorly and How Can We Do Better?
    41. 41. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy CUPIC: Telaprevir or Boceprevir + P/R in GT1 Treatment-Experienced Cirrhotics Fontaine H, et al. EASL 2013. Abstract 60. Hezode C, et al. J Hepatol. 2013;59:434-441. n/N = 118/ 295 79/ 190 61/ 116 43/ 85 43/ 135 32/ 80 8/ 28 1/9 100 80 60 40 20 0 SVR12(%) Overall Relapsers PRs NRs 40 41 53 51 32 40 29 11 Telaprevir + P/R Boceprevir + P/R Risk of Death or Severe Complications, % (n/N) Platelet Count > 100,000 cells/mm3 Platelet Count ≤ 100,000 cells/mm3 Albumin ≥ 35 g/L 3.4 (10/298) 4.3 (3/69) Albumin < 35 g/L 7.1 (2/28) 44.1 (15/34)
    42. 42. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Impact of Cirrhosis on SVR12 With Next-Generation PI + P/R Jacobson I, et al. EASL 2013. Abstract 1425. Ferenci P, et al. EASL 2013. Abstract 1416. 18/ 31n/N = 5/ 17 188/ 229 60/ 113 82 53 58 29 Simeprevir + P/R P/R 100 80 60 40 20 0 SVR12(%) No Cirrhosis Cirrhosis QUEST-1: Simeprevir + P/R Treatment-Naive GT1 172/ 212 30/ 45 9/ 16 100 80 60 40 20 0 81 67 56 < F3 ≥ F3 F4 STARTVerso1: Faldaprevir + P/R Treatment-Naive GT1 Faldaprevir + P/R
    43. 43. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Impact of Cirrhosis on SVR12 With Sofosbuvir-Based Therapy in Tx-Naive Pts Lawitz E, et al. EASL 2013. Abstract 1411. Zeuzem S, et al. AASLD 2013. Abstract 1085. SVR12(%) 92 80 252/ 273 43/54 NEUTRINO: 12 Wks of SOF + P/R GT1/4/5/6 Genotype 2 Genotype 3 58/59 10/11 89/145 13/38 100 80 60 40 20 0 n/N = 98 91 61 34 FISSION: 12 Wks of SOF + RBV GT2/3 CirrhoticNoncirrhotic 94 86/92 12/13 92 VALENCE: 24 Wks of SOF + RBV GT3 Genotype 1/4/5/6 Genotype 3 100 80 60 40 20 0 100 80 60 40 20 0
    44. 44. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy 100 80 60 40 20 0 37 63 87 19 61 60 No Cirrhosis Cirrhosis Impact of Duration, Addition of PegIFN on Efficacy of SOF in Tx-Experienced GT2/3 FUSION: 12 wks of SOF/RBV FUSION: 16 wks of SOF/RBV VALENCE: 24 wks of SOF/RBV LONESTAR-2: 12 Wks of SOF + PegIFN/RBV Sofosbuvir FDA hearing. October 25, 2013. Lawitz E, et al. AASLD 2013. SVR12(%) 14/ 38 25/ 40 87/ 100 5/ 26 14/ 23 27/ 45 Genotype 3 100 80 60 40 20 0 96 93 100 83 83 83 Genotype 2 Genotype 3 SVR12(%) Overall Cirrhotic Noncirrhotic n/N = 22/ 23 13/ 14 9/ 9 20/ 24 10/ 12 10/ 12
    45. 45. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Efficacy of IFN-Free DAA Combinations in Tx-Naive and Tx-Experienced Cirrhotics COSMOS: 12-Wk Regimens in GT1 HCV Cirrhotic Tx-Naive or Previous Null Responders SVR4/12(%) Jacobson IM, et al. AASLD 2013. Abstract LB-3. Lawitz E, et al. AASLD 2013. Abstract 215. Everson GT, et al. AASLD 2013. Abstract LB-1. LONESTAR: 12-Wk Regimens in GT1 HCV PI Failures (55% Cirrhotic) AI443-014: 12-Wk Regimen in GT1 Tx-Naive Cirrhotics 100 80 60 40 20 0 91 100 10/11 7/7 Simeprevir + sofosbuvir + RBV Simeprevir + sofosbuvir 100 80 60 40 20 0 18/19 21/21 95 100 Sofosbuvir/ledipasvir Sofosbuvir/ledipasvir + RBV 100 80 60 40 20 0 87 Daclatasvir + asunaprevir + BMS-791325 13/15n/N =
    46. 46. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Conclusions  Eradication of HCV optimal before progression to cirrhosis  Poorer response of cirrhotic patients likely multifactorial – Poor prior IFN response and GT3 most challenging  Treatment approaches – GT3 experienced, cirrhotic: 12 wks of SOF + pegIFN/RBV – GT3 naive, cirrhotic: 24 wks of SOF + RBV  Further improvements anticipated with DAA combinations
    47. 47. Michael W. Fried, MD Professor of Medicine Director, UNC Liver Center University of North Carolina at Chapel Hill Chapel Hill, North Carolina How Will High-Risk Patients Be Managed Going Forward?
    48. 48. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Goals of Antiviral Therapy  Decompensated cirrhosis – Eradicate HCV to prevent further deterioration – Eradicate HCV to prevent reinfection of graft – Improve hepatic functional status – Delay or obviate the need for transplantation  Posttransplantation – Treat acute complications of HCV reinfection – Prevent/arrest progression to cirrhosis – Improve morbidity and mortality – Liver related – Extrahepatic effects on cardiovascular disease
    49. 49. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy HCV Management Issues Unique to Pre- and Posttransplantation Patients  Pretransplantation – Intolerance to peginterferon regimens – Impaired hepatic metabolism – Renal insufficiency  Posttransplantation – High HCV RNA/impact of immunosuppression – Fibrosing cholestatic hepatitis – Drug–drug interactions – Renal insufficiency – Other medical comorbidities
    50. 50. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy PegIFN/RBV Before Transplantation to Minimize HCV Recurrence Post-LT Everson GT, et al. Hepatology. 2013;57:1752-1762. P = .6011 TreatedLTPatients(%) 100 80 60 40 20 0 Overall (n = 44) GT1/4/6 (n = 23) GT2/3 (n = 44) 59 25 52 22 67 29 HCV RNA negative at LT HCV RNA negative 12 wks of post-LT
    51. 51. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Characteristic SOF + RBV (N = 61) Median age, yrs (range) 59 (46-73) HCV genotype, %  1a 39  1b 34  2 13  3a 12  4 2 Non-CC IL28B genotype, % 78 CTP score, %  5-7 96  8 5 Previous HCV treatment, % 75 Pretransplant Sofosbuvir + RBV to Prevent Posttransplant HCV Recurrence  Study 025: single-arm, open-label, phase II study from 16 LT sites – Listed for LT due to HCC meeting Milan criteria – MELD exception for HCC – CTP score ≤ 7  Excluded decompensated cirrhosis, renal impairment, living donor LT  Pre-LT therapy: SOF 400 mg/day + RBV 1000-1200 mg/day for 48 wks or until time of LT – Post-LT immunosuppression: ≥ 12 wks of tacrolimus + prednisone + MMF Curry MP, et al. AASLD 2013. Abstract 213.
    52. 52. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Duration of Undetectable HCV RNA Before Transplant Predicted Lack of Recurrence  64% of pts HCV RNA negative 12 wks post-LT (93% at LT)  Continuous days TND pre-LT only factor predicting HCV recurrence in multivariate analysis – Only 1/24 pts with > 30 days TND experienced recurrence Curry MP, et al. AASLD 2013. Abstract 213. 3300 30 60 90 120 150 180 210 240 270 300 Days With HCV RNA Continuously TND Prior to LT > 30 days TND No recurrence (n = 28) Recurrence (n = 10) Median days TND (P < .001) No recurrence: 95 Recurrence: 5.5
    53. 53. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy CRUSH C: PI + PegIFN/RBV in Liver Transplantation Recipients  112 patients: 30 were F4 or FCH  Treatment: TVR 88% or BOC 12% – P/R lead-in 96% Verna EC, et al. EASL 2013. Abstract 23. HCVRNA<LOD(%) 100 80 60 40 20 0 EOTR SVR4 67 65 n = 43 Adverse Effect All Patients (N = 112) AE requiring treatment d/c, % 11 Dose reduction, % PegIFN/RBV 34/80 Transfusion, % 46 Erythropoietin, % 79 G-CSF 41 Hospitalization, %* 21 Renal function Cr increase > 0.5 mg/dL, % Max ↑ in Cr, mg/dL (range) 34 0.4 (0-2.5) Rejection, %† 4 Death, % 6 *Significantly differed between groups (P = .02). † Any treated rejection during or after TT.
    54. 54. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Daclatasvir 60 mg/day + Sofosbuvir 400 mg/day Case Report: Sofosbuvir + Daclatasvir in Post-LT Fibrosing Cholestatic Hepatitis Fontana RJ, et al. Am J Transplant. 2013;13:1601-1605. 8 7 6 5 4 3 2 1 0 LogHCVRNA(IU/mL) Treatment Wk 400 350 300 250 200 150 100 50 0 ALT(IU/L) AlkPhos(IU/L) 0 1 2 3 4 6 8 1012 14 1618 20 222425 2848 56 60 ALT Alk Phos HCV RNA
    55. 55. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Sofosbuvir + RBV for Treatment of Post-LT HCV Recurrence  Ongoing prospective, multicenter, single-arm, open-label pilot study – Median time since LT: 4.3 yrs (range: 1.02-10.6) – CTP ≤ 7 and MELD ≤ 17 – 83% GT1, 33% IL28B CC, 40% with comp’d cirrhosis  SOF 400 mg/day + RBV 400-1200 mg/day for ≤ 24 wks – RBV started at 400 mg/day and increased based on hemoglobin levels Charlton MR, et al. AASLD 2013. Abstract LB-2. Reproduced with permission. Virologic Response Rates *1 patient still on treatment. † 4 patients had not reached SVR4 visit. Wk 4 EOT* SVR4 Response(%) 100 80 60 40 20 0 100 100 77 40/40 39/39 27/35†
    56. 56. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Other Studies Recruiting  Sofosbuvir/ledipasvir FDC + RBV for 12 or 24 wks in patients with advanced liver disease or posttransplantation recurrence[1]  Simeprevir + daclatasvir + RBV for 24 wks in genotype 1b patients with posttransplantation recurrence[2]  ABT-450/RTV/ABT-267 FDC + ABT-333 + RBV for 24 wks in liver transplantation recipients[3] 1. ClinicalTrials.gov. NCT01938430. 2. ClinicalTrials.gov. NCT01938625. 3. ClinicalTrials.gov. NCT01782495.
    57. 57. clinicaloptions.com/hepatitis Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy Conclusions  Pre- and post-LT patients greatest challenge to eradication of HCV – Recent data encouraging – Significant challenges remain
    58. 58. Go Online for More From This Program! CME-certified module that goes in-depth on each of the key questions addressed in this slideset clinicaloptions.com/shaping

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