1. Case Discussion: Redefining Best Practices in HCV Management in the Transplant Setting This activity is supported by an independent educational grant from Gilead Sciences

2. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Faculty Program Director Norah Terrault, MD, MPH Professor of Medicine and Surgery Department of Medicine Division of Gastroenterology University of California, San Francisco San Francisco, California Additional Faculty Jean C. Emond, MD Thomas S. Zimmer Professor of Surgery Executive Director, Transplant Initiative NewYork-Presbyterian Hospital Columbia University Medical Center New York, New York Paul Y. Kwo, MD Professor of Medicine Medical Director of Transplantation Division of Medicine/Gastroenterology/ Hepatology Indiana University School of Medicine Indianapolis, Indiana

4. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 1: 62-Yr-Old Female With Cirrhosis and HCC  GT1a HCV, IL28B CT  Previous treatment –Standard IFN for 1 yr followed by 5 yrs of maintenance IFN –Most recently triple therapy with pegIFN/RBV + boceprevir in 2012: nonresponder  History of varices (on nadolol) but no prior bleeding  No ascites, hepatic encephalopathy, or infectious complications  3-mm HCC treated with TACE and RFA without residual HCC on latest CT  History of depression, on citalopram

5. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 1: Laboratory Analysis and Transplantation Listing  CBC –WBC 3.4 –Hct 32.1, Hb 10.9 –Platelets 76, INR 1.4  Chemistries –Albumin 3.1 –Total bilirubin 1.4 –AST 45, ALT 29 –Na 139 –Creatinine 0.95  Current HCV RNA 35,079,260 IU/mL  Listed for LT –Blood type A –MELD 22 with exception status, native MELD 11  At this transplant program, the average MELD for LT for blood group A is 31

6. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Panel Discussion: Should Further Tests Be Ordered?  Some experts would order additional testing if simeprevir is being considered –Resistance testing, given the failure on boceprevir and the potential for cross resistance –Q80K, since SVR rates are reduced with simeprevir for patients having this polymorphism

7. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Panel Discussion: What HCV Treatment Approach Would You Recommend?  2 potential approaches –Viral suppression –Try for SVR  Sofosbuvir + RBV for long-term suppression or sofosbuvir + simeprevir ± RBV for SVR were approaches favored by the panel  Child’s-Pugh classification should be considered when making choice to ensure medications are safe for the individual patient

8. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 1: Follow-up  Treatment deferred until exception MELD = 29, then started on sofosbuvir 400 mg/day and RBV 800 mg/day  HCV RNA results –Baseline: 35 million IU/mL –Wk 1: 14,334 IU/mL –Wk 2: 2274 IU/mL –Wks 4, 6, and 8: < 43, DETECTED  Tolerating well except for mild anemia –RBV reduced to 600 mg/day for Hct decline to 29 at Wk 4 –MELD upgraded to 31 (average MELD at LT in this region)

9. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings On-Treatment VR With SOF + RBV in Patients With CTP-A and CTP-B Cirrhosis Afdhal N, et al. EASL 2014. Abstract O68. HCV RNA < LLOQ (%) 100 80 60 40 20 0 Wk 2Wk 4Wk 8Wk 12 56 100 94 Wk 24 CTP A CTP B 44 75 100 9493 N = 25

10. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Panel Discussion: What Would You Do Next?  Some experts would consider adding an additional agent to try to achieve SVR prior to transplantation –Simeprevir or daclatasvir (compassionate use)  Timing of expected transplantation an important consideration

11. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Days HCV RNA Negative Prior to LT and Rate of Recurrence Median days TND (P <.001)  No recurrence: 95.0  Recurrence: 5.5 No recurrence (n = 30) > 30 days TND Recurrence (n = 10) Curry MP, et al. ILTS 2014. Abstract O-137. 0306090120150180210240270300330360390420450480 Days With HCV RNA Continuously TND Prior to Liver Transplant

12. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings DAAPrimary Metabolic Pathway Suitable in Patients With Cirrhosis CTP-A CTP-B CTP-C Suitable if Renal Impairment SofosbuvirRenalYes Not if CrCl < 30 mL/min SimeprevirHepaticYesNo Not if CrCl < 15 mL/min AsunaprevirHepaticYesNo Unknown ABT-450/RTVHepaticYesNo Unknown LedipasvirHepaticYes Unknown OmbitasvirHepaticYesNo (as combo) Unknown DaclatasvirHepaticYes DasabuvirHepaticYesNo Unknown Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clinical Pharm 2014. Abstract P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German, et al. AASLD 2013. Abstract 467. Kirby R, et al. Clinical Pharm 2013. Abstract PO20. Studies on PK/PD in Patients With Renal and Hepatic Impairment

13. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Panel Discussion: New Considerations With All-Oral Therapy in the Pretansplant Setting  All-oral therapy offers safe, effective option for wait-list patients  Best outcomes with sofosbuvir + RBV pre-LT achieved if HCV RNA is undetectable for > 4 wks prior to LT –Approved for treatment up to 48 wks  Lack of data on safety in patients with advanced renal and liver disease may limit treatment options –Sofosbuvir not recommended if CrCl < 30 mL/min –Simeprevir not recommended if CTP B or C disease –Daclatasvir (compassionate access) may be option if advanced liver or renal disease

14. Case 2

15. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 2: 59-Yr-Old Male With GT3 HCV Who Received Liver Transplantation  59-yr-old male with cirrhosis due to HCV  Underwent transplantation with deceased donor (age 50 yrs, CDC high risk)  GT3A HCV, IL28B CT, treatment naive  Past history –CAD, s/p LAD stent placement 2013 –Hypertension and dyslipidemia  Early posttransplantation course complicated by early mild rejection, managed with increase in tacrolimus dose

16. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 2: Posttransplantation Course  At Month 3, increase in liver tests noted TestWk 10Wk 12Wk 13Wk 14 AST 59136209279 ALT 47123154155 Total bilirubin 1.30.84.78.3 Alk phos 53341355340 Creatinine 1.12--2.392.01

17. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 2: Additional Laboratories  HCV RNA 29 million IU/mL  Na 136, K 4.8, urea 28, Cr 2.01, WBC 1.9, Hb 9.6, platelets 141, INR 1.0, glucose 100, albumin 2.9, cryoglobulins negative  CMV DNA negative  HBcAb, IgM negative  HBsAg negative  HBcAb positive, HBV DNA negative  HAV Ab, IgM negative  HEV Ab negative

18. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 2: Follow-up Liver Biopsy  Ultrasound results –Heterogeneity of liver parenchyma, no biliary dilatation, hepatic and portal veins patent, spleen normal size, no fluid collections  Liver transplantation biopsy –Chronic hepatitis consistent with recurrent hepatitis C with septal fibrosis and features suggestive of an aggressive/fibrocholestatic variant; no evidence of rejection

19. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Panel Discussion: Management Approach for Severe Recurrence  For a patient with genotype 3, options are limited –Sofosbuvir plus ribavirin or sofosbuvir plus daclatasvir (compassionate use)  Additional options could be considered for genotype 1

20. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Sofosbuvir + Ribavirin for Advanced Disease Post-LT: Compassionate Access  N = 104, GT1-4  72 completed 24-48 wks of treatment –7 d/c due to AEs, 12 repeat LT, and 13 deaths  Median MELD: 15 (range:6-43) –Included patients with FCH  Median mos from LT: 17 (range: 1-262) Forns X, et al. EASL 2014. Abstract O62. EOTSVR12 HCV RNA < LLOQ (%) 100 80 60 40 20 0 87 62 81/9353/85 Patients were excluded from this analysis if received an LT (n = 8 at EOT; n = 12 at SVR12) and/or no data were available (n = 3 at EOT; n = 7 at SVR12).

21. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Clinical Case: Fibrosing Cholestatic Hepatitis 048/04812162024/048 HCV RNA (IU/mL) Bilirubin Level (mg/dL) 10 8 10 6 10 4 10 2 LOD Wk 25 20 15 10 5 1 HCV RNA: 541,000,000 IU/mL Fibrosing Cholestatic Hepatitis Diagnosed 2 Mos After LT TE: 9.6 kPaLTTE: 17 kPaAscitesNo Ascites *Bilirubin normalized at Wk 9. After LTSOF + RBV Treatment Post- treatment Follow-up HCV RNA Bilirubin level * Forns X, et al. AASLD 2013. Abstract 1084.

22. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Panel: New Considerations With All-Oral Therapy for Severe Recurrence  PegIFN is best avoided in the early post-LT period  SOF + RBV offers pangenotypic option for FCH and safety supported by compassionate access experience  Other oral combinations likely in future, but applicability will be depend on safety and PK/PD in moderate to severe hepatic impairment (typical of FCH)  GT3 recurrence has limited options for treatment –SOF + RBV ± pegIFN –Combination of SOF + NS5A inhibitors (LDV or DCV) can be considered in future –Protease inhibitors not effective

23. Case 3

24. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 3: 63-Yr-Old Male Transplanted 13 Yrs Ago With Cirrhosis on Recent Biopsy  63-yr-old male with transplanted HCV in 2001  Recent liver biopsy shows recurrent disease with stage 4 fibrosis (cirrhosis) and grade 2 necroinflammation  Previous post-LT treatment –PegIFN/RBV (null response, stopped after 3 mos) –PegIFN/RBV + telaprevir x 48 wks (response with relapse) –No treatment in past yr  Returns to discuss treatment options in light of newly approved therapies  GT1b HCV, IL28B TT

25. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 3: History and Laboratories  Past history –Hypertension, controlled –Diabetes, HbA1c 7.6 –Mild renal insufficiency, creatinine 1.6 –Depression, stable on citalopram –No history of rejection  Immunosuppression: tacrolimus 1 mg BID with trough level 4.6  Laboratories –WBC 4.3, Hb 11, platelets 74, INR 1.2 –AST 70, ALT 65, alk phos 104, total bilirubin 1.0, albumin 3.4 –Cr 1.6, Na 139, K 3.8 –HCV RNA 1.2 million IU/mL –NS3A/4 GenoSure: negative for resistance mutations

26. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings New HCV Regimens Under Study in Posttransplantation Patients 1. Samuel D., et al. EASL 2014. Abstract P1232. 2. Forns X, et al. EASL 2014. Abstract O62. 3. Kwo PY, et al. EASL 2014. Abstract O114. 4. Pellicelli A, et al. Dig Liver Dis. 2014;46:923-927.

27. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings HCV DAAs and Immunosuppressives Drug–Drug Interactions Drug ClassDrugDDI With CNIs Yes No Protease inhibitors Boceprevir ✔ Telaprevir ✔ Simeprevir CsA ✔ Tac ✔ ABT-450/RTV ✔ NucleosideSofosbuvir ✔ NonnucleosideDasabuvir ✔ NS5ALedipasvir ✔ Daclatasvir ✔ Ombitasvir ✔ (in combo) ✔ Tischer S, et al. J Hepatol. 2014;60:872-884.

28. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Case 3: Initial Treatment and Results  Started on sofosbuvir 400 mg/day + simeprevir 150 mg/ day with planned treatment duration of 12 wks  HCV RNA on treatment –Baseline: 1,357,200 –Wk 2: 3100 –Wk 4: < 25, DETECTED –Wk 6: < 25, DETECTED –Wk 8: < 25, DETECTED

29. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings COSMOS: Sofosbuvir + Simeprevir ± RBV in Patients With Cirrhosis Lawitz E, et al. EASL 2014. Abstract 165. Null responders Treatment naive Relapse in 3 pts in Cohort 1 and 1 pt in Cohort 2; all with GT1a and Q80K polymorphism at baseline 24 Wks12 WksOverall SVR12 (%) n/N = 100 80 60 40 20 0 SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOFSMV/SOF ± RBV 9/93/34/45/54/56/64/42/321/2216/17 100 80 100 67 96 94

30. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Panel Discussion: New Considerations With All-Oral Therapy for Posttransplant  IFN-free therapies offer advantages over previous pegIFN/RBV/ PI therapy –High efficacy and significantly improved tolerability  Anticipate more IFN-free and RBV-free options in near future (within 2014 in the US)  As choices increase, the factors that are likely to influence treatment choices are: –DDIs –Previous treatment experience (resistance) –Availability/cost

31. clinicaloptions.com/hepatitis Transforming HCV Management in the Pretransplant and Posttransplant Settings Summary  Renal and hepatic clearance of DAAs –Impact on management/treatment choice pretransplantation and posttransplantation  NS5A inhibitors and polymerase inhibitors do not have clinically significant DDIs with immunosuppression –Simeprevir has DDI with cyclosporine, but not tacrolimus  IFN-free therapy add a much greater degree of safety and tolerability than previous therapies

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