Best of EASL White Nights

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1 Best of EASL White Nights Saint Petersburg 8 June 2017 Patients with HCC and HCV:do we really need to cure HCV? Massimo Colombo, MD Center for Translational Research in Hepatology,Humanitas Hospital, Rozzano, Italy. EASL International Liver Foundation, Geneva, Switzerland

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, Alfa Wassermann Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen, AbbVie

3 Antiviral Therapy for HCV and Risk of Liver Cancer Patient and HCV factors associated with increased risk of HCC Chemoprevention with IFN of HCV-related HCC Occurrence and recurrence of HCC after a SVR to DAA Recommendations from International Societies HCV, hepatitis C virus

4 Increased Mortality of HCV Patients from Liver Cancer The REVEAL Cohort Study Causes of Death Multivariate-adjusted HR (95%CI) All causes 1.89 ( ) All liver-related ( ) HCC ( ) All extrahepatic diseases 1.35 ( ) All cancer, except HCC 1.32 ( ) Cardiovascular diseases 1.50 ( ) Nephritis/nephrosis 2.77 ( ) Lee et al, J Infect Dis 2012;206: HR hazard ratio CI confidence intervals

5 Direct vs Indirect Mechanisms of Carcinogenesis in the HCV-infected Liver Direct Indirect HCV infection deregulates host cell cycle checkpoints Immune- and virusmediated oxidative stress and DNA damage Infected cells accumulate mutations, eventually resulting in transformation Immune- or virus-mediated apoptosis Compensatory proliferation and reinfection Uninfected normal hepatocyte HCV-infected normal hepatocyte Transformed hepatocyte HCV-infected, transformed hepatocyte Uninfected bystander cells accumulate mutations in an environment of inflammation and oxidative stress Proliferation of transformed hepatocytes Lemon SM, Gastroenterology 2012;142:1274 8

6 Factors Associated with Increased Risk of HCC in HCV Patients.The HCV VA Cohort Patient characteristic Cirrhosis HCC Events, No. (%) 17,926 (14.5%) 4,517 (3.5%) Male sex 1.35 ( ) 3.41 ( ) Age 1.02 ( ) 1.07 ( ) Race White Black Other HCV genotype Other 1 (reference) 0.54 ( ) 0.73 ( ) 1 (reference) 0.64 ( ) 1.24 ( ) 0.87 ( ) 1 (reference) 0.73 ( ) 0.80 ( ) 1 (reference) 0.52 ( ) 1.63 ( ) 0.77 ( ) Diabetes at baseline 1.38 ( ) 1.31 ( ) McCombs, JAMA Intern Med 2014;174:

7 Alcohol Boosts the Risk of HCC in HCV Patients The Cleveland Clinic A Prospective Study of HCC in Cirrhotic Patients Evaluated for OLT Social Alcohol Intake vs No Alcohol HCV NASH Alcohol Alcohol No Alcohol No Alcohol Ascha et al, Hepatology 2010;51:1972-8

8 HCV and Host-related Molecular Changes Associated to HCC Development Molecular change Assay Significance Author HCV-1b core glu70 Dir.sequencing HR 10.5 Akuta 2011 NBS1 CC PCR-RFLP HR 2.27 Huang genes AT/TT GWAS 47% at 10 yr Ono 2017 TLL1 GWAS OR 1.78 Matsura 2017 Histone changes GWAS (+) after SVR Juhling 2017 Hypermethilation p16 PCR (+) after SVR Hayashi 2008

9 Antiviral Therapy for HCV and Risk of Liver Cancer Patient and HCV factors associated with increased risk of HCC Chemoprevention with IFN of HCV-related HCC Occurrence and recurrence of HCC after a SVR to DAA Recommendations from International Societies HCV, hepatitis C virus

10 Reduced Incidence of HCC Following an SVR to IFN A Meta-analysis of 59 Studies Bang and Song BMC Gastroenterology 2017,17;46

11 Predictors of HCC Development in SVR Patients The HCV VA Cohort 22,028 patients treated with Peg-IFN ± RBV( ) HCC x 1000 pp x yr : 3.27 SVR vs 13.2 non-svr (HR: 0.358) Predictor of HCC Following SVR* HR (95% CI) P Value Cirrhosis at SVR 4.45 ( ) < Age at SVR, year (vs < 55 year) ( ) or older 4.69 ( ) Diabetes 2.07 ( ) HCV genotype (vs genotype 1) HCV ( ) HCV ( ) *Cox proportional hazards model adjusted for competing risk of death. El-Serag HB, et al Hepatology 2016

12 Life-long Risk of HCC in Cirrhotics with a SVR to IFN A Cohort Study in Milan & Palermo Hepatocellular Carcinoma Liver Decompensation 10.3% at 10 yrs 23.7% at 20 yrs 5.2% at 10 yrs 13.6% at 20 yrs yr yr Bruno S et al J Hepatol 2016

13 Interferon-Induced Regression of Cirrhosis Does Not Prevent HCC in HCV Patients Second biopsy in 38 patients 5 yrs after SVR to Peg IFN-RBV : 6-monthly surveillance* Six monthly surveillance of the SVR cohort ** Follow-up months from SVR HCC 3/23 (13%) regressors 2/15 (13%) non regressors Other site malignancies 1/23(4%) regressors 1/15((6%) non regressors *D Ambrosio et al Hepatology 2012; ** D Ambrosio et al EASL ILC Amsterdam 2017

14 Antiviral Therapy for HCV and Risk of Liver Cancer Patient and HCV factors associated with increased risk of HCC Chemoprevention with IFN of HCV-related HCC Occurrence and recurrence of HCC after a SVR to DAA Recommendations from International Societies HCV, hepatitis C virus

15 De-novo HCC After DAA Therapy of HCV Cirrhosis Author HCC /Cirrhosis Follow-up Months HCC Incidence Kozbial 16/ % (4.8% SVR) Cardoso 4/ % (all SVR) Conti 9/ % (2.5% SVR) Cheung 38/ % SVR 6.7% NR 8.9% Untreated Kobayashi 2/ % Kozbial et al. J Hepatol 2016, Cardoso et al. J Hepatol 2016, Conti et al. J Hepatol 2016, Cheung et al. J Hepatol Kobayashi et al J Med Virol2017 ;89:476-83

16 De-novo HCC After DAA Therapy of HCV Cirrhosis Population Studies in Italy The Navigator Study Veneto* The Resist HCV Study Sicily** Cohort 3,381 F3 / F4 Cohort 1,903 F3 / F4 HCC 1.6 x 100 pp x yr HCC 2.7 x 100 pp x yr HCC Pattern 51% < Milan HCC Pattern 89% < Milan 39% > Milan 11% > Milan *Romano et al. AASLD Meeting Boston 2016 **Calvaruso et al EASL HCC Summit Geneva 2017

17 De Novo HCC Following a SVR to DAA Therapy Reports From EASL ILC 2017 Courtesy of Prof M.Bourilere

18 The Incidence of HCC is Reduced in HCV Patients After a SVR to DAA. The VA Cohort Study period Jan 2015 march 2016 Patients 22,579 on IFN-free DAA (37% cirrh.,44% DMT2) Follow up /- 3.6 months Developed HCC 369 (88 during DAA) HCC risk x 100 PY * SVR 0.89 vs non-svr 3.65 Kanwall et al AASLD DDW 2017 # 419 *after exclusion of 88 HCC during DAA

19 Patients (%) UK Expanded Access to SOF/NS5A for 12 Weeks in Advanced Cirrhosis due to HCV Outcomes in 329 SVR patients after 3 months therapy plus 12 months follow-up Months 0-6 Months 6-15 p < 0, p < 0,05 De novo HCC Foster et al, J Hepatol 2016: 64,

20 No evidence of Increased Occurrence of HCC After DAA Therapy for HCV Meta-analysis of 41 studies,13 with DAA only,13,875 patients Waziry R et al EASL ILC Amsterdam 2017

21 HCC Occurrence According to Risk Factors.RESIST Calvaruso V et al EASL ILC Amsterdam 2017

22 HCC Occurrence Following SVR to IFN or DAA A Meta-analysis (100 pp x yr) author year IFN % ES (95% CI) Weight DAA Ogawa D'Ambrosio Bruno (1.75, 7.70) 0.71 (0.23, 2.20) 1.74 (0.83, 3.64) author year ES (95% CI) % Weight Mallet (0.25, 2.43) 4.41 Cardoso Yu Hung (0.75, 3.70) 2.04 (1.06, 3.93) 2.22 (0.92, 5.34) Cardoso Conti (2.78, 19.74) 4.51 (2.35, 8.67) Morgan (0.05, 0.80) 3.27 Rinaldi (4.91, 21.59) Aleman Cheinquer Moon (0.46, 2.29) 0.98 (0.14, 6.98) 1.12 (0.16, 7.94) Kozbial Lei-Zeng (0.97, 3.35) 0.04 (0.00, 1.30e+07) Fernandez-Rodriguez (0.41, 2.37) 6.12 Romano (1.22, 2.59) Janjua Rutter Velosa (0.33, 1.64) 0.95 (0.48, 1.91) 0.36 (0.05, 2.56) Affronti Muir (1.25, 8.88) 0.12 (0.02, 0.85) Nahon (0.61, 1.28) Carrat (2.67, 4.08) Marco 2016 Overall (I-squared = 45.7%, p = 0.021) NOTE: Weights are from random effects analysis 0.85 (0.41, 1.78) 7.34 Overall (I-squared = 78.3%, p = 0.000) 1.14 (0.86, 1.52) (0.86, 1.52) NOTE: Weights are from random effects analysis 3.09 (1.92, 4.96) 3.09 (1.92, 4.96) HCC occurrence rate (/100 person-years) HCC occurrence rate (/100 person-years) Waziry R et al EASL ILC Amsterdam 2017

23 Recurrence of HCC after Resection or Ablation The Storm Study Resection n.900 Local ablation n.459 Number of nodules vs vs vs 4 Bruix et al Lancet Oncology 2015

24 HCC Recurrence in Patients with Cirrhosis Following IFN-free Therapy for HCV Author CR after N.Pt. Months from Recurrence x100 pp/mo. Res / RFA CR to DAA Reig (27.6%) - Conti (28.8%) - Pol (13%) (7.7%) 1.11 Zavaglia (3.2%) - Virlogeoux 2017* + 23 vs ,4 11(48%) vs 33(73%) 1.7 Reig 2017** (27.3%) - J Hepatolol 2016 and 2017 * Liver Intern 2017 ** EASL ILC Amsterdam 2017

25 A Retrospective Multicenter Confirmatory Study of HCC Recurrence After DAA. Whole cohort (n=77) Median follow-up,months 12.4 (IQR: ) HCC progression n= 24 (31.2%) Death n=5 (6.5%) HCC recurrence (n=24) Median months between start DAA and 1 st HCC recurrence 3.5 (IQR: 2-7.6) 2 nd recurrence / progression n=10 Median months between 1 st - 2 nd HCC recurrence/progression 6 (IQR: ) Recurrence/progression within 6 months of 1 st recurrence 6/20 (30%) 16.7% BSC 37.5 % Ablation Resection LT 45.8 % TACE Sorafenib Regorafenib RE Clinical Trials Death n=5 (20.8%) Reig M et al EASL ILC Amsterdam 2017

26 Courtesy of Prof M.Bourliere HCC Recurrence After DAA Therapy Reports From EASL ILC 2017

27 No evidence of Increased Recurrence of HCC After DAA Therapy for HCV Meta-analysis of 41 studies,13 with DAA only,13,875 patients Waziry R et al EASL ILC Amsterdam 2017

28 HCC Recurrence Following SVR to IFN or DAA A Meta-analysis(100 pp x yr) author IFN DAA % year ES (95% CI) Weight author year ES (95% CI) % Weight Hagihara (4.58, 18.30) Conti Pol, CO (28.49, 73.71) 8.11 (5.43, 12.10) Kanogawa (3.49, 12.05) Pol, CO (0.62, 31.20) 8.86 Kunimoto (4.82, 12.84) Pol, CO (1.35, 5.92) Jeong (7.14, 24.65) Reig (33.23, 88.53) Saito (6.14, 27.01) Rinaldi Minami (3.76, ) (9.43, 46.70) Sanefuji (4.30, 41.34) 4.84 Torres (0.00, 2.28e+07) 0.20 Minami 2016 Overall (I-squared = 0.0%, p = 0.638) NOTE: Weights are from random effects analysis (4.05, 16.19) (7.18, 11.81) (7.18, 11.81) Zavaglia 2016 Lei-Zeng 2016 Overall (I-squared = 89.1%, p = 0.000) NOTE: Weights are from random effects analysis (0.20, 10.07) (0.00, 2.60e+07) (5.00, 29.46) (5.00, 29.46) HCC recurrence rate (/100 person-years) HCC recurrence rate (/100 person-years) Waziry et al EASL ILC Amsterdam 2017

29 Post-transplant HCC Recurrence Following IFN-free Therapy of HCV in the Wait List Study Pts HCC at Explant From HCC Dg Recurrence to LT Yang % > Milan n.a. N.5 = 27.8% * 4-17 mo.post-lt 60% MVI Donato % > Milan 3-38 mo. N.3 =10.7% * 35% complete necrosis mo. post-lt 35% MVI 100% MVI * All bridged with RFA or TACE Yang et al J Hepatol 2016 ; Donato et al J Hepatol in press

30 Reduced Recurrence of HCC in Patients Treated with DAA Post-transplant n.50 n.27 n.74 Nyiazi et al AASLD DDW 2017

31 Increased Occurrence and Recurrence of HCC after IFN-free Therapy. Facts or Artifacts? Hypothesis - a swift removal of HCV might cause: Impairment of NK cells-mediated tumor immuno-surveillance. TRAIL-related de-escalation of apoptosis. Impaired tumor control following reduction of non-specific inflammatory cells. Warning : confounding factors and methodological issues in the cohorts investigated. Debes J D et al Lancet Gastroent Hepatol in press

32 Antiviral Therapy for HCV and Risk of Liver Cancer Patient and HCV factors associated with increased risk of HCC Chemoprevention with IFN of HCV-related HCC Occurrence and recurrence of HCC after a SVR to DAA Recommendations from International Societies HCV, hepatitis C virus

33 Surveillance for HCC of Patients With an SVR AASLD/ISDA:Updated Recommendations Surveillance for HCC with twice-yearly US examination of Metavir F3 or F4 Rating : Class I, Level C Caveats Diagnosis by Liver Stiffness of Metavir F3 and F4 is inaccurate in viremic patients and mostly inaccurate in SVR patients. AASLD/IDSA HCV Guidance: Recommendations for Testing,Managing,and Treating Hepatitis C

34 Surveillance of HCC of Patients With an SVR EASL : Updated Recommendations Non-cirrhotic patients with SVR should be retested for ALT and HCV RNA (or HCV core antigen) at 48 weeks post-treatment, then discharged if ALT is normal and HCV RNA is negative (A1) Patients with advanced fibrosis (F3) and cirrhotic patients with SVR should undergo surveillance for HCC every 6 months by ultrasound (A1) EASL Clinical Practice Guidelines, J Hepatol 2016

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36 Surveillance for HCC of Patients With an SVR AGA Recommendations AGA Institute Clinical Practice Update Expert Review for SVR Patients Jacobson I et al Gastroenterol 2017

37 Low Sensitivity of Fibroscan (TE) to Detect Cirrhosis Regression in SVR Patients Diagnosis of Residual Cirrhosis by Fibroscan Is Biased By Liver Morphometry TE vs liver biopsy TE vs liver biopsy TE > 12Kpa TE < 12Kpa 8/9 F4 by LB 5/24 F4 by LB Cut off of 12 Kpa for Cirrhosis: Specificity = 95% (85-100%) Sensitivity = 61% (35-87%) D Ambrosio et al, J Hepatol 2013;59:

38 Persistence of HCV-RNA in the Liver of Patients Achieving a SVR to DAA Explants from 39 SVR patients > 26(67%) had HCV-RNA (LLD of IU/ML) > Liver HCV-RNA more likely in patients with shorter therapy and/or shorter RNA negative window to liver transplantation > Down-regulation of type II & III IFN and ISGs > Delayed clearance from the liver Confirmatory studies El Masry et al Gastroenterology 2017 Wintcamle et al Clin Gastroent Hepatol 2017 Gambato et al Gastroenterology 2016;15:1535

39 AFP Surveillance of HCV Cirrhosis with SVR. True (TPR) and False (FPR) Positive Results Naives at VA : 12,124 cirrhosis SVR : 3,979 cirrhosis 902 incident HCC 168 incident HCC Tayob et al AASLD DDW 2017

40 Decision-tree and Random Forest Models Prospective ANRS CO12 CirVir Audureau et al EASL ILC Amsterdam 2017

41 A Multicenter Study of HCC Recurrence Following IFN-free Therapy of Hepatitis C Fifty six patients treated with Resection(39%),Ablation(39%) or TA(C)E(21%) HCC diagnosis : 21 months from HCC Tx and 9.3 months from DAA Tx DFS = 75% at month 6 after DAA therapy and 56% at month 24 cumulatively. Kolby et al J Hepatol 2017

42 HCC Occurrence After IFN vs DAA Therapy * After adjustment for: age, gender, ethnicity, Child-Pugh score, thrombocytopenia, AFP, HCV genotype, number of prior treatment episodes, and clinic location Innes et al EASL ILC Amsterdam 2017

43 Efficacy of IFN-free HCV Therapy in Patients with Active HCC. VA Cohort Beste L et al J Hepatol in press

44 SVR is Associated with a Reduced Mortality HCC and Liver Transplant Systematic review of 129 studies of IFN therapy in 34,563 HCV patients Achieving SVR was associated with: 62 84% reduction in all-cause mortality 68 79% reduction in risk of HCC 90% reduction in risk of liver transplant Saleem J, et al. Hepatology 2014:60:218A-219A

45 Competing Risk Analysis on Outcome after Hepatic Resection of HCC in Cirrhotic Patients 864 resections for HCC in CPT A cirrhosis, INT-Milan and Bologna University, Death due to tumor recurrence (59.6%) vs liver failure (19.9% ) Deaths From Liver Failure Deaths From Tumor Recurrence 16 months Cucchetti A et al in press

46 HCC Decreases the Chance of Successful HCV Therapy with Direct-acting Antivirals 12-wk failure: 21% HCC vs 12% non HCC (P = 0.009) Prenner S B et al J Hepatol 2017; 66 :

47 Association Between IFN and Improved HCV-related Outcomes Following Ablation or Resection HCC Recurrence Overall Survival Singal et al, Aliment Pharmacol Ther 2010;32:

48 Risk Factors for HCC Development in HCV Patients Following SVR To IFN Chronic hepatitis + SVR Liver cirrhosis + SVR Chronic hepatitis + Non-SVR Liver cirrhosis + Non-SVR Arase et al, Hepatology 2013;57:

49 Better Outcome of Radical Therapy of HCC in SVR Than in Non-SVR Patients 1061 patients with HCV cirrhosis treated in Milan and Palermo 181(17%) achieved a SVR. HCC developed in 20 SVR patients vs 194 non SVR patients. Overall survival Time to decompensation Time to HCC recurrence Bruno S et al Liver Intern in press