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

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

2 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

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

4 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

5 Fattovich et al, J Hepatol 2008;48: ΔΣΗΙΟ ΚΙΝΓΤΝΟ ΔΜΦΑΝΙΗ ΗΚΚ ΣΗ ΥΡΟΝΙΑ HBV ΛΟΙΜΧΞΗ Αλελεξγνί θνξείο Κίξξσζε Υξόληα επαηίηηδα % % % ΗΚΚ

6 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 > 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

7 Cumulative incidence (%) ΗΒeAg KAI ΚΙΝΓΤΝΟ ΓΙΑ ΗΚΚ HBsAg+, HBeAg+ HBsAg+, HBeAg- HBsAg-, HBeAg Year Yang et al. N Engl J Med 2002, 347:

8 Δπίπησζε ΗΚΚ ζε 13 ρξόληα (%) ΜΔΛΔΣΗ REVEAL: ΤΥΔΣΙΗ HBV DNA ΜΔ ΔΠΙΠΣΧΗ ΗΚΚ N = < ,000-99, ,000 HBV DNA (γνληδηώκαηα/ml) Chen CJ, et al. JAMA. 2006;295:65-73.

9 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

10 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 Male 2.2 ( ) Age (years) Per 5 years 1.64 ( ) < ALT (U/L).. < ( ) ( ) HBeAg Negative Positive 2.3 ( ) HBV DNA level (copies per ml) <300 (undetectable) ( ) ( ) ( ) < ( ) < * Yang H et al. Lancet Oncol 2011; 12:

11 Yang H et al. Lancet Oncol 2011; 12: 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% % 2.0% 5.2% % 3.3% 8.4% % 5.3% 13.4% % 8.5% 21.0% % 13.6% 32.0% % 21.3% 46.8% % 32.4% 64.4% % 47.4% 81.6%

12 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< % 5.3% 3.7% 3.0% 2.2% 1.1% P< % 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

13 RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA WITH REFERENCE TO THE HBV DNA AND HBSAG LEVELS AT STUDY ENTRY IN THE ERADICATE-B COHORT HBV DNA IU/mL HBV DNA IU/mL HBV DNA IU/mL HBV DNA IU/mL HBV DNA < 200 IU/mL HBV DNA < IU/mL and HBsAg IU ml HBV DNA < IU/mL and HBsAg < 1.000IU ml Risk of HCC (per person-year) Editorials. Gastroenterology 2012;142:

14 Simonetti J et al. Hepatology 2010;51: 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

15 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 /7 cirrhotics HBsAg seroclearance at Age of HBsAg seroclearance HBsAg seroclearance at < Follow-up (month) No. of patients at risk < Yuen et al. Gastroenterology 2008;135:

16 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 Family hx (-) / HBsAg (-) Family hx (+) / HBsAg (-) Family hx (-) / HBsAg (+) Family hx (+) / HBsAg (+) 15.8% B 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 < Yes / HBsAg (+) HBeAg (-) / HBV DNA < No / HBsAg (+) HBeAg (-) / HBV DNA > Yes / HBsAg (+) HBeAg (-) / HBV DNA > No / HBsAg (+) HBeAg (+) Yes / HBsAg (+) HBeAg (+) 40.0% % % 17.6% % % 0.62% % 2.5% 0.64% 0.62% Follow-up time (years) Follow-up time (years) Loomba R et al. Clin Gastroenterol Hepatol 2013; 11:

17 SINGLE NUCLEOTIDE POLYMORPHISMS AND RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOSIS Study Odds ratio (95% Cl) % weight Dong et al., (1.30, 3.82) 4.7 Yu et al., (0.65, 1.68) 5.3 Sun et al., (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., (1.15, 3.63) 4.4 Munaka et al., (0.64, 1.96) 4.5 Yu et al., (0.79, 1.32) 7.9 McGlynn et al., (0.59, 1.31) 6.1 Li et al., (0.84, 1.82) 6.3 Deng et al., (1.38, 2.85) 6.6 Covolo et al., (0.55, 1.37) 5.5 Kirk et al., (0.73, 1.61) 6.2 Long et al., (1.25, 2.66) 6.4 Zhang et al., (0.99, 3.98) 3.5 Ladera et al., (0.89, 2.03) 6.0 Long et al., (1.17, 2.09) 7.5 Kiran et al., (1.10, 4.52) 3.4 He et al., (0.84, 2.35) 4.9 Overall 1.28 (1.09, 1.51) Odds ratio Nahon P J Hepatol 2012; 57:

18 -log10p Recombination rate (cm/mb) SINGLE NUCLEOTIDE POLYMORPHISMS AND RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOSIS r rs 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 BAT 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:

19 Patients without HCC (%) Cumulative rate SINGLE NUCLEOTIDE POLYMORPHISMS AND RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOSIS A B P< Group 1 (n=20) Group 2 (n=50) Group 3 (n=27) Group 4 (n=93) Time (months) Low risk n=466 Intermediate risk n=237 High risk n= Years after randomization 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%) Intermediated risk High risk Nahon P J Hepatol 2012; 57:

20 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)

21 (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 *Παλεζληθόο εκβνιηαζκόο ζηελ Σατβάλ, πινπνηήζεθε ηνλ Ινύιην ηνπ Chang MH, et al. N Engl J Med. 1997;336:

22 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/ [0.25, 2.75] 7.2 Benvegnu, 1998 (18) 1/13 7/ [0.04, 1.92] 6.0 Brunetto, 1998 (19) 8/49 18/ [0.41, 1.88] 5.8 Ikeda, 1998 (20) 10/94 51/ [0.24, 0.86] 7.0 Krogsgaaed, 1998 (21) 2/210 1/ [0.09, 10.17] 4.7 DiMarco, 1999 (22) 2/109 6/ [0.12, 2.87] 7.8 Mazzella, 1999 (23) 1/33 2/ [0.04, 4.92] 7.2 Papatheodoridis, 2001 (24) Tangkijvanich, 2001 (25) 17/209 15/ [0.54, 2.06] 6.0 2/67 9/ [0.05, 1.07] 5.0 Yuen, 2001 (26) 6/208 0/ [0.72, ] 8.9 Truong, 2005 (27) 1/27 0/ [0.16, 91.12] 6.5 Lin, 2007 (28) 5/233 16/ [0.12, 0.84] 6.5 Total (95% Cl) [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 Favours interferon Favours placebo/ no treatment HCC cases:controls:9% IFN treated:4.6% Sung Jjy et al Alim pharm ther 2008

23 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/ [0.25, 2.75] 7.2 Benvegnu, 1998(18) 1/13 7/ [0.04, 1.92] 6.0 Brunetto, 1998 (19) 8/49 18/ [0.41, 1.88] 5.8 Ikeda, 1998 (20) 10/94 51/ [0.24, 0.86] 7.0 Di Marco, 1999 (22) 2/26 6/ [0.17, 3.56] 7.8 Lin, 2007 (28) 3/19 14/ [0.09, 0.84] 6.5 Subtotal (95% Cl) [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/ [0.04, 4.92] 7.2 Lin, 2007 (28) 2/214 2/ [0.14, 6.84] 6.5 Subtotal (95% Cl) [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: ΗΚΚ: κάξηπξεο: 21.5% IFN : 11.6% ΗΚΚ: κάξηπξεο: 1.1% IFN : 0.9%

24 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 Na Na - P Someya T, 2006 Pilot observ. 80 (11) IFNα> 6 months Na Na 0.06 Lo CM, 2007 [75] RCT TNM I/II 41 (20) IFNα2b > 4 months TNM III/Iva 39 (20) IFNα2b > 4 months Qu, 2010 [76] Retrosp 568 (101) IFNα1bX 18 months 4.4 Na Na Up to now, no evidence exists on preventive role of IFN-α after potentially curative treatment for HCC

25 Diagnosis of Hepatocellular Carcinoma (% of patients) ΑΝΑΠΣΤΞΗ ΗΚΚ Δ ΜΑΚΡΟΥΡΟΝΙΑ ΘΔΡΑΠΔΙΑ ΜΔ ΛΑΜΙΒΟΤΓΙΝΗ Placebo 5 Lamivudine No. at risk Months Placebo Lamivudine Όπσο ζηα woodchucks ρσξίο θίξξσζε N Engl J Med 2004; 351:

26 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/ [0.27, 1.02] 2.7 Matsumoto, 2005 (30) 4/377 50/ [0.03, 0.22] 2.7 Papatheodoridis, 2005 (31) 5/201 15/ [0.12, 0.87] 3.8 Yuen, 2007 (32) 1/142 3/ [0.03, 2.76] 8.2 Eun, 2007 (33) 5/111 36/ [0.06, 0.34] 4.4 Total (95% Cl) [0.10, 0.50] Total events: 32 (Nucleotide/side analogues), 120 (Placebo/no treatment), Test for heterogeneity: x 2 = df = 4 (P = 0.01), I 2 = 68.2%, Test for overall effect: Z = 3.65 (P = ) ΗΚΚ:κάξηπξεο:11.7% LAM, ADV:2.5% Favours Nucleotide/side analogues Favours placebo/ no treatment Sung et al, Aliment PharmacolTher 2008;28:

27 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/ [0.26, 1.28] 2.7 Papatheodoridis, 2005 (31) 4/109 15/ [0.16, 1.40] 3.8 Yuen, 2007 (32) 1/108 3/ [0.04, 3.63] 8.2 Subtotal (95% Cl) [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/ [0.21, 1.11] 2.7 Papatheodoridis, 2005 (31) 1/92 15/ [0.02, 1.05] 3.8 Yuen, 2007 (32) 0/34 3/ [0.03, 9.65] 8.2 Subtotal (95% Cl) [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: ΗΚΚ: ρσξίο αληίζηαζε 2.6%

28 Cumulative development rates of HCC (%) LONG-TERM ENTECAVIR TREATMENT REDUCES HEPATOCELLULAR CARCINOMA INCIDENCE IN PATIENTS WITH HEPATITIS B VIRUS INFECTION Log-rank test: P< % 10.0% 7.2% 4.0% 0.7% 1.2% 2.5% 3.7% Control (n = 316) ETV (n = 316) No. at risk Treatment duration (yr) ETV Control Hosaka et al. Hepatology, 2013; 58:98-107

29 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 % % 28.5% 19.7% 22.2% LAM % 4.8% 12.2% 2.6% 4.3% 7.0% 7.0% ETV % 3.2% 3.2% 1.0% 1.6% 2.2% 0% 0% 0.8% 4.9% 3.6% 2.5% LAM Control ETV No. at risk Treatment duration (yr) ETV LAM No. at risk Treatment duration (yr) ETV LAM Control Control Hosaka et al. Hepatology, 2013; 58:98-107

30 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, Week Noncirrhotic * Cirrhotic * *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

31 Cumulative no. of HCC cases OBSERVED vs PREDICTED (REACH-B SCORE) HCC CASES: COMBINED ANALYSIS Predicted Observed SIR = % CI (0.294, 0.837) Week 1 st significant difference *Statistically significant at nominal -level of SIR, standardized incidence ratio.

32 Cumulative no. of HCC cases Cumulative no. of HCC cases 20 Non-cirrhotics Predicted 15 Observed 10 55% reduction 12 Cirrhotics st significant difference Predicted Week 8 Observed Week

33 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 %/yr 1.4%/yr ETV Italy %/yr 2.6%/yr TDF EU %/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

34 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

35 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

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

37 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: Bruix J, et al. Hepatology 2011; 53:

38

39 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)

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

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

42 Cumulative development rates of HCC (%) Cumulative probability of HCC in cirrhotic patients LONG-TERM ETV THERAPY AND HCC DEVELOPMENT Japan cohort 38.9% Control Hong Kong cohort Control % 22.2% LVD % 4.3% 7.0% ETV 0.1 ETV 0 0 Log-rank test: P=0.036 No. at risk ETV Control LVD Treatment duration (years) Follow-up duration (months) Patients at risk ETV Control Cirrhotic patients are mostly protected Hosaka, et al. Hepatology Wong, et al. Hepatology Su T-H, et al. AASLD 2013, Washington, DC. Oral 189.

43 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

44 REVEAL-HBV: CLEARANCE OF HBV DNA, NOT HBeAg OR HBsAg, REDUCES RISK OF HCC REVEAL-HBV study cohort (N = 2946; aged yrs) Pts recruited , 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 Abstract 40.

45 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 Abstract 43.

46 HCC CASES OVER TIME BY STUDY Day on study when HCC cases emerged Study 103 Study Week totally:14 cases (6 cirrhotics, 8 non-cirrhotics) Cirrhotic at baseline (Ishak fibrosis score = 6).

47 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, % % vs 3.2%,P< Cirrhosis 0 Patients at risk CHB Cirrhosis CHB Follow-up, 3 years Papatheodoridis et al, Gut 2011; 60:

48 HCC incidence, % 100 CUMULATIVE INCIDENCE OF HCC IN RELATION TO AGE GROUP %, 6.7% and 11.7% of patients <50, and >60 years old, respectively,p< Age groups <60 years years <50 years Patients at risk Follow-up, years <50 years years >60 years Papatheodoridis et al, Gut 2011; 60:

49 HCC incidence, % MAINTENANCE OF ON-THERAPY VIROLOGICAL REMISSION DID NOT SIGNIFICANTLY AFFECT THE HCC INCIDENCE IN ALL PATIENTS P= All patients No virological remission 0 Virological remission Follow-up, years Patients at risk No remission On remission P

50 HCC incidence, % INPATIENTS WITH COMPENSATED OR DECOMPENSATED CIRRHOSIS P= Patients with cirrhosis Virological remission 0 No virological remission Follow-up, years Patients at risk No remission On remission Papatheodoridis et al, Gut 2011; 60:

51 HCC incidence, % A TREND FOR LOWER HCC INCIDENCE IN PATIENTS WITH CHB WITHOUT CIRRHOSIS 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= CHB patients No virological remission 0 Virological remission Patients at risk Follow-up, years No remission On remission Papatheodoridis et al, Gut 2011; 60:

52 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 (%) Patients with HCC (%) 20 0 Patient n No cirrhosis Cirrhosis P < NUC naïve 2233/1054 P < With LAM resistance 241/ Patient n Virological remission No virological remission P < NUC naïve 982/852 P = NS With LAM resistance 320/91 PapatheodoridisGV et al. J Hepatol 2010; 53:

53 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 e3 (December 2013) DOI: /j.cgh

54 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

55 Cumulative incidence of HCC,% CUMULATIVE INCIDENCE OF HEPATOCELLULAR CARCINOMA Cumulative incidence of HCC,% A Group of Long-term HBV DNA Change P = Group I: Persistence at > 10 7 Group G-H: Decrease to/persistence at Group E-F: Decrease to/persistence at Group D: Persistence at Group A-B-C: Decrease to<10 4 Control Group: <10 4 at enrollment 19.8% 7.1% B Long-term Pattern of ALT P = Persistent Abnormal Transient Abnormal Ever High Normal All Low Normal 13.5% 4.9% Year of Follow-up Chen CF et al. Gastroenterology 2011; 141: % 2.3% 2.1% 0.9% Data were not available for 326 participants because of 2 measurements of ALT level % 1.3% 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.

56 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

57 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 at both time points (P < 0.001) 5 at baseline and < 5 at 2 years (P=0.002) < 5 at baseline (referent) at both time points (P< 0.001) 101 at baseline and < 101 at 2 years (P = 0.07) < 101 at baseline (referent) at both time points < 8 at baseline and/or 2 years P = Follow-up duration (months) Follow-up duration (months) 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:

58 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 (%) P = at both time points < 8 at baseline and/or 2 years REACH-B score at baseline and 2 years 8 at both < 8 at baseline or 2 years Follow-up duration (months) Wong LG et al.gastroenterology 2013;144:

59 Su T-H, et al. AASLD 2013, Washington, DC. Oral 189. HCC INCIDENCE UNDER ETV TREATMENT AND IN CONTROL GROUP (TAIWAN) Kaplan-Meier failure estimates Adjusted HR: 0.41 (95%CIL ) Log-rank test P=0.053 No Treatment Entecavir Age (year) No. at Risk tx = tx = tx = 0 tx = 1

60 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) Follow-up duration 2.6 (1.21) 2.7 (0.22) Follow-up (person-year) 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

61 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 = Years of TDF Treatment Patients in observation* van Boemmel F, et al. AASLD Washington, DC. #941

62 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) HCC = 16 (10 in cirrhosis) HCC rate/yr in cirrhotics: 4.2% HCC rate/yr in chronic hepatitis: 1% Cirrhotics 17% 0 0 Chronic hepatitis % Months Patients at risk *Kaplan-Meier estimates Lampertico P, et al. AASLD Washington, DC. #933

63 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 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%) Years since NUC initiation Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral 190.

64 HCC PREVENTION WITH NAS IN CHB HCC rate per 100 HBV patients years follow-up (49 studies, 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