3 Workshop on HCV THERAPY ADVANCES New Antivirals in Clinical Practice

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1 3 Workshop on HCV THERAPY ADVANCES New Antivirals in Clinical Practice Rome, 13 December 2013 Management and monitoring of HCC in the future era of DAA s Prof. Massimo Colombo Chairman Department of Liver, Kidney, Lung and Bone Marrow Units and Organ Transplant Head 1st Division of Gastroenterology Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico University of Milan Milan, Italy

2 Financial Disclosures Grant and research support: BMS, Gilead Science Advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen

3 Management and Monitoring of HCC in the Future Era of DAA s Widespread application of IFN-free DAA therapy of HCV may improve: 1. Prevention of HCV-related HCC thereby attenuating costeffectiveness ratio of HCC screening in SVR patients. 2. Access to & outcome of curative treatments for HCC 3. Prevention and reversal of clinical decompensation leading to a shift of OLT allocation from decompensated to HCC patients

4 Primary Prevention of Hepatocellular Carcinoma 1. Avoiding exposure to environmental risk factors 2. Chemoprevention Cause specific agents universal HB vaccination anti-hbv/hcv therapy Cancer modifying agents statins, metformin, TZD, coffee, aspirin

5 Predicting Cost Effectiveness of HCC Surveillance by Markov Modelling Cost-effectiveness: a gain of life expectancy of 3 months with a cost < US$ 50,000 for year of life saved Surveillance is cost-effective: HCC incidence 1.5% per year in cirrhotics 1 HCC incidence 0.2% per year in HBV carriers 2 1. Sarrazin et al, Am J Med 1996; 2. Bruix & Sherman Hepatology 2011

6 Eradication of HCV Infection and the Development of HCC A Meta-analysis Of Observational Studies Forest Plot Of Adjusted Hazard Effects In Persons At All Stages Of Fibrosis Morgan et al, Ann Int Med 2013;158:

7 Cirrhosis Regression in HCV Patients Responding to Interferon-based Therapy Study Patients with Months Staging System Regression cirrhosis (n) from SVR Rates Reichard et al, Scheuer 3 (100%) Arif et al, Ishak 5 (83%) George et al, Ishak 6 (75%) Poynard et al, <24 Metavir 25 (68%) D Ambrosio et al, Metavir 23 (61%) Everson et al, Metavir 20 (50%) Shiratori et al, Metavir 11 (46%) Mallet et al, Metavir 17 (44%) Pol et al, NA Metavir 4 (24%)

8 Effect Of Aging On Risk For Hepatocellular Carcinoma In Chronic Hepatitis C Virus Infection Annual incidence of HCC after IFN Group Total, % < 65 years, % 65 years, % F0/F F F F Total SVR Non-SVR Asahina Y, et al, Hepatology 2010;52:

9 A Novel Predictive Score For HCC Development In Patients With HCV After SVR To PegIFN and Ribavirin HCC Score 871 patients with SVR to PR Age 60 yr Platelets < 150 x10 9 /L AFP 20 mg/ml F3, F4 Auroc = 84.8% Chang et al, JAC 2012;67:

10 Management and Monitoring of HCC in the Future Era of DAA s Widespread application of IFN-free DAA therapy of HCV may improve: 1. Prevention of HCV-related HCC thereby attenuating costeffectiveness ratio of HCC screening in SVR patients. 2. Access to & outcome of curative treatments for HCC 3. Prevention and reversal of clinical decompensation leading to a shift of OLT allocation from decompensated to HCC patients

11 Incidence and Treatment of HCC in a Referral Center (AM & A Migliavacca Liver Center, Milan) Year Newly Diagnosed vs Total HCC BCLC 0/A Non Curative Treatments * /399 (13%) 42 (84%) 14/42 (33%) /410 (15%) 42 (70%) 20/42 (48%) Total 110/809 (14%) 84 (76%) 34/84 (40%) * Causes: advanced age (n=9, 11%), co-morbidities (n=5, 6%), strategic location (n=20, 24%) Colombo, Sangiovanni & Iavarone, unpublished

12 SVR to IFN Is Associated with Improved Survival in Hepatitis C Patients With a HCC Cohort 1: 307 Cohort 2: 352 Compensated Cirrhosis SVR: 71 (20%) Untreated: 307 Non-SVR: 281 (80%) HCC: 11 (15%) HCC: 94 (33%) 2 Decompensated at diagnosis 16 9 (13%) 78 (28%) HCC on Study Bruno S, Iavarone M et al, AISF Annual Meeting 2013

13 SVR to IFN Is Associated with Improved Survival in Hepatitis C Patients With a HCC Treatment Overall SVR Non-SVR P value OLT 8 (9%) 2 (22%) 6 (8%) 0.19 Resection 10 (11%) 3 (33%) 7 (9%) 0.06 PEI/RFTA 37 (43%) 3 (33%) 34 (44%) 0.73 TAE/TACE 19 (22%) 0 19 (24%) 0.20 BSC 11 (13%) 1 (11%) 10 (13%) 1.00 Bruno S, Iavarone M et al, AISF Annual Meeting 2013

14 SVR to IFN Is Associated with Improved Survival in Hepatitis C Patients With a HCC SVR Non-SVR P-value Patients, N 9 78 Study time, mo. (range) 44 (7-104) 28 (1-214) 0.31 Males, N 8 (89%) 55 (71%) 0.43 Age, yr (range) 65 (46-79) 65 (46-82) 0.69 Single HCC, N 8 (89%) 58 (74%) 0.68 Liver decompensation, N 0 (0%) 43 (55%) Deaths, N 2 (22%) 58 (74%) 0.04 Yearly mortality rates 5% 21% Bruno S, Iavarone M et al, AISF Annual Meeting 2013

15 Early HCC: Survival after Resection Is Influenced by Portal Hypertension and Bilirubin Best candidates for resection : Solitary HCC 5 cm Child-Pugh A: Low portal hypertension Normal bilirubin 74% Survival (%) % 25% Log Rank months < 10 mmhg HVPG (n= 35) 10 mmhg HVPG and normal bilirubin (n=15) 10 mmhg HVPG and Bilirubin >1 mg/dl (n=27) Llovet JM et al, Hepatology 1999;30:

16 Is Portal Hypertension a Contraindication to Hepatic Resection? Single Tumor in Child-Pugh A Study Country No Patients Five Year Survival PHT (+) PHT (-) P-Value Capussotti 1 Italy % 62% Ishizawa 2 Japan % 71% Cucchetti 3 Italy % 64% World J. Surgery 2006;30:992-9; 2. Gastroenterology 2008;134: ; 3. Ann. Surgery 2009:250:922-8

17 The Impact of an SVR on Development of Esophageal Varices in HCV Cirrhotics Log-Rank p=0.03 Cumulativee Incidence (%) Non-SVR 30% SVR 6% Patients at risk Yrs Bruno S, et al. Hepatology 2010:51; D Ambrosio R et al. Antivir Ther. 2011;16(5):677-84

18 Cumulative Incidence of Clinical Events in HCV Patients with Cirrhosis Stratified by Treatment Response Endpoint Patients SVR (+) SVR (-) Reference Hepatocellular Carcinoma % 35.0% Shiratori % 19.6% Cardoso % 16.0% Bruno % 17.9% Yoshida 1999 Clinical Decompensation % 13.7% Cardoso % 12.0% Veldt 2007 Development of Esophageal Varices % 15.1% D Ambrosio % 39.0% Bruno 2010 Liver-related Death % 8.8% Cardoso % 11.4% Bruno % 2.0% Yoshida % 15.0% Shiratori 2005 Aghemo et al, J Hepatol 2012;57:

19 Management and Monitoring of HCC in the Future Era of DAA s Widespread application of IFN-free DAA therapy of HCV may improve: 1. Prevention of HCV-related HCC thereby attenuating costeffectiveness ratio of HCC screening in SVR patients. 2. Access to & outcome of curative treatments for HCC 3. Prevention and reversal of clinical decompensation leading to a shift of OLT allocation from decompensated to HCC patients

20 Treatment of Early Stage HCC: Liver Transplantation in Cirrhotic Patients Selected by Milan Criteria Center HCC Cases 5-yr survival Recurrence Reference Milan Single 5 cm 3 nodes 3 cm 48 75%* 8% Mazzaferro et al 1996 Barcelona Single 5 cm 79 75% 4% Llovet et al 1998 Paris 3 nodes 3 cm 45 74% 11% Bismuth et al 1999 Berlin Single 5 cm 3 nodes 3 cm % 16% Jonas et al 2001 * Explanted livers: 35 (73%) Milan (+) with 95% survival 13 (27%) Milan ( ) with 59% survival * 4-yr survival

21 Reduced Liver-related Mortality in SVR Liver Graft Recipients with Recurrent HCV Picciotto et al, J. Hepatology 2007 Berenguer, Am. J. of Transplant. 2008

22 Sofosbuvir + Ribavirin in the OLT Setting: Genotype 1-4 Treatment during the pretransplant phase Treatment of established recurrent HCV Curry et al, AASLD Liver Meeting 2013, Washington. Charlton et al, AASLD Liver Meeting 2013, Washington

23 Predicting Survival After LT in Patients with HCC Beyond The Milan Criteria Mazzaferro et al, Lancet Oncology 2009;10:35-43

24 Management and Monitoring of HCC in the Future Era of DAA s Conclusions HCC risk is attenuated in SVR cirrhotics (<1% x yr). Liver Societies recommend US surveillance, however tailoring by propensity scores might improve C/E ratio of screening Both access to and outcome of anti HCC treatments are expected to improve following the advent of IFN-free DAA therapies Prevention of clinical decompensation and recurrent HCV after OLT might tip the balance of OLT candidacy based on criteria of urgency for clinical decompensation vs cost benefit ratio for HCC

25 Incidence of HCC and Survival in HCV Patients with Cirrhosis Following PegIFN & Rbv Therapy Cardoso et al, Journal of Hepatology 2010;52:652-7

26 HCV Elimination Reduces The Incidence of Type 2 Diabetes Retrospective analysis of 2842 HCV patients treated with IFN based therapies Mean follow-up: 6.4 years Arase Y, et al. Hepatology 2009;49: