1. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations November 1-5, 2013 Washington, DC Other Highlights & Special Populations: CCO Official Conference Coverage of the 2013 Annual Meeting of the American Association for the Study of Liver Diseases This program is supported by an educational grant from This program is supported by educational grants from In partnership with Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC

2. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Faculty Jordan J. Feld, MD, MPH Assistant Professor of Medicine University of Toronto Hepatologist Toronto Centre for Liver Diseases Sandra Rotman Centre for Global Health Toronto, Ontario, Canada Paul Y. Kwo, MD Professor of Medicine Medical Director of Transplantation Division of Medicine/ Gastroenterology/Hepatology Indiana University School of Medicine Indianapolis, Indiana Nancy Reau, MD Associate Professor of Medicine Center for Liver Disease University of Chicago Chicago, Illinois

3. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Disclosures Jordan J. Feld, MD, MPH, has disclosed that he has received consulting fees from Achillion, Boehringer Ingelheim, Bristol ‐ Myers Squibb, Gilead Sciences, Janssen, Merck, and Vertex; fees for non ‐ CME/CE speaking engagement from a commercial interest or their agents from AbbVie and Roche; and funds for research support from AbbVie, Boehringer Ingelheim, Gilead Sciences, Roche, and Vertex. Paul Y. Kwo, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Vertex; fees for non-CME/CE services received directly from a commercial interest or their agents (ie, speaker bureau) from Merck; and funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Vertex. Nancy Reau, MD, has disclosed that she has received consulting fees from AbbVie, Gilead Sciences, and Janssen and funds for research from AbbVie, Gilead Sciences, and Vertex.

4. Please review the slide notes for a discussion and clinical context for each study by the expert faculty

5. HCV Screening

6. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Opt-Out HCV Screening of Baby Boomers in Urban Emergency Department  University of Alabama ED –Interim report: screening from 9/3/13 to 10/17/13  Screening population and methods –Born between 1945-1965 and medically and surgically stable –Verbal questionnaire administered by ED nurse –Anti-HCV testing provided results within 29 mins –Quantitative HCV RNA testing followed Galbraith JW, et al. AASLD 2013. Abstract LB-6. Reproduced with permission. 2363 persons born between 1945-1965 1721 (72.8%) questioned about HCV status based on birth year 79 (4.6%) Known HCV+ 315 (18.3%) Known HCV- 40 (2.3%) Unable to obtain 1287 (74.8%) HCV status unaware

7. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Opt-Out HCV Screening in ED: High Rates of HCV Ab+ Individuals Identified  Program projected to screen 7872 people and identify 864 HCV Ab+ individuals over 1 yr Galbraith JW, et al. AASLD 2013. Abstract LB-6. Reproduced with permission. 118 (12.0%) anti-HCV+ 1287 (74.8%) unaware of HCV status 1148 (90.8%) accepted test offering 984 (85.7%) anti-HCV tests performed 27 (27.5%) HCV RNA- 71 (72.5%) HCV RNA+ 866 (88.0%) anti-HCV- Baseline FactorHCV Ab+, % (n/N) Insurance (P <.001)  Uninsured  Public/Medicaid  Medicare  Private 17 (35/210) 17 (35/203) 11 (33/315) 4 (10/226) Race (P =.54)  White  Black 13 (67/515) 11 (50/454) Sex (P <.001)  Female  Male 8 (39/505) 17 (79/479)

8. HCV Natural History

9. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Meta-analysis: Risk of HCC in HCV Pts With Advanced Fibrosis Following SVR  1000 patients with bridging fibrosis or cirrhosis who achieved SVR following IFN-based HCV therapy followed for median of 5.7 yrs  Cirrhotics at greatest risk of HCC following SVR Van der Meer AJ, et al. AASLD 2013. Abstract 143. Reproduced with permission. Cumulative HCC Occurrence (%) Cirrhosis Bridging Fibrosis P =.064 8-Yr HCC Rate, % (95% CI) 8.5 (5.8-11.2) 1.8 (0-4.3) Yrs 12 10 8 6 4 2 0 012345678

10. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Age as a Risk Factor for HCC Following SVR in HCV Pts With Advanced Fibrosis Van der Meer AJ, et al. AASLD 2013. Abstract 143. Reproduced with permission.  HCC risk increased with age; highest for those > 60 yrs Cumulative HCC Occurrence (%) 12 10 8 6 4 2 0 013456728 Yrs > 60 yrs of age 45-60 yrs of age < 45 yrs of age P =.006 12.2% (5.3-19.1) 9.7% (5.8-13.6) 2.6% (0-5.5) 8-Yr HCC Rate, % (95% CI)

11. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Yrs Cumulative HCC Occurrence (%) Laboratory Markers of Disease Severity Predicted HCC Occurrence After SVR  Diabetes also associated with increased HCC risk by multivariate analysis AST/ALT ratio Yrs Platelets < 150 x 10 9 cells/L Platelets ≥ 150 x 10 9 cells/L AST/ALT ratio ≥ 0.90 AST/ALT ratio < 0.90 P =.045P =.017 Platelet Count Van der Meer AJ, et al. AASLD 2013. Abstract 143. Reproduced with permission. 12 10 8 6 4 2 0 801245673 12 10 8 6 4 2 0 801245673

12. Real-World Experiences With HCV PIs

13. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations HCV-TARGET: Protease Inhibitor Use in a Real-World Setting  North America–based ongoing longitudinal patient registry from 103 academic and community sites –838 treated with telaprevir; 262 treated with boceprevir Di Bisceglie A, et al. AASLD 2013. Abstract 41. Reproduced with permission. SVR12 (%) Telaprevir + P/R Boceprevir + P/R 100 80 60 40 20 0 NaiveTx Exp’d TotalCirrhoticNoncirrhotic 61 44 73 59 53 64 196/ 320 56/ 127 138/ 189 305/ 517 133/ 249 172/ 267 100 80 60 40 20 0 NaiveTx Exp’d TotalCirrhoticNoncirrhotic 58 39 64 37 27 42 59/ 102 9/ 23 50/ 78 59/ 160 15/ 55 44/ 105 n/ N =

14. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations HCV-TARGET: Risk Factors for Poor Outcomes in PI-Treated Pts  Risk factors for decompensation among cirrhotic patients during PI therapy identified [1]  Pts with history of decompensation at highest risk for SAEs with PIs [2] 1. Afdhal N, et al. AASLD 2013. Abstract 1865. 2. Gordon S, et al. AASLD 2013. Abstract 1866. Reproduced with permission. Patients (%) Baseline Characteristic Odds Ratio Minimally Adjusted Estimates P Value CrCl (mL/min)0.99.03 Albumin (g/dL)0.30<.01 HCV RNA (log IU/mL) 0.76<.01 Bilirubin (log mg/dL) 2.93.02 100 80 60 40 20 0 SAEDecomp AE Decomp SAE Completed Treatment Noncirrhotics (n = 639) Cirrhotics w/prior decomp’n (n = 49) Cirrhotics w/o prior decomp’n (n = 412) 10 33 12 1 24 7 0 10 1 71 43 55

15. Management of HCV in HIV-Coinfected Patients

16. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations PHOTON-1: Sofosbuvir + Ribavirin in GT1, 2, or 3 HCV Patients Coinfected With HIV  Ongoing, nonrandomized, open-label phase III study  Stable ART (HIV-1 RNA 8 wks before enrollment) –CD4+ cell count > 200 cells/mm 3 if on ART, > 500 cells/mm 3 if not on ART  7% of patients had cirrhosis  Primary endpoint: SVR12 Sulkowski M, et al. AASLD 2013. Abstract 212. Wk 24 Sofosbuvir + Ribavirin (n = 114) Sofosbuvir + Ribavirin* (n = 41) Sofosbuvir + Ribavirin (n = 68) Wk 12 Tx-naive GT1 patients Tx-naive GT2/3 patients Tx-experienced GT2/3 patients* *Data not presented for this arm.

17. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations PHOTON-1: Virologic Response Rates  Breakthrough only in the setting of noncompliance  Regimen effective across several types of ART: PIs, NNRTIs, integrase inhibitors n/N = Sulkowski M, et al. AASLD 2013. Abstract 212. Reproduced with permission. 100 80 60 20 0 40 HCV RNA < LLOQ (%) Genotype 1Genotype 2Genotype 3 SOF + RBV 24 WksSOF + RBV 12 Wks Wk 4 EOT SVR12 100 96 76 96 88 100 98 67 110/ 114 103/ 103 87/ 114 25/ 26 22/ 23 23/ 26 41/ 41 39/ 40 28/ 42

18. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Faldaprevir 240 mg QD + PegIFN/RBV* Faldaprevir 120 mg QD + PegIFN/RBV Patients coinfected with HIV and GT1 HCV, HCV treatment naive or previous relapser (N = 310) Wk 12 RGT † *At Wk 12, pts receiving FDV 240 mg QD + P/R were rerandomized 1:1 to continue triple therapy or P/R to Wk 24. † At Wk 24, pts with ETS were rerandomized to continued P/R vs no further treatment; pts without ETS continued P/R to Wk 48. ETS defined as HCV RNA < 25 IU/mL at Wk 4 and Wk 8. Faldaprevir 240 mg QD + PegIFN/RBV Wk 24 PegIFN/RBV Randomization or allocation based on ART regimen PegIFN/RBV No further tx Wk 48 RGT † PegIFN/RBV No further tx Rockstroh J, et al. AASLD 2013. Abstract 1099. STARTVerso 4: Faldaprevir + PegIFN/RBV in GT1 HCV/HIV–Coinfected Pts  Interim analysis of phase III STARTVerso 4 trial –83% white/14% black, 79% GT1a HCV, 4% ART naive, 27% on EFV-based ART, 22% on ATV/RTV or DRV/RTV-based ART, 47% on RAL-based or “other” ART

19. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations STARTVerso 4: SVR4 With Faldaprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection  High SVR4 rates in both cirrhotic and noncirrhotic patients –Cirrhotic: 76% –Noncirrhotic: 74%  SVR4 and AEs comparable to HCV- monoinfected patients treated with FDV + pegIFN/RBV Overall population FDV 120 mg 24 wks FDV 240 mg 12 wks FDV 240 mg 24 wks FDV 240 mg total* 140/ 185 n/N = 100 80 60 40 20 0 SVR4 (%) 74 72 79 84 229/ 308 89/ 123 66/ 84 72/ 86 76 *Includes additional pts who dropped out before Wk 12. Rockstroh J, et al. AASLD 2013. Abstract 1099. Reproduced with permission.

20. Management of HCV in the Transplant Setting

21. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations TVR or BOC + PegIFN/RBV for Posttransplant GT 1 HCV Recurrence  Prospective multicenter cohort study of 79 pts from 17 European transplant centers –Active, chronic GT1 HCV –HCV recurrence: ≥ F1 or cholestatic hepatitis  Pts treated with 1 of 3 regimens (planned duration, 48 wks) –P/R lead-in for 4 wks, followed by BOC 800 mg TID + P/R (n = 35) –P/R lead-in for 4 wks, followed by TVR 750 mg TID + P/R (n = 19) –TVR 750 mg TID + P/R (n = 25) Coilly A, et al. AASLD 2013. Abstract 216. CharacteristicBOC + P/R (n = 35) TVR + P/R (n = 44) Mean MELD score (SD)11.0 (4.5)11.2 (6.8) METAVIR stage, %  ≥ F3 3948  F42423 FCH, %616 GT1b HCV, %6372 IL28B CC genotype, %236 Mean HCV RNA, log 10 IU/mL (SD) 6.69 (0.68)6.54 (0.73) Previous P/R post-LT, %  Naive4051  Nonresponse5458  Relapse2123  Breakthrough2519 Mean time from LT, yrs (SD) 5.5 (6.0)4.3 (4.0)

22. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations PI + P/R in Posttransplant Setting: Virologic and Safety Outcomes  RBV dose reduction + EPO: 94% –Required transfusion: 49%  Required GCSF: 19%  FCH only factor independently associated with infection (P =.04) Virologic Outcomes SAEs, % BOC + P/R (n = 35) TVR + P/R (n = 44) Rehospitalization2659  Acute kidney injury314 Biopsy-proven acute rejection 179 Infections3321 Death87 Fold Increase in CNI at PI Completion BOC + P/R (n = 35) TVR + P/R (n = 44) Tacrolimus5.520.2 Cyclosporine1.12.4 Coilly A, et al. AASLD 2013. Abstract 216. Reproduced with permission. TVR + P/R BOC + P/R 100 80 60 40 20 0 Patients (%) EOTSVR12 43 60 41 51 N = 44 3544 35

23. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Compassionate Use of Sofosbuvir + RBV ± PegIFN in Post-LT Severe Recurrent HCV  All patients who received treatment had severe HCV recurrence, including fibrosing cholestatic hepatitis (N = 44) –Sofosbuvir 400 mg/day + RBV for ≤ 48 wks; pegIFN added at physician’s discretion Forns X, et al. AASLD 2013. Abstract 1084. Reproduced with permission. CharacteristicSofosbuvir + RBV (n = 32) Sofosbuvir + RBV + PegIFN (n = 12) Mean laboratory values  Bilirubin, mg/dL (range)7.9 (0.4-27.1)2.6 (0.4-5.1)  Albumin, g/L (range)3.2 (1.3-12.2)3.4 (2.0-4.8)  INR (range)1.4 (0.9-3.9)1.2 (1.0-1.6)  ALT, IU/L (range)124 (13-717)81 (8-197)  AST, IU/L (range)223 (14-1331)112 (36-270) Histologically documented FCH, n (%)15 (47)5 (33) Mean MELD score (range)16 (6-43)13 (8-22) Mean time post-LT, mos (range)40 (3-178)31 (5-124)

24. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Sofosbuvir + RBV ± PegIFN in Post-LT HCV: Virologic and Safety Outcomes  69% of pts had SVR4; 56% had SVR12 –2/36 pts relapsed –1/36 pts had on-treatment nonresponse –8/36 pts died  64% demonstrated improvement of decompensation events  11% showed stabilization of events Forns X, et al. AASLD 2013. Abstract 1084. Reproduced with permission. OverallSOF + RBVSOF + PegIFN/RBV SVR4 (%) 100 80 60 40 20 0 SVR4 Outcomes 69 74 56 25/36 20/27 5/9 n/N =

25. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Pretransplant Sofosbuvir + RBV to Prevent Posttransplant HCV Recurrence  Study 025: single-arm, open-label phase II study from 16 liver transplantation 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 tacrolimus + prednisone + MMF Curry MP, et al. AASLD 2013. Abstract 213. Reproduced with permission. CharacteristicSOF + RBV (N = 61) Median age, yrs (range)59 (46-73) HCV genotype, %  1a39  1b34 2213  3a12 442 Non-CC IL28B genotype, %78 CTP score, %  5-796 885 Previous HCV treatment, %75

26. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations 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. Reproduced with permission. 3300306090120150180210240270300 Days With HCV RNA Continuously TND Prior to Liver Transplant > 30 days TND No recurrence (n = 28) Recurrence (n = 10) Median days TND (P <.001)  No recurrence: 95  Recurrence: 5.5

27. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations 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 Week 4EOT*SVR4 Response (%) 100 80 60 40 20 0 100 77 40/40 39/39 27/35 †

28. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations Sofosbuvir + RBV for Post-LT HCV Recurrence: Safety Outcomes  No deaths, graft loss, or rejection  No drug–drug interactions with immunosuppressive agents  RBV dose reduction in 28%; 20% received epoetin and/or blood products Charlton MR, et al. AASLD 2013. Abstract LB-2. Reproduced with permission. Hemoglobin (mg/dL) Serum Creatinine (mg/dL) Wk 15 14 13 12 11 10 1.2 1.1 1.0 0.9 0.8 FU-401234812162024FU-2 Median RBV dose, mg/day400 600 800 600800

29. HBV Reactivation

30. clinicaloptions.com/hepatitis Highlights of AASLD 2013: Other Highlights and Special Populations HBV Reactivation With Rituximab in Pts With Hematologic Malignancies  Single-center study of HBsAg- negative anti-HBc–positive pts receiving rituximab-containing chemotherapy (N = 62) –Baseline HBV DNA undetectable (< 10 IU/mL) –No previous HBV treatment –No chronic liver disease  24.2% of patients experienced HBV reactivation within 9 mos –Reactivation occurred early (86.7% within 6 mos)  Lower baseline anti-HBs levels associated with subsequent HBV reactivation (P =.015) Seto WK, et al. AASLD 2013. Abstract 34. Reproduced with permission HBV Reactivation No HBV Reactivation 100 75 50 25 0 Patients (%) P =.015 Anti-HBs Levels, mIU/mL ≥ 300 100 - < 300 10 - < 100 < 10

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32. Go Online for More CCO Coverage of AASLD 2013! Capsule Summaries of all the key data Additional CME-certified slideset on investigational HCV agents including expert faculty commentary on the key studies clinicaloptions.com/AASLD2013