Managing HCV in Liver Transplant: Optimizing Success with New DAA Regimens

Transcription

1 Activity presentations are considered intellectual property. These slides may not be published or posted online without permission from Vindico Medical Education Please be respectful of this request so we may continue to provide you with presentation materials. Paul Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Indiana University Indianapolis, IN LI 1.2 Distribution of Adult Patients Waiting for a Liver Transplant United States Organ Transplantation. SRTR & OPTN Annual Data Report, 212.

2 LI 1.3 Characteristics of Adult Patients on Liver Transplant Waiting List: December 31, 22 & December 31, 212 United States Organ Transplantation. SRTR & OPTN Annual Data Report, 212. LI 4.9 Median MELD Score for Adult, Deceased Donor Liver Transplants, by DSA, 212 United States Organ Transplantation. SRTR & OPTN Annual Data Report, 212. Managing HCV in Liver Transplantation Reframing the Paradigm in the Context of New HCV Therapies Michael Abecassis, MD, MBA J. Roscoe Miller Distinguished Professor Departments of Surgery and Microbiology-Immunology Founding Director, Comprehensive Transplant Center Northwestern University Feinberg School of Medicine Chicago, IL

3 Case Studies/Questions A 6-year-old woman 4 weeks status-post OLT for HCV cirrhosis; SVR pre-treatment; sudden elevation of LFTs (3X) Biopsy versus empiric treatment of rejection? Please Select Your Approach 1. Biopsy 2. Empiric treatment of rejection Live Polling Results 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 82% Biopsy 18% Empiric treatment of rejection

4 Case Studies/Questions A 56-year-old man with cirrhosis complicated by HCC within Milan; HCV+ serologically but SVR. Liver offer: a 7-year-old, otherwise good donor, HCV- Accept offer? Would you accept a liver offer of a 7-year-old, otherwise good donor, HCV? 1. Yes 2. No Live Polling Results 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 82% Yes 18% No

5 Case Studies/Questions A 67-year-old man with NASH cirrhosis complicated by HCC just outside Milan; no living donor. Liver offer: a 4-year-old otherwise good donor, HCV+ Accept offer? Would you accept a liver offer of a 4-year-old otherwise good donor, HCV+? 1. Yes 2. No Live Polling Results 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 54% Yes 46% No

6 Back in the Day HCV as an important indication for transplantation Natural history with and without Tx DDLT versus LDLT Waiting for the next new drug HCV recurrence and outcomes Impact on outcomes and need for retreatment Tolerability of HCV therapies both before and after treatment Timing, efficacy, and effectiveness of HCV therapies Use of HCV+ donors Use of older donors (>4) Today Where Tomorrow Begins Treatment options perfection is the enemy of good with respect to available organs Timing of treatment Before makes intuitive sense, but so does after Making our waitlists HCV- has disadvantaged HCV+/- recipients because we can no longer use HCV+ donors Management of post-tx Maintenance immunosuppression Biopsy vs empiric Rx for elevated LFTs Ethical concerns should we allocate HCV+ organs to all HCV- recipients (including HCV+/-) just because we have an effective treatment? Cost Questions for Tomorrow Should we develop criteria for who gets treated before and who gets treated after Tx? What about living donors who are HCV+/-? Will patients who meet criteria for Tx get better with HCV treatment? Will the risk of HCC remain the same even with effective treatment?

7 Closing Comments We should recognize and applaud the development of these HCV treatments that now cause us to ask these questions. Truly the only true cure, other than a vaccine, that I have witnessed in >25 years in practice. Thank you. HCV Pharmacotherapy: Efficacy in the Pre- and Post-transplant Settings Steven L. Flamm, MD Chief, Liver Transplantation Professor of Medicine and Surgery Northwestern University Feinberg School of Medicine Chicago, IL Clinical Considerations in the Pre-transplant Setting Patients with decompensated cirrhosis have differential metabolism of drugs/metabolites that could affect efficacy and toxicity. Patients with decompensated disease are more susceptible to renal failure; this could cause differential metabolism of drugs/metabolites that could affect efficacy and toxicity. Treatment of patients may affect organ availability, as patients would NOT be eligible for HCV+ organs. Patients with decompensated disease may improve slightly, lowering the MELD score and thereby lowering priority for liver allocation.

8 HCV Management in Decompensated Cirrhosis LDV/SOF + RBV: SVR12 in Genotype 1 or 4 with Decompensated Cirrhosis Comparable efficacy between SOLAR-1 and SOLAR-2 studies LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks SVR12 (%) SVR12 (%) n/n = 26/ 3 24/ 27 19/ 22 18/ 2 CTP B CTP C SOLAR-1: GT 1 and 4 [1.2] 2 n/n = 2/ 23 CTP B 22/ 23 17/ 2 13/ 18 CTP C SOLAR-2: GT 1 [3] AE, adverse event; CTP, Child-Turcotte-Pugh; LDV, ledipasvir; RBV, ribavirin; SAE, serious adverse event; SOF, sofosbuvir. 1. Charlton M, et al. Gastroenterology, 215 [epub ahead of print] 2. Flamm SL, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. LDV/SOF + RBV: Safety in Advanced Liver Disease Pre OLT Safety Outcome, n (%) Pre-transplant CTP B + C (n = 215) Grade 3/4 AE 51 (24) SAE 61 (28) Serious treatment-related AE 5 (2) AE leading to discontinuation of LDV/SOF 9 (4) > 2 patients HCC Sepsis 2 (<1) 2 (<1) Death 1 (5) Liver Transplantation 11 (5) Treatment-related serious adverse events (SAEs) mostly related to RBV No deaths or D/C attributed to treatment with study drug (LDV/SOF) Samuel D, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Poster P774. SOLAR-1 and SOLAR-2

9 LDV/SOF + RBV: Change in MELD Score from Baseline to Follow-up Week 4 in CTP B or C Disease 4 Pre/Post-transplantation (CTP B and C; n = 136)* * (8) Change in MELD Score n = 18-1 (-11) (-17) ** *Missing FU-4: n = 24. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. SOLAR-2 Real-world Efficacy of SOF/SMV ± RBV & SOF/RBV Regimens in Cirrhosis Pts With MELD > 1 HCV-Target Network: North America, Germany, Israel SOF + RBV (n = 12) SOF + SMV (n = 117) SOF + SMV + RBV (n = 34) SVR12 (%) GT1 Naive GT 1Exp d GT 2 GT 3 MELD 1-15 MELD MELD > n/n = 3/7 31/4 6/1 8/14 8/ 14 48/67 48/ 67 13/19 21/26 1/26 37/67 67/92 19/28 5/8 7/1 2/3 /1 6/6 1/1 Reddy RK, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract O7. HCV-TARGET HCV-TARGET: SAEs, Death, Liver Transplantation SOF/RBV N=88 SOF/SMV N=114 SOF/SMV/ RBV N=32 Total N=234 Total patients with SAEs, N (%) 27 (31) 8 (7) 9 (26) 44 (17) Hepatic decompensation* 1 (11) 2 (2) 4 (12) 16 (6) Infections 2 (2) 1 (3) 1 (4) Death 2 (2) 1 (3) 3 (1) Unspecified 1 (3) 1 (.4) Hepatic Failure 1 (1) () 1 (.4) Shock 1 (1) 1 (.4) Underwent OLT on treatment 4 (5) 3 (3) 5 (16) 12 (5) *Hepatic encephalopathy, variceal bleeding, hepatic failure, hepatic hydrothorax, bacterial peritonitis Reddy RK, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract O7.

10 Management of HCV in Decompensated Cirrhosis: Future Options Treatment of Decompensated HCV Cirrhosis in Patients with Diverse Genotypes: 12 weeks Sofosbuvir and NS5A Inhibitors With/Without Ribavirin Non-randomized observational cohort study of National Health Service of England (N = 467) Patients received 12 weeks SOF + LDV or DCV ± RBV at treating MD discretion (non-randomized) 12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV P< N = All GT1 GT3 Other GT SVR12, % (ITT) DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat. Foster GR, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract O2. SOF + DCV + RBV for 12 Weeks in Patients With Genotype 1 HCV and Cirrhosis SVR12, % Treatment naïve or treatment experienced adults with any HCV genotype DAA failures allowed, except NS5A All Genotypes a 1b Genotype Child-Pugh score: A, B, or C MELD scores 8-4 Hepatocellular carcinoma allowed Poordad F, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract LO8. SVR12, % /12 3/32 9/16 A B C Child-Pugh class ALLY-1

11 European Compassionate Use Program (CUP): SOF + DCV ± RBV for 24 Weeks 24-wk DCV + SOF 24-wk DCV + SOF + RBV All patients SVR12, % n/n = 39/ 4 19/ 2 58/ 6 24/ 24 A B C CP Score Treatment naïve or treatment experienced CP Category: 57% CP A; 36% CP B; 6% CP C MELD Scores: >5% had MELD Scores 9 and < 15 DCV dose determined by country; inclusion of RBV based on physician discretion 21/ 22 45/ 46 1/1 1/1 2/2 Welzel TM, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract P772. Summary: Management of HCV in Decompensated Cirrhosis Patients with decompensated liver disease generally tolerate current regimens well, and SVR rates approach the rates observed in patients with compensated cirrhosis. The regimens are generally well tolerated in the decompensated population. New regimens will likely be available in the near future to add to our armamentarium for HCV. Note: Daclatasvir was approved on July 24, 215 for use with sofosbuvir for treatment of chronic HCV genotype 3 infection Ribavirin is still used in current regimens; it is reasonably well tolerated, but hemoglobin must be monitored carefully and renal dysfunction can be problematic. AASLD/IDSA/IAS USA: Recommendations for testing, managing, and treating hepatitis C. Accessed June 1, 215. Press Release. HCV Management in the Post-transplant Setting

12 Clinical Considerations: Post-transplant Setting Post-liver transplantation patients with HCV recurrence may have an aggressive natural history with fibrosing cholestatic hepatitis or, more commonly, a relatively rapid progression to cirrhosis. The leading cause of mortality in the post-transplantation setting for HCV is recurrent HCV; hence, eradication of HCV in this population is very important. Post-liver transplantation patients are more susceptible to renal insufficiency; this could cause differential metabolism of drugs/ metabolites that could affect efficacy and toxicity ribavirin may be problematic. Drug-drug interactions with immunosuppression agents (particularly calcineurin inhibitors) may affect dosing of anti-viral agents and the other agent. Recommendations for Recurrent HCV Infection Post-liver Transplantation: HCV Genotype 1 Recommended regimen for treatment-naïve and -experienced patients with HCV genotype 1 or 4 infection in the allograft, including compensated cirrhosis Alternative regimen for treatment-naive patients with HCV genotype 1 or 4 infection in the allograft with compensated liver disease who are RBV intolerant or ineligible. Alternative regimen for patients with HCV genotype 1 in the allograft, including compensated cirrhosis. Alternative regimen for patients with HCV genotype 1 in the allograft, including early (Metavir fibrosis stage F-F2) recurrence. Daily fixed-dose combination of ledipasvir (9 mg)/sofosbuvir (4 mg) with weight-based RBV (1 mg [<75 kg] to 12 mg [ 75 kg]) for 12 weeks Daily fixed-dose combination of ledipasvir (9 mg)/sofosbuvir (4 mg) for 24 weeks Daily sofosbuvir (4 mg) plus simeprevir (15 mg) with or without weight-based RBV (1 mg [<75 kg] to 12 mg [>75 kg]) for 12 weeks Daily fixed-dose combination of paritaprevir (15 mg)/ritonavir (1 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (25 mg) and weight-based RBV (1 mg [<75 kg] to 12 mg [>75 mg]) for 24 weeks AASLD/IDSA/IAS USA: Recommendations for testing, managing, and treating hepatitis C. Prevention of Post-transplant HCV Week SOF 4 mg + RBV 1 12 mg (n=61) ptvr12 Entry criteria DDLT candidates with HCV and HCC meeting MILAN criteria MELD <22 and HCC-weighted MELD 22 CTP 7 Enrollment at 16 sites across 8 UNOS regions and 2 international sites 61 patients enrolled Original protocol: 24 weeks of treatment or until LT Amendment: extend treatment duration to 48 weeks or LT Curry M, et al. Gastroenterology. 215;148:1-17.

13 Prevention of Post-transplant HCV: On-treatment Viral Response Mean Change in HCV RNA ± SD (log 1 IU/mL) BL HCV RNA Change from Baseline (n=61) Study Week Patients (%) HCV RNA <LLOQ Before Transplant /33 41/44 12 Week Treatment Any Treatment Curry M, et al. Presented at AASLD; November 1-5, 213; Washington, DC. Abstract 213. Prevention of Post-transplant HCV: Post-transplant Virologic Response /44* 25/39* Transplant ptvr12 Subjects with HCV RNA <LLOQ (%) *3 subjects were >LLOQ at transplant. 1 subject has not reached ptvr12, 1 subject LTFU at Week 8 post-transplant. Viral Response Rate (%) Curry M, et al. Presented at AASLD; November 1-5, 213; Washington, DC. Abstract 213. PTV/OMB/DSB + RBV: Genotype 1 Patients After Liver Transplantation PTV/OMB/DSB + RBV (n=34) SVR12 Day Week 24 To Week 72 PTV/OMB/DSB: co-formulated paritaprevir/r/ombitasvir, 15 mg/1 mg/25 mg QD; dasabuvir, 25 mg BID RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol Kwo PY, et al. N Engl J Med. 214;371(25): CORAL-I

14 PTV/OMB/DSB + RBV: SVR Rates in Genotype 1 Liver Transplant Patients 1% 1% 97% 97% 97% 9% 8% 7% 6% 5% 4% 3% 2% 1% 34/34 33/34 33/34 33/34 % EOTR SVR4 SVR12 SVR24 No patient had breakthrough One patient had a relapse (post-treatment day 3) At the time of relapse, this patient had R155K in NS3 protease, M28T+Q3R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline Kwo PY, et al. N Engl J Med. 214;371(25): CORAL-I LDV/SOF + RBV: Genotype 1 and 4 With Advanced Liver Disease Week Week 12 Week 24 Week 36 LDV/SOF + RBV SVR12 LDV/SOF + RBV SVR12 SOLAR-1 Treatment naïve or experienced CTP Class B CTP Class C Post liver transplantation SOLAR-2 Treatment naïve or experienced CTP Class B CTP Class C Post liver transplantation Charlton M, et al. Gastroenterology, 215 [epub ahead of print] Reddy RT, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract 8. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2. SOLAR-1 and SOLAR-2 SVR12 Rates in OLT Patients Receiving LDV/SOF + RBV weeks LDV/SOF + RBV 24 weeks LDV/SOF + RBV 8 SVR12 (%) n/n = 53/55 55/56 25/26 24/25 22/26 15/18 3/5 2/3 F-F3 CTP A CTP B CTP C In the 24-week arm, 8 patients with CTP B and 1 patient with CTP C have not reached the follow-up week 12 visit MELD scores improved from baseline through follow-up Week 4 in 15/48 patients with CTP A and 8/41 patients with CTP B disease Charlton M, et al. Gastroenterology, 215 [epub ahead of print] Reddy RT, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract 8. SOLAR-1

15 Post-transplant HCV RNA Outcomes for SOF + SMV ± RBV: Genotype 1 Interim Analysis 1 9% 87% 95% 88% 96% 88% 95% 9% 8% 8 SVR % /14 Overall 52/6 42/44 Tx Experienced Yes No 51/58 27/28 Genotype 1a 1b 59/67 35/37 Cirrhotic Yes No 19/21 8/1 MELD < 1 1 O'Leary J, et al. Presented at: American Transplant Congress; May 2-6, 215. Abstract 148. HCV-TARGET Clinical Considerations in Patients with Renal Impairment Dose Adjustments in Chronic Kidney Disease Creatinine Clearance PEG-IFN alfa 2a, μg/wk PEG-IFN alfa 2b, μg/kg/wk Ribavirin Daily > 5 ml/min mg/day 3-5 ml/min Alternating doses, 2 mg and 4 mg every other day Less than 3 ml/min mg/day Hemodialysis mg/day Creatinine Clearance Sofosbuvir Simeprevir Ledipasvir/ sofosbuvir PTV/OMB/DSB 6-89 (Mild) 4 mg 15 mg 9 mg/4 mg 75/5/12.5 mg + 25 mg 3-59 (Moderate) 4 mg 15 mg 9 mg/4 mg 75/5/12.5 mg + 25 mg (Severe) No data 15 mg No data 75/5/12.5 mg + 25 mg <15 (Kidney failure/dialysis) No data No data No data 75/5/12.5 mg + 25 mg AASLD/IDSA/IAS USA: Recommendations for testing, managing, and treating hepatitis C. Accessed June 1, 215. See prescribing information:

16 Summary Treatment of patients with current regimens post-liver transplantation is now possible, with very high expected SVR rates. Drug-drug interactions must be accounted for, particularly with protease inhibitors and calcineurin inhibitors. Renal insufficiency must also be accounted for, with appropriate dose modifications of anti-viral medications implemented. Case Presentation: IFN-free Therapy in the Pre-transplant Setting Paul Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Indiana University Indianapolis, IN Case Presentation A 64-year-old white male with hepatitis C genotype 1a presents to your transplant clinic with decompensated cirrhosis. He was recently hospitalized for spontaneous bacterial peritonitis. Ascites is moderately controlled with diuretics. Encephalopathy is controlled with lactulose. Varices have been banded.

17 Case Presentation Medications: lactulose, rifaximin, furosemide, spironolactone, trimethoprim sulfamethoxazole Exam: BP: 9/6 mm Hg, pulse: 84, R: 18, temp: 37 HEENT: mild icterus Lungs : clear Cor: RRR, soft systolic murmur Abd: moderate ascites, splenomegaly Ext: muscle wasting, spider angiomata Neuro: asterixis Database Hgb: 1.6 g/dl, Platelets: 55,/mm 3, WBC: 2.1 x 1 9 /L TB: 3.3 mg/dl, AST: 58 IU/L, ALT: 31 IU/L INR 1.7, Cr 1.4 mg/dl (MELD 2) Blood group A, hepatitis C viral load 4, IU/mL MRI: small nodular liver, mild ascites, patent vessels, intra-abdominal varices Please Select Your Approach 1. Evaluate and list for transplant with the plan to treat him post-transplantation 2. Follow patient closely 3. Initiate ledipasvir/sofosbuvir with 6 mg RBV for 12 weeks 4. Initiate sofosbuvir/rbv for up to 48 weeks 5. Not sure

18 Live Polling Results 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 38% Evaluate/list for transplant and treat posttransplant 5% Follow patient closely 52% Initiate LDV/SOF w/ 6 mg RBV for 12 wks 3% 2% Initiate SOF/RBV for up to 48 wks Not sure Case Presentation: Discussion Safety and Tolerability of HCV Pharmacotherapy: Focus on Drug-drug Interactions Michael R. Charlton, MD, FRCP Professor of Medicine Medical Director of Hepatology and Liver Transplantation Intermountain Medical Center Salt Lake City, UT

19 Safety Paritaprevir + RTV + Ombitasvir + Dasabuvir + RBV in LT Recipients With Recurrent HCV Genotype 1 Infection Phase 2 single-arm trial of 3D regimen for 24 weeks in 34 adult liver transplant recipients with recurrent HCV GT1 infection, fibrosis stage F2, excluding post-transplant treatment experience Pre-Rx on-rx Adjusted doses of TAC:.5 mg/week or.2 mg every 3 days Adjusted dose of CYA: 1/5 th daily dose Tacrolimus Concentration (ng/ml) * SVR12 of 96% Kwo P, et al. N Engl J Med. 214;371: * 4 patients experienced a TAC level > 15 ng/ml ( ng/ml); All 4 patients had TAC dosing errors; 2 patients had associated creatinine increases (1.8 and 1.4 mg/dl), which normalized when dosing was corrected. Results: Overall Safety Summary 3D Regimen Symptom N, (%) AEs 33 (97%) Serious AEs 2 (6%) Treatment discontinuation due to AE 1 (3%) Fatigue 17 (5%) Headache 15 (44%) Anemia 1 (29%) Grade 2 Anemia (Hb 8, <1 g/dl) 9 (26%) Grade 3 Anemia (Hb < 8 g/dl) 1 (3%) No on-treatment rejection Kwo P, et al. N Engl J Med. 214;371: CORAL-I

20 Results: Overall Safety Summary GT 1 or 4: Post-transplant F F3, CTP A, B, C F-F3 CTP A CTP B CTP C Patients, n (%) 12 Wk n=55 24 Wk n=56 12 Wk n=26 24 Wk n=25 12 Wk n=26 24 Wk n=26 12 Wk n=5 24 Wk n=4 AEs 55 (1) 55 (98) 25 (96) 24 (96) 25 (96) 26 (1) 5 (1) 4 (1) Grade 3 4 AEs 15 (27) 14 (25) 4 (15) 7 (28) 6 (23) 9 (35) 1 (2) 1 (25) Serious AEs 6 (11) 12 (21) 3 (12) 4 (16) 5 (19) 11 (42) 1 (2) 4 (1) Serious and related AEs 2 (4) 1 (2) 2 (8) 2 (8) 1 (4) Treatment DC due to AE 2 (4) 1 (4) 3 (12) Treatment emergent Death 1 (4) 1 (4) 2 (8) AE s leading to DC: shortness of breath, hemoperitoneum, thoracic aorta aneurysm dissection, seizure, elevated ALT/AST, dyspnea Charlton M, et al. Gastroenterology, 215 [epub ahead of print]. Overall Safety Summary* Results SOLAR-1 and -2 Combined Post-transplant Patients, n (%) F-F3 + CTP A n=33 CTP B + C n=114 Total N=659 Any AE 316 (96) 19 (96) 633 (96) Grade 3 or 4 AE 76 (23) 33 (29) 16 (24) SAE 49 (15) 34 (3) 144 (22) Serious treatment-related AE 1 (3) 4 (4) 19 (3) AE leading to d/c of LDV/SOF 5 (2) 5 (4) 19 (3) Death 4 (1) 6 (5) 2 (3) Rejection episode 1 1 Graft loss 1 2 Liver transplantation 11 *Between first dose and 3 days post-dose. Charlton MR, et al. Presented at: DDW; May 17-19, 215; Washington, DC. Oral Presentation 226. Combined SOLAR-1 and -2 Treatment-emergent Serious Adverse Events Results Patients, n (%) Pre-transplant CTP B + C n=215 Post-transplant F-F3 + CTP A n=33 CTP B + C n=114 SAEs were mostly due to progression of decompensated liver disease. Total N=659 Any SAE 61 (28) 49 (15) 34 (3) 144 (22) Anemia 4 (2) 7 (2) 3 (3) 14 (2) Hepatic encephalopathy 1 (5) 1 (<1) 2 (2) 13 (2) Renal failure acute 3 (1) 3 (1) 4 (4) 1 (2) Sepsis 4 (2) 4 (4) 8 (1) Ascites 4 (2) 2 (2) 6 (1) Gastric variceal hemorrhage 4 (2) 1 (<1) 1 (1) 6 (1) Diarrhea 1 (<1) 3 (1) 1 (1) 5 (1) Pneumonia 4 (2) 1 (1) 5 (1) Charlton MR, et al. Presented at: DDW; May 17-19, 215; Washington, DC. Oral Presentation 226.

21 Laboratory Values Over the First 12 Weeks of Treatment and Follow-up Week 4 Median creatinine remained at baseline levels during and after treatment Charlton MR, et al. Presented at: DDW; May 17-19, 215; Washington, DC. Oral Presentation 226. Conclusions: Safety 3D/RBV x 24 weeks and LDV/SOF/RBV x 12 weeks can be used safely and with high efficacy in mild fibrosis stages (F-2) of recurrence. LDV/SOF/RBV x 12 weeks can be used safely and with high efficacy in moderate and severe stages of recurrence. Drug-Drug Interactions

22 LDV/SOF: Metabolism Sofosbuvir: 8% of dose excreted in urine (most as 7) - 7 t 1/2 is 27 hours AUC (% increase) compared to GFR >8 Mild Moderate Severe SOF 61% 17% 171% % 85% 451% HD: 12-2 fold increase in 7 AUC Ledipasvir: Primarily eliminated in feces (>7%) Limited (<2.%) urinary excretion No changes in exposure with GFR <3 Cornpropst M, et al. Presented at: EASL; April 18-22, 212; Barcelona, Spain. Abstract 111; Kirby B, et al. Presented at: International Workshop on Clinical Pharmacology of Hepatitis Therapy; June 26-27, 213; Cambridge, MA. Poster O22; HARVONI (ledipasvir and sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences; October 214. SOVALDI (sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences; December D Regimen: Metabolism All components: hepatic metabolism <2% excreted in urine AUC (% increase) when GFR <3 PAR RTV OMB DAS Cmax 66% AUC 45% 114% 5% OMB:Ombitasvir, PAR: Paritaprevir, RTV: Ritonavir, DAS: Dasabuvir VIEKIRA PAK (ombitasvir, paritaprevir and ritonavir + dasabuvir) tablets [package insert]. North Chicago, IL: AbbVie Inc.; December 214. Transporter-mediated Interactions Like enzymes, transporter expression can be induced and transporter function can be inhibited. OATP1B1 Hepatocyte P-gp, MRP2, BCRP, BSEP

23 DAAs as Victims (Other drugs affect DAA metabolism or transport) Medication Daclatasvir Ledipasvir Sofosbuvir Simeprevir Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cyclosporine 4% 4% ND ND 154% 353% 374% 481% Tacrolimus 7% 5% ND ND 3% 13% 79% 85% Dick TB, et al. Hepatology [Epub ahead of print] DAAs as Culprits Medication Ribavirin Cyclosporine Tacrolimus Sirolimus Everolimus Cmax AUC Cmax AUC Cmax AUC Cmax AUC Ledipasvir ND ND ND ND ND ND Sofosbuvir 27% 9% ND ND ND ND Simeprevir 16% 19% 24% 17% ND ND ND ND Daclatasvir 4% 3% 5% ND ND ND ND 3D Regimen 1% 482% 299% 5613% Expected increase in both Cmax and AUC. Expected increase in both Cmax and AUC. HCV infection inhibits cytochrome P45 through direct and indirect mechanisms. SVR leads to lower CNI levels and risk of ACR. Dick TB, et al. Hepatology [Epub ahead of print] Effect of Proton Pump Inhibition and Juices on Gastric ph Gastric PH is very variable in patients who have PPI administration and giving a drug at the same time as a PPI, you'll still have a gastric ph of about 4 Abu-Sneineh A, et al. Aliment Pharmacol Ther. 21;32(8):

24 Effect of Proton Pump Inhibition (PPI) and Juices on Gastric ph ph US Food and Drug Administration. Omeprazole Magnesium Tablets October 2, 2. Document #NDA No Effect of Proton Pump Inhibition (PPI) and Juices on Gastric ph ph Gastric production falls by 96% on 6 mg/day of omeprazole 1 It takes 3-5 days for gastric acid secretion to return to normal after discontinuation of PPI. Requires generation of new proton pumps..5 US Food and Drug Administration. Omeprazole Magnesium Tablets October 2, 2. Document #NDA No Conclusions: Acid Suppression Stop PPIs and transfer to H2 receptor agonists when possible PPIs often started at LTx for reasons that do not persist (eg, MMF) If the patient must use a PPI, 2 mg/day equivalent of omeprazole, give with cranberry juice at same time as PPI

25 Renal Failure What Do the Package Labels Say About Renal Impairment? Drug/Regimen SOF LDV/SOF SMV 3D + RBV RBV Label Language No dose adjustment for mild-moderate renal disease. No dose recommendation can be given for egfr <3 ml/min/1.73m 2 or ESRD. Accumulation of SOF metabolite (GS-3317) up to 2x expected. Safety and efficacy not established. Same as SOF alone. No dose adjustment necessary for mild, moderate, or severe renal impairment. Not studied in patients with GFR <3 or on dialysis. No dose adjustment necessary for mild, moderate, or severe renal impairment. Not studied in patients on dialysis. Moderate (3-5 ml/min): 2 mg/4 mg alternating QOD Severe or HD (<3 ml/min): 2 mg QD See individual prescribing information at Can SOF Be Used Effectively and Safely in Advanced Renal Disease? Pilot study of SOF/RBV in those with severe renal impairment (egfr<3) or on HD 1 non-cirrhotic GT1 or 3 subjects Study Design Week Part 1 n=2 Part 2 n=2 SOF 2 mg QD + RBV SVR12 SOF 4 mg QD + RBV SVR12 SOF 2 mg QD + RBV QD: once daily; SVR12: sustained virologic response at post-treatment week 12. SVR12 SOF 4 mg QD + RBV SVR12 Gane EJ, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Poster 966.

26 SOF and 7 Plasma Exposures Gane EJ, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Poster 966. Label Be Damned Real-world Experience with SOF/SMV in ESRD Miami: 16 patients GFR <15 or HD 42% naïve, 58% cirrhotic SOF 2 mg QD + SMV 15 mg QD; no RBV 3 patients: SOF 4 mg QOD with SMV Texas: 11 patients GFR <3 or HD 82% naïve, 47% cirrhosis SOF 4 mg QD + SMV 15 mg QD; no RBV 88% on HD SVR12(%) U Miami 1 SVR12 1a 1b 11 Texas Czul F, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Poster P878. Nazario HE, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Poster P82. 3D + RBV in Treatment-naïve Patients With ESRD Ombitasvir/Paritaprevir Ritonavir + Dasabuvir Ombitasvir/Paritaprevir Ritonavir + Dasabuvir + RBV 2 patients enrolled; SVR4 data on 1 1% SVR4 8/13 genotype 1a with RBV dose interruption Pockros PJ, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Oral Presentation LO1.

27 Grazoprevir/Elbasvir in ESRD GZR/EBR: both <1% renal elimination No dose adjustment needed 94% SVR12 81% CKD stage 5 (GFR <15 or HD) GZR: HCV NS3/4A inhibitor EBR: HCV NS5A inhibitor Roth D, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Poster LP2. Conclusions: Post-transplant Renal Insufficiency In patients with recurrent HCV post transplantation and GFR > 3 ml/min, prescribe normally for DAAs In patients with recurrent HCV post transplantation and GFR 3 ml/min: Consider 3D, if compensated liver disease Use SOF-based regimens with caution For RBV in moderate (GFR 3-5 ml/min): 2 mg/4 mg alternating QOD For RBV in severe or HD (<3 ml/min): 2 mg QD Case Presentation: IFN-free Therapy in the Post-transplant Setting Paul Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Indiana University Indianapolis, IN

28 Case Presentation A 61-year-old African-American woman with hepatitis C genotype 1b is seen in the posttransplant clinic She was transplanted for HCV cirrhosis with a 3.5 cm hepatoma Her postoperative course was unremarkable She returns for 6-month visit Case Presentation Medications: Tacrolimus 1 mg BID, trimethoprim sulfamethoxazole, metoprolol 5 mg BID Exam: BP: 13/6 mm Hg, pulse: 64, R: 18, temp: 36 HEENT: Normal Lungs : Clear Cor: RRR Abdominal: Subcostal scar well healed Database Hgb: 11.2 g/dl, Platelets 155,/mm 3, WBC: 2.9 x 1 9 /L TB: 1.8mg/dL, AST: 98 IU/L, ALT: 131 IU/L INR: 1., Cr: 1.4 mg/dl Hepatitis C viral load > 17,, IU/mL CT: Transplanted liver, mild residual splenomegaly, no varices, no recurrent hepatoma

29 Please Select Your Next Step 1. Staging liver biopsy and treat if > F2 fibrosis 2. Elastography and treat if > 9 kpa 3. See patient back at 1 year 4. Initiate therapy for hepatitis C 5. Not sure Live Polling Results 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 13% 12% Staging liver biopsy - treat if >F2 Elastography - treat if >9 kpa 1% See patient in 1 year 73% Initiate Tx for HCV 1% Not sure Case Presentation: Discussion

30 Please Select Your Therapy of Choice 1. Sofosbuvir 4 mg + ribavirin 1-12 mg daily 2. Ledipasvir / sofosbuvir for 24 weeks 3. Ledipasvir / sofosbuvir / ribavirin 6 mg for 12 weeks 4. Ombitasvir, paritaprevir, ritonavir / dasabuvir / ribavirin 6 mg for 24 weeks 5. Something else Live Polling Results 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 8% SOF 4 mg/ RBV 1-12 mg daily 21% LDV/SOF 24 weeks 56% LDV/SOF/RBV 6 mg for 12 weeks 15% % OMB/PTV/r Something else DSB/RBV 6 mg for 24 weeks Case Presentation: Discussion

31 What if Her hemoglobin was 9 g/dl? What if She had genotype 2 infection? What if She had genotype 3 infection?

32 Fibrosing Cholestatic Hepatitis C What if she presented at month 6 with ascites and bilirubin of 17 mg/dl, alkaline phosphatase of 4 IU/mL with liver biopsy showing fibrosing cholestatic hepatitis? If she cleared virus and was still further decompensated, would you evaluate for repeat transplant? HCV and Nonhepatic Solid Organ Transplant: Focus on Renal, Heart, and Lung Transplant Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine HCV and Renal Disease HCV infection may lead to renal disease or be associated with renal disease Mixed cryoglobulinemia (type II cryoglobulins, or + RF) Membranoproliferative glomerulonephritis (MPGN) Polyarteritis nodosa Less common Focal segmental glomerular sclerosis Proliferative glomerulonephritis Membranous GN Fibrillary and immunotactoid glomerulopathies Diabetes (direct link to HCV) and hypertension common in HCV infection Fabrizi F, et al. Expert Opin Pharmacother. 215;16(12):

33 Dose Adjustments in Chronic Kidney Disease Creatinine Clearance PEG-IFN alfa 2a, μg/wk PEG-IFN alfa 2b, μg/kg/wk Ribavirin Daily > 5 ml/min mg/day 3-5 ml/min Alternating doses, 2 mg and 4 mg every other day Less than 3 ml/min mg/day Hemodialysis mg/day Creatinine Clearance Sofosbuvir Simeprevir Ledipasvir/ sofosbuvir PTV/OMB/DSB 6-89 (Mild) 4 mg 15 mg 9 mg/4 mg 75/5/12.5 mg + 25 mg 3-59 (Moderate) 4 mg 15 mg 9 mg/4 mg 75/5/12.5 mg + 25 mg (Severe) No data 15 mg No data 75/5/12.5 mg + 25 mg <15 (Kidney failure/dialysis) No data No data No data 75/5/12.5 mg + 25 mg No dosage adjustment of daclatasvir is required for patients with any degree of renal impairment. AASLD/IDSA/IAS USA: Recommendations for testing, managing, and treating hepatitis C. Accessed June 1, 215. See prescribing information: Total Kidney Transplants Transplants (in Thousands) All Deceased Donor Living Donor Year SRTR Report 212. Am J Transplant. 214;14 Suppl 1: Reprinted with permission. Adult Kidney Donor-recipient Hepatitis C Serology Matching, Deceased Donor Living Donor Recipient Neg. Pos. Unk. Total Neg. Pos. Unk. Total Negative Positive Unknown Total SRTR Report 212. Am J Transplant. 214;14 Suppl 1:5-192.

34 Shorter Waiting Times for HCV+ Patients Who Accept HCV+ Donor Kidney 1. Graft Survival (death-censored) Death Censored Graft Survival R+D+ vs R+D-, P.1 R-D- vs R+D-, P=.5 R+D+ vs R-D-, P=.6 n=195, R+D+ n=1418, R-Dn=66, R+D Post Transplant Years Waitlist times for patients accepting HCV+ grafts was 318 days (for R+/D+ patients) versus 613 days (R /D ) or 57 days (R+/D ) Scalea JR, et al. Transplantation. 215;99: Reprinted with permission. Renal Transplant Patients Renal transplantation is associated with a 68% reduction in long-term mortality compared to remaining on the waiting list Lower rate of hepatic fibrosis progression post renal transplant than prior to renal transplant (mean change in fibrosis.28±.64 vs.4±.26 per year (P=.8) Cumulative Hazard Transplant Occurred During the Past 6 Months (N=11, 9 Deaths, P=.2 vs Pretransplant Pretransplant (N=175, 28 Deaths Transplant Occurred Greater than 6 Months Ago 1 (N=95, 27 Deaths, P=.1 vs Pretransplant Months Since Listing Roth D, et al. J Am Soc Nephrol. 211:22: Reprinted with permission. HCV: Virologic Status of Renal Transplant Recipients Graft and Recipient Survival Graft 5 Patient 4 4 Survival Survival HCV 2 HCV Log-rank P=.7 1 Log-rank P= Survival Time (Years) HCV infection is associated with lower graft and recipient survival Gentil MA, et al. Nephrol Dial Transplant. 1999;14: Reprinted with permission.

35 Total Heart Transplants: 212 2,5 2, Transplants 1,5 1, Year SRTR 212 Annual report. Am J Transplant. 214;14 Suppl 1: Reprinted with permission. Heart Transplant SRTR database review HCV-positive and 2,244 HCV-negative heart recipients Mortality rates were higher among HCV-positive heart transplant recipients at 1 year, 5 years, 1 years, and 15 years post-transplantation Lee I, et al. J Heart Lung Transplant. 211;3: Total Lung Transplants Transplants 2, 1,5 1, 5 All Lung (Including HL) Bilateral Single Year First Transplant Retransplant Year SRTR 212 Annual report. Am J Transplant. 214;14 Suppl 1: Reprinted with permission.

36 Lung Transplants UNOS database HCV-positive recipients Survival was significantly lower in HCV-positive individuals (median survival: 3.8 vs 5.1 years; P=.5) Survival Probability Kaplan-Meier Survival Curves for HCV+ vs. HCV- Lung Transplant Recipients HCV- Recipient HCV+ Recipient Years HCV Recipient HCV+ Recipient Englum BR, et al. J Heart Lung Transplant. 214:53;S182-S183. Reprinted with permission. What About our Current Therapies? Drug-Drug Interactions TAC CYA Sirolimus Everolimus MMF AZA Ribavirin Sofosbuvir Ledipasvir P P Simeprevir Contraindicated P P Paritaprevir/ Y Y P Contraindicated P Ombitasvir/ Reduce TAC Reduce CYA to to.5 1/5 th of dose Dasabuvir weekly Daclatasvir P = No clinically significant interaction or no interaction expected Y= Interaction, adjustment required P = Potential interaction, monitor/adjust drug level Liverpool HEP ichart.

37 PTV/OMB/DSB + RBV: SVR Rates in Genotype 1 Liver Transplant Patients 1% 1% 97% 97% 97% 8% 6% 4% 2% 34/34 33/34 33/34 33/34 % EOTR SVR4 SVR12 SVR24 No patient had breakthrough 1 patient had a relapse (post-treatment day 3) At the time of relapse, this patient had R155K in NS3 protease, M28T+Q3R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline Kwo PY, et al. N Engl J Med. 214;371: CORAL-I PEARL-III: SVR12 and Virologic Failure Rates With 3D Regimen + RBV in HCV Genotype 1b Patients (%) % 3D Regimen ± RBV 99% 2.5% % With RBV No RBV With RBV No RBV (n=21) (n=29) (n=21) (n=29) SVR12 Virologic Failure Ferenci P, et al. Presented at EASL; London, England; April 9-13, 214. Abst. P1299. SOLAR-1 and SOLAR-2: Genotype 1 and 4 With Advanced Liver Disease Week Week 12 Week 24 Week 36 LDV/SOF + RBV SVR12 LDV/SOF + RBV SVR12 SOLAR-1 Treatment naïve or experienced CTP Class B CTP Class C Post liver transplantation SOLAR-2 Treatment naïve or experienced CTP Class B CTP Class C Post liver transplantation Reddy RT, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract 8. Manns M, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract G2.

38 SOLAR-1: SVR12 Rates in OLT Patients Receiving LDV/SOF + RBV weeks LDV/SOF + RBV 24 weeks LDV/SOF + RBV 8 SVR12 (%) n/n = 53/ 55 55/ 56 25/ 26 24/ 25 22/ 26 15/ 18 3/ 5 F-F3 CTP A CTP B CTP C 2/ 3 In the 24-week arm, 8 patients with CTP B and 1 patient with CTP C have not reached the follow-up week 12 visit MELD scores improved from baseline through follow-up Week 4 in 15/48 patients with CTP A and 8/41 patients with CTP B disease Reddy RT, et al. Presented at: AASLD; November 7-11, 214; Boston, MA. Abstract 8. Sofosbuvir (SOF) +Daclatasvir (DCV) +RBV 6 mg 12 weeks Post-liver transplant N = 53 DCV 6 mg QD + SOF 4 mg QD + RBV Week Week Week SVR12 a Follow-up Week 36 SVR12, % a All Patients Genotype 1 Primary Endpoint Poordad F, et al. Presented at: EASL; April 22-26, 215; Vienna, Austria. Abstract LO8. a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals. Preliminary Data Post Renal Transplant Retrospective chart review of all kidney transplant recipients treated with DAAs from September 213 November 214 at Indiana University with follow up data up to April 3, 215 Sofosbuvir (SOF) + Ribavirin (RBV) = 4 SOF + Simeprevir (SMV) = 6 SOF + SMV + RBV = 1 SOF + Ledipasvir (LDV) = 1 All receiving tacrolimus based immunosuppression 11/12 achieved SVR No change in Cr levels or tacrolimus levels Sharfuddin, et al. Presented at: ATC; Philadelphia, PA; May 5, 215. Abstract 334.

39 Hepatitis C and Nonhepatic Solid Organ Transplant There are all-oral DAA therapies for heart, lung, and kidney recipients Must be aware of drug-drug interactions Dose adjust for GFR Genotype 1, 4: SOF/LDV±RBV, SOF/DCV±RBV, PTV/OMB/DSB/RBV, SOF/SMV±RBV Genotype 2, 3: SOF/RBV, SOF/DCV±RBV