Associate Professor of Medicine University of Chicago

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1 Nancy Reau, MD Associate Professor of Medicine University of Chicago Management of Hepatitis C: New Drugs and New Paradigms HCV is More Lethal than HIV Infection HCV superseded HIV as a cause of death Comorbid conditions increase mortality: HBV co-infection HIV infection Alcohol-related l l te per 1, Persons Rat Mortality Rates of HCV, HIV, and HBV; United States HIV Hepatitis C Hepatitis B Year Ly KN, et al. Ann Intern Med. 212;156(4):

Highest Prevalence of HCV Cirrhosis is Now! Davis Gastroenterology 21 SVR is Associated with Reduced Mortality Among HCV-infected Persons 53 adults in Europe prospectively followed for median 8.

at risk Without SVR 45 393 382 363 344 317 295 25 27 164 135 With SVR 192 181 168 162 156 144 125 88 56 4 28 Liver-related mortality or liver tra ansplantation, % 3 2 1 Liver-related mortality or

2 Highest Prevalence of HCV Cirrhosis is Now! Davis Gastroenterology 21 SVR is Associated with Reduced Mortality Among HCV-infected Persons 53 adults in Europe prospectively followed for median 8.4 years after HCV treatment 192 (36%) achieved SVR All-cause mortality, % P<.1 All-cause mortality Without SVR With SVR Time, y No. at risk Without SVR With SVR Liver-related mortality or liver tra ansplantation, % Liver-related mortality or liver transplantation P<.1 Without SVR With SVR Time, y No. at risk Without SVR With SVR Van der Meer, et al. JAMA 212:38:

Cirrhosis 12 1 # of persons # of persons 12 F4 8 F3 6 F2 1 SVR 8 Decompensated Cirrhosis 6 4 F1 4 Non-Liver Death F2 2 F 2 F3 F1 F4

585 million 5 1 15 2 25 3 Year In Model Desai AASLD 213 75% of Infected Individuals Are Not Aware of Their HCV Status Institute of

3 Nancy S. Reau, MD Potential Impact of Effective Therapy No Treatment All Treated Non-Liver Death Liver Death Decompensated Cirrhosis 12 1 # of persons # of persons 12 F4 8 F3 6 F2 1 SVR 8 Decompensated Cirrhosis 6 4 F1 4 Non-Liver Death F2 2 F 2 F3 F1 F4 Liver Death F Year in Model 3 total N = million Year In Model Desai AASLD % of Infected Individuals Are Not Aware of Their HCV Status Institute of Medicine. Hepatitis and Liver Cancer, A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC. The National Academies Press, 21; 2.United States Department of Health and Human Services. Combating the Silent Epidemic of Viral Hepatitis, Action Plan for the Prevention, Care & Treatment of Viral Hepatitis

New 212 Recommendations Individuals Who Should Be Screened for HCV Baby Boomers Born from 1945 1965 965 Adults born during 1945 1965 should receive onetime testing for HCV without prior ascertainment

4 New 212 Recommendations Individuals Who Should Be Screened for HCV Baby Boomers Born from Adults born during should receive onetime testing for HCV without prior ascertainment of HCV risk As of 214, this includes all individuals between 49 and 69 years of age! Division of Viral Hepatitis, National Center for H. I. V. Aids Viral Hepatitis S. T. D. T. B. Prevention. MMWR Recomm Rep. 212;61(RR-4):1-32. Hepatitis C in the United States Testing people in this age group will help identify many undiagnosed cases CDC Fact Sheet. Available at Accessed 8/18/12. 4

Milestones in Therapy of HCV: Overall SVR Rates Average SVR Rates from Clinical

68%* 9% 3% 2% 1% 6% 16% % IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m Peg-IFN 12m

Strader DB, et al. Hepatology. 24;39(4):1147-1171. Hezode C, et al. N Engl J Med.

Presented at: EASL; April 23, 29; Copenhagen, Denmark. Abstract 4. Kwo PY, et al.

211;364:245-2416; Poordad F, et al. N Engl J Med. 211;364(13):1195-126.

5 Milestones in Therapy of HCV: Overall SVR Rates Average SVR Rates from Clinical Trials SVR (%) 8% 7% 6% 5% 4% 34% 42% 39% 54-56% 42-46% 79%* 68%* 9% 3% 2% 1% 6% 16% % IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m Peg-IFN 12m Peg-IFN/ RBV 12m T12/PR24 P/R/B (48 wk) + lead-in DAA+DAA DAA+PR Adapted from Strader DB, et al. Hepatology. 24;39(4): Hezode C, et al. N Engl J Med. 29; 36(18): Kwo P, et al. Presented at: EASL; April 23, 29; Copenhagen, Denmark. Abstract 4. Kwo PY, et al. Lancet. 21;376(9742): Jacobson IM, et al. N Engl J Med. 211;364: ; Poordad F, et al. N Engl J Med. 211;364(13): Telaprevir prescribing information at Accessed September 12, 212. For most: where are we now? Presentation Title Here 1 5

6 Currently Available Agents Protease Inhibitor (PI) Additional Regimen Components Considerations Boceprevir (TID) PEGIFN alfa + Genotype Telaprevir (TID) Simeprevir (QD) weight-based RBV Naïve Previous treatment failure Compensated cirrhosis Response guided therapy Polymerase Inhibitor Additional Regimen Considerations Components Sofosbuvir (QD) PEGIFN alfa + SOF+RBV for genotype 2/3 weight-based RBV SOF+PEG/RBV G1 PEGIFN alfa = peginterferon alfa RBV = ribavirin Currently Available Agents Protease Inhibitor (PI) Additional Regimen Considerations Components Boceprevir (TID) PEGIFN alfa + Genotype Telaprevir (TID) Simeprevir (QD) weight-based RBV Naïve Previous treatment failure Compensated cirrhosis Response guided therapy Polymerase Inhibitor Additional Regimen Considerations Components Sofosbuvir (QD) PEGIFN alfa + SOF+RBV for genotype 2/3 weight-based RBV SOF+PEG/RBV G1 PEGIFN alfa = peginterferon alfa RBV = ribavirin 6

7 Simeprevir (SMV) + PEG-RBV SMV 15mg QD + PEG-IFN + RBV PEG-IFN + RBV 85% RVR 91% SVR f/u 24 wk Continue therapy only if HCV RNA <25 IU/mL at Week Weeks 48 Fried MW, et al. Hepatology. 213 Aug 2:. doi: 1.12/hep Sofosbuvir G1 PATIENTS SOF 4 mg QD + PEG-IFN + RBV f/u 24 wk 9% SVR Weeks 48 G2/3: ALL ORAL THERAPY SOF 4 mg QD + RBV G3 G2 NR 67% SVR G2 97% G % f/u 24 wk Weeks Lawitz EM, et al. N Engl J Med. 213;368:

8 What is Ideal Therapy? Pan-genotypic Short course Few pills Simple rules (one for everyone) High efficacy (>95%) No side effects Available to everyone What the Future Holds 15 Multiple Classes of Direct Acting Antiviral Agents 5 UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B p7 3 UTR Protease Polymerase Ribavirin NS3 protease inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non-NUC Inhibitors Telaprevir Boceprevir Simepreviri Asunaprevir ABT-45 MK-5172 Faldaprevir Sovaprevir ACH-2684 Daclatasvir Ledipasvir ABT-267 MK-8742 GS-5885 GS-5816 ACH-312 PPI-668 GSK Samatasvir Sofosbuvir VX-135 IDX2963 ACH-3422 ABT-333 Deleobuvir BMS PPI-383 GS-9669 TMC

9 Expectations: What we learned from clinical trials 1. All oral therapy is efficacious and safe 2. Baseline characteristics are losing impact 3. Special populations are no longer special 4. Ideal duration is a moving target What the Future Holds 17 Off-Label: COSMOS Sofosbuvir (NUC) and Simeprevir (PI) SMV + SOF + RBV SMV + SOF SV VR12 (%) Cohort 1 (F-F2 Nulls): SVR12 (N = 8, all arms) SV VR12 (%) Cohort 2 (F3-F4 Naives/Nulls): SVR /24 14/15 26/27 13/14 25/27 13/14 28/3 16/16 24-Wk Arms 12-Wk Arms 12 Weeks 24 Weeks 94 Overall Sulkowski, et al. EASL 214. Lawitz et al. EASL 214 9

10 ABT-45/r (PI) + ABT-267 (NS5A) + ABT-333 (NNI) + RBV SAPPHIRE and TURQUOISE: Weeks SVR SAPPHIRE-I N=473 ABT-45/r + ABT Treatment Naïve 96% ABT RBV No cirrhosis SAPPHIRE-II Experienced No cirrhosis N=297 ABT-45/r + ABT ABT RBV 96% TURQUOISE-II Treatment Naïve/ Experienced 1% w/cirrhosis N=28 N=172 ABT-45/r + ABT ABT RBV ABT-45/r + ABT ABT RBV 92% 96% Feld et al. EASL 214; Zeuzem et al. EASL 214; Poordad et al EASL 214 LDV/SOF Phase 3 Program (ION-1, ION-2, ION-3) Sofosbuvir (NUC) + Ledipasvir (NS5A) +/- RBV in G1 97% (1886/1952) overall SVR rate Wk Wk 8 Wk 12 Wk 24 SVR 12 LDV/SOF + RBV 99% ION-1 ION-2 ION-3 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV LDV/SOF 98-99% 96-97% 94-99% 93% 94% ION-1 treatment naïve: N = 865 ION-2 treatment experienced: N = 44 ION-3 treatment naïve: N = 64 1

11 Expectations: What we learned from clinical trials 1. All oral therapy is efficacious and safe 2. Baseline characteristics are losing impact 3. Special populations are no longer special 4. Ideal duration is a moving target What the Future Holds 21 11

Effect of Negative Predictors on SVR Rates Across SOF Studies SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative

failure, cirrhosis, IL28B non-cc, HCV RNA 8, IU/mL, body weight 75kg, male gender 89% of patients in the Phase 3 program had up to 4 negative predictors SVR12

POSITRON, FUSION, VALENCE %) SVR12 ( 1 8 6 4 1 1 1 1 1 1 99 1 96 93 93 86 94 86 61 79 62 67 53 GT 3 n=247 SOF + RBV 24 weeks VALENCE 2 4/ 5/ 26/ 22/ 22/ 69/ 69/

12 Effect of Negative Predictors on SVR Rates Across SOF Studies SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors Retrospective multivariate analysis of Phase 2 and 3 SOF data identified 6 negative predictors associated with relapse: Prior treatment failure, cirrhosis, IL28B non-cc, HCV RNA 8, IU/mL, body weight 75kg, male gender 89% of patients in the Phase 3 program had up to 4 negative predictors SVR12 Rates by Number of Negative Predictors and Genotype GT 1 GT 2 GT 3 GT 1 n=339 GT 2 n=285 SOF + PegIFN + RBV 12 weeks ATOMIC, NEUTRINO SOF + RBV 12 weeks FISSION, POSITRON, FUSION, VALENCE %) SVR12 ( GT 3 n=247 SOF + RBV 24 weeks VALENCE 2 4/ 5/ 26/ 22/ 22/ 69/ 69/ 43/ 114/ 78/ 55/ 89/ 65/ 57/ 11/ 26/ 23/ 4/ N/A Number of Negative Predictors 8/ 15 Foster G, EASL, 214, O

13 Expectations: What we learned from clinical trials 1. All oral therapy is efficacious and safe 2. Baseline characteristics are losing impact 3. Special populations are no longer special 4. Ideal duration is a moving target What the Future Holds 25 ION-1 (LDV/SOF±RBV x 12 or 24 weeks) SVR12 by Presence of Cirrhosis Absence of Cirrhosis Cirrhosis SVR12 (%) /179 32/33 178/178 33/33 181/182 31/32 179/179 36/36 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV Error bars represent 95% confidence intervals Mangia A, EASL, 214, O164 Afdhal N, et al. N Engl J Med 214; 214 Apr 12 [Epub ahead of print] 12 Weeks 24 Weeks 13

Pre-Liver Transplant Study (SOF+RBV) Analysis of Post-Transplant Recurrence in GT 1

(n=1) No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days

1* 28 3 6 9 12 15 18 21 24 27 3 33 36 39 Days with HCV RNA Continuously TND Prior

14 Pre-Liver Transplant Study (SOF+RBV) Analysis of Post-Transplant Recurrence in GT 1 4 Days HCV RNA Continuously TND Prior to Transplant No Recurrence (n=29) Recurrence (n=1) No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days Median days TND No recurrence: 99 Recurrence: 5.5 p <.1* Days with HCV RNA Continuously TND Prior to Liver Transplant *Wilcoxon rank sum test. Curry MP, et al. APASL 214. Brisbane, Australia. Oral presentation 28 14

15 ERADICATE Study (NIAID, LDV/SOF) LDV/SOF STR for Treatment of HCV GT 1 Co-infected with HIV (Interim Analysis) N = 5 GT 1, TN, stable HIV disease Study Weeks ARV Untreated: LDV/SOF ARV Treated*: LDV/SOF ARV Untreated SVR 12 SVR 4 Interim results ARV Treated % of patie ents with HCV RNA < LLOQ / 13 37/ 37 13/ 13 37/ 37 13/ 13 3/ 3 Week 4 Week 8 EOT SVR4 SVR8 SVR12 12/ 12 22/ 22 1/ 1 1/ 1 LDV/SOF STR was well tolerated with no discontinuations Osinusi A, EASL, 214, O14 29 Expectations: What we learned from clinical trials 1. All oral therapy is efficacious and safe 2. Baseline characteristics are losing impact 3. Special populations are no longer special 4. Ideal duration is a moving target What the Future Holds 3 15

Sofosbuvir (NUC) + Ledipasvir (NS5A) in Genotype 1 ION-3: Shorter Duration is Possible Weeks 6 8 12 SVR ION-3 N=215 SOF + LDV 94% Treatment Naive N=216 SOF + LDV

combination The addition of third DAA could allow for shorter therapy* Gilead Press Release, 214; Kowdley et al, EASL 214 ; Gane EJ, et al. AASLD 213.

16 Sofosbuvir (NUC) + Ledipasvir (NS5A) in Genotype 1 ION-3: Shorter Duration is Possible Weeks SVR ION-3 N=215 SOF + LDV 94% Treatment Naive N=216 SOF + LDV + RBV 93% No cirrhosis N=216 SOF + LDV 95% ELECTRON* Treatment Naive No cirrhosis N=25 SOF+LDV+RBV 68% Treatment Duration > 6 weeks is needed for this combination The addition of third DAA could allow for shorter therapy* Gilead Press Release, 214; Kowdley et al, EASL 214 ; Gane EJ, et al. AASLD 213. Abstract 73; Kohli et al, CROI, 214* NIH SYNERGY: HCV Treatment Naïve G1 SOF+LDV (NPI-NS5A)+/- NNPI or PI 1% 95% 1% Kohli A, et al. CROI 214 Abstract 27LB What the Future Holds 32 16

HCV Care Cascade Afdhal NH, et al. J Viral Hepat 213; 2:745-76.

Treatment t duration of 12 weeks (maybe shorter) Well-tolerated across all populations

17 HCV Care Cascade Afdhal NH, et al. J Viral Hepat 213; 2: Summary Dual and triple DAA regimens yield the highest SVR rates (9+%) ever described Treatment t duration of 12 weeks (maybe shorter) Well-tolerated across all populations Baseline characteristics are becoming irrelevant Special populations have equal efficacy What the Future Holds 34 17

Hepatitis C Emerging Treatment Paradigms

Hepatitis C Emerging Treatment Paradigms David R Nelson MD Assistant Vice President for Research Professor of Medicine Director, Clinical and Translational Science Institute University of Florida Gainesville,