Can a One-Size-Fits-All Approach Be Applied to All Treatment-Naïve GT1 HCV Patients?

Transcription

1 Can a One-Size-Fits-All Approach Be Applied to All Treatment-Naïve GT1 HCV Patients? Ira M. Jacobson, MD Vincent Astor Distinguished Professor of Medicine Chief, Division of Gastroenterology and Hepatology Weill Cornell Medical College New York, New York

2 K.C., A Newly Diagnosed Patient With Hepatitis C Presentation K.C. is a 56-year old African American male; presents for evaluation of elevated ALT found on routine screening BMI = 32 kg/m 2 ; waist circumference is 38 He used IV drugs while in college Examination Notes HCV RNA is 8,400,000 copies/ml; genotype 1a FibroSURE score is 0.22, indicating stage 1/2 fibrosis ALT: alanine transaminase; BMI: body mass index; HCV: hepatitis C virus; IV: intravenous.

3 HCV Therapy: Past, Present, and Future Interferon Ribavirin Proof of concept for DAA (PI) Suppression of HCV with DAA combination (PI + NI) Telaprevir and boceprevir Frequent curability of diverse populations without IFN Daclatasvir (Japan and Europe) Ledipasvir + sofosbuvir Paritaprevir/rombitasvir/ dasabuvir ± RBV Simeprevir + sofosbuvir Daclatasvir + asunaprevir (GT1b) Pegylated IFNs Curability of HCV without IFN DAA: direct-acting antiviral; GT: genotype; IFN: interferon; PI: protease inhibitor; NI: nucleoside/nucleotide inhibitor; RBV: ribavirin; r: ritonavir. Simeprevir and sofosbuvir with IFN (GT1) First approved IFN-free therapy: sofosbuvir + RBV (GT2,3) Simeprevir + sofosbuvir (off-label use)

4 What s the Next Stage in the Evolution of HCV Treatment? / IFN monotherapy, wk IFN + RBV pegifn BOC: boceprevir; pegifn: pegylated interferon; SOF: sofosbuvir; SMV: simeprevir; SVR: sustained virologic response; TVR: telaprevir. pegifn + RBV pegifn SMV + RBV or + BOC/ SOF + TVR pegifn + RBV 1. Davis GL et al. N Engl J Med. 1989;321: Poynard T et al. N Engl J Med. 1995;332: McHutchison JG et al. N Engl J Med. 1998;339: Poynard T et al. Lancet 1998;352: Zeuzem S et al. N Engl J Med. 2000;343: Linsay KL et al. Hepatology. 2001;34: Pockros PJ et al. Am J Gastroenterol. 2004;99: Manns MP et al. Lancet. 2001;358: Fried MW et al. N Engl J Med. 2002;347: Poordad F et al. N Engl J Med. 2011;364: Jacobson IM et al. N Engl J Med. 2011;364: Simeprevir prescribing information, November Lawitz E et al. N Engl J Med. 2013;368: ; 14. Zeuzem S et al. Hepatology. 2013;58(Suppl 1):733A. 15. AbbVie press release Accessed October 22, Gilead press release Accessed October 22, Sulkowski MS et al. N Engl J Med. 2014;370: SOF + RBV DAA combos

5 Major Classes of Direct-Acting Antiviral Drugs NS3/4A Protease Inhibitors NS5A Inhibitors Nucleoside NS5B Polymerase Inhibitors Non-Nucleoside NS5B Polymerase Inhibitors Boceprevir Telaprevir Simeprevir Asunaprevir ABT-450 Vaniprevir Sovaprevir Danoprevir GS-9451 MK-5172 ACH-2684 ABT-493 Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5816 ABT-530 ACH-3102 Samatasvir PPI-668 Sofosbuvir VX-135 IDX21437 ACH-3422 Dasabuvir BMS GS-9669 Setrobuvir Adapted from Manns MP, von Hahn T. Nat Rev Drug Discov. 2013;12:

6 The Pillars of HCV DAA Therapy Viral suppression Prevention of resistance Sufficient duration of therapy

7 Approaches to Erecting a High Barrier to Resistance With DAA Therapy for HCV A combination of DAAs, each with a low resistance barrier, that collectively confer a high barrier to resistance on the regimen A combination containing a DAA with a high resistance barrier that confers a high resistance barrier on the regimen

8 Oral Regimens With 90% SVR for GT1 Patients No nucleotide Nucleotide PI NS5A PI NS5A NS5A Nuc PI Nuc NNI RBV NNI ± RBV ± RBV PI* NS5A* NNI Nuc RBV ± RBV * Second generation. NS5A: NS5A (replication complex) inhibitor; NNI: non-nucleoside inhibitor; Nuc: nucleotide inhibitor.

9 Increasing Treatment Options, But What Defines the Ideal Therapy? Efficacy Safety and tolerability Adherence High efficacy across all patient groups GT1a/GT1b IL28B CC/non-CC Naïve/experienced ± cirrhosis Forgiving PK No baseline resistance or no impact on regimen if present Manageable AEs No or low rate of serious AEs Minimal treatmentlimiting side effects Manageable DDIs Easy to take Minimal restrictions Low pill burden Once or twice a day AEs: adverse events; DDIs: drug-drug interactions; PK: pharmacokinetics.

10 Why One Regimen May Not Fit All Potential Considerations Different combinations may be needed for different patients Longer duration of treatment may be necessary for some patients Not all patients may be candidates for ultra-short treatment duration

11 SAPPHIRE-I: Paritaprevir-Ritonavir-Ombitasvir/ Dasabuvir (3D) + RBV Genotype 1, treatment naïve, noncirrhotic, 12 weeks, n = SVR12, % 455/ / /151 Feld JJ et al. N Engl J Med. 2014;370:

12 SAPPHIRE-I: SVR12 for 3D + RBV According to Subgroup Genotype 1, treatment naïve, 12 weeks, n = 473 SVR12, % Male Female Black Non-black <55 >55 <30 >30 F0-2 F3 CC Non-CC <800K >800K Yes No Feld JJ et al. N Engl J Med. 2014;370:

13 SAPPHIRE-I: Adverse Events Occurring in >10% of Patients in Either Group Event, n (%) 3D + RBV (n = 473) Placebo (n = 158) P Value Any AE a 414 (87.5) 116 (73.4) <.05 Fatigue 164 (34.7) 45 (28.5) NS Headache 156 (33.0) 42 (26.6) NS Nausea 112 (23.7) 21 (13.3) <.05 Pruritus 80 (16.9) 6 (3.8) <.05 Insomnia 66 (14.0) 12 (7.6) <.05 Diarrhea 65 (13.7) 11 (7.0) <.05 Asthenia 57 (12.1) 6 (3.8) <.05 Rash 51 (10.8) 9 (5.7) NS a AEs were generally mild. Feld JJ et al. N Engl J Med. 2014;370:

14 SAPPHIRE-I: Study Drug Discontinuation Due to Adverse Events and Serious Adverse Events 1,2 Study drug discontinuation due to AEs 3 of 473 patients (0.6%) discontinued study drug due to AEs in 3D + RBV group a Patient 1: Lobar pneumonia Patient 2: Acute respiratory failure and hypoxia Patient 3: Abdominal pain, sinus tachycardia, diarrhea, chills, vomiting, nausea, and ventricular extrasystoles Serious AEs 10 of 473 patients (2.1%) experienced serious AEs in the 3D + RBV group 2 patients had serious AEs considered possibly related to 3D treatment by the investigator (Patients 2 and 3 above) a Patient 1 achieved SVR12 after discontinuing at week 11; patients 2 and 3, who discontinued at day 12 and day 1, respectively, did not achieve SVR Feld JJ et al. N Engl J Med. 2014;370: Feld JJ. The International Liver Congress 2014, 49th annual meeting of the European Association for the Study of the Liver (EASL 2014). Oral abstract O60.

15 SAPPHIRE-I: Laboratory Abnormalities Event, n (%) AST: aspartate transaminase; EPO: erythropoietin. Feld JJ. EASL Oral abstract O60. 3D + RBV (n = 469) ALT >5X ULN 4 (0.9) AST >5X ULN 3 (0.6) Alkaline phosphatase >5X ULN 0 Total bilirubin >3X ULN 13 (2.8) Hemoglobin < g/dl 27 (5.8) < g/dl 0 <6.5 g/dl 0 There were no discontinuations due to laboratory abnormalities Elevations in total bilirubin were mainly transient and predominantly indirect bilirubin; no cases consistent with Hy s law 1 patient received EPO; no patient was transfused RBV dose was modified due to AE(s) in 26 (5.5%) 3D + RBV recipients

16 PEARL-IV: 3D ± RBV in Genotype 1a Patients Genotype 1a, noncirrhotic, treatment naïve, 12 weeks SVR12, % Ferenci P et al. N Engl J Med. 2014;370:

17 PEARL-III: 3D ± RBV in Genotype 1b Patients Genotype 1b, noncirrhotic, treatment-naïve, 12 weeks SVR12, % Ferenci P et al. N Engl J Med. 2014;370:

18 Resistance-Associated Variants (RAV) Present at Time of Virologic Failure in Patients Receiving 3D + RBV SAPPHIRE-I 1 Virologic failure occurred in 8/473 (1.7%) patients; each of these patients had at least 1 RAV 0.2% breakthrough rate 1.5% relapse rate SAPPHIRE-II 2 Virologic failure occurred in 7/297 (2.4%) patients; 5 of these patients had at least 1 RAV No patient had breakthrough and 2.4% of patients had a relapse 1. Feld JJ et al. N Engl J Med. 2014;370: Ferenci P et al. N Engl J Med. 2014;370:

19 ION-1: Sofosbuvir + Ledipasvir ± RBV for 12 vs 24 Weeks Genotype 1, treatment naïve, n = 865 Cirrhosis in 16% SVR12, % weeks LDV: ledipasvir. Afdhal N et al. N Engl J Med. 2014;370: weeks

20 ION-1: Rates of SVR According to Subgroup Afdhal N et al. N Engl J Med. 2014;370:

21 ION-1: Reasons for Failure to Attain SVR 12 weeks 24 weeks On treatment failure SOF/LDV SOF/LDV + RBV SOF/LDV SOF/LDV + RBV a 0 Relapse Lost to follow-up Withdrew consent a Undetectable drug levels. Afdhal N et al. N Engl J Med. 2014;370:

22 ION-1: Safety and Tolerability a 12 weeks, % 24 weeks, % LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV D/C for AEs Serious AEs < Fatigue Insomnia Nausea Cough Rash Pruritus Anemia Hb <10 g/dl Bilirubin >2.5x 0 4 <1 3 a List of AEs is not all inclusive. D/C: drug discontinued; Hb: hemoglobin. Afdhal N et al. N Engl J Med. 2014;370:

23 ION-3: Ledipasvir + Sofosbuvir ± RBV for 8 vs 12 Weeks Genotype 1, treatment naïve, noncirrhotic SVR12, % 202/ / /216 8 weeks 12 weeks Kowdley K et al. N Engl J Med. 2014:370:

24 Does ION-3 Establish 8 Weeks as Standard Duration for GT1 Noncirrhotic Patients? LDV/SOF 8 weeks LDV/SOF 12 weeks SVR overall 94% (202/215) 96% (208/216) Relapse overall 5% (11/215) 1% (3/216) HCV RNA <6 M 2% (2/123) 2% (2/131) HCV RNA 6 M 10% (9/92) 1% (1/85) 59% of patients had baseline HCV RNA <6 M IU/mL Relapse rates identical SVR12: 97% with LDV/SOF 8 weeks, 96% with 12 weeks 8 weeks LDV/SOF can be considered for patients with baseline HCV RNA <6M IU/mL Harvoni (ledipasvir and sofosbuvir) Prescribing Information. medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed October 22, 2014.

25 Resistance Data From the ION Studies Treatment naïve, genotype 1 ION-1 1 ION-3 2 Baseline NS5A variants in 140/861 (16%) by deep sequencing 96% had SVR 2 relapsers, 1 breakthrough: all 3 had NS5A RAVs at relapse Both relapsers had NS5A RAVs at baseline Viral breakthrough: no NS5A RAVs at baseline Baseline NS5A variants in 116/647 (18%) by deep sequencing 90% had SVR 23 relapsers: 15 had NS5A RAVs at relapse 9 had NS5A RAVs at baseline 1. Afdhal N et al. N Engl J Med. 2014;370: Kowdley K et al. N Engl J Med. 2014:370:

26 Daclatasvir + Sofosbuvir ± RBV DCV 60 mg, SOF 400 mg, RBV 1,000-1,200 mg GT1, naïve, noncirrhotic, 12 weeks a SVR12, % /41 39/41 DCV+SOF DCV+SOF+RBV a 1 missing at follow-up week, had SVR24; 1 lost to follow-up. DCV: daclatasvir. Sulkowski M et al. N Engl J Med. 2014;370:

27 Potential Drivers of Regimen Choices in GT1 Patients Need for ribavirin

28 K.C. Follow-Up and Conclusions K.C. s treatment options were discussed, including approved and emerging regimens Number of approved treatment options will vary across countries Access and price are relevant barriers in most healthcare systems

29 Overcoming Challenges in Treatment-Experienced Patients Stefan Zeuzem, MD Professor of Medicine Chief Department of Medicine Johann Wolfgang Goethe University Hospital Frankfurt, Germany

30 V.J., A Warehoused, Treatment-Experienced Patient With Hepatitis C Presentation V.J. is a 63-year-old Caucasian male Diagnosed with HCV 3 years ago Prior nonresponse with pegifn + RBV for 12 weeks Examination Notes: HCV RNA is 6,100,000 copies/ml HCV GT1b No cirrhosis

31 Management of Treatment Failures Peginterferon + ribavirin Peginterferon + ribavirin + protease inhibitor

32 COSMOS: SVR12 in Cohorts 1 and 2 by HCV Subgenotype and Baseline Q80K Cohort 1 (F0-F2 Nulls)* Cohort 2 (F3-F4 Naïves/Nulls)* weeks 12 weeks Overall 24 weeks 12 weeks Overall *Excluding patients who discontinued for nonvirologic reasons. Lawitz E et al. Lancet Jul 26. doi: /s (14) [Epub ahead of print].

33 SAPPHIRE-II: SVR12 Rates Paritaprevir-ritonavir-ombitasvir/dasabuvir (3D) + RBV for 12 weeks in treatment-experienced, GT1 patients (N = 297) SVR12, % SVR12, % Zeuzem S et al. N Engl J Med. 2014;370:

34 TURQUOISE-II: SVR12 Rates 3D + RBV for 12 or 24 weeks in naïve and treatment-experienced patients, GT1 with compensated cirrhosis Patients With SVR, % Poordad F et al. N Engl J Med. 2014;370:

35 TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a 3D + RBV SVR12, % ITT: intention to treat. Poordad F et al. N Engl J Med. 2014;370: HCV Subtype 1a

36 TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1b 3D + RBV SVR12, % Poordad F et al. N Engl J Med. 2014;370: HCV Subtype 1b

37 C-WORTHy: MK MK-8742 ± RBV SVR4/8 Rates GT1 previous null responders for 12 or 18 weeks Prior Null Responders With or Without Cirrhosis SVR4/8, % Discontinuation Lawitz E et al. EASL Abstract O61. FU4/8 Relapse Breakthrough

38 Management of Treatment Failures Peginterferon + ribavirin Peginterferon + ribavirin + protease inhibitor

39 ION-2 SVR12 Rates: PegIFN/RBV vs PI + PegIFN/RBV Failures Sofosbuvir/ledipasvir ± RBV for 12 or 24 weeks in GT1, treatment-experienced patients with or without cirrhosis Failed PegIFN/RBV SVR12, % weeks Afdhal N et al. N Engl J Med. 2014;370: weeks

40 Daclatasvir + Sofosbuvir for Previously Treated Chronic HCV Infection GT1 prior PI nonresponder: (80% GT1a) N = 41: DCV + SOF ± RBV for 24 weeks SVR12, % DCV 60 mg once daily, SOF 400 mg once daily ± RBV 1,000/1,200 mg/day Sulkowski et al. N Engl J Med. 2014;370:

41 HCV-TARGET: Patient Demographics SOF/PegIFN/RBV SOF/RBV SOF/SMV SOF/SMV/RBV Total Enrolled a (N = 366) (N = 645) (N = 697) (N = 205) (N = 1,913) Male 66% 64% 62% 64% 65% Age % 7% 3% 3% 6% % 73% 72% 79% 75% % 20% 25% 18% 19% Race/ethnicity White 70% 80% 73% 77% 75% Black 18% 6% 13% 16% 12% Treatment status Naïve 54% 56% 41% 37% 48% Experienced 46% 44% 59% 63% 52% DAA failure 13% 4% 7% 14% 8% a Total who started therapy.

42 V.J. Follow-Up and Conclusions The patient s treatment options were discussed, including approved regimens and available clinical trials Number approved treatment options will vary across countries The patient indicated he was open to participating in a clinical trial using experimental IFN-free regimen Management of treatment-experienced patients requires detailed information on previous drugs, treatment duration, adverse events, and RAVs Multiple treatment options for non-responders to pegifn/rbv with excellent chances for SVR Access and price are relevant barriers in most healthcare systems

43 How Can We Improve Care for the Patient With HIV/HCV Coinfection? Mark S. Sulkowski, MD Professor, Division of Infectious Diseases Medical Director for the Viral Hepatitis Center Johns Hopkins School of Medicine Baltimore, Maryland

44 S.G., An HIV/HCV Coinfected Patient With Liver Cirrhosis Presentation S.G. is a 61-year-old Caucasian male HIV antiretroviral regimen: atazanavir/ritonavir + tenofovir DF/ emtricitabine Examination Notes: HIV-1 RNA <50 copies/ml HCV RNA is 4,600,000 copies/ml HCV GT1a Abdominal ultrasound revealed no cirrhosis DF: disoproxil fumarate; HIV: human immunodeficiency virus.

45 SVR Is Associated With Improved Survival in HIV/HCV Coinfected Patients Limketkai et al. JAMA. 2012;308:

46 PHOTON-1: Open-Label Trial of Sofosbuvir/Ribavirin in HIV/HCV Coinfected Patients Wk 12 Wk 24 Week 4 EOT SVR12 SVR24 Naïve Naïve GT1 SOF + RBV (n = 114) GT2/3 SOF + RBV (n = 68) GT GT GT Experienced GT2/3 SOF + RBV (n = 41) GT GT EOT: end of treatment. Sulkowski MS et al. JAMA. 2014;312:

47 PHOTON-1: Safety Summary Patients on SOF + RBV, % 24 Weeks (n = 155) 12 Weeks (n = 68) AEs AEs in 10% of patients Fatigue Insomnia Headache Nausea Diarrhea 11 9 Irritability Upper RTI Grade 3-4 AEs Serious AEs 6 7 Treatment D/C due to AEs a 3 4 Death 0 1 b a Weight loss, insomnia/agitation, suicide attempt, increased anxiety, pneumonia, foreign body sensation in throat, dyspnea. b Suicide 9 days after completing study tx; patient had history of depression. RTI: respiratory tract infection. Sulkowski MS et al. JAMA. 2014;312:

48 PHOTON-2: SOF/RBV in HIV/HCV Coinfected Patients Naïve Naïve Experienced Wk 12 Wk 24 GT1/3/4 SOF + RBV (n = 200) GT2 SOF + RBV (n = 19) GT2/3 SOF + RBV (n = 55) SVR12 GT1 85 GT3 91 GT4 84 GT2 89 GT2 83 GT3 86 SVR12 at 24 Wk in GT1 Treatment-Naïve Patients ±Cirrhosis SVR, % No Cirrhosis Cirrhosis GT GT1a GT1b Molina et al. 20th International AIDS Conference (AIDS 2014). Abstract MOAB0105LB.

49 TURQUOISE-I: Paritaprevir-Ritonavir-Ombitasvir/ Dasabuvir (3D) + RBV in HCV and HIV-1 Coinfection Open-label treatment 3D + RBV (N = 31) 3D + RBV (N = 32) SVR12 SVR4 All patients will be followed for 48 weeks after HCV treatment end Day 1 Week 12 Week 24 Week 36 Key Eligibility Criteria: HCV GT1 infection, HCV treatment-naïve or peg- IFN/RBV-experienced, Child-Pugh A Cirrhosis allowed, stable HIV-1 infection on ATV or RAL-inclusive ART regimen ART: antiretroviral; RAL: raltegravir. Sulkowski et al. AIDS Abstract MOAB0104LB.

50 TURQUOISE-I Results: Virologic Response Rates Patients, % D + RBV Regimen 12-week arm 24-week arm RVR EOTR SVR4 SVR12 (Week 4) (Week 12 or 24) EOTR: virologic response at end-of-treatment; RVR: rapid virological response. Sulkowski et al. AIDS Abstract MOAB0104LB.

51 TURQUOISE-I: Treatment-Emergent Adverse Events Event, n (%) 12-Week Arm (N = 31) 24-Week Arm (N = 32) Any AE 28 (90.3) 28 (87.5) Fatigue 18 (58.1) 12 (37.5) Insomnia 5 (16.1) 7 (21.9) Nausea 5 (16.1) 6 (18.8) Headache 6 (19.4) 4 (12.5) Upper RTI 4 (12.9) 5 (15.6) Pruritus 6 (19.4) 2 (6.3) Cough 2 (6.5) 5 (15.6) Ocular icterus 5 (16.1) 1 (3.1) Diarrhea 1 (3.2) 4 (12.5) The majority of adverse events were mild or moderate in severity 5 severe adverse events were reported: insomnia, hypophosphatemia, disseminated herpes zoster, tooth abscess, and vertigo No treatment-emergent serious adverse events were reported Sulkowski et al. AIDS Abstract MOAB0104LB.

52 C-WORTHy Study Design: MK MK-8742 ± RBV in GT 1 HIV/HCV-Infected Patients n = 29 MK MK RBV Follow-up n = 30 MK MK-8742 (no RBV) Follow-up Primary endpoint D1 TW2 TW4 TW8 TW12 SVR4 SVR12 SVR24 Sulkowski M et al. EASL Abstract #O63.

53 MK MK-8742 ± RBV in GT 1 HIV/HCV-Infected Patients (C-WORTHy): Interim Virological Response a Virologic Failures: 1 relapse in +RBV arm; 2 breakthrough and 1 lost to follow-up in no-rbv arm a One patient has not yet reached FU4. Sulkowski M et al. EASL Abstract #O63.

54 Drug Interactions HCV DAAs and HIV ART Are the Remaining Challenge Drug interactions are expected and must be investigated for all HCV regimens CYP3A4 inhibition (ritonavir); induction (efavirenz) Must study the DAA regimen + ART regimen in healthy volunteers However, long-term adherence to ART/clinic visits also demonstrate ability to adhere to HCV therapy

55 DDI Example: Simeprevir and Antiretroviral Drugs Interaction With Simeprevir (SMV) DRV/r EFV ETR, NVP EVG/cobi/TDF/FTC May increase SMV concentration Significant reduction in SMV exposure Reduction in SMV exposure expected Increase in SMV exposure expected All other HIV PIs not evaluated in PK studies, but likely similar to DRV/r TDF; RPV; RAL no significant PK interactions have been identified to date DTG not evaluated in PK studies, but not expected to alter the PK of SMV; SMV not expected to alter PK of DTG cobi: cobicistat; DRV/r: darunavir/ritonavir; DTG: dolutegravir; EFV: efavirenz; ETR: etravirine; EVG: elvitegravir; FTC: emtricitabine; NVP; nevirapine; RPV: rilpivirine; TDF: tenofovir disoproxil fumarate.

56 Infection and/or Reinfection With DAA-Resistant HCV HIV-infected male partners (patients A and B) with documented infection and reinfection with telaprevirresistant HCV (V36M) Patient A early Patient A late Patient B early Patient B late * NS3 clones carrying resistance genotype. Franco et al. Gastroenterology. 2014;147:

57 S.G. Follow-Up and Conclusions HCV is a major cause of morbidity and mortality Clinical trial data indicate that HCV treatment with interferon-free regimens is promising High SVR rates Similar safety and tolerability Drug interaction between HIV and HCV treatment regimens must be considered S.G. s treatment options were discussed, including approved regimens and emerging IFN-free options

58 Optimizing SVR for Patients With HCV and Liver Cirrhosis Fred Poordad, MD Clinical Professor of Medicine Chief, Hepatology University of Texas Health Science Center VP, Academic and Clinical Affairs The Texas Liver Institute San Antonio, Texas

59 L.K., A Treatment-Experienced Patient With Hepatitis C and Compensated Cirrhosis Presentation L.K. is a 57-year-old Caucasian male Patient failed pegifn/rbv in past but details of treatment not available Examination Notes: HCV RNA is 6,800,000 copies/ml HCV GT1b Ultrasound of his liver demonstrated a nodular liver with mild splenomegaly

60 TURQUOISE II: 3D ± RBV in Patients With Compensated Cirrhosis 3D + RBV for 12 or 24 weeks in naïve and treatment-experienced patients, GT1 with compensated cirrhosis Patients With SVR, % Poordad F et al. N Engl J Med. 2014;370:

61 TURQUOISE-II: SVR12 by Genotype Arm A: 12-week regimen Arm B: 24-week regimen SVR12, % GT1a GT1b Poordad F et al. N Engl J Med. 2014;370:

62 TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a 3D + RBV SVR12, % Poordad F et al. N Engl J Med. 2014;370: HCV Subtype 1a

63 TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1b 3D + RBV SVR12, % Poordad F et al. N Engl J Med. 2014;370: HCV Subtype 1b

64 TURQUOISE-II: Adverse Events Occurring in >10% of Patients in Either Group Event, % Poordad F et al. N Engl J Med. 2014;370: D + RBV x 12 weeks (n = 208) 3D + RBV x 24 weeks (n = 172) Any AE AE leading to stopping study drug Any serious AE Most common AE Fatigue Headache Nausea Pruritus Insomnia Diarrhea Asthenia Rash Irritability Anemia Dyspnea

65 ION-1: Noncirrhotic vs Cirrhotic Patients 1,2 SVR12, % 179/180 32/34 178/184 33/33 181/184 31/33 179/181 36/36 12 weeks 24 weeks 1. Afdhal N et al. N Engl J Med. 2014;370: Mangia A et al. EASL Oral abstract LB O164.

66 ION-1: Noncirrhotic vs Cirrhotic Patients (Cont d) Excludes Withdrawn Consent or Lost to Follow-Up SVR12, % 179/179 32/33 178/184 33/33 181/182 31/32 179/179 36/36 12 weeks 24 weeks 1. Afdhal N et al. N Engl J Med. 2014;370: Mangia A et al. EASL Oral abstract LB O164.

67 ION-2: Impact of Cirrhosis on SVR12 Rates Sofosbuvir/ledipasvir ± RBV for 12 or 24 wk in GT1, treatment-experienced patients with or without cirrhosis (N = 440) 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 Afdhal N et al. N Engl J Med. 2014;370: weeks 24 weeks

68 COSMOS: SMV/SOF ± RBV for 12 vs 24 Weeks SVR12 in F3-F4 naïve patients SVR12, % Weeks 24 Weeks /12 6/ /13 8/8 0 SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOF Lawitz E et al. Lancet July 26. doi: /S (14) [Epub ahead of print].

69 C-WORTHy: SVR4/8 Rates MK MK-8742 ± RBV for 12 or 18 wk in GT1, cirrhotic patients (n = 121) and previous null responders (n = 127) Lawitz E et al. EASL Abstract O61.

70 C-WORTHy: Adverse Events AEs, n (%) Treatment-Naive With Cirrhosis With RBV (n = 63) No RBV (n = 63) Null Responders ± Cirrhosis With RBV (n = 63) No RBV (n = 63) Any serious AE, n (%) 1 (2) 2 (3) 2 (3) 2 (3) AE leading to discontinuation, n (%) Laboratory abnormalities, n (%) 2 (3) 0 1 (2) 0 Hemoglobin <10 g/dl 8 (13) 0 4 (6) 0 Hemoglobin <8.5 g/dl 1 (2) Total bilirubin >2 x ULN 6 (10) 0 9 (14) 3 (5) Total bilirubin >5 x ULN ALT/AST >2 x ULN* 0 2 (3) 1 (2) 3 (5) ALT/AST >5 x ULN* (2) 0 * After initial normalization. Lawitz E et al. EASL Abstract O61.

71 L.K. Follow-Up and Conclusions L.K. s treatment options were discussed, including approved regimens and emerging IFN-free options Cirrhosis: when present, are those patients most in need of treatment today

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