White Nights of Hepatology 2016

White Nights of Hepatology 2016 Saint Petersburg, 3 June 2016 Long-term treatment of Chronic hepatitis B - a key to HCC prevention Massimo Colombo Chairman Department of Liver, Kidney, Lung and Bone Marrow Units and Organ Transplant Head Division of Gastroenterology and Hepatology Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico University of Milan Milan, Italy

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

Is HCC Prevented by Anti-HBV Therapy? Outline Prevalence and risk factors of HBV-related HCC Recommendations for screening & propensity scores Retrospectve scrutiny of HCC chemoprevention in HBV Should surveillance of treated patients be modified?

Geographic Distribution of HCC Risk Factors The Bridge Study Risk factors N. America Europe China Taiwan S. Korea Japan n (%) n = 2,243 n = 3,466 n = 8,538 n = 1,580 n = 1,172 n = 446 HBV 522 (23) 362 (10) 6,575 (77) 987 (63) 884 (75) 64 (14) HCV 876 (39) 1,590 (46) 255 (3) 489 (31) 112 (10) 284 (64) ALD 471 (21) 1,290 (37) 416 (5) 66 (4) 110 (9) 59 (13) NASH 275 (12) 334 (10) 53 (1) 84 (5) 68 (6) 9 (2) Park JH et al, Liver Int. 2015;35:2155-66

Diverse Roles of Hepatitis B Virus in Liver Cancer 1. Immune responses elicited by HBV induce inflammation, apoptosis and regeneration leading to accumulation of genetic and epigenetic alterations. 2. Integration of HBV-DNA into host chromosomes leads to insertional mutagenesis of cancer-related genes and chromosomal instability. 3. HBV proteins (HBx transactivator) act as co-factors in liver oncogenesis 4. The crucial role of cccdna in viral replication and viral persistence Fallot et al, Curr Opin Virol 2012;2:467-473

% Survival Cumulative incidence of HCC (%) Liver-related Mortality and HCC According to Baseline HBV DNA Levels. The REVEAL Study Liver-related Mortality: all subjects (n = 3,653) Cumulative incidence of HCC: all subjects (n = 3,653) 100 95 90 85 80 Baseline HBV DNA Level, copies/ml <300 300 <10 4 10 4 <10 5 10 5 <10 6 10 6 p<0.001 16 14 12 10 8 6 4 2 0 Baseline HBV DNA level, copies/ml 10 6 10 5 <10 6 10 4 <10 5 300 <10 4 < 300 14.89% 12.17% 3.57% 1.37% 1.30% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of follow-up Year of follow-up Iloeje UH et al. Clin Gastroenterol Hepatol. 2007;5:921-31; Chen et al. JAMA 2006;295:65-73.

Factors Other Than Virus Replication Affecting HCC Risk in HBV Patients Virus Genotype (C) Pre-S mutations Enhancer-H mutations(t 1653) Core promoter mutations(v 1753,T 1762,A 1764) Host & Environment Increasing age Male gender Cirrhosis Alcohol/Tobacco Aflatoxin Diabetes/Obesity Genetic polymorphisms (SNIPs) Yeung et al JID 2011;203:646-54; Yuen et al GUT 2008;57:98-102

Factors Affecting HCC Risk in HBV Patients West vs East Factor West East Age of acquisition Older Younger Duration of infection Shorter Longer Host genetics? Familial aggregation HBV genotype A, D B, C Environmental factors Alcohol Aflatoxin Co-morbidities Diabetes Diabetes Adapted from Kim, EASL Monothematic Conference, Athens 2014

Is HCC Prevented by Anti-HBV Therapy? Outline Prevalence and risk factors of HBV-related HCC Recommendations for screening & propensity scores Retrospective scrutiny of HCC chemoprevention in HBV Should surveillance of treated patients be modified?

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

Surveillance for HCC as Recommended by AASLD, APASL and EASL STRATEGY AASLD 2011 APASL 2010 EASL 2012* Target population Cirrhosis, CHB 1 NAFLD Viral cirrhosis Cirrhosis, CHB 2 HCV F3 1 Asian males > 40 years and females > 50 years Family history of HCC African/North American blacks > 20 years 2 Active hepatitis Family history of HCC *EASL-EORTC: Evidence 1B/3A recommendation 1A/B Bruix & Sherman, Hepatology. 2011;53:1020-2. Omata, Hepatol Int. 2010;18;4:439-74. EASL-EORTC J Hepatol. 2012;56:908-43

Risk scores for Hepatocellular Carcinoma in HBV Patients at Risk Risk score Variables Externally validated Yang et al. (REACH-B) Age, gender, ALT, HBeAg status, HBV DNA concentration Yes (only in Asia) Wong et al. (CU-HCC) Age, albumin, bilirubin, HBV DNA concentration, cirrhosis No Yuen et al (GAG-HCC) Age, gender, HBV DNA concentration, core promoter mutation, cirrhosis No Sherman et al, Hepatology 2015;61:1784-6.

Risk Score for HCC in Chronic HBV. REACH-B Age, gender, ALT, HBeAg, HBV-DNA Yang et al, Lancet Oncology 2011;12:568-74

Risk Score for HCC in Patients with HBV. GAG-HCC Age, gender, HBV-DNA, core promoter mutation, cirrhosis Yuen et al, J Hepatol 2009;50:80-8

Risk Score for HCC in Patients with HBV. CU-HCC Age, albumin, bilirubin, HBV-DNA, cirrhosis Wong et al, JCO 2010;28:1660-5

CU-HCC. Liver Stiffness-based Optimization of HCC Risk Score in Patients with HBV Wong et al, J Hepatol 2014;60:339-45

HCC Risk in Chronic Hepatitis B Patients with Transient Elastography Defined Subclinical Cirrhosis All SCC patients Diagnostic accuracy of liver biopsy vs fibroscan F4 (N=21) 17 (80.9%) LS 13 KPa 4 (19.1%) LS < 13 KPa F0-3 (N=183) 10 (5.5%) LS 13 KPa 173 (94.5%) LS < 13 KPa Kim et al, Hepatology 2015;61:1851-1859

The Applicability of HCC Risk Prediction Scores in a North American Patient Population with HBV Abou-Amara et al. Gut 2015

Is HCC Prevented by Anti-HBV Therapy? Outline Prevalence and risk factors of HBV-related HCC Recommendations for screening & propensity scores Retrospective scrutiny of HCC chemoprevention in HBV Should surveillance of treated patients be modified?

HBV: Who Should Be Treated? Patients with cirrhosis compensated/decompensated HBsAg pos and HBV-DNA detectable (any level >10 IU/ml) Patients without cirrhosis HBsAg pos and HBV-DNA >2000 IU/ml and ALT >ULN and Liver disease S2 EASL & AASLD Recommendations

Meta-analyses on HBV-related HCC Chemoprevention by IFN-based Regimens Authors No. Studies No. treated vs controls Relative risk/risk difference* (95% CI) P-value Sung et al 2008 3 12 1,292 vs 1,458 0.66 (0.48 0.89) 0.006 Yang et al 2009 4 11 1,006 vs 1,076 0.59 (0.43 0.81) 0.001 Miyake et al 2009 2 8 553 vs 750 5.0%* (9.40 0.50) 0.028 Camma et al 2001 1 7 853 vs 652 4.8%* (0.11 0.02) NS Zhang et al 2011 5 2 176 vs 171 0.23 (0.05 1.04) NS Jin et al 2011 6 9 1,291 vs 1,048 0.274 (0.06 1.03) NS 1. Camma et al. J Hepatol 2001;34:593-602. 2. Miyake Y et al. J Gastroenterol 2009;44:470-5. 3. Sung JJ, et al. Aliment Pharmacol Ther 2008;28:1067-77. 4. Yang YF et al. J Viral Hepat 2009;16:265-71. 5. Zhang CH et al. Int J Cancer 2011;129:1254-64. 6. Jin H et al. Hepatol Res 2011;41:512-23.

Meta-analysis of NUC Therapy: Pooled Data On the HCC Rate Per 100 HBV Patient Years Follow-up HCC rate: 0.9 vs 2.0* HCC rate: 0.3 vs 3.0* HCC rate : 1.0 vs 1.9* HCC rate : 1.7 vs 1.1* Singal et al, AP&T 2013;38:99-106 *statistically significant differences

Prevention of Hepatitis B-related HCC by NUCs Propensity Score Studies 1. Wu CY, Gastroenterology 2014;147:143 151. 2. Hosaka T, Hepatology 2013;58:98 107. 3. Kumada T, J Hepatol 2013;58:427 433. 4. Gordon SC, Clin Gastroenterol Hepatol 2014;12:885 893. Author Patients Follow-up (yr) HCC % at 5 yr RR (95% C.I.) P-value NUC+ NUC- NUC+ NUC- NUC+ NUC- Wu et al 1 (Taiwan) Hosaka et al 2 (Japan) Kumada et al 3 (Japan) Gordon et al 4 (United States) 21,595 21,595 3.4 5.2 7.3 22.7 0.31 (0.27 0.53) <.001 316 316 3.3 7.6 3.7 13.7 0.37 (0.15 0.91).03 117 117 12.3 11.6 2.7 11.3 0.28 (0.13 0.62).002 820 1,851 5.2 5.2 n.a. n.a. 0.48 (0.27 0.86) <.01 n.a. = not available

NUC Therapy With Reduced Risk of HCC in Patients with HBV. A Nationwide Cohort Study, Taiwan Wu CY, Gastroenterology 2014;147:143 151.

Prevention of HBV-related HCC by NUC Therapy The Importance of Treatment Duration 1,946 caucasian patients, 794 treated with ETV/TDF > 5 yrs Developed HCC: 90 (4.6%) within the first 5 yrs of therapy 7 (0.9%) beyond 5 yrs of therapy HCC rate x yr: 1.22% (C.I. 0.99-1.50%) within 5 yrs 0.63% (CI 0.30-1.32%) beyond 5 yrs Decrease in yearly HCC incidence in cirrhosis First 5 yrs vs beyond 5 yrs: 3.27% vs 1.07%, P=0.046 HCC risk factors after 5 yrs: age, or age at TDF/ETV onset Papatheodoridis et al, AASLD 2015

Is HCC Prevented by Anti-HBV Therapy? Outline Prevalence and risk factors of HBV-related HCC Recommendations for screening & propensity scores Studies of chemoprevention of HBV-related HCC Should surveillance of treated patients be modified?

Risk Scores for HCC in Eastern HBV Patients Under Continuous Entecavir Treatment CU-HCC GAG-HCC REACH-B Age Albumin Bilirubin HBV-DNA Cirrhosis Age Gender HBV-DNA Core promoter mutations Cirrhosis Age Gender ALT HBV-DNA HBeAg Wong et al, Gastroenterology 2013;144:933 944

PAGE-B Prediction Score for HCC in Caucasian HBV Patients under ETV or TDF Age (years) Gender Platelets (mm 3 ) 16-29: -4 Female: 0 200,000: 0 30-39: -2 Male: 5 100,000-199,999: 6 40-49: 0 <100,000: 11 50-59: 2 60-69: 4 70: 6 Papatheodoridis et al, J Hepatol. 2016;64:800-6

HBsAg Loss Is Associated with Improved Prognosis 110 Korean patients who achieved HBsAg seroclearance during NUC therapy Transplant free survival HCC incidence Kim et al, Gut. 2014;63:1325-32

The Risk of Developing HCC is Reduced not Abolished in Patients Following HBsAg Seroclearance HCC: 1.95 % in 803 HBsAg(-) vs 6.4% in 4,346 HBsAg(+) Liu et al, AP&T 2016 in press

Recommendations for Surveillance in Patients Responding to Antiviral Therapy AASLD 1 HBV HCV Surveillance should be continued in cirrhotics after HBsAg clearance or remission of inflammation treatment related regression of cirrhosis is not a reason to withhold surveillance EASL/EORTC 2 Surveillance should be offered to treated patients with chronic hepatitis B and SVR patients with advanced HCV 1. Bruix & Sherman Hepatology 2011;53:1020-2. 2. Llovet et al, J Hepatol 2012;56:908-43