Μπνξεί ε αληηηθή αγσγή ζε αζζελείο κε ρξνλία επαηίηηδα Β λα πξνιάβεη ηελ αλάπηπμε ηνπ επαηνθπηηαξηθνύ θαξθίλνπ; Καζεγεηήο Σ. Π.

Μπνξεί ε αληηηθή αγσγή ζε αζζελείο κε ρξνλία επαηίηηδα Β λα πξνιάβεη ηελ αλάπηπμε ηνπ επαηνθπηηαξηθνύ θαξθίλνπ; Καζεγεηήο Σ. Π.Nηνπξάθεο

YXETIH HBV KAI ΗΚΚ Ο HBV πξνθαιεί ην 60-80% ησλ ΗΚΚ παγθνζκίσο πζρέηηζε: Eπηδεκηνινγηθά Zών-κνληέιιν (ηξσθηηθό-woodchuck) Kπηηαξηθέο ζεηξέο Ο HBV ην κεγαιύηεξν θαξθηλνγόλν κεηά ην θάπληζκα

ΥΑΡΣΗ ΔΠΙΠΟΛΑΜΟΤ HBV & ΔΠΙΠΣΧΗ ΗΚΚ HBsAg επηπνιαζκόο <2% 2 7% >8% απνπζία δεδνκέλσλ Δηήζηα επίπησζε ΗΚΚ / 100.000 πιεζπζκνύ 1 3 3 10 10 150 απνπζία δεδνκέλσλ WHO 2003

ΠΑΘΟΓΔΝΔΙΑ ΚΑΡΚΙΝΟΓΔΝΔΗ ΑΠΟ HBV Μεηαιιαγέο θαηαζηαιηηθώλ γνληδίσλ (P53) Κίξξσζε Δλζσκάησζε ΑΠΟΓΙΟΡΓΑΝΧΗ ΚΤΣΣΑΡΙΚΟΤ DNA Ογθνγόλεο ηδηόηεηεο πξσηεηλώλ θαθέινπ Απμεηηθνί παξάγνληεο Γηαδηεγεξηηθή δξάζε πξσηετλεο Υ ΚΑΡΚΙΝΟ Καλέλα από ηα γλσζηά νγθνγνλίδηα

Fattovich et al, J Hepatol 2008;48:335-52 ΔΣΗΙΟ ΚΙΝΓΤΝΟ ΔΜΦΑΝΙΗ ΗΚΚ ΣΗ ΥΡΟΝΙΑ HBV ΛΟΙΜΧΞΗ Αλελεξγνί θνξείο Κίξξσζε Υξόληα επαηίηηδα 2.2-3.7% 0.02-0.2% 0.3-0.6% ΗΚΚ

ΠΑΡΑΓΟΝΣΔ ΑΤΞΗΜΔΝΟΤ ΚΙΝΓΤΝΟΤ ΗΚΚ Σχετιζόμενοι με τον ξενιστή Ηιηθία > 40 εηώλ Άξξελ θύιν Παξνπζία θίξξσζεο Οηθνγελεηαθό ηζηνξηθό ΗΚΚ Φπιή (Αζηάηεο, Αθξηθαλνί) Fattovich G et al. J Hepatol 2008 Lok et al Hepatology 2009 Σχετιζόμενοι με τον ιό HBV DNA > 20.000 IU/ml, HBeAg (+) Yςειό HBsAg Μεηαιιαγκέλα ζηειέρε HBV (core promoter, pre-s) Γνλόηππνο HBV (C>B) Σπιινίκσμε κε HCV, HDV, HIV Άλλοι παπάγοντερ Καηάρξεζε αιθνόι Αθιαηνμίλεο Κάπληζκα Σαθρ. Γηαβήηεο Παρπζαξθία

Cumulative incidence (%) ΗΒeAg KAI ΚΙΝΓΤΝΟ ΓΙΑ ΗΚΚ 12 10 8 6 4 2 0 HBsAg+, HBeAg+ HBsAg+, HBeAg- HBsAg-, HBeAg- 0 1 2 3 4 5 6 7 8 9 10 Year Yang et al. N Engl J Med 2002, 347:168-174

Δπίπησζε ΗΚΚ ζε 13 ρξόληα (%) ΜΔΛΔΣΗ REVEAL: ΤΥΔΣΙΗ HBV DNA ΜΔ ΔΠΙΠΣΧΗ ΗΚΚ 50 40 N = 3653 30 20 12.17 14.89 10 1.30 1.37 3.57 0 < 300 300-999 1000-9999 10,000-99,999 100,000 HBV DNA (γνληδηώκαηα/ml) Chen CJ, et al. JAMA. 2006;295:65-73.

ΠΡΟΒΛΔΦΗ ΣΗ ΑΝΑΠΣΤΞΗ ΗΚΚ CU-HCC score CAG-HCC score REACH-B score Age Albumin Bilirubin HBV-DNA Cirrhosis Age Gender Core-promoter mutations HBV-DNA Cirrhosis Age Gender ALT HBV-DNA HBeAg

ΠΡΟΒΛΔΦΗ ΚΙΝΓΤΝΟΤ ΓΙΑ ΑΝΑΠΣΤΞΗ ΗΚΚ Δ ΑΘΔΝΔΙ ΥΧΡΙ ΚΙΡΡΧΗ (REACH-B) (β COEFFICIENT AND HAZARD RATIO ESTIMATION FROM DEVELOPMENT COHORT WITH MULTIVARIATE COX PROPORTIONAL HAZARDS MODEL AND CORRESPONDING RISK SCORE) Sex Hazard ratio (95% CI) β coefficient P value Risk score Female 1.00 1.00.. 0 Male 2.2 (1.4 3.4) 0.78798 0.0004 2 Age (years) Per 5 years 1.64 (1.48 1.81) 0.49295 <0.0001 1 30 34...... 0 35 39...... 1 40 44...... 2 45 49...... 3 50 54...... 4 55 59...... 5 60 65...... 6 ALT (U/L).. < 15 1.00 1.00.. 0 15 44 1.5 (1.0 2.2) 0.38823 0.0559 1 45 2.6 (1.5 4.4) 0.96311 0.0003 2 HBeAg Negative 1.00 1.00.. 0 Positive 2.3 (1.3 3.8) 0.81308 0.0026 2 HBV DNA level (copies per ml) <300 (undetectable) 1.00 1.00.. 0 300 9999 1.1 (0.4 2.9) 0.11648 0.8063 0 10 000 99 999 3.7 (1.6 8.5) 1.31467 0.0017 3 100 000 999 999 9.7 (4.4 21.3) 2.27028 <0.0001 5 106 8.1 (3.5 19.0) 2.09258 <0.0001 4* Yang H et al. Lancet Oncol 2011; 12:568 574

Yang H et al. Lancet Oncol 2011; 12:568 574 ΠΡΟΒΔΛΦΗ ΚΙΝΓΤΝΟΤ ΓΙΑ ΑΝΑΠΣΤΞΗ ΗΚΚ (REACH-B) (CUMULATIVE RISK SCORE AND ASSOCIATED 3-YEAR, 5-YEAR, AND 10-YEAR RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B) 3 years 5 years 10 years 0 0.0% 0.0% 0.0% 1 0.0% 0.0% 0.1% 2 0.0% 0.0% 0.1% 3 0.0% 0.1% 0.2% 4 0.0% 0.1% 0.3% 5 0.1% 0.2% 0.5% 6 0.1% 0.3% 0.7% 7 0.2% 0.5% 1.2% 8 0.3% 0.8% 2.0% 9 0.5% 1.2% 3.2% 10 0.9% 2.0% 5.2% 11 1.4% 3.3% 8.4% 12 2.3% 5.3% 13.4% 13 3.7% 8.5% 21.0% 14 6.0% 13.6% 32.0% 15 9.6% 21.3% 46.8% 16 15.2% 32.4% 64.4% 17 23.6% 47.4% 81.6%

QUANTITATIVE SERUM L EVELS OF HBV DNA AND HBsAg ARE INDEPENDENT RISK PREDICTORS OF HCC Study examined the effects of HBV DNA and HBsAg levels on the development of hepatocellular carcinoma (HCC) (N=3,411) Correlation between HBV DNA and HBsAg (r=0.59) HBV DNA and HBsAg levels were significantly associated with HCC risk HCC risk associated with increasing serum HBV DNA and HBsAg levels remained, even in HBeAg(-) participants without cirrhosis Conclusion: Serum levels of HBV DNA and HBsAg should be monitored Cumulative incidence of hepatocellular carcinoma by HBV DNA/HBsAg levels at study entry Entire Cohort (N=3,411) HBeAg(-) without Cirrhosis (N=2,840) 17.2% 15.3% 13.6% 17.2% P<0.001 5.6% 5.3% 3.7% 3.0% 2.2% 1.1% P<0.001 11.1% 10.7% 5.8% 4.9% 3.8% 3.1% 2.2% 1.1% Chen C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 1095.

RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA WITH REFERENCE TO THE HBV DNA AND HBSAG LEVELS AT STUDY ENTRY IN THE ERADICATE-B COHORT HBV DNA 200.000 IU/mL HBV DNA 20.000-199.999 IU/mL HBV DNA 2.00-19.999 IU/mL HBV DNA 200-1.999 IU/mL HBV DNA < 200 IU/mL HBV DNA < 2.000 IU/mL and HBsAg 1.000 IU ml HBV DNA < 2.000 IU/mL and HBsAg < 1.000IU ml 0 100 200 300 400 500 600 700 800 900 1000 Risk of HCC (per 100.000 person-year) Editorials. Gastroenterology 2012;142:1057-1059

Simonetti J et al. Hepatology 2010;51:1531-1537 HCC DEVELOPMENT AFTER HBsAg CLEARANCE 1,271 patients with CHB, median F-UP 19.6 yrs 158 lost HBsAg (0.7%/yr) 6 ptshcc (2 cirrhotics, 4 non-cirrhotics), median time 7.3 yrs HCC incidence HBsAg(-) HBsAg(+) 36.8/100,000/yr 195.7/100,000/yr

Cumulative risk of HCC (%) HCC DEVELOPMENT AFTER HBsAg CLEARANCE 298 CHB patients, median f-up: 108 mos median age of HBsAgseroclearance: 49.6yrs 7 pts developed HCC (2.4%), in 43.5 mos (median time) afterhbsag loss 20 15 10 6/7 cirrhotics HBsAg seroclearance at 50 0 5 0 12 Age of HBsAg seroclearance HBsAg seroclearance at < 50 24 36 48 60 72 84 96 108 120 Follow-up (month) No. of patients at risk <50 151 124 102 87 71 56 47 37 21 15 10 50 147 120 86 63 51 46 38 31 24 18 12 Yuen et al. Gastroenterology 2008;135:1192-1199

Cumulative incidence of HCC (%) SYNERGISTIC EFFECTS OF FAMILY HISTORY OF HEPATOCELLULAR CARCINOMA AND HEPATITIS B VIRUS INFECTION ON RISK FOR INCIDENT HEPATOCELLULAR CARCINOMA Cumulative incidence of HCC (%) A Family history of HCC, HBsAg serostatus, and risk of incident HCC. 0.18 0.16 0.14 0.12 Family hx (-) / HBsAg (-) Family hx (+) / HBsAg (-) Family hx (-) / HBsAg (+) Family hx (+) / HBsAg (+) 15.8% B 0.45 0.40 0.35 0.30 Family history of HCC, HBsAg and HBeAg serostatus, HBV DNA level, and risk of incident HCC. No / HBsAg (-) Yes / HBsAg (-) No / HBsAg (+) HBeAg (-) / HBV DNA < 10.000 Yes / HBsAg (+) HBeAg (-) / HBV DNA < 10.000 No / HBsAg (+) HBeAg (-) / HBV DNA > 10.000 Yes / HBsAg (+) HBeAg (-) / HBV DNA > 10.000 No / HBsAg (+) HBeAg (+) Yes / HBsAg (+) HBeAg (+) 40.0% 0.10 0.25 0.08 0.06 7.5% 0.20 0.15 19.1% 17.6% 0.04 0.10 10.3% 0.02 0.00 0.65% 0.62% 0 2 4 6 8 10 12 14 16 18 0.05 0.00 0 2 4 6 8 10 12 14 16 18 5.4% 2.5% 0.64% 0.62% Follow-up time (years) Follow-up time (years) Loomba R et al. Clin Gastroenterol Hepatol 2013; 11:1636-1645.

SINGLE NUCLEOTIDE POLYMORPHISMS AND RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOSIS Study Odds ratio (95% Cl) % weight Dong et al., 1997 2.23 (1.30, 3.82) 4.7 Yu et al., 1999 1.05 (0.65, 1.68) 5.3 Sun et al., 2001 0.54 (0.30, 0.98) 4.2 Tiemersma et al., 2001 (African) 0.99 (0.51, 1.94) 3.7 Tiemersma et al., 2001 (Caucasian) 0.77 (0.35, 1.68) 3.0 Liu et al., 2002 2.04 (1.15, 3.63) 4.4 Munaka et al., 2003 1.12 (0.64, 1.96) 4.5 Yu et al., 2003 1.02 (0.79, 1.32) 7.9 McGlynn et al., 2003 0.88 (0.59, 1.31) 6.1 Li et al., 2004 1.24 (0.84, 1.82) 6.3 Deng et al., 2005 1.98 (1.38, 2.85) 6.6 Covolo et al., 2005 0.87 (0.55, 1.37) 5.5 Kirk et al., 2005 1.09 (0.73, 1.61) 6.2 Long et al., 2005 1.82 (1.25, 2.66) 6.4 Zhang et al., 2005 1.98 (0.99, 3.98) 3.5 Ladera et al., 2006 1.35 (0.89, 2.03) 6.0 Long et al., 2006 1.56 (1.17, 2.09) 7.5 Kiran et al., 2008 2.23 (1.10, 4.52) 3.4 He et al., 2008 1.40 (0.84, 2.35) 4.9 Overall 1.28 (1.09, 1.51) 100.0 0.221 1 4.515 Odds ratio Nahon P J Hepatol 2012; 57:663 674.

-log10p Recombination rate (cm/mb) SINGLE NUCLEOTIDE POLYMORPHISMS AND RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOSIS 14 100 12 10 8 r 2 0.8 0.6 0.4 0.2 rs2596542 80 60 6 4 2 40 20 0 0 DDR1 GTF2H4 VARS2 SFTA2 DPCR1 MUC21 HCG22 TCF19 C6ort15 PSORS1C1 י יייי יי י CDSN PSORS1C2 CCHCR1 יייי POU5f1 PSORS1C3 יי HLA-C HLA-B MICA MICB AJF1 LY6G6E HSPA18 HCP5 LTA APOM C6ort26 HCG26 י TNF י BAT4 י C6ort27 י MCCD1 י יייי י י י BAT1 SNORD117 SNORD84 ATP6V1G2 BAT2 BAT3 LY6G5B LY6G5C DDAH2 BAT5 31.0 31.2 31.4 31.6 31.8 ייי י יייי ייי ייי י י ייי י י י י יי ייי י ייי MSH5 C6ort48 VARS LSM2 NEU1 HSPA1L י י י י י י יייי יייי י י יייי י י Nahon P J Hepatol 2012; 57:663 674.

Patients without HCC (%) Cumulative rate SINGLE NUCLEOTIDE POLYMORPHISMS AND RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOSIS A B 1.00 0.75 0.50 0.25 0.00 0.40 0.30 0.20 0.10 0.00 P< 0.0001 Group 1 (n=20) Group 2 (n=50) Group 3 (n=27) Group 4 (n=93) 0 25 50 75 100 125 150 Time (months) Low risk n=466 Intermediate risk n=237 High risk n=111 0 25 50 75 100 125 150 Years after randomization 466 457 442 425 395 395 322 Low risk 5-year HCC Incidence rate Group 1 0/20 (0%) Group 2 and 3 4/77 (5.1%) Group 4 32/93 (34.4%) 237 222 216 198 175 149 123 Intermediated risk 111 111 98 85 70 62 47 High risk Nahon P J Hepatol 2012; 57:663 674.

H ΠPOΛHΦH TOY HKK Δ HBV ΛΟΙΜΧΞΗ Πξόιεςε κεηάδνζεο ηνπ ηνύ - Oξνινγηθόο-ηνινγηθόο έιεγρνο ησλ αηκνδνηώλ - Mείσζε αλάγθεο κεηαγγίζεσλ - Tξνπνπνίεζε ηξόπνπ δσήο - Bειόλεο κηαο ρξήζεσο Η πξνθύιαμε κέζσ ηνπ εκβνιηαζκνύ ζεσξείηαη ε θαιύηεξε πξόιεςε (πξσηνγελήο) Aληηïθή ζεξαπεία (δεπηεξνγελήο)

(6-14 εηώλ) Αλά 100,000 παηδηά (6-14 εηώλ) ΤΥΔΣΙΗ ΣΟΤ ΔΜΒΟΛΙΑΜΟΤ* ΜΔ ΣΗΝ ΔΠΙΠΣΧΗ ΚΑΙ ΣΗ ΘΝΗΣΟΣΗΣΑ ΑΠΟ ΗΚΚ 1.0 Δπίπησζε 1.0 Θλεηόηεηα Αλά 100,000 παηδηά 0.8 0.6 0.4 0.2 0.70 0.57 0.36 0.8 0.6 0.4 0.2 0.80 0.58 0.34 0 1981-86 1986-90 1990-94 0 1981-86 1986-90 1990-94 *Παλεζληθόο εκβνιηαζκόο ζηελ Σατβάλ, πινπνηήζεθε ηνλ Ινύιην ηνπ 1984. Chang MH, et al. N Engl J Med. 1997;336:1855-1859.

META-ANALYSIS EVALUATING THE EFFECT OF INTERFERON TREATMENT ON HCC IN PATIENTS WITH CHRONIC HEPATITIS B Study, Year (Reference) Interferon n/n Placebo/no treatment n/n RR (fixed) 95% Cl RR (fixed) 95% Cl Μείσζε θαηά 34% Years of follow-up Fattovich, 1997 (17) 4/40 6/50 0.83 [0.25, 2.75] 7.2 Benvegnu, 1998 (18) 1/13 7/24 0.26 [0.04, 1.92] 6.0 Brunetto, 1998 (19) 8/49 18/97 0.88 [0.41, 1.88] 5.8 Ikeda, 1998 (20) 10/94 51/219 0.46 [0.24, 0.86] 7.0 Krogsgaaed, 1998 (21) 2/210 1/98 0.93 [0.09, 10.17] 4.7 DiMarco, 1999 (22) 2/109 6/193 0.59 [0.12, 2.87] 7.8 Mazzella, 1999 (23) 1/33 2/31 0.47 [0.04, 4.92] 7.2 Papatheodoridis, 2001 (24) Tangkijvanich, 2001 (25) 17/209 15/195 1.06 [0.54, 2.06] 6.0 2/67 9/72 0.24 [0.05, 1.07] 5.0 Yuen, 2001 (26) 6/208 0/203 12.69 [0.72, 223.79] 8.9 Truong, 2005 (27) 1/27 0/35 3.86 [0.16, 91.12] 6.5 Lin, 2007 (28) 5/233 16/233 0.31 [0.12, 0.84] 6.5 Total (95% Cl) 1292 1450 0.66 [0.48, 0.89] Total events: 59 (Interferon), 131 (Placebo/no treatment), Test for heterogeneity: x 2 = 14.16, df = 11 (P = 0.22), I 2 = 22.3%, Test for overall effect: Z = 2.75 (P = 0.006) Benefit is more significant among patients with early cirrhosis than among those without cirrhosis 0.001 0.01 0.1 1 10 100 1000 Favours interferon Favours placebo/ no treatment HCC cases:controls:9% IFN treated:4.6% Sung Jjy et al Alim pharm ther 2008

META-ANALYSIS EVALUATING THE EFFECT OF INTERFERON TREATMENT ON HCC IN PATIENTS WITH CHRONIC HEPATITIS B Study, Year (Reference) (a) Cirrhosis Interferon n/n Placebo/no treatment n/n RR 95% Cl RR 95% Cl Years of follow-up Fattovich, 1997 (17) 4/40 6/50 0.83 [0.25, 2.75] 7.2 Benvegnu, 1998(18) 1/13 7/24 0.26 [0.04, 1.92] 6.0 Brunetto, 1998 (19) 8/49 18/97 0.88 [0.41, 1.88] 5.8 Ikeda, 1998 (20) 10/94 51/219 0.46 [0.24, 0.86] 7.0 Di Marco, 1999 (22) 2/26 6/60 0.77 [0.17, 3.56] 7.8 Lin, 2007 (28) 3/19 14/25 0.28 [0.09, 0.84] 6.5 Subtotal (95% Cl) 241 475 0.53 [0.36, 0.78] Total events: 28 (Interferon), 102 (Placebo/no treatment), Test for heterogeneity: x 2 = 4.45 df = 5 (P = 0.49), I 2 = 0%, Test for overall effect: Z = 3.19 (P = 0.001) (b) Non-cirrhosis Di Marco, 1999 (22) 0/83 0/133 Not estimable 7.8 Mazzella, 1999 (23) 1/33 2/31 0.47 [0.04, 4.92] 7.2 Lin, 2007 (28) 2/214 2/206 0.97 [0.14, 6.84] 6.5 Subtotal (95% Cl) 330 372 0.72 [0.16, 3.15] Total events: 3 (Interferon), 4(Placebo/no treatment), Test for heterogeneity: x 2 = 0.22, df = 1 (P = 0.64q), I 2 = 0%, Test for overall effect: Z = 0.44(P = 0.66 Sung et al, Aliment Pharmacol Ther 2008;28:1067-1077 ΗΚΚ: κάξηπξεο: 21.5% IFN : 11.6% ΗΚΚ: κάξηπξεο: 1.1% IFN : 0.9%

INTERFERON TREATMENT AND HCC RECURRENCE AFTER CURATIVE RESECTION OR ABLATION IN PATIENTS WITH CHRONIC HEPATITIS B First author, year, ref. Sun HC, 2006 [73] Study design Patients (treated) Treatment regimen RCT 236(118) IFNα2bX 18 months Followup (years) Reccurence of HCC (%) Treatment Controls Five-year disease free survival (%) Treatment Controls 3 57 60 Na Na - P Someya T, 2006 Pilot observ. 80 (11) IFNα> 6 months 16.8 27 65 Na Na 0.06 Lo CM, 2007 [75] RCT TNM I/II 41 (20) IFNα2b > 4 months 5.0 35 33 90 90 0.917 TNM III/Iva 39 (20) IFNα2b > 4 months 70 79 69 24 0.038 Qu, 2010 [76] Retrosp 568 (101) IFNα1bX 18 months 4.4 Na Na 37.5 33.5 0.082 Up to now, no evidence exists on preventive role of IFN-α after potentially curative treatment for HCC

Diagnosis of Hepatocellular Carcinoma (% of patients) ΑΝΑΠΣΤΞΗ ΗΚΚ Δ ΜΑΚΡΟΥΡΟΝΙΑ ΘΔΡΑΠΔΙΑ ΜΔ ΛΑΜΙΒΟΤΓΙΝΗ 25 20 15 10 Placebo 5 Lamivudine 0 0 6 12 18 24 30 36 No. at risk Months Placebo 215 209 198 184 173 153 43 Lamivudine 436 429 417 400 385 347 122 Όπσο ζηα woodchucks ρσξίο θίξξσζε N Engl J Med 2004; 351: 1521-31

META-ANALYSIS EVALUATING THE EFFECT OF LAM, ADV ON HCC IN PATIENTS WITH CHRONIC HEPATITIS B Μείσζε θαηά 78% Study, Year (Reference) Nucleoti de/side analogu es n/n Placebo/no treatment n/n RR (random) 95% Cl RR (random) 95% Cl Years of follow-up Liaw, 2004 (29) 17/436 16/215 0.52 [0.27, 1.02] 2.7 Matsumoto, 2005 (30) 4/377 50/377 0.08 [0.03, 0.22] 2.7 Papatheodoridis, 2005 (31) 5/201 15/195 0.32 [0.12, 0.87] 3.8 Yuen, 2007 (32) 1/142 3/124 0.29 [0.03, 2.76] 8.2 Eun, 2007 (33) 5/111 36/111 0.14 [0.06, 0.34] 4.4 Total (95% Cl) 1267 1022 0.22 [0.10, 0.50] Total events: 32 (Nucleotide/side analogues), 120 (Placebo/no treatment), Test for heterogeneity: x 2 = 12.57 df = 4 (P = 0.01), I 2 = 68.2%, Test for overall effect: Z = 3.65 (P = 0.0003) ΗΚΚ:κάξηπξεο:11.7% LAM, ADV:2.5% 0.01 0.1 1 10 100 Favours Nucleotide/side analogues Favours placebo/ no treatment Sung et al, Aliment PharmacolTher 2008;28:1067-1077

HCC PREVENTION WITH NAS (LAM, ADV) IN CHB AND DEVELOPMENT OF RESISTANCE Study, Year (Reference) (c) With drug resistance Nucleotide/si de n/n Placebo/no treatment n/n RR 95% Cl RR 95% Cl Years of follow-up Liaw, 2004 (29) 9/209 16/215 0.58 [0.26, 1.28] 2.7 Papatheodoridis, 2005 (31) 4/109 15/195 0.48 [0.16, 1.40] 3.8 Yuen, 2007 (32) 1/108 3/124 0.38 [0.04, 3.63] 8.2 Subtotal (95% Cl) 426 534 0.52 [0.28, 0.97] Total events: 14 (Nucleotide/side analogues), 34 (Placebo/no treatment), Test for heterogeneity: x 2 =0.16, df = 2 (P = 0.92), I 2 = 0%, Test for overall effect: Z = 2.07(P = 0.04) (d) Without drug resistance HKK: κάξηπξεο: 6.4% κε αληίζηαζε: 3.3% Liaw, 2004 (29) 8/221 16/215 0.49 [0.21, 1.11] 2.7 Papatheodoridis, 2005 (31) 1/92 15/195 0.14 [0.02, 1.05] 3.8 Yuen, 2007 (32) 0/34 3/124 0.51 [0.03, 9.65] 8.2 Subtotal (95% Cl) 347 534 0.37 [0.17, 0.77] Total events: 9 (Nucleotide/side analogues), 34(Placebo/no treatment), Test for heterogeneity: x 2 = 1.36, df = 2 (P = 0.51), I 2 = 0%, Test for overall effect: Z = 2.65 (P = 0.008) Sung et al, Aliment Pharmacol Ther 2008;28:1067-1077 ΗΚΚ: ρσξίο αληίζηαζε 2.6%

Cumulative development rates of HCC (%) LONG-TERM ENTECAVIR TREATMENT REDUCES HEPATOCELLULAR CARCINOMA INCIDENCE IN PATIENTS WITH HEPATITIS B VIRUS INFECTION 50 40 Log-rank test: P< 0.001 30 20 10 0 13.7% 10.0% 7.2% 4.0% 0.7% 1.2% 2.5% 3.7% Control (n = 316) ETV (n = 316) 0 1 2 3 4 5 6 7 No. at risk Treatment duration (yr) ETV 316 316 264 185 101 44 2 2 Control 316 316 277 246 223 200 187 170 Hosaka et al. Hepatology, 2013; 58:98-107

Cumulative development rates of HCC (%) LONG-TERM ENTECAVIR TREATMENT REDUCES HEPATOCELLULAR CARCINOMA INCIDENCE IN PATIENTS WITH HEPATITIS B VIRUS INFECTION Cumulative development rates of HCC (%) 50 A Cirrhosis 50 Control B. No Cirrhosis 40 38.9% 40 30 20 20.9% 28.5% 19.7% 22.2% LAM 30 20 10 0 11.4% 4.8% 12.2% 2.6% 4.3% 7.0% 7.0% ETV 10 0 3.2% 3.2% 3.2% 1.0% 1.6% 2.2% 0% 0% 0.8% 4.9% 3.6% 2.5% LAM Control ETV 0 1 2 3 4 5 6 No. at risk Treatment duration (yr) ETV 79 79 72 53 35 17 LAM 49 49 41 35 32 29 0 1 2 3 4 5 6 No. at risk Treatment duration (yr) ETV 237 237 192 132 66 27 LAM 133 133 124 119 117 112 Control 85 85 76 65 54 47 Control 231 231 201 181 169 143 Hosaka et al. Hepatology, 2013; 58:98-107

Long-term TenofovirDisoproxilFumarate (TDF) Therapy HCC INCIDENCE BASED ON CIRRHOSIS STATUS AT BASELINE HCC (%) No. at risk 5 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 0 48 96 144 192 240 288 336 Week Noncirrhotic 482 453 425 396 377 360 343 324* Cirrhotic 152 146 137 132 126 120 115 109* *Patients completing 336 weeks in study as defined by protocol; 4 of 437 patients completing Week 336 did not have baseline biopsy data available. Cirrhotic Noncirrhotic

Cumulative no. of HCC cases OBSERVED vs PREDICTED (REACH-B SCORE) HCC CASES: COMBINED ANALYSIS 30 25 20 Predicted Observed 15 10 SIR = 0.50 95% CI (0.294, 0.837) 5 0 0 48 96 144 192 240 288 336 Week 1 st significant difference *Statistically significant at nominal -level of 0.05. SIR, standardized incidence ratio.

Cumulative no. of HCC cases Cumulative no. of HCC cases 20 Non-cirrhotics Predicted 15 Observed 10 55% reduction 12 Cirrhotics 5 0 1 st significant difference 0 48 96 144 192 240 288 336 10 Predicted Week 8 Observed 6 4 2 0 0 48 96 144 192 240 288 336 Week

HKK Δ ΘΔΡΑΠΔΙΑ ΜΔ ΝΔΟΣΔΡΑ ΑΝΣΙΙΚΑ Study F-up (mos) HCC (non-cirrhotics) HCC (cirrhotics) ETV Hong Kong 1 42±13 0.8%/yr 2.7%/yr ETV Japan 2 38 0.5%/yr 1.4%/yr ETV Italy 3 60 0.3%/yr 2.6%/yr TDF EU 4 48 1.0%/yr 4.2%/yr TDF EU 5 17 (2-58) 0.5%/yr 4.1%/yr Untreated 6 Asia 0.6%/yr 3.7%/yr Europe 0.3%/yr 2.2%/yr 1.Wong et al, Gastroenterology 2013, 2.Hosaka Hepatology 2013, 3. Lampertico EASL 2013, 4. Lampertico AASLD 2013, 5. Papatheodoridis AASLD 2013, 6.Fattovich J Hepatol 2008

HKK Δ ΘΔΡΑΠΔΙΑ ΜΔ ΑΝΣΙΙΚΑ Η αληηηηθή ζεξαπεία κεηώλεη αιιά δελ εμαθαλίδεη ηνλ θίλδπλν αλάπηπμεο ΗΚΚ Πξνγλσζηηθνί παξάγνληεο: HBV-DNA, ειηθία>50, άλδξαο θαη θίξξσζε Η πξόιεςε ζε πξνθηξξσηηθό ζηάδην απνηειεζκαηηθόηεξε Η αλάπηπμε ΗΚΚ ζε θηξξσηηθνύο νθείιεηαη ζπρλά ζε παξαηεηακέλε επηβίσζε πνπ επηηπγράλεηαη Η θαξθηλνγέλεζε μεθηλά ζε πξώηκα ζηάδηα ηεο λόζνπ

ΣΑ ΒΗΜΑΣΑ ΣΗΝ ΤΠΟΘΔΗ ΣΗ ΗΠΑΣΟΚΑΡΚΙΝΟΓΔΝΔΗ Γπζπιαζηηθή εζηία Πξώηκν ΗΚΚ Κισληθή αλάπηπμε Ηπαηνθύηηαξν Γνληδηαθέο θαη επηγελεηηθέο δηαηαξαρέο Ππιαίν δηάζηεκα Αζύδεπθηε αξηεξία Γπζπιαζηηθόο όδνο ΗΚΚ ζε δπζπιαζηηθό όδν Κιαζζηθό ΗΚΚ Hytiroglou P. Semin Liver Dis 2004;24:65-75

ΦΤΙΚΗ ΙΣΟΡΙΑ ΗΚΚ Πξνλενπιαζκαηηθή θάζε δηάξθεηαο 10-30 εηώλ Γπζπιαζηηθή θάζε δηάξθεηαο 3-5 εηώλ Νενπιαζκαηηθή θάζε (δηάξθεηαο πεξίπνπ 5 εηώλ κε καθξά ππνθιηληθή πνξεία)

Δ ΥΡΟΝΙΑ HBV ΛΟΙΜΧΞΗ ΔΛΔΓΥΟ ΓΙΑ ΠΡΧΙΜΗ ΓΙΑΓΝΧΗ HKK Άλδξεο > 40 εηώλ Γπλαίθεο > 50 εηώλ Όινη νη θηξξσηηθνί Oηθνγελεηαθό ηζηνξηθό Lok AS, et al. Hepatology 2009; 50:661-662 Bruix J, et al. Hepatology 2011; 53:1020-1022

EFFICACY OF ANTIVIRAL THERAPY IN PREVENTING HEPATOCELLULAR CARCINOMA (HCC) IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS (HBV). Does HBV Treatment Prevent HCC? Chronic Hepatitis Cirrhosis Suppress HBV replication but not eradicate HBV Decrease necroinflammation and over time reverse fibrosis HCC Decrease but not eliminate risk of HCC Benefit mainly in patients with sustained / maintained virus suppression Lok AS. J GastroenterolHepatol 26 (2011) 221 227

AMEOIΣΟΥΟΙ THΘEPAΠEIA TH XPONIAHBVΛOIMΧΞΗ Kαηαζηνιήηνπηηθνύπνιιαπιαζηαζκνύ: HBV DNA ζηνλ νξό <10 4-5 γoληδηώκαηα/ml HBeAg (-), +/- αληη-hbe πλεπάγεηαη: ALT: θθ Κιηληθώο: βειηίσζε Iζηνινγηθώο: ππνρώξεζεηεοθιεγκνλήο (θαη ηεο ίλσζεο;)

AΠΧTEPOIΣΟΥOI THΘEPAΠEIA ΠξόιεςεηεοθίξξσζεοθαηηνπHKK. Bειηίσζεηεοεπηβίσζεο. Eπηηπγράλνληαη (ΗΚΚ κεξηθώο) EθξίδσζεηνπHBV HBsAg (-),αληη-hbs (+),HBV DNA (-) κεpcrζηνλνξόθαηζηνήπαξ, cccdna (-) ζηνήπαξ. Γελ επηηπγράλεηαη

Cumulative development rates of HCC (%) Cumulative probability of HCC in cirrhotic patients LONG-TERM ETV THERAPY AND HCC DEVELOPMENT 50 40 Japan cohort 38.9% Control 0.4 0.3 Hong Kong cohort Control 30 20.9% 22.2% LVD 0.2 20 10 12.2% 4.3% 7.0% ETV 0.1 ETV 0 0 Log-rank test: P=0.036 No. at risk ETV Control LVD 0 1 3 5 Treatment duration (years) 79 79 72 53 35 17 85 85 76 65 54 47 49 49 41 35 32 29 0 12 24 36 48 60 Follow-up duration (months) Patients at risk ETV 482 466 365 194 81 20 Control 69 65 60 52 45 41 Cirrhotic patients are mostly protected Hosaka, et al. Hepatology 2013. Wong, et al. Hepatology 2013. Su T-H, et al. AASLD 2013, Washington, DC. Oral 189.

Long-term TenofovirDisoproxilFumarate (TDF) Therapy and the Risk of Hepatocellular Carcinoma Studies:102 (HBeAg-) and 103 (HBeAg+) W. Ray Kim 1, Thomas Berg 2, Rohit Loomba 3, Raul Aguilar Schall 4, Phillip Dinh 4, Leland J. Yee 4, Eduardo Bruno Martins 4, John F. Flaherty 4, Selim Gurel 5, Maria Buti 6, Patrick Marcellin 7 1 Mayo Clinic, Rochester, MN, USA; 2 Universitätsklinikum Leipzig, Germany; 3 University of California at San Diego, USA; 4 Gilead Sciences, Inc., Foster City, CA; 5 University of Uludag, Bursa, Turkey; 6 Hospital General Universitari Vall d Hebron, Barcelona, Spain; 7 Hôpital Beaujon, University of Paris, Clichy, France EASL 2013, Amsterdam

REVEAL-HBV: CLEARANCE OF HBV DNA, NOT HBeAg OR HBsAg, REDUCES RISK OF HCC REVEAL-HBV study cohort (N = 2946; aged 30-65 yrs) Pts recruited 1991-1992, serum markers evaluated every 6-12 mos until June 30, 2004; HCC rates followed until December 31, 2008 HBV DNA suppression independently associated with significantly reduced risk of HCC Pts with HBeAg suppression (n = 185) still had high HBV DNA levels and still at high risk of HCC HBsAg suppression not associated with reduced incidence of HCC, but study not powered to detect difference Greatest reduction in HCC incidence observed among pts with high baseline HBV DNA ( 100,000 copies/ml) who cleared HBV DNA during follow-up HCC incidence highest in pts HBeAgseropositive throughout follow-up Liu J, et al. EASL 2013. Abstract 40.

HCC INCIDENCE IN TDF STUDIES LOWER THAN PREDICTED BY REACH-B RISK MODEL Analysis of actual HCC incidence vs REACH-B predictions in 152 cirrhotic, 482 noncirrhotic pts treated with TDF for 8 yrs in studies 102 (HBeAg-) and 103 (HBeAg+) Noncirrhotics: 8 observed cases vs 18 predicted over 7 yrs Significant difference from Wk 240: 55% reduction in HCC Cirrhotics: observed cases matched prediction over first 4 yrs; no observed cases in last 3 yrs Combined analysis: 50% lower HCC incidence at Yr 7 Kim WR, et al. EASL 2013. Abstract 43.

HCC CASES OVER TIME BY STUDY Day on study when HCC cases emerged Study 103 Study 102 197 121 323 350 797 799 1206 782 872 1222 1359 1442 1697 2227 Week 48 96 144 192 240 288 336 totally:14 cases (6 cirrhotics, 8 non-cirrhotics) Cirrhotic at baseline (Ishak fibrosis score = 6).

CUMULATIVE INCIDENCE OF HCC IN 818 PATIENTS WITH HBEAG-NEGATIVE CHB WITH OR WITHOUT CIRRHOSIS TREATED WITH NUCS STARTING WITH LAM MONOTHERAPY IN RELATION TO DISEASE SEVERITY HCC incidence, % 100 75 11.5% vs 3.2%,P<0.001 50 25 Cirrhosis 0 Patients at risk CHB 517 513 438 376 302 227 160 Cirrhosis 216 202 156 124 98 72 47 CHB 0 1 2 Follow-up, 3 years 4 5 6 Papatheodoridis et al, Gut 2011; 60:1109-1116

HCC incidence, % 100 CUMULATIVE INCIDENCE OF HCC IN RELATION TO AGE GROUP 75 50 0.7%, 6.7% and 11.7% of patients <50, 50-60 and >60 years old, respectively,p<0.001 25 0 Age groups 0 1 2 3 4 5 6 <60 years 50-60 years <50 years Patients at risk Follow-up, years <50 years 307 306 257 228 188 138 100 50-60 years 255 250 213 185 154 120 83 >60 years 256 243 203 153 111 80 53 Papatheodoridis et al, Gut 2011; 60:1109-1116

HCC incidence, % MAINTENANCE OF ON-THERAPY VIROLOGICAL REMISSION DID NOT SIGNIFICANTLY AFFECT THE HCC INCIDENCE IN ALL PATIENTS 100 75 50 P=0.388 25 All patients No virological remission 0 Virological remission 0 1 2 3 4 5 6 Follow-up, years Patients at risk No remission 578 570 509 449 366 278 196 On remission 228 221 159 113 85 59 39 P

HCC incidence, % INPATIENTS WITH COMPENSATED OR DECOMPENSATED CIRRHOSIS 100 75 P=0.327 50 25 Patients with cirrhosis Virological remission 0 No virological remission 0 1 2 3 4 5 6 Follow-up, years Patients at risk No remission 147 142 115 95 75 60 39 On remission 62 57 40 28 22 11 7 Papatheodoridis et al, Gut 2011; 60:1109-1116

HCC incidence, % A TREND FOR LOWER HCC INCIDENCE IN PATIENTS WITH CHB WITHOUT CIRRHOSIS 100 75 In fact, HCC developed in only one (<1%) of 147 non-cirrhotic patients remaining in virological remission compared with 5.2% (19/368) of those without maintained virological response (P = 0.020) 50 P=0.076 25 CHB patients No virological remission 0 Virological remission 0 1 2 3 4 5 6 Patients at risk Follow-up, years No remission 368 366 336 302 247 184 130 On remission 147 145 101 73 55 43 30 Papatheodoridis et al, Gut 2011; 60:1109-1116

INCIDENCE OF HCC IN CHRONIC HEPATITIS B PATIENTS WHO WERE TREATED WITH NUCLEOS(T)IDE ANALOGUE(S) (NUC) FOR A MEAN/MEDIAN OF 40 (24 102) MONTHS IN RELATION TO THE PRESENCE OF CIRRHOSIS, VIROLOGICAL REMISSION, AND DEVELOPMENT OF LAMIVUDINE (LAM) RESISTANCE. Patients with HCC (%) 16 12 8 4 Patients with HCC (%) 20 0 Patient n No cirrhosis Cirrhosis P < 0.001 0.5 10.8 NUC naïve 2233/1054 P < 0.001 0 17.6 With LAM resistance 241/170 20 16 12 8 4 0 Patient n Virological remission No virological remission P < 0.001 2.3 7.5 NUC naïve 982/852 P = NS 5.6 8.8 With LAM resistance 320/91 PapatheodoridisGV et al. J Hepatol 2010; 53:348 356

SYNERGISTIC EFFECTS OF FAMILY HISTORY OF HEPATOCELLULAR CARCINOMA AND HEPATITIS B VIRUS INFECTION ON RISK FOR INCIDENT HEPATOCELLULAR CARCINOMA RohitLoomba, Jessica Liu, Hwai I. Yang, Mei Hsuan Lee, Sheng Nan Lu, Li Yu Wang, Uchenna H. Iloeje, San Lin You, David Brenner, Chien Jen Chen and REVEAL HBV Study Group Clinical Gastroenterology and Hepatology Volume 11, Issue 12, Pages 1636-1645.e3 (December 2013) DOI: 10.1016/j.cgh.2013.04.043

5ΔΣΗ ΚΙΝΓΤΝΟ ΔΞΔΛΙΞΗ ΣΗ ΥΡΟΝΙΑ HBV ΛΟΙΜΧΞΗΔ ΗΚΚ Αλελεξγνί θνξείο Χξόληα επαηίηηδα Κίξξσζε Απσ Αλαηνιή 1% 3% 17% Γύζε 0.1% 1% 10% Fattovich et al, J Hepatol 2008;48:335-52

Cumulative incidence of HCC,% CUMULATIVE INCIDENCE OF HEPATOCELLULAR CARCINOMA Cumulative incidence of HCC,% A 22 20 18 16 14 12 10 8 Group of Long-term HBV DNA Change P = 0.001 Group I: Persistence at > 10 7 Group G-H: Decrease to/persistence at 10 6-10 7 Group E-F: Decrease to/persistence at 10 5-10 6 Group D: Persistence at 10 4-10 5 Group A-B-C: Decrease to<10 4 Control Group: <10 4 at enrollment 19.8% 7.1% B 16 14 12 10 8 6 Long-term Pattern of ALT P = 0.001 Persistent Abnormal Transient Abnormal Ever High Normal All Low Normal 13.5% 4.9% 6 4 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of Follow-up Chen CF et al. Gastroenterology 2011; 141:1240 1248 5.1% 2.3% 2.1% 0.9% Data were not available for 326 participants because of 2 measurements of ALT level. 4 2 0 0 2.4% 1.3% 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of Follow-up ALT level 45 U/L in50% of sequential ALT measurements. cat least one ALT level45 U/L but50% of sequential ALT measurements45 U/L. dall sequential ALT measurements 45 U/L and at least one ALT level 30 U/L. eall sequential ALT measurements 30 U/L.

META-ANALYSIS EVALUATING THE EFFECT OF LAM, ADV ON HCC IN PATIENTS WITH CHRONIC HEPATITIS B Σε HBeAg-ζεηηθνύο πιένλ εκθαλήο Χσξίο θίξξσζε νθεινύληαη πεξηζζόηεξν Η αληίζηαζε εμαθαλίδεη ην όθεινο

Cumulative incidence of HCC (%) Cumulative incidence of HCC (%) Cumulative incidence of HCC (%) ΠΡΟΒΛΔΦΗ ΣΗ ΑΝΑΠΣΤΞΗ ΗΚΚ CU-HCC score CAG-HCC score REACH-B score 0.20 0.15 5 at both time points (P < 0.001) 5 at baseline and < 5 at 2 years (P=0.002) < 5 at baseline (referent) 0.30 0.25 0.20 101 at both time points (P< 0.001) 101 at baseline and < 101 at 2 years (P = 0.07) < 101 at baseline (referent) 0.20 0.15 8 at both time points < 8 at baseline and/or 2 years P = 0.06 0.10 0.15 0.10 0.10 0.05 0.05 0.05 0.00 0 12 24 36 48 60 Follow-up duration (months) 0.00 0 12 24 36 48 60 Follow-up duration (months) 0.00 0 12 24 36 48 60 Follow-up duration (months) Age Albumin Bilirubin HBV-DNA Cirrhosis at baseline and 2 years of ETV treatment Age Gender Core-promoter mutations HBV-DNA Cirrhosis Age Gender ALT HBV-DNA HBeAg Wong et al, Gastroenterology 2013;144:933-944

KAPLAN MEIER ANALYSIS OF THE CUMULATIVE INCIDENCE OF HCC IN PATIENTS ACCORDING TO REACH-B SCORES AT BASELINE AND 2 YEARS: 8 AT BASELINE AND/OR 2 YEARS (REFERENT) AND 8 AT BOTH TIME POINTS Cumulative incidence of HCC (%) 0.20 0.15 P = 0.06 8 at both time points < 8 at baseline and/or 2 years 0.10 0.05 REACH-B score at baseline and 2 years 8 at both < 8 at baseline or 2 years 0.00 0 12 24 36 48 60 Follow-up duration (months) 499 499 495 371 176 64 616 616 609 412 231 115 Wong LG et al.gastroenterology 2013;144: 933 944

Su T-H, et al. AASLD 2013, Washington, DC. Oral 189. HCC INCIDENCE UNDER ETV TREATMENT AND IN CONTROL GROUP (TAIWAN) 1.00 0.75 Kaplan-Meier failure estimates Adjusted HR: 0.41 (95%CIL 0.20 0.84) Log-rank test P=0.053 No Treatment 0.50 0.25 Entecavir 0.00 0 20 25 30 35 40 45 50 55 60 65 70 75 80 Age (year) No. at Risk tx = 0 1 5 11 23 50 66 62 74 55 46 28 13 8 tx = 1 0 0 1 14 21 39 54 61 60 36 35 14 9 tx = 0 tx = 1

Per 1,000 person-years Su T-H, et al. AASLD 2013, Washington, DC. Oral 189. FOLLOW-UP CONDITION IN THE FIRST 3 YEARS Variable ETV treatment N=666 Historical Control N=621 P value HCC, n (%) 16 (2.4) 32 (5.2) 0.009 Follow-up duration 2.6 (1.21) 2.7 (0.22) 0.239 Follow-up (person-year) 1742 2255 Incidence of HCC in the first 3 years P=0.08 Incidence of HCC in the first 3 years Incidence of HCC in the first 3 years

LONG TERM TDFMONOTHERAPY IN A REAL-LIFE SETTING Efficacy, safety, influence of prior treatments, and incidence of HCC in a European real-life cohort of 798 patients treated with TDF monotherapy for > 6 months 798 patients (44[5,5%]cirrhotics) with 6 months TDF trx (mean 54±SD24 [range 6 141]) Incidences and Timepoints of Newly Diagnosed HCC Incidences of HCC Trx history: 404 (51%) LAM-exp., 308(39%) ADV-exp., 13 (1.6%) ETV-exp HCC detected in 8 patients (1%) after a mean treatment period of 32 ± SD 31(range 3 68) months n = 0 1 2 3 4 5 6 7 8 9 10 Years of TDF Treatment Patients in observation* 699 634 528 499 437 389 276 99 28 19 18 van Boemmel F, et al. AASLD 2013. Washington, DC. #941

HCC rates over time* (%) FOUR YEARS OF TDF MONOTHERAPY IN NUC-NAÏVE PATIENTS Retrospective/prospective cohort study of TDF monotherapy in 374 naïve CHB patients from 21 European centers HCC developed in 10 compensated cirrhotics (4-year cumulative probability: 17%, 4.2%/year) 6 in non cirrhotics (4-year cumulative probability: 4%, 1%/year) 80 60 HCC = 16 (10 in cirrhosis) HCC rate/yr in cirrhotics: 4.2% HCC rate/yr in chronic hepatitis: 1% 40 20 Cirrhotics 17% 0 0 Chronic hepatitis 6 12 18 24 30 36 42 48 4% Months Patients at risk 99 92 91 86 74 59 49 30 11 244 234 224 215 197 162 128 83 42 *Kaplan-Meier estimates Lampertico P, et al. AASLD 2013. Washington, DC. #933

Cumulative probability of HCC HCC INCIDENCE IN CHB PATIENTS UNDER ETV/TDF TREATMENT Total HCC cases: 52/1231 (4.2%) in17 (2 58) months (median) from start of ETV/TDF Incidence of HCC until the 5 th yr: 51 cases in 3,772 patients-yrsat risk: 13.5 new HCC cases/1,000 patients/yrs 1.00 0.80 0.60 0.40 0.20 Current antiviral therapy in the 1231 patients ETV monotherapy 516 (42%) ETV + ADV 14 (1%) ETV + TDF 25 (2%) TDF monotherapy 369 (30%) TDF + LVD 305 (25%) TDF + LdT 2 (0.2%) 0.00 0 1 2 3 4 5 Years since NUC initiation Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral 190.

HCC PREVENTION WITH NAS IN CHB HCC rate per 100 HBV patients years follow-up (49 studies, 10059 patients) age <50 vs age 50: 0.9 vs 2.0* chronic hepatitis vs cirrhosis: 0.3 vs 3.0* HBV-DNA (-) vs HBV-DNA (+): 1.0 vs 1.9* HCC screening vs no screening: 1.7 vs 1.0* *all statistically significant Singal et al, Aliment PharmacolTher 2013;38:98-106