HCV TREATMENT PRE- AND POST TRANSPLANTATION Mitchell L. Shiffman, MD, FACG Medical Director Liver Institute of Virginia Bon Secours Health System Richmond and Newport News, VA, USA IVer Liver Institute of Virginia Education, Research and Treatment for Patients with Liver Disease Bon Secours Health System HCV AND LIVER TRANSPLANTATION SURVIVAL 100 URVIVAL (%) S 90 80 70 60 50 SRTR database 1995-2005 0 1 2 3 4 5 YEARS ML Shiffman et al. Am J Transpl 2006; 6:1170-1187. Non-HCV HCV Copyright 2015 American College of Gastroenterology 1
HCV AND LIVER TRANSPLANTATION FIBROSIS PROGRESSION % of Patients 100 80 60 40 20 Cirrhosis Bridging Portal 0 N Yilmaz et al. Liver Transpl 2007; 13:975-983. 1 2 3 4 5 6-10 YEARS AFTER TRANSPLANTATION HCV AND LIVER TRANSPLANTATION TIMING OF TREATMENT Prevent transplant After transplant Prevent recurrence Liver Transplant Copyright 2015 American College of Gastroenterology 2
SIMEPREVIR-SOFOSBUVIR ADVANCED CIRRHOSIS ML Shiffman et al Am J Gastroenterol 2015; (in press) N: 120 Cirrhosis: 100% HCV Genotype 1A: 69% Prior PEGINF/RBV: 36% Prior PI/PEGINF/RBV: 15% Child class B, C: 21%, 12% Platelet < 70,000: 20% Hemoglobin < 10 gm: 10% Variceal bleeding: 15% Ascites: 10% Hepatic Encephalopthy: 22% Prior HCC: 3% Age >65 years: 20% Serum creatinine >1.5 mg: 5% PEGINF/RBV Intolerant: 15% SOFOSBUVIR/SIMEPREVIR SVR BY SELECTED PARAMETERS Category Parameter N SVR Age <65 years 96 77% >65 years 24 94% Prior Treatment IL28B HCV Genotype HCV RNA Titer ML Shiffman et al. Am J Gastroenterol 2015; (in press) None PEGINF/RBV TPVor BOC PEGINF/RBV CC CT TT 1A 1B < 1 million (IU/ml) 1-10 million (IU/ml) >10 million (IU/ml) 58 42 19 4 60 38 82 34 39 75 6 87% 75% 81% 100% 84% 74% 81% 83% 75% 87% 67% Copyright 2015 American College of Gastroenterology 3
SOFOSBUVIR/LEDEPISVIR ADVANCED CIRRHOSIS SOF/LDV/RBV SOF/LDV 0 12 24 Weeks of Treatment Male 67% Prior non-response 69% Prior non-response to 67% PI/PEGINF/RBV Genotype 1A 60% IL28B non-cc 79% Platelet count < 90 18% Albumin < 3.5 11% M Bourliere et al. AASLD 2014; A82 SOFOSBUVIR/LEDEPISVIR ADVANCED CIRRHOSIS M Bourliere et al. AASLD 2014; A82 12 weeks 24 weeks Relapsers N 5 Male 5 Genotype 1A 2 IL28B genotype CT/TT 4/1 Platelet count < 90 1 Albumin < 3.5 1 Esophageal varices 3 NS5A RAV 2 Copyright 2015 American College of Gastroenterology 4
LDV-SOF-RBV DECOMPENSATED CIRRHOSIS Chronic HCV genotype 1 N = 108 Child class B and C cirrhosis RBV starting dose 600 mg QD then increased as tolerated Death 6 patients (6%) Underwent liver transplant 4 (4%) Treatment 12 weeks 24 weeks Child Class B C B C N 30 29 23 26 SVR 87 89 86 90 S Flamm et al. AASLD 2014; A239 TREATMENT OF ADVANCED CIRRHOSIS CHANGE IN MELD SCORE CHILD CLASS B CHILD CLASS C 12 weeks 24 weeks 12 weeks 24 weeks S Flamm et al. AASLD 2014; A239 Copyright 2015 American College of Gastroenterology 5
SVR MAY NOT CURE THE LIVER THE POINT OF NO RETURN SMV SOF LT HCC N=120 patients Advanced cirrhosis Treated 12 weeks SOF+SMV Overall SVR = 81% Patients with MELD >20 did not appear to improve HCC developed d in some patients that appeared to improve ML Shiffman et al. Hepatology 2015; (submitted). SVR MAY NOT CURE THE LIVER PERSISTANCE OF HCC RISK AJ van der Meer et al. JAMA 2012; 308:2584-2593. Copyright 2015 American College of Gastroenterology 6
HCV AND LIVER TRANSPLANTATION TIMING OF TREATMENT Prevent transplant t After transplant t Prevent recurrence Liver Transplant TREATMENT OF HCV PRIOR TO LT A2ALL STUDY LDLT and MELD exception for HCC PegINF-2b + RBV LADR schedule No Treatment Control = 16, Treatment = 31 No differences in GTs GT Everson et al. Hepatology 2013; 57:1752-1762. Copyright 2015 American College of Gastroenterology 7
TREATMENT OF HCV PRIOR TO LT A2ALL STUDY Overall SAE/Pt Death GT Everson et al. Hepatology 2013; 57:1752-1762. Tx 2.7 15% Control 1.3 10% Death 15% 10% Pre-LT SAE/Pt Infection 1.6 12% 1.3 0% SBP Liver related 5% 14% 0% 15% Post-LT SAE/Pt Surgical complications 1.2 18% 1.0 0% SOFOSBUVIR AND RBV PRE-LIVER TRANSPLANT SOF+RBV initiated prior to undergoing g LT All patients had HCC with MELD exception Treatment continued up until the time of LT MP Curry et al. AASLD 2013 N 61 Age 59 years (46-73) Male 80% Caucasian 90% HCV genotype: 1A, 1B, 2, 3 39%, 34%, 13%, 12% IL28B non-cc 78% Median MELD 8 (6-14) Previous HCV treatment 75% Copyright 2015 American College of Gastroenterology 8
SOFOSBUVIR AND RIBAVIRIN PRE-LT TREATMENT MP Curry et al. AASLD 2013 at LT Post -LT SVR when HCV RNA UD at LT HCV AND LIVER TRANSPLANTATION TIMING OF TREATMENT Prevent transplant After transplant Prevent recurrence Liver Transplant Copyright 2015 American College of Gastroenterology 9
SOFOSBUVIR AND RBV POST-LT HCV N 40 Age 59 years (49-75) Male 78% Caucasian 85% HCV genotype: 1A, 1B, 2, 3 55%, 28%, 0%, 15% IL28B non-cc 68% HCV RNA (IU/ml) 6.55 Previous HCV treatment 88% Mean time since LT 4.3 years (6-150 mos) Tacrolimus, Cyclosporin 70%, 25% M Charlton et al. AASLD 2013 SOFOSBUVIR/LEDEPISVIR POST-LT HCV TREATMENT Weeks of Treatment: N=223 Stage 0-3: 112 Cirrhosis: 111 Child A: 52 Child B: 50 Child C: 9 Genotype 1 and 4 Mean HCV RNA Log 6.4 IU/ml Post-LT mean 4.4 yrs Male 83% KR Reddy et al. AASLD 2014: A8 Copyright 2015 American College of Gastroenterology 10
PTV/rtv/OBV/DSV/RBV POST-LIVER TRANSPLANT N= 34 24 weeks Abbvie 3D + ribavirin Post-LT > 12 months No HCV treatment since LT Fibrosis < F2 Immune suppression dosing reduced to: Tacrolimus 0.5 mg Q week Cyclosporin 20% of the pretreatment dose PS Mantry et al. AASLD 2014; A198 NEED FOR LIVER TRANSPLANT IMPACT OF ANTI-VIRAL TREATMENT 700 5000 HBV Additions 600 500 400 300 200 100 0 Approval of anti-hbv therapy % HBV with HCC: 8% 12% HBV HCV 1993 1995 1997 1999 2001 2003 2005 2007 YEAR 4000 3000 2000 1000 0 HCV Additons WR Kim et al. Hepatology 2007; AASLD abstract 12. Copyright 2015 American College of Gastroenterology 11