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HCV Treatment With New Therapies in Patients With Cirrhosis

Learn about the latest advancements in HCV treatment for patients with cirrhosis. Discover the benefits of new therapies and the importance of fibrosis assessment. Supported by educational grants from Gilead Sciences and Janssen.

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HCV Treatment With New Therapies in Patients With Cirrhosis

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  1. HCV Treatment With New Therapiesin Patients With Cirrhosis Paul Y. Kwo, MD Professor of MedicineMedical Director of TransplantationDivision of Medicine/Gastroenterology/ HepatologyIndiana University School of MedicineIndianapolis, Indiana This activity is supported by educational grants from Gilead Sciences and Janssen.

  2. Estimated 1 Million HCV-Infected Persons in the US Will Have Cirrhosis by 2020 • Projection based on multicohort natural history model 6,000,000 Acute hepatitisCirrhosisEver infectedChronic HCV 5,000,000 4,000,000 Total Number of HCV-Infected Persons 3,000,000 2,000,000 1,000,000 0 1950 1960 1970 1980 1990 2000 2010 2030 2020 Yr Peak incidence Peak cirrhosis 40 yrs Davis GL, et al. Gastroenterology. 2010;138:513-521.

  3. GBD 2010: HCV-Related Cirrhosis, Liver Cancer, and Death in the United States • Estimated 19,500 liver cancer and 49,500 cirrhosis deaths in US in 2010 • Total liver-related deaths increased from 45,000 to 70,000 over 20 yrs Causes of CLD Death, US 2010 Causes of CLD Death, US Liver cancer–HCV Cirrhosis–HCV Liver cancer–alcohol Cirrhosis–alcohol Liver cancer–HBV Cirrhosis–HBV AlcoholOther HBVHCV 50 25,000 41 40 39 40 20,000 29 30 15,000 Deaths (%) Deaths (n) 20 16 10,000 14 13 8 10 5000 0 0 Liver Cancer Cirrhosis 1990 1995 2000 2005 2010 Yr Cowie BC, et al. AASLD 2013. Abstract 23.

  4. Birth Cohort Screening and DAA Tx Could Greatly Reduce HCV-Related Transplants • Markov model[1] based on birth cohort developed to predict transplant rate[2] • Assumptions in model: All stages of fibrosis treated at same rate; 90% response rate to new Tx; all pts with decompensated cirrhosis or HCC within Milan criteria considered potential transplant candidates 180,000 162,559 162,747 150,617 160,000 126,296 140,000 No treatment 120,000 91,310 25% treated Liver Transplants (n) 100,000 80,000 50% treated 49,013 60,000 75% treated 40,000 All treated 20,000 27,175 25,573 26,207 24,258 21,994 18,193 0 2013 2018 2023 2028 2033 2038 2043 Yr in Model 1. Davis GL, et al. Gastroenterology. 2010;138:513. 2. Desai AP, et al. AASLD 2013. Abstract 1427.

  5. Fibrosis Assessment: Important to Diagnose Cirrhosis • AASLD/IDSA guidance • An assessment of the degree of hepatic fibrosis, using noninvasive testing or liver biopsy, is recommended (rating: Class I, Level A) • Fibrosis assessment used to determine treatment urgency if limited resources prevent treatment of all cases of HCV infection and need for additional screening • Cirrhotic patients require regular screening for HCC, varices, other complications • Achieving SVR in cirrhotic HCV pts highly beneficial AASLD/IDSA HCV Management Guidance. October 2014.

  6. Options for Liver Fibrosis Assessment Liver biopsy: gold standard Elastography: approved in United States Serum Biomarkers Axial CT/MRI, US can demonstrate cirrhotic morphology, portal hypertension Liver Biopsy Serum markers of fibrosis

  7. Strategies for Noninvasive Fibrosis Assessment • AASLD/IDSA guidance[1] • Most efficient strategy combines direct serum biomarkers and transient liver elastography[2] • Consider biopsy for any patient with discordant results between 2 testing methods if the information will affect clinical decisions • Persons with clinical evidence of cirrhosis do not require further disease staging 1. AASLD/IDSA HCV Management Guidance. October 2014. 2. Boursier J, et al. Hepatology. 2012;55:58-67.

  8. AASLD/IDSA: Patients With F3/F4 Fibrosis Have Highest Priority for HCV Treatment • Treatment recommended for all patients with chronic HCV infection (rating: Class I, Level A) • When constrained resources prevent treatment of all HCV infection cases, highest priority should be given to patients with advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C • Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications are given high priority AASLD/IDSA HCV Management Guidance. October 2014.

  9. Direct-Acting Antiviral Agents: Key Characteristics C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3/4A Protease Inhibitors (PI) High potency Limited genotypic coverage Low barrier to resistance NS5B Nucleos(t)ide Inhibitors (NI) Intermediate potency Pangenotypic coverage High barrier to resistance NS5A Inhibitors High potency Multigenotypic coverage Low barrier to resistance NS5B Nonnucleoside Inhibitors (NNI) Intermediate potency Limited genotypic coverage Low barrier to resistance

  10. Evolving Options for HCV Therapy • New in 2013: beginning of all-oral therapy • Sofosbuvir • Simeprevir • New in 2014 and early 2015: all-oral therapy options for all • Sofosbuvir/ledipasvir • Paritaprevir/ritonavir/ombitasvir + dasabuvir • Daclatasvir • Additional development of new therapies ongoing

  11. Management of Genotype 1 HCV With Cirrhosis

  12. Current AASLD/IDSA Guidance: GT1, Previous Nonresponders to pegIFN/RBV • Note that guidelines do not yet reflect FDA approval of sofosbuvir/ledipasvir or other agents that may be approved in coming months *Pts with cirrhosis must have well compensated liver disease to receive simeprevir. AASLD/IDSA HCV Management Guidance. October 2014.

  13. Current AASLD/IDSA Guidance: GT1, Tx-Naive and Previous Relapsers • Note that guidelines do not yet reflect FDA approval of sofosbuvir/ ledipasvir or other agents that may be approved in coming months • Recommendations for Tx-naive/previous relapse pts with compensated cirrhosis, including those with HCC, same as for pts without cirrhosis *Likely less effective than sofosbuvir + simeprevir, particularly among pts with cirrhosis. AASLD/IDSA HCV Management Guidance. October 2014.

  14. Sofosbuvir • Oral, once-daily nucleotide NS5B polymerase inhibitor • Potent antiviral activity; pangenotypic • High barrier to resistance • Pharmacology profile • No significant drug interactions, including tacrolimus or cyclosporine • Approved for combination treatment of HCV in following settings • GT1-4 HCV • HCC meeting Milan criteria; awaiting transplantation • HIV coinfection Sofosbuvir [package insert].

  15. NEUTRINO: SVR12 With Sofosbuvir + pegIFN/RBV in Tx-Naive GT1/4/5/6 • Open-label, single-arm, phase III study (N = 327): sofosbuvir 400 mg QD + pegIFN/RBV for 12 wks • 17% cirrhosis SVR12 by Biopsy Fibrosis Stage SVR12 by FibroTest Stage F0 F1-F2 F3 F4 100 97 96 100 100 91 89 85 79 78 80 80 60 60 SVR12 (%) 40 40 20 20 16/16 124/137 34/38 32/41 76/78 101/105 46/54 68/86 n/N = 0 0 Patel K, et al. AASLD 2013. Abstract 1093.

  16. Cirrhosis Predictive of Relapse With Sofosbuvir + pegIFN/RBV in GT1 • Pooled multivariate regression analysis from NEUTRINO and ATOMIC* studies[1] *ATOMIC: Open-label multicenter phase II study of sofosbuvir + pegIFN/RBV in noncirrhotic treatment-naive patients; SVR rates 87% to 89% in GT1 HCV[2] 1. Foster GR, et al. EASL 2014. Abstract O66. 2. Kowdley KV, et al. Lancet. 2013;381:2100-2107.

  17. Simeprevir • Oral, once-daily NS3 PI for GT1 HCV • Improved adverse effect profile vs previous PIs: no anemia • Fewer drug–drug interactions vs previous PIs: no meaningful drug–drug interactions with tacrolimus • No data yet in CTP class B/C pts, but higher simeprevir exposure in CTP class B/C individuals without HCV infection makes dosing problematic • Approved for combination treatment of GT1 HCV • Screening for Q80K in GT1a pts recommended Simeprevir [package insert].

  18. COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV Patients • Randomized phase IIa study Wk 24 Wk 12 Simeprevir + Sofosbuvir + RBV (n = 54) Patients With GT1 HCV Cohort 1: Previous null responders, F0-F2 (N = 80) Cohort 2: Naives and previous null responders, F3-F4 (N = 87) Simeprevir + Sofosbuvir (n = 31) Simeprevir + Sofosbuvir + RBV (n = 54) Simeprevir + Sofosbuvir(n = 28) Simeprevir 150 mg QD; sofosbuvir 400 mg QD; weight-based RBV 1000-1200 mg/day. Lawitz E, et al. Lancet. 2014;[Epub ahead of print].

  19. COSMOS: SVR12 in Tx-Naive and Previous Null Responders With F3-F4 Fibrosis • Treatment-naive patients and previous null responders 100 100 94 93 93 93 80 60 SVR12 (%) 40 20 28/30 16/16 25/27 13/14 82/87 n/N = 0 SMV + SOF + RBV SMV + SOF SMV + SOF + RBV SMV + SOF SMV + SOF + RBV 24 Wks 12 Wks Overall Lawitz E, et al. Lancet. 2014;[Epub ahead of print].

  20. HCV-TARGET: Adverse Events With Sofosbuvir + Simeprevir ± RBV in GT1 • Longitudinal observational analysis of patients receiving DAA-based HCV therapy in North America and Europe • 60% of patients with GT1 HCV initiated sofosbuvir + simeprevir ± RBV • Most frequent adverse events: mild fatigue, headache, nausea • Discontinuations for virologic failure or adverse event: n = 3 • Serious adverse events: 10 in 8 patients • Deaths: n = 1 (hepatic decompensation) Sulkowski MS, et al. AASLD 2014. Abstract 955. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.

  21. Sofosbuvir + RBV in Pts With Cirrhosis and Portal HTN ± Decompensation • Interim results of an open-label phase II trial Wk 24 Current analysis Wk 48 Wk 72 Sofosbuvir + Ribavirin (n = 25) HCV-infected patients with portal HTN ± decompensated liver disease*(N = 50) Observation (n = 25) Sofosbuvir + Ribavirin (n = 25) Sofosbuvir 400 mg once daily; RBV 1000-1200 mg/day divided twice daily. *Among 25 patients allocated sofosbuvir + RBV, 10 had GT1a HCV, 9 had GT1b, 2 had GT2, 2 had GT3, and 2 had GT4. Afdhal N, et al. EASL 2014. Abstract O68.

  22. Sofosbuvir + RBV in Pts With Cirrhosis and Portal HTN: On-Tx Virologic Response 100 100 100 100 100 94* 94 93 80 75 56 60 HCV RNA < LLOQ (%) 44 CTP A CTP B 40 20 n/N = 5/9 7/16 9/9 12/16 8/8 15/16 8/8 15/16 7/7 14/15 0 Wk 2 Wk 4 Wk 8 Wk 12 Wk 24 *1 patient with nonresponse at Wk 8. Afdhal N, et al. EASL 2014. Abstract O68.

  23. Sofosbuvir + RBV in Pts With Cirrhosis/ Portal HTN: Disease Marker Changes SOF + RBV (n = 25) Observation 24 wks (n = 25) Platelets (103/µL) Albumin (g/dL) ALT (U/L) P = .003 P = .001 P = .001 13 20 20 17 0.6 0 0.5 0.5 15 0 0.4 P = NS 0.4 10 -20 0.3 5 1 -40 0.2 0 0.1 0 -60 0 -1 -5 -0.1 -80 -72 -10 -75 -0.1 -9 -0.2 -15 CTP A CTP B CTP B CTP B CTP A CTP A Afdhal N, et al. EASL 2014. Abstract O68.

  24. Sofosbuvir/Ledipasvir • Oral, once-daily fixed-dose combination of nucleotide NS5B polymerase inhibitor and NS5A inhibitor • Sofosbuvir: potent antiviral activity; pangenotypic • Ledipasvir: potent antiviral activity against GT1a, 1b, 4a, 5a, 6a • Combination has high barrier to resistance • Pharmacology profile • Clinically significant drug interactions include with P-gp inducers • No clinically significant drug interactions with tacrolimus or cyclosporine • Approved for treatment of GT1 HCV Sofosbuvir/ledipasvir [package insert].

  25. Sofosbuvir/Ledipasvir 400/90 mg: Prescribing Information for GT1 HCV *8-wk duration can be considered in treatment-naive patients without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL. †Treatment-experienced patients who have experienced treatment failure with either pegIFN/RBV or an HCV PI plus pegIFN/RBV. Sofosbuvir/ledipasvir [package insert].

  26. ION-1: SOF/LDV FDC ± RBV for 12 or 24 Wks in Treatment-Naive GT1 Patients • Open-label phase III trial[1,2] • 15% to 17% of participants had cirrhosis • No upper age or BMI limit; platelet count ≥ 50,000/mm3, no neutrophil min Wk 12 Wk 24 Stratified by HCV subtype (1a vs 1b) and cirrhosis SOF/LDV (n = 214) SOF/LDV + RBV (n = 217) Treatment-naive pts with GT1 HCV (N = 865) SOF/LDV (n = 217) SOF/LDV + RBV (n = 217) Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.

  27. ION-1: SVR12 According to Cirrhosis Status • SVR12 rates did not differ by GT1a vs GT1b in any treatment arm 100 99.5 97 100 100 100 96.9 100 100 80 No cirrhosis 60 Cirrhosis SVR12 (%) 40 20 179/179 32/33 178/178 33/33 181/182 31/32 179/179 36/36 n/N = 0 SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV 12 Wks 24 Wks Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.

  28. ION-2: SOF/LDV FDC ± RBV for 12 or 24 Wks in Tx-Experienced GT1 Pts • Open-label phase III trial • 20% of participants had cirrhosis, 41% to 46% were previous nonresponders, and 46% to 61% had experienced PI failure • No upper age or BMI limit; platelet count ≥ 50,000/mm3, no neutrophil min Stratified by HCV subtype (1a vs 1b), cirrhosis, and previous Tx response Wk 12 Wk 24 SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) Tx-experienced pts with GT1 HCV (N = 440) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.

  29. ION-2: SVR12 According to Cirrhosis Status • Absence of cirrhosis was significantly associated with SVR12 in multivariate exact logistic regression model (OR: 5.1; P = .012) 100 99 100 99 100 95 86 100 82 80 60 No cirrhosis SVR12 (%) Cirrhosis 40 20 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 n/N = 0 SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV 12 Wks 24 Wks Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.

  30. Pooled Efficacy/Safety Analysis of Sofosbuvir/Ledipasvir in Cirrhosis • Pooled analysis of GT1 HCV–infected pts with cirrhosis from phase II and III trials of sofosbuvir/ledipasvir ± RBV for 12-24 wks • Safety similar to that observed in pts without cirrhosis • AEs more frequent in pts treated with RBV; no other AE or SAE trends observed • SVR12 rate in 284 pts with available data: 95% Bourlière M, et al. AASLD 2014. Abstract 82. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.

  31. Opportunities and Challenges With Current Therapies in GT1 Cirrhosis • Higher SVR rates in GT1 HCV with compensated cirrhosis with just 12 wks of therapy with sofosbuvir + pegIFN/RBV than with first-generation protease inhibitors • No adjustment of sofosbuvir required • Adverse effects of pegIFN/RBV still problematic in cirrhotics • All oral therapy now available for patients with GT1 HCV with 2 different regimens • Sofosbuvir/ledipasvir • Sofosbuvir + simprevir ± RBV • Based on limited data in F3/F4 disease (39 patients) • Viral suppression associated with clinical improvement

  32. Current AASLD/IDSA Guidance: Genotype 2/3 *Previous nonresponders to pegIFN/RBV with cirrhosis may benefit from extending treatment to 16 wks. AASLD/IDSA HCV Management Guidance. October 2014.

  33. FISSION: Sofosbuvir + RBV vs pegIFN/ RBV in Tx-Naive GT2/3 HCV Patients • Randomized, controlled, open-label phase III noninferiority trial • 20% to 21% had cirrhosis; 71% to 72% had GT3 HCV Stratified by HCV GT (2 vs 3), HCV RNA (< vs ≥ 106 IU/mL), cirrhosis (yes vs no) Wk 12 Wk 24 Sofosbuvir 400 mg/day + RBV 1000-1200 mg/day (n = 256) Treatment-naive patients with GT2/3 HCV(N = 499) PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day (n = 243) Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  34. FISSION: SVR12 According toGenotype and Fibrosis Level PegIFN + RBV Sofosbuvir + RBV 98 100 91 82 80 71 62 61 60 SVR12 (%) 40 34 30 20 n/N = 58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 0 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Genotype 2 Genotype 3 Gane E, et al. EASL 2013. Abstract 5.

  35. FUSION: Sofosbuvir + RBV for 12 or 16 Wks in Tx-Experienced GT 2/3 HCV Pts • Randomized, double-blind, placebo-controlled phase III trial • 62% to 64% had GT3 HCV, 33% to 35% had cirrhosis, 74% to 76% were previous relapsers Stratified by HCV GT (2 vs 3), cirrhosis (yes vs no) Wk 12 Wk 16 Sofosbuvir 400 mg/day + RBV 1000-1200 mg/day (n = 103) Placebo Tx-experienced pts with GT2/3 HCV (N = 201) Sofosbuvir 400 mg/day + RBV 1000-1200 mg/day (n = 98) Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  36. FUSION: SVR12 According to Genotype and Fibrosis Level Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks 100 96 100 100 78 80 80 63 61 60 60 60 SVR12 (%) SVR12 (%) 37 40 40 19 20 20 25/26 23/23 14/38 25/40 14/23 n/N = 6/10 7/9 5/26 0 0 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Genotype 2 Genotype 3 Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

  37. VALENCE: Sofosbuvir + RBV for 12 or 24 Wks in Naive and Exp’d GT2/3 HCV Pts • Phase III study in Europe • 21% had cirrhosis, 58% previously treated with IFN-based therapy • Original protocol amended to lengthen treatment for all GT3 pts when emerging data suggested benefit of additional treatment for this group* Wk 12 Wk 24 Sofosbuvir 400 mg/day +RBV 1000 mg or 1200 mg/day (n = 73) GT2 HCV-infected Tx-naive or exp’d pts(N = 323) Sofosbuvir 400 mg/day +RBV 1000 mg or 1200 mg/day (n = 250) GT3 *Small number of GT3 pts (n = 11) who had already completed 12 wks at time of protocol amendment were included in safety analysis with GT2 but analyzed separately for efficacy. Pts randomized to placebo in original protocol offered alternative treatment protocol. Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.

  38. VALENCE: SVR12 • No increase in AEs seen with longer duration treatment • AEs consistent with RBV GT2 12-Wk Treatment(n = 73) GT3 24-Wk Treatment(n = 250) 100 97 100 95 100 94 92 87 78 80 80 62 60 60 SVR12 (%) SVR12 (%) 40 40 20 20 12/13 29/47 87/92 85/98 29/30 2/2 30/32 7/9 n/N = n/N = 0 0 Naive, Noncirrhotic Naive, Cirrhotic Exp’d Noncirrhotic Exp’d, Cirrhotic Naive, Noncirrhotic Naive, Cirrhotic Exp’d Noncirrhotic Exp’d, Cirrhotic Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.

  39. LONESTAR-2: Sofosbuvir + P/R for 12 Wks in Treatment-Exp’d GT2/3 HCV Pts • Single-arm trial of pts with treatment failure on P/R • Approximately 50% with compensated cirrhosis Cirrhosis No cirrhosis 100 100 93 83 83 Wk 12 80 Pts with GT2 or GT3 HCV and previous treatment failure with P/R(N = 47) 60 Sofosbuvir 400 mg/day + PegIFN180 µg once wkly +RBV 1000 mg or 1200 mg/day SVR12 (%) 40 20 9/ 9 13/ 14 10/ 12 10/ 12 n/N = 0 GT2 GT3 Lawitz E, et al. AASLD 2013. Abstract LB-4.

  40. Anticipated Changes in HCV Therapy • All-oral regimens will be the standard of care by end of 2014 for all genotypes • Excellent efficacy in pts with compensated cirrhosis • More data required in pts with decompensated cirrhosis

  41. On-Treatment Monitoring: GT1 With Cirrhosis • Safety data from phase II/III studies suggest no difference in monitoring required for patients with CTP class A cirrhosis • Assessments for drug-related adverse events should be conducted more frequently if clinically indicated (eg, CBC count for patients receiving RBV) *If using a 24-wk treatment option. AASLD/IDSA HCV Management Guidance. October 2014.

  42. On-Treatment Monitoring: GT2 With Cirrhosis • Safety data from phase II/III studies suggest no difference in monitoring required for patients with CTP class A cirrhosis • Assessments for drug-related adverse events should be conducted more frequently if clinically indicated (eg, CBC count for patients receiving RBV) *Previous nonresponders to pegIFN/RBV with cirrhosis may benefit from extending treatment to 16 wks. AASLD/IDSA HCV Management Guidance. October 2014.

  43. On-Treatment Monitoring: GT3 With Cirrhosis • Safety data from phase II/III studies suggest no difference in monitoring required for patients with CTP class A cirrhosis • Assessments for drug-related adverse events should be conducted more frequently if clinically indicated (eg, CBC count for patients receiving RBV) AASLD/IDSA HCV Management Guidance. October 2014.

  44. Triple DAA Therapy With Paritaprevir/ Ritonavir/Ombitasvir + Dasabuvir + RBV • Paritaprevir is a potent NS3/4A protease inhibitor • Ritonavir boosting of paritaprevir increases the peak, trough, and overall drug exposures of paritaprevir to enable once-daily dosing • Ombitasvir is a potent NS5A inhibitor • Dasabuvir is a nonnucleoside NS5B polymerase inhibitor

  45. TURQUOISE II: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV in Cirrhotic GT1 Pts • Open-label phase III trial • Inclusion criteria: GT1, compensated cirrhosis (CTP class A), DAA naive, radiographic ascites and varices permitted, serum albumin ≥ 2.8 g/dL, total bilirubin < 3 mg/dL, serum AFP ≤ 100 ng/mL, INR ≤ 2.3, platelets ≥ 60,000 cells/mL Wk 24 Wk 12 Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 208) DAA-naive cirrhotic pts with GT1 HCV (N = 380) Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 172) Paritaprevir/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day. Poordad F, et al . N Engl J Med. 2014;370:1973-1982.

  46. TURQUOISE-II: ITT SVR12 P = .09 • Superiority threshold: 54%[1] • Noninferiority threshold: 43%[1] • High SVR12 rates regardless of sex, age, BMI, or baseline HCV RNA in subgroup analyses[2] • Pts with platelet counts < 100,000/mm3: 89% to 97% • Pts with serum albumin < 3.5 g/dL: 84% to 89% 96 100 92 80 60 SVR12 (%) 40 20 191/208 n/N = 165/172 0 12 wks 24 wks Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV 1. Poordad F, et al. N Engl J Med. 2014;370:1973-1982. 2. Fried MW, et al. AASLD 2014. Abstract 81. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.

  47. TURQUOISE II: SVR12 According to GT1 HCV Subtype and Treatment Experience • Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders GT1a GT1b 12 wks 100 93.3 100 100 92.9 100 100 100 100 85.7 100 100 100 24 wks 92.9 92.2 100 100 80.0 80 80 60 60 SVR12 (%) 40 40 20 20 3/3 22/22 18/18 6/7 10/10 25/25 20/20 14/14 59/64 52/56 14/15 13/13 11/11 10/10 40/50 39/42 n/N = 0 0 Naive Relapse PR Null Response Naive Relapse PR Null Response Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

  48. TURQUOISE-II: Laboratory Abnormalities • ALT elevation • Asymptomatic, transient, and improved or resolved with ongoing study drug dosing • Bilirubin elevation • Transient, predominantly indirect, no discontinuations due to hyperbilirubinemia • Hemoglobin decrease • Managed with reduction of ribavirin dose in 34 pts (8.9%) Poordad F, et al. EASL 2014. Abstract O163. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

  49. GT1 HCV SVR Summary: Treatment-Naive Patients With Cirrhosis COSMOS[1] ION-1[2] TURQUOISE-II[3] 100 100 100 100 100 97 97 95 94 100 80 67 60 SVR (%) 40 20 2/3 6/6 6/6 3/3 32/33 33/33 31/32 36/36 81/86 70/74 n/N = 0 SOF + SMV 12 Wks SOF + SMV + RBV 24 Wks SOF/ LDV 12 Wks SOF + SMV 24 Wks SOF/ LDV + RBV 12 Wks SOF/ LDV 24 Wks SOF + SMV + RBV 12 Wks SOF/ LDV + RBV 24 Wks 3DAA + RBV 12 Wks 3DAA + RBV 24 Wks 1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

  50. GT1 HCV SVR Summary: Treatment-Experienced Patients With Cirrhosis COSMOS[1] ION-2[2] TURQUOISE-II[3] 100 100 100 100 97 100 90 90 86 82 80 80 60 SVR (%) 40 20 9/ 10 110/ 122 95/ 98 19/22 18/22 22/22 22/22 4/4 4/5 4/4 n/N = 0 SOF + SMV 12 Wks SOF + SMV + RBV 24 Wks SOF/ LDV 12 Wks SOF + SMV 24 Wks SOF/ LDV + RBV 12 Wks SOF + SMV + RBV 12 Wks SOF/ LDV + RBV 24 Wks 3DAA + RBV 12 Wks 3DAA + RBV 24 Wks SOF/ LDV 24 Wks 1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

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