HCV treatment focusing on transplant setting in the era of DAA Yonsei University College of Medicine Gangnam Severance Hospital Jung Il Lee

HCV Prevalence Country Prevalence (%) Vietnam 6.1 Pakistan 5.3 Taiwan 4.4 Mainland China 3.2 Cambodia 2.3 Thailand 2.2 Indonesia 2.1 South Korea 1.3 Laos 1.1 Myanmar 0.9 India Japan 0.5 Philippines Singapore 0.4 Hong Kong 0.1 Nguyen LH, Nguyen MH. Aliment Pharmacol Ther 2013;37:921–36.

Annual proportion of liver transplantation Proportion of liver transplantation for HCV was gradually increased in Korea A total of 5,663 adult liver transplantations (LTs) were performed between 2000 and 2010. HCV-related liver disease was responsible for 277 LTs (4.9%). The annual proportion of LT for HCV fluctuated during the study period, but largely showed a gradually increasing pattern Although <20% of patients transplanted for HCV may have no significant lesions 5 years after LT, most recipients display progressive chronic hepatitis, which is clearly more aggressive than in immunocompetent subjects, and leads to cirrhosis in 10∼50% of recipients at 5 years post-LT. Annual proportion of liver transplantation for hepatitis C virus (HCV) Proportion (%) Year 8 2000 1.3 7 6 5 4 3 2 1 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2.9 5.6 3.0 2.2 5.2 3.7 6.3 7.4 5.3 Lee HW, et al. J Korean Soc Transplant. 2012;26:269-76.

HCV and Liver Transplantation Recurrence of HCV infection post-transplant occurs in nearly all transplanted patients Post–liver transplantation outcomes are worse for those who undergo transplantation for HCV than other etiologies Progression to graft cirrhosis and subsequent complications can be rapid and compromises patient and graft survival Fibrosing cholestatic hepatitis: 2 ~ 8% Peg-IFN + RBV-based therapy is poorly tolerated in patients with advanced liver disease on transplant waiting lists and also in post- transplant patients with deteriorating liver function

Post-transplant survival rate is lower in HCV+ recipient vs HCV- recipients 365 730 1095 1460 1825 2190 2555 2920 3285 3650 25 Days Since Transplant Patient Survival, % 50 75 100 HCV– HCV+ Factors Leading to Worse Outcome2 Donor/Recipient Donor age >60 y Female gender and non-white race HLA matching IL-28b genotype Pre-transplant Factors Higher recipient age High viral load Post-transplant Factors Prolonged ischemic time Shorter time to recurrence Treatment of acute rejection Higher immunosuppressive intensity Based on 2009 OPTN/SRTR Annual Report and deceased donor transplants Significant difference in unadjusted 3-year and 5-year patient survival between HCV-positive (82%, 75%) and HCV-negative (86%, 81%, P<0.0001) recipients with living donor liver transplants 1. Thuluvath et al. Am J Transplant. 2010 ;10(4 Pt 2):1003; 2. Wertheim et al. Am J Transplant. 2011;11:1773.

Problems concerning treatment In Pre- and Post-transplant setting has been… Pre-transplantation Poor tolerance of Peg-IFN regimens Impaired hepatic metabolism Renal insufficiency Post-transplantation Impact of immunosuppression Drug–drug interactions Rejection Outcome of recurrence: accelerated fibrosis in post-transplant patients with recurrence Overall SVR rates with Peg-IFN plus RBV are low, ranging between 10 and 40%

Progress in HCV Treatment The great days are coming !! ≒ 90~100 Boceprevir or Telaprevir + P/R Simeprevir or Sofosbuvir + P/R 67~75 Interferon + Ribavirin SVR (%) 2011 54~56 2013 2015 GT1 IFN-free DAA combinations (GT1) 1991 1998 2001 38~43 GT2/3 Peginterferon/ Ribavirin 25~30 Standard Interferon 2013 15~20 8~12 Sofosbuvir + Ribavirin IFN 6m IFN 12~18m IFN/RBV 6~12m PegIFN 6~12m PegIFN/RBV 6~12m PI + PegIFN/RBV 6~12m DAAs

Direct Acting Agents (DAAs) p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3 NS5A NS5B The NS3/4A serine protease is essential for post-translational processing of HCV polyproteins Multifunctional membrane-associated pho sphoprotein essential component of the H CV RNA replication complex NS5B is an HCV-specific RNA-dependent RNA polymerase Boceprevir Telaprevir Asunaprevir Simeprevir ABT-450/r Faldaprevir Danoprevir/r GS-9451 GS-9256 MK-5172 Vaniprevir SovaprevirACH-806/GS-9132 Daclatasvir Ledipasvir MK-8742 ABT-267 ACH-2928 ACH-3102 Samatasvir PPI-561 PPI-668 AZ-689 GSK2336805 Nucleos(t)ide analogues Sofosbuvir Mericitabine PSI-6130 VX-135 Non-nucleoside analogues ABT-333 BMS-791325 TMC-647055 VX-759, 222 Tegobuvir Setrobuvir Filibuvir

Sofosbuvir + Ribavirin to Prevent Post-Transplant HCV recurrence Curry MP, et al. Gastroenterology. 2015;148:100-7.

Sofosbuvir + Ribavirin to Prevent Post-Transplant HCV recurrence Virologic Response at Transplant and Post-Transplant Conclusions: “Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence.” 43/46 31/43 31/43 30/43 Data for the 43 patients with HCV RNA <25 IU/mL at time of transplant Curry MP, et al. Gastroenterology. 2015;148:100-7.

Days With HCV RNA Continuously TND Prior to Liver Transplant Duration of undetectable HCV RNA before transplant predicted lack of recurrence Median days undetectable(P < 0.001) No recurrence: 95 Recurrence: 5.5 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 330 30 60 90 120 150 180 210 240 270 300 Days With HCV RNA Continuously TND Prior to Liver Transplant > 30 days TND (target not detected) No recurrence (n = 28) Recurrence (n = 10) Curry MP, et al. Gastroenterology. 2015;148:100-7.

Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4 SOLAR-1 and SOLAR-2 study Week 0 12 24 36 Pre-Transplant CTP B (7–9) CTP C (10–12) LDV/SOF + RBV SVR12 Post-Transplant Fibrosis (F0–F3) CTP A (5–6) LDV/SOF + RBV CTP B (7–9) SVR12 CTP C (10–12) FCH Broad inclusion criteria: No hepatocellular carcinoma (HCC) Total bilirubin ≤ 10 mg/dL, Hemoglobin ≥ 10 g/dL CrCl ≥ 40 mL/min, Platelets > 30,000/mL RBV dosing F0–F3 and CTP A cirrhosis: weight-based (< 75 kg = 1000 mg; ≥ 75 kg = 1200 mg) CTP B and C cirrhosis: dose escalation, 600–1200 mg/d Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4 Pre-Transplant Post-Transplant Total n=659 Patients, n (%) CTP B + C n=215 F0–3 + CTP A n=330 CTP B + C n=114 HCV GT, n (%) 1a 124 (58) 197 (60) 71 (62) 392 (59) 1b 78 (36) 111 (34) 36 (32) 225 (34) 4 13 (6) 22 (7) 7 (6) 42 (6) IL28B non-CC, n (%) 167 (77) 272 (83) 92 (81) 431 (81) Prior HCV treatment, n (%) 150 (70) 270 (82) 96 (84) 516 (78) Cirrhosis, n (%) 215 (100) 118 (36) 114 (100) 447 (68) Median eGFR, mL/min/1.73 m2 (range) 84 (34–224) 63 (20–132) 64 (29–124) 69 (20–224) MELD, n (%) <10 24 (11) 64 (54) 26 (23) 114 (26) 10-15 132 (61) 51 (43) 69 (61) 252 (56) 16–20 54 (25) 3 (3) 16 (14) 73 (16) 21–25 5 (2) 8 (2) Median albumin, g/dL (range) 2.8 (1.6–4.0) 3.9 (2.4–4.8) 3.0 (1.6–4.2) NR Median platelets, x 103/µL (range) 76 (27–212) 136 (35–434) 90 (32–237) Ascites, n (%) 163 (76) 9 (3) 83 (73) Encephalopathy, n (%) 140 (65) 4 (1) 53 (46) Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

Sofosbuvir-Ledipasvir + Ribavirin in Pre-transplant HCV GT 1,4 SOLAR-1 SOLAR-2 SVR12 (%) 26/30 22/26 24/27 24/25 19/22 17/21 20/23 14/20 LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks CTP B CTP C Comparable efficacy between SOLAR-1 and SOLAR-2 studies The SVR12 analysis included all subjects except those who had undergone transplantation prior to SVR12 at last visit prior to transplantation. Error bars represent 90% confidence intervals. Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

Sofosbuvir-Ledipasvir + Ribavirin in Post-transplant HCV GT 1,4 SOLAR-1 SOLAR-2 SVR12 (%) 78/81 82/86 79/81 64/65 22/26 21/22 23/26 19/19 3/5 1/3 3/4 3/4 LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks F0-F3 & CTP A CTP B CTP C Comparable efficacy between SOLAR-1 and SOLAR-2 studies The SVR12 analysis included all subjects except those who had undergone transplantation prior to SVR12 at last visit prior to transplantation. Error bars represent 90% confidence intervals. Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4 Pre-Transplant Post-Transplant Total n=659 Patients, n (%) CTP B + C n=215 F0–3 + CTP A n=330 CTP B + C n=114 Any AE 208 (97) 316 (96) 109 (96) 633 (96) Grade 3–4 AE 51 (24) 76 (23) 33 (29) 160 (24) Serious AE 61 (28) 49 (15) 34 (30) 144 (22) Serious treatment-related AE 5 (2) 10 (3) 4 (4) 19 (3) AE leading to D/C of LDV/SOF 9 (4) 5 (4) Death 10 (5) 4 (1) 6 (5) 20 (3) Rejection episode 1 Graft loss 2 Liver transplantation 11 Treatment-related SAEs were mostly related to RBV treatment Deaths and AEs that led to D/C of LDV/SOF were not attributed to study treatment LDV/SOF+RBV was safe and well tolerated in decompensated cirrhosis and post-transplantation Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

Liver Function Change from Baseline to Follow-Up Week 4 ‡ SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients Liver Function Change from Baseline to Follow-Up Week 4 MELD Score Change Change in CTP Class Pre/Post-Transplant (CTP B and C, n=136*) Baseline CTP A (5–6) n=73 B (7–9) n=100 C (10–12) n=54 Follow- up Week 4 CTP A (5–6) 67 (96) 31 (35) 2 (5) B (7–9) 3 (4) 57 (65) 20 (48) C (10–12) n=95 (-17) Change in MELD Score (-11) (+8) n=18 n=22 no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12 *Missing FU-4: n=24 Majority of patients showed improvements in MELD and CTP scores Manns, EASL, 2015, GO2

DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 Design: Multicenter, prospective, open-label, phase 3 study of daclatasvir plus sofosbuvir plus ribavirin in treatment-naïve and treatment-experienced patients with advanced cirrhosis or post-liver transplant HCV recurrence. Setting: Five centers in United States Entry Criteria - Treatment-naïve or treatment-experienced - Chronic HCV genotypes 1-6 - HCV RNA >10,000 IU/ml - Cirrhosis (compensated and decompensated) allowed - Post-liver transplant: received transplant ≥3 months prior to screening Outcome Measure: Primary = SVR12 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by Genotype DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by Genotype 50/60 26/34 11/11 4/5 5/6 4/4 0/0 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by CTP DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by CTP 50/60 11/12 30/32 9/16 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

ALLY-1: SVR12 Results for Post-Transplant Cohort by Genotype DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1 ALLY-1: SVR12 Results for Post-Transplant Cohort by Genotype Conclusion: “The pan-genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post-liver transplant recurrence or advanced cirrhosis.” 50/53 30/31 9/10 0/0 10/11 0/0 1/1 Poordad F, et al. Hepatology. 2016 January 11. [Epub ahead of print]

Guidance for Decompensated Cirrhosis KASL HCV Guidelines 2015 .

Guidance for Recurrent HCV Post Liver Transplant The is the summary of KASL guidelines for recurrent HCV after liver transplantation. Please pay attention to the changes that would come in the very near future. KASL HCV Guidelines 2015 .

Drug-Drug interactions between HCV DAAs and immunosuppresants Drug Class Drug DDI With CNIs Yes No Protease inhibitors Boceprevir ✔ Telaprevir Simeprevir CsA ✔ Tac ✔ ABT-450/RTV Nucleoside Sofosbuvir Nonnucleoside Dasabuvir NS5A Ledipasvir Daclatasvir Ombitasvir ✔ (in combo) Finally I would like to emphasize the drug-drug interactions especially between the immune suppressant and DAA that you might be using. You can always look up the information from the websites. www.hep-druginteractions.org (University of Liverpool) Tischer S et al. J Hepatol 2014;60:872-84.

Drug-Drug interactions between HCV DAAs and lipid lowering drugs EASL HCV Guidelines 2015 .

Drug-Drug interactions between HCV DAAs and cardiovascular drugs EASL HCV Guidelines 2015 .

Summary and Key Messages HCV eradication in advanced liver disease Reduces decompensation Does not prevent HCC Prevents HCV recurrence post-transplant IFN-based therapy is suboptimal in decompensated cirrhosis and post- transplantation Lower SVR rate Higher toxicity Data with new DAAs evolving Promise for IFN-free therapy pre- and post-transplant High efficacy and significantly improved tolerability As choices increase, the factors that are likely to influence treatment choices are Drug-Drug interactions Availability/Cost Previous treatment experience (resistance)

Cure Assessment Testing Treatment Counseling Screening Thank you !