Curing Hepatitis C in 2015

Transcription

1 Curing Hepatitis C in 2015 K. Rajender Reddy M.D. Ruimy Family President s Distinguished Professor of Medicine Director of Hepatology Director, Viral Hepatitis Center Medical Director, Liver Transplantation University of Pennsylvania

2 Global Distribution and Prevalence of HCV Genotypes Messina JP et al, Hepatology, 2015; 61:

3 Cure Rates for Chronic Hepatitis C Therapy Peginterferon 2001 Direct Acting Antivirals Protease inhibitor 2011 Nucleoside inhibitor 2013 >90% SVR (%) Standard Interferon 1991 Ribavirin % 42% 55% >70% 6% 16% 6 Months IFN 12 Months 6 Months IFN + RBV 12 Months 12 Months PegIFN + RBV 6-12 Months PegIFN+ RBV+PI 8-12 weeks IFN-Free

4 SVR is Associated with Reduced Mortality Among HCV-infected Persons 530 adults in Europe prospectively followed for median 8.4 years after HCV treatment 192 (36%) achieved SVR All-cause mortality y, % P<0.001 All-cause mortality Without SVR Time, y With SVR No. at risk Without SVR With SVR Liver-related mortalit ty or liver transplantation, % P<0.001 Liver-related mortality or liver transplantation Without SVR Time, y With SVR No. at risk Without SVR With SVR Van der Meer AJ, et al. JAMA. 2012:308:

5 Interferon Back bone of HCV Therapy Recombinant Interferon An Obituary

6 Multiple Validated Drug Targets in UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B p7 4A 3 UTR Protease HCV PIs inhibitors Simeprevir Paritaprevir Protease NS5A Inhibitors Ledipasvir Daclatasvir Ombitasvir NS5B Nucs Sofosbuvir Polymerase NS5B Non-nucs Dasabuvir Regimens in Use DAA Class SVR (G1) PEG/RBV + sofosbuvir NUC 90% Sofosbuvir + RBV NUC 70% Current In EU Sofosbuvir + simeprevir NUC + PI >90% Sofosbuvir + ledipasvir NUC + NS5A Inhibitor >90% Paritaprevir+ Ombitasvir+ Dasabuvir +/- RBV PI + NS5B + NNI >90% Sofosbuvr + daclatasvir NUC + NS5A Inhibitor >90%

7 Pill Burden in HCV Therapy Fixed Dose Combination Ledipasvir/Sofosbuvir-approved Grazoprevir and Elbasvir Sofosbuvir and GS DAA Regimen -approved Paritaprevir/r/Ombitasvir +Dasabuvir Phase III Simeprevir plus Sofosbuvir Daclatasvir and Sofosbuvir Asunaprevir+ Daclatasvir+BMS Ribavirin 5-6 pills a day

8 Treatment Duration for Sofosbuvir and Ledipasvir Patient Population Treatment-naïve with or without cirrhosis Treatment-experienced** without cirrhosis Treatment-experienced** with cirrhosis Recommended Treatment Duration 12 weeks* 12 weeks 24 weeks * Treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL can be treated with 8 weeks of therapy ** Treatment-experienced patients who previously failed treatment with either PEG/RBV or a PI/PEG/RBV Ledipasvir/sofosbuvir (HARVONI ) Prescribing Information. Gilead Sciences, Foster City, CA. October, 2014.

9 Sofosbuvir (NUC) + Ledipasvir (NS5A) in G1 Insights on Treatment Duration and Role of Ribavirin ION-1 Treatment Naïve ~16% w/cirrhosis N=214 N=217 N=217 0 Weeks SOF + LDV SOF + LDV + RBV SOF + LDV SVR 99% 97% 98% N=217 SOF + LDV + RBV 99% ION-2 N=109 SOF + LDV 94% Treatment Experienced ~20% w/cirrhosis N=111 N=109 SOF + LDV + RBV SOF + LDV 96% 99% N=111 SOF + LDV + RBV 99% Afdhal N et al. N Engl J Med. 2014;370: ; Afdhal N et al. N Engl J Med. 2014;370:

10 Sofosbuvir (NUC) + Ledipasvir (NS5A) in Genotype 1: ION-2 Special Subgroups ION-2 N=22 SOF + LDV 86% Treatment Experienced Cirrhosis N=22 N=22 SOF + LDV + RBV SOF + LDV 82% 100% 100% N=22 100% SOF + LDV + RBV ION-2 N=66 SOF + LDV 94% Treatment Experienced PI Failures N=64 N=50 SOF + LDV + RBV SOF + LDV 97% 98% N=51 SOF + LDV + RBV 100% Afdhal N et al. N Engl J Med. 2014;370:

11 Sofosbuvir (NUC) + Ledipasvir (NS5A) in Genotype 1: Shorter Duration Is Possible 0 Weeks 8 12 SVR ION-3 1 Treatment Naïve No cirrhosis N=215 N=216 N=216 SOF + LDV SOF + LDV + RBV SOF + LDV 94% 93% 96% 1. Kowdley KV et al. N Engl J Med. 2014;370(20): ;

12 8 Weeks as Standard Duration for G1 Noncirrhotics LDV/SOF 8 weeks LDV/SOF 12 weeksa SVR - overall 94% (202/215) 96% (208/216) Relapse - overall 5% (11/215) 1% (3/216) HCV RNA < 6M 2% (2/123) 2% (2/131) HCV RNA > 6M 10% (9/92) 1% (1/85) ~60% of patients had baseline HCV RNA < 6M IU/ml Relapse rates identical SVR12: 97% with LDV/SOF 8 weeks, 96% 12 weeks Package Insert for Havroni (LDV/SOF); Kowdley K et al, NEJM 2014

13 LDV/SOF in Cirrhotic Patients Who Previously Failed PI-Based Triple Therapy Double-blind, placebo-controlled study in cirrhotic GT1 patients who failed both PegIFN+RBV and PI+PegIFN+RBV regimens in France (null or partial responders) Wk 0 Wk 12 Wk 24 N=77 LDV/SOF + Placebo (RBV) N=77 Placebo LDV/SOF + RBV 30% of patients were previously enrolled in the CUPIC cirrhotic study RBV dosing was weight-based (<75 kg = 1000 mg; 75 kg = 1200 mg) Randomization was stratified by: HCV genotype 1a vs. 1b (mixed or other GT 1 results stratified as GT 1a) Prior HCV therapy treatment response Never achieved HCV RNA <LLOQ vs. Achieved HCV RNA <LLOQ Cirrhosis was determined by: Biopsy, Fibroscan >12.5 kpa, or FibroTest score of >0.75 AND an AST:platelet ratio index (APRI) of >2 Bourliere, AASLD, 2014, Oral #LB-6

14 Retreatment of Cirrhotic Patients Who Failed Both PegIFN+RBV and PI+PegIFN+RBV LDV/SOF in TE Cirrhotic Patients: SVR SV VR12, % /77 LDV/SOF+RBV 12 Weeks 75/77 LDV/SOF 24 Weeks Error bars represent 95% confidence intervals. TE cirrhotics had a similar response to LDV/SOF+RBV for 12 weeks and LDV/SOF for 24 weeks Bourliere, AASLD, 2014, Oral #LB-6

15 LDV/SOF ± RBV: Compensated Cirrhosis Integrated Analysis of 5 Studies: SVR12 by Treatment Duration LDV/SOF ± RBV, N= SVR12 (% %) / / Weeks 24 Weeks SVR rates were similar with 12 or 24 weeks of LDV/SOF ± RBV Error bars represent 95% confidence intervals. Reddy KR et al Hepatology ( in press)

16 LDV/SOF ± RBV: Compensated Cirrhosis Results: SVR12 by Treatment Regimen Overall SVR wk wk Duration 24 wk Treatment Naïve 98% 97% 99% Treatment Experienced 95% 94% 98% Regimen LDV/SOF LDV/SOF + RBV 96% 99% 95% 96% LDV/SOF 12 wk 96% 90% Duration/± RBV LDV/SOF + RBV 12 wk LDV/SOF 24 wk 98% 97% 96% 98% LDV/SOF + RBV 24 wk 100% 100% Among TE cirrhotic patients, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone 16 Reddy KR et al Hepatology ( in press)

17 Treatment Recommendations for 3 DAA Regimen Patient Population Treatment* Recommended Duration Treatment naïve and experienced Genotype 1a without cirrhosis Treatment naïve and experienced Genotype 1a with cirrhosis paritaprevir/ritonavir/ombitasvir and dasabuvir + ribavirin paritaprevir/ritonavir/ombitasvir and dasabuvir + ribavirin 12 weeks 24 weeks** Treatment naïve and paritaprevir/ritonavir/ombitasvir 12 weeks experienced Genotype 1b without cirrhosis Treatment naïve and experienced Genotype 1b with cirrhosis and dasabuvir paritaprevir/ritonavir/ombitasvir and dasabuvir + ribavirin 12 weeks *Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection **VIEKIRA PAK administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history Paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekira Pakl ) Prescribing Information. AbbVie Inc., North Chicago, IL. Febraury 2015.

18 Paritaprevir/r (PI) + Ombitasvir(NS5A) + Dasabuvir (NNI) + RBV SAPPHIRE-1 Treatment Naïve 0% w/cirrhosis 1 N=473 0 Weeks 12 Paritaprevir/r + Ombitasvir + Dasabuvir+ RBV 24 SVR 96% SAPPHIRE-2 Treatment Experienced 0% w/cirrhosis 2 N=297 Paritaprevir/r + Ombitasvir + Dasabuvir+ RBV 96% 1. Feld JJ et al. N Engl J Med. 2014;370(17): ; 2. Zeuzem S et al. N Engl J Med. 2014:370: ;

19 3 DAA Regimen in Treatment Naïve and Treatment Experienced Cirrhosis P= SVR12, % Pa atients Superiority threshold: 54% Non-inferiority threshold: 43% 0 191/ Weeks 3D + RBV 165/ Weeks 3D + RBV Poordad F et al. N Engl J Med. 2014; 370(21):

20 ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a D + RBV 12-week arm 24-week arm SVR12, % Patients /64 52/56 14/15 13/13 11/11 10/10 40/50 39/42 Naïve Prior Relapse Response HCV Subtype 1a Prior Partial Response Prior Null Response Poordad F et al. N Engl J Med. 2014; 370(21):

21 ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1b D + RBV 12-week arm 24-week arm SVR12, % Patients /22 18/18 25/25 20/20 6/7 3/3 14/14 10/10 Naïve Prior Relapse Response HCV Subtype 1b Prior Partial Response Prior Null Response Poordad F et al. N Engl J Med. 2014; 370(21):

22 Treatment-Naïve, Prior Relapsers and Non- TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 2 Treatment-Naïve, Prior Relapsers and Non- Responders

23 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 2 Chronic HCV Patients with GT 2 HCV: Initial Treatment & Retreatment of Relapsers* Recommended Therapy, Regardless of Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 12 weeks Alternative Therapy, Regardless of Eligibility for Interferon Therapy None Not Recommended Peginterferon + Ribavirin x 24 weeks Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Any Regimen with Telaprevir, Boceprevir, or Simeprevir *Patients who experienced relapse after Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014 Hepatitis web study

24 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 2 Chronic HCV Patients with GT 2 HCV: Retreatment of Prior Nonresponders* Recommended Therapy Sofosbuvir + Ribavirin x 12 weeks^ Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Recommended Peginterferon + Ribavirin +/- [Telaprevir, Boceprevir, or Simeprevir] Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Treatment of Decompensated Cirrhosis with Peginterferon *Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy ^Patients with cirrhosis may benefit by extension of therapy to 16 weeks Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014 Hepatitis web study

25 Sofosbuvir and Ribavirin for HCV Genotype 2 Treatment naive Treatment experienced No cirrhosis No cirrhosis SVR12 (%) Cirrhosis SVR12 (%) Cirrhosis /26 6/10 23/23 7/9 30/33 7/8 68/7010/11 29/30 2/2 0 FISSION POSITRON VALENCE FUSION FUSION VALENCE 12 weeks 12 weeks 12 weeks 12 weeks 16 weeks 12 weeks >80% naive

26 Treatment-Naïve, Prior Relapsers and Non- TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 3 Treatment-Naïve, Prior Relapsers and Non- Responders

27 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 3 Chronic HCV Patients with GT 3 HCV: Initial Treatment & Retreatment of Relapsers* Recommended Therapy, Regardless of Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 24 weeks Alternative Therapy, Eligible for Interferon Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Recommended Peginterferon + Ribavirin x weeks Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Any Regimen with Telaprevir, Boceprevir, or Simeprevir *Patients who experienced relapse after Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014

28 Sofosbuvir + Ribavirin For Genotype 3 VALENCE: 24 weeks, n= No cirrhosis Cirrhosis /92 2/13 87/100 28/45 Naïve Experienced Implication: SOF+RBV suboptimal for genotype 3 Zeuzem S et al, N Engl J Med 2014;370:

29 Sofosbuvir + PEG-IFN + RBV in Genotype 3 Treatment-Experienced Patients SOF 400 mg QD + PEG-IFN + RBV mg for 12 weeks 100 SVR12 (%) /12 10/12 No cirrhosis Cirrhosis Lawitz E, et al. AASLD 2013, Abstract #LB-4.

30 Treatment Outcomes With Daclatasvir + Sofosbuvir in HCV Genotype 3 No virologic breakthroughs Virologic relapse (n=16) Cirrhosis (n=11) Y93H at relapse (n=9) Generally safe and well tolerated No discontinuations due adverse events Further options for optimizing SVR rates with daclatasvir + sofosbuvir in genotype 3 patients with cirrhosis are being evaluated SVR12 (%) Treatment-naïve 90% 86% SVR12 Treatment-experienced 97% 94% 58% 69% 0 Overall (n=101/51) No (n=75/34) Cirrhosis Yes (n=19/13) Nelson DR, et al. Hepatology. 2014;60(suppl 1). Abstract LB-3.

31 SVR12 Rates: Sofosbuvir + GS RBV in Treatment- Experienced HCV Patients (Genotype 3) No Cirrhosis With Cirrhosis % 96% 100% 100% % 88% 96% SVR12 (% %) SVR12 (% %) % Relapse (n=4) Relapse (n=1) No Relapse No Relapse Relapse (n=11) Relapse (n=3) Relapse (n=3) Relapse (n=1) 0 No RBV (n=26) RBV (n=28) No RBV (n=27) RBV (n=26) 0 No RBV (n=26) RBV (n=25) No RBV (n=26) RBV (n=26) Sofosbuvir + GS mg Sofosbuvir + GS mg Sofosbuvir + GS mg Sofosbuvir + GS mg Pianko S, et al. Hepatology. 2014;60(suppl 1):297A-298A. Abstract 197.

32 SOF/RBV/PegIFN for 12 Weeks vs. SOF/RBV for 16 or 24 Weeks in GT 2 or 3 Wk n=196 SOF + RBV SVR12 n=199 SOF + RBV SVR12 n=197 SOF + PEG/RBV SVR12 SOF + RBV SOF + RBV SOF + PEG/RBV 16 weeks 24 weeks 12 weeks n=196 n=199 n=197 Total n=592 Mean age, y (range) 51 (20-69) 49 (23-71) 50 (19-73) 50 (19-73) Male, n (%) 134 (68) 129 (65) 132 (67) 395 (67) Asian, n (%) 28 (14) 26 (13) 25 (13) 79 (13) Mean BMI, kg/m 2 (range) 28 (18-50) 28 (18-55) 28 (19-45) 28 (18-55) IL28B CC, n (%) 75 (38) 73 (37) 78 (40) 226 (38) HCV genotype 3, n (%) 181 (92) 182 (92) 181 (92) 544 (92) Mean baseline HCV RNA, log 10 IU/mL (range) 6.3 ( ) 6.2 ( ) 6.3 ( ) 6.3 ( ) Treatment experienced, n (%) 105 (54) 105 (53) 103 (52) 313 (53) Cirrhosis, n (%) 72 (37) 73 (37) 74 (38) 219 (37) Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. LO5.

33 SVR SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks SVR12 (%) /15 17/17 15/16 128/ / /181 GT 2 GT 3 Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. LO5.

34 SVR12 By Prior Treatment and Cirrhosis SVR12 (%) No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Treatment Naïve Treatment Experienced Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. LO5.

35 Treatment-Naïve, Prior Relapsers and Non- TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 4 Treatment-Naïve, Prior Relapsers and Non- Responders

36 Pegylated Interferon, Sofosbuvir and RBV for 12 weeks n = 292 n = 28 n = 7 295/ /292 27/28 7/7 E. Lawitz et al, Abstract EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368:

37 U.S. GT 4 Egyptian Study (SOF+RBV) SOF+RBV for GT 4 HCV Randomized, open-label, single-center study conducted in the US of the safety and efficacy of alloral SOF + RBV in patients of Egyptian ancestry with HCV GT % cirrhotics; 52-55% treatment-experienced HCV GT 4 TN/TE Wk 0 Wk 12 Wk 24 SOF+RBV (n=31)* SOF+RBV (n=29)* SVR4 *SOF 400 mg/d; RBV mg/d SVR12 SVR4 Wk 36 Wk 48 SVR24 SVR12 SVR24 SOF+RBV was well-tolerated for up to 24 weeks of treatment No discontinuation due to AEs No Grade 4 AEs or lab abnormalities were reported No SOF resistance mutation S282T was found in any patient with virologic failure SVR12 (%) 11/14 14/14 10/17 13/15 12 Weeks SOF+RBV 24 Weeks SOF+RBV 12 Weeks SOF+RBV 24 Weeks SOF+RBV *1 patient had RBV D/C after Day 35 due to AE of dyspnea, and completed SOF 24 wk Ruane P, EASL, 2014, P1243 Treatment Naïve Treatment Experienced

38 100 SVR in GT4 Patients: 3 DAA regimen or Paritaprevir/r/ombitasvir+ RBV 80 Patie ents, % ,7 97, ,2 90,9 RVR SVR4 SVR Treatment Naïve Treatment Experienced Hézode, C. et al Lancet 2015.

39 SVR in GT4 Patients: Daclatasvir Based Regimen Null 90 77,3 100 Patients s, % Partial Cirrhosis SVR12 45, DCV+ASV+BCV 150mg , DVC+ASV+P/R Hassanein, T. et al. J Hepatology; Jensen, D. et al. J Hepatology

40 SVR in GT4 Patients Null Partial Cirrhosis SVR ,3 Patients, % , , DVC+ASV+P/R DCV+ASV+BCV 150mg Hassanein, T. et al. J Hepatology; Jensen, D. et al. J Hepatology

41 Next Wave of HCV Treatment

42 C-EDGE TN: Study Design n = 316 Grazoprevir (GZR) 100 mg + Elbasvir (EBR) 50 mg Follow-Up FUW12 n = 105 Placebo GZR 100 mg + EBR 50 mg D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16 Phase 3, randomized, placebo-controlled trial GZR/EBR fixed-dose combination tablet given once daily, without ribavirin, for 12 weeks After a 4-week follow-up period, placebo recipients were unblinded and received open-label GZR/EBR Stratification by cirrhosis and HCV geno/subtype Zeuzem S, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. G07.

43 C-EDGE TN: Results - SVR Patie ents, (%) /316 All Patients 144 / / /18 GT1a GT1b GT4 8 /10 GT6 Non-Virologic Failure Breakthrough Relapse Zeuzem S, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. G07.

44 C-SWIFT: Study Design All treatment arms: Grazoprevir 100 mg QD/Elbasvir 50 mg QD FDC + Sofosbuvir 400 mg QD Ge enotype 1 Genotype 3 Cirrhotic Noncirrhotic Noncirrhotic Cirrhotic 4 wk; n = 31 6 wk; n = 30 6 wk; n = 20 8 wk; n = 21 8 wk; n = wk; n = wk; n = 12 SVR12: Primary End Point D1 TW4 TW6 TW8 TW12 SVR4 SVR8 SVR12 Poordad F, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. O006.

45 C-SWIFT: SVR Results - HCV G1 Modified Intent To Treat Analysis SVR12 (% %, 95% CI) Treatment Duration * Weeks 6 Weeks 6 Weeks 8 Weeks Breakthrough Relapse Early discon Non-cirrhotic Cirrhotic Poordad F, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. O006.

46 C-SWIFT: SVR Results - HCV 3 Modified Intent To Treat Analysis HCV RNA <15 IU/mL (%, 95% CI) Treatment Duration Weeks 12 Weeks 12 Weeks Non-cirrhotic Cirrhotic Breakthrough Relapse Early discon * Poordad F, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. O006.

47 Gane: SOF/GS-5816 (2nd Gen NS5A Inhibitor) + GS-9857 (Protease Inhibitor): SVR12 in GT 1 Patients SVR12 Results (All failures due to relapse) SVR1 12 (%) Weeks Weeks 6 Weeks 6 Weeks Treatment Naïve No Cirrhosis Treatment Naïve No Cirrhosis Treatment Naïve Cirrhosis Prior DAA Failure ± Cirrhosis Gane E, et al. 50th EASL; Vienna, Austria; April 22-26, Abst. LP03.

48 Treatment Options for HCV Other NS5B Nonnucleoside Polymerase Inhibitor ± RBV NS5A Inhibitor ± RBV NS5B Nucleotide Polymerase Inhibitor ± RBV Platform Pangenotypic Protease Inhibitor ± RBV Interferon ± RBV Issues that may dictate treatment regimen 1. Treatment duration: 6,8,12 weeks 2. Genotype 1b vs 1a 3. Non-genotype 1 4. Cirrhosis 5. Race and ethnicity 6. IL28B status 7. Viral resistance 8. Cost

49 Treatment Options for HCV Other NS5B Nonnucleoside Polymerase Inhibitor ± RBV NS5A Inhibitor ± RBV NS5B Nucleotide Polymerase Inhibitor ± RBV Platform Pangenotypic Protease Inhibitor ± RBV Interferon ± RBV Issues that may dictate treatment regimen 1. Treatment duration: 6,8,12 weeks 2. Genotype 1b vs 1a 3. Non-genotype 1 4. Cirrhosis 5. Race and ethnicity 6. IL28B status 7. Viral resistance 8. Cost

50 Treatment Options for HCV NS5B Nucleotide Polymerase Inhibitor ± RBV Pangenotypic Protease Inhibitor ± RBV Other NS5B Nonnucleoside Polymerase Inhibitor ± RBV NS5A Inhibitor ± RBV Platform Interferon ± RBV Issues that may dictate treatment regimen 1. Treatment duration: 6,8,12 weeks 2. Genotype 1b vs 1a 3. Non-genotype 1 4. Cirrhosis 5. Race and ethnicity 6. IL28B status 7. Viral resistance 8. Cost

51 Challenges and Advances in the Future CURE from SIMPLE and TOLERABLE pangenotypic treatment regimens 6 weeks (3 drugs) 4 weeks (2 or 3 drugs) 8 weeks 12 weeks Weeks

52 Standard of Care for Treatment of Chronic HCV Infection 2015 and Beyond Genotype Regimen Duration Considerations GT 2 GT 3 Sofosbuvir 400 mg QD + RBV 1000 or 1200 mg/day in 2 divided doses BID Sofosbuvir 400 mg QD + RBV 1000 or 1200 mg/day in 2 divided doses BID GT 1 Sofosbuvir 400 mg QD + Ledipasvir 90 mg QD (FDC) [Paritaprevir/r + Ombitasvir] + Dasabuvir BID ± RBV BID 12 weeks 24 weeks Data to support addition of PegIFN along with SOF + RBV for 12 weeks weeks Phase 3 trials completed-fda approved weeks Phase 3 trials completed-fda approved FDC, fixed-dose combination Jacobson IM et al. 64th AASLD; Washington, DC; November 1-5, 2013; Abstract LB-3. (B)