Τελοθοβίρε. Μαθροτρόληα ηζηοιογηθά δεδοκέλα ζεραπείας. Γεώξγηνο Σ. Γεξκαλίδεο Α Παζνινγηθή Κιηληθή Α.Π.Θ Π.Γ.Ν.Θ. ΑΦΔΠΑ

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1 Τελοθοβίρε. Μαθροτρόληα ηζηοιογηθά δεδοκέλα ζεραπείας Γεώξγηνο Σ. Γεξκαλίδεο Α Παζνινγηθή Κιηληθή Α.Π.Θ Π.Γ.Ν.Θ. ΑΦΔΠΑ

2 Ιοιογηθή & Βηοτεκηθή αληαπόθρηζε-ύθεζε ζε ΧΗΒ, αζζελείς HBeAg+ve,-ve αλάιογα κε ηο είδος ζεραπείας Θεξαπεία νξηζκέλνπ ρξόλνπ (=,>48 εβδ.) (Peg IFN a-2a, NUCs) Σηόρνο: Μαθξνρξόληα ηνινγηθή & βηνρεκηθή αληαπόθξηζε κεηά δηαθνπή ηεο ζεξαπείαο Θεξαπεία επί καθξόλ κε αληηηθά (NUCs), >5 έηε, ή δηα βίνπ Σηόρνο: Γηαηήξεζε ηνινγηθήο & βηνρεκηθήο ύθεζεο ππό ζεξαπεία HBeAg ve / anti-hbe +ve, ΗΒV DNA <2,000 IU/mL 12 κήλεο & ΑLT θπζηνινγηθή επί καθξόλ (Ιζηνινγία Α ειάηησζε 2 β.,0-1) HBV DNA (-) <15-(69)/80 IU/mL & ΑLT θπζηνινγηθή επί καθξόλ (Ιζηνινγία -Α 0-1,-<F >1ζηάδην)

3 ΧΗΒ,HBeAg +ve θαη -ve : Θεραπεία επί καθρόλ κε αληηηθά (NUCs): EASL 2012 Η ζηξαηεγηθή απηή είλαη αλαγθαία σο επαλαζεξαπεία γηα ηνπο αζζελείο ρσξίο Μαθξνρξόληα Ινινγηθή Αληαπόθξηζε εθηόο Θεξαπείαο ( Υπνηξνπή- Με νξνκεηαηξνπή ζην HBeAg ) ΦΗΒ, αζζελείο HBeAg-ve Πξνο ην παξόλ, δελ ππάξρνπλ ζαθείο ζπζηάζεηο σο πξνο ηε δηάξθεηα ρνξήγεζεο ησλ αληηηθώλ θαξκάθσλ ζε HBeAg-αξλεηηθή ΦΗΒ Η έλδεημε είλαη ζεκαληηθνύ βαζκνύ ηζηνινγηθέο αιινηώζεηο (> ή = A2F2) ζηελ επαηηθή βηνςία Μηθξή πηζαλόηεηα (κε ηα κέρξη ζήκεξα ζρήκαηα) καθξνρξόληαο αληαπόθξηζεο κεηά ηε δηαθνπή ηνπο κε ζπλέπεηα ηελ αλάγθε γηα καθξνρξόληα ( 5 έηε θαη ίζσο δηα βίνπ) ρνξήγεζή ηνπο Η ζηξαηεγηθή απηή ζπληζηάηαη γηα ηνπο θηξξσηηθνύο αζζελείο (HBeAg +ve θαη ve),αλεμάξηεηα από ηελ νξνκεηαηξνπή ζην HBeAg ππό ζεξαπεία EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection Journal of Hepatology 2012;57:

4 Ishak Score Reductions After Long-Term Antiviral Treatment in CHB Patients with Cirrhosis at Baseline Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124: Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351: Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006;131: Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348: Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008;48:750 8 Schiff ER, Lee SS, Chao YC, et al. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2011;9: Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:

5 Σσζηεκαηηθή Αλαζθόπεζε Οη ζπγθεθξηκέλεο κειέηεο ήηαλ πεξηνξηζκέλνπ εύξνπο θαη πεξηιάκβαλαλ ζεξαπείεο ζρεηηθά κηθξήο ή όρη ζηαζεξήο δηάξθεηαο. Αμηνζεκείσηα, θάζε κία πεξηιακβάλεη κία νκάδα αζζελώλ κε ζνβαξή ίλσζε ή θίξξσζε,ην δείγκα κεγέζνπο ηεο νπνίαο είλαη ζρεηηθά κηθξό (π.ρ. 10 αζζελείο ζηηο κειέηεο κε εληεθαβίξε). Τν κηθξό δείγκα απνθιείεη πνιππαξαγνληηθή αλάιπζε ησλ παξακέηξσλ πνπ ζρεηίδνληαη κε ππνζηξνθή ηεο θίξξσζεο Δπηπιένλ, ε επηβεβαίσζε ελόο επλντθνύ ζεξαπεπηηθνύ απνηειέζκαηνο ζηηο ελ ιόγσ κειέηεο δπζρεξαίλεη εμαηηίαο δηαθνξεηηθώλ ρξνλνδηαγξακκάησλ ζηηο επαλαιεπηηθέο βηνςίεο ήπαηνο, πνπ ν ρξόλνο δηελέξγεηάο ηνπο θπκαίλεηαη από 3 έσο θαη 7 έηε. Σαθήο εξκελεία ηεο ππνζηξνθήο ηεο ίλσζεο ζηηο κειέηεο ησλ πξώησλ εγθεθξηκέλσλ αληηηθώλ όπσο ε LAM θαη ην ADV είλαη δύζθνιε,δεδνκέλνπ ηνπ γεγνλόηνο ηεο απώιεηαο ηεο ηζηνινγηθήο βειηίσζεο ε νπνία έρεη πεξηγξαθεί ζηελ ππννκάδα ησλ αζζελώλ πνπ αλαπηύζζεηαη αληνρή ζηα αληηηθά απηά ππό αγσγή επί καθξόλ.

6 Aζθενείς (N) Η Eληεθαβίρε επηησγτάλεη σποζηροθή ίλφζες θαηά Ishak ζηελ πιεηουεθία αζζελώλ κε κε αλητλεύζηκο HBV DNA Ishak score Αποσζία δεδομένφν 0 Baseline Εβδομ. 48 Μακροτρόνια τορήγηζη* N=57 * Ενδιάμεζος τρόνος βιουίας: 6 έηη (range: 3 7 έηη) Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A. Chang TT et al Hepatology. 2010;52:

7 Regression of Cirrhosis During Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B Patrick Marcellin, Edward Gane, Maria Buti, Nezam Afdhal, William Sievert, Ira M. Jacobson, Mary Kay Washington, George Germanidis, John F. Flaherty, Raul Aguilar Schall, Jeffrey D. Bornstein, Kathryn M. Kitrinos, G. Mani Subramanian, John G. McHutchison, and E. Jenny Heathcote From Hôpital Beaujon, Service d Hépatologie and INSERM CRB3, Clichy, France (P.M.), Auckland City Hospital, Auckland, New Zealand (E.G.), Liver Unit, Hospital General Universitari Vall d Hebron and Ciberehd, Barcelona, Spain (M.B.), Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA (N.A.), Monash University and Monash Medical Centre, Melbourne, VIC, Australia (W.S.), Weill Cornell Medical College, New York, NY (I.M.J.), Vanderbilt University, Nashville, TN (M.K.W.), AHEPA University Hospital, Aristotle University Medical School, Thessaloniki, Greece (G.G.), Gilead Sciences, Inc., Foster City, CA (R.A.S.., J.F.F., J.D.B., K.M.K., G.M.S., J.G.M), and University of Toronto, Toronto, Ontario, Canada (E.J.H.) Lancet 2013, in press

8 Σθοπός ηες κειέηες Αμηνιόγεζε ηεο ηζηνινγηθήο αληαπόθξηζεο ππό ζεξαπεία κε TDF επί καθξόλ (5 έηε) ηεο ρξόληαο HBV ινίκσμεο, πεξηιακβαλνκέλσλ αιιαγώλ ζηελ επαηηθή ίλσζε, ζε HBeAgαξλεηηθνύο θαη HBeAg-ζεηηθνύο αζζελείο κε ΧΗΒ Αμηνιόγεζε ηεο απνηειεζκαηηθόηεηαο θαη ηεο αζθάιεηαο ππό ζεξαπεία κε TDF επί καθξόλ (5 έηε) ηεο ρξόληαο HBV ινίκσμεο, ζε HBeAg-αξλεηηθνύο θαη HBeAg-ζεηηθνύο αζζελείο κε ΧΗΒ Marcellin, P, et al. Lancet 2013, in press

9 RANDOMIZATION 2:1 Study Design of Phase 3 Tenofovir DF Pivotal Studies 102 (HBeAg- Patients) and 103 (HBeAg+ Patients) Double Blind Year 1 Open-label Year 8 Tenofovir DF 300 mg N=250 & N=176 N=235 N=154 Tenofovir DF 300 mg Adefovir Dipivoxil 10 mg N=125 & N=90 N=112 N=84 Tenofovir DF 300 mg Pre-treatment Liver Biopsy Year 1 Liver Biopsy 1 Year 5/ Week 240 Week 72 Year 3 2 Liver Biopsy Year 8 At Week 72, patients with HBV DNA 400 copies/ml had the option at the discretion of the investigator to add emtricitabine (FTC)* Retention rate at Week 240: 81% for HBeAg-, 70% for HBeAg+ *Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV Marcellin, P, et al. Lancet 2013, in press 1 Marcellin et al NEJM; 359: Heathcote et al Gastroenterology; 140:

10 Study Disposition and Availability of Liver Biopsy Data 641 patients were randomized and treated; 634 with available baseline liver biopsy data 615 (96%) completed the 48 week double-blind phase 585 (91%) entered the open-label phase 26 (4%) discontinued during the 48 week double-blind phase without liver biopsy 9 Lost to follow-up 7 Safety, tolerability, or efficacy reason 7 Withdrew consent 3 Protocol violation 30 (5%) did not roll over to the open-label phase; 20 completed double-blind phase without a biopsy, 10 completed double-blind phase with a biopsy 4 Declined participation in extension phase 3 Lost to follow-up 2 Seroconversion 21 Withdrew consent 489 (76%) completed Year 5 of the open-label phase 96 (15%) discontinued prior to Year 5 25 Lost to follow-up 15 Safety, tolerability, or efficacy reason 10 Investigator discretion 4 Protocol violation 8 Seroconversion 33 Withdrew consent 1 Study discontinued by sponsor 141 (22% ) completed Year 5 without liver biopsy data 348 (54%) had evaluable biopsies at Year 5 (Week 240)

11 Σηαηηζηηθή αλάισζε Αμηνιόγεζε απνηειεζκαηηθόηεηαο επί καθξόλ (Long-term evaluation of efficacy), αλάιπζε κόλνλ ππό TDF [LTE-TDF] Τξνπνπνηεκέλε ΙΤΤ( intent-to-treat), ειιείπνληα δεδνκέλα= απνηπρία; κέζνδνο αλάιπζεο γηα % HBV DNA <400 copies/ml, θαη νκαινπνίεζε ALT Οη αζζελείο κε πξνζζήθε FTC κεηά ηελ εβδνκάδα 72 ( πνπ επεηξάπε θαηά δηάθξηζε γηα επηβεβαησκέλεο ηηκέο HBV DNA 400 c/ml), ζεσξήζεθαλ απνηπρίεο Αλάιπζε ππό Θεξαπεία (On-Treatment analysis )[παξαηεξνύκελα δεδνκέλα, ειιείπνληα δεδνκέλα= απνθιείνληαη] Οη αζζελείο κε πξνζζήθε FTC ζπκπεξηιακβάλνληαη Μέζνδνο αλάιπζεο γηα ηελ ηζηνινγία, νκαινπνίεζε ηεο ALT, απώιεηα ηνπ HBeAg, θαη % HBV DNA < 400 c/ml Kaplan-Meier Μέζνδνο αλάιπζεο γηα ηελ απώιεηα ηνπ HBsAg θαη ηελ νξνκεηαηξνπή Marcellin, P, et al. Lancet 2013, in press Το Truvada (TVD = TDF + FTC) και η emtricitabine (FTC) δεν είναι εγκεκριμένα θάρμακα για χρήζη ζηην ΧΗΒ

12 Σηαηηζηηθή αλάισζε- Τροποποηεκέλε ΙΤΤ (intent-to-treat) A modified last observation carried forward (mlocf) analysis was implemented, -that carried forward year 1 results if year 5 results were missing, -and for those missing data at years 1 and 5, it was assumed that their disease progressed to cirrhosis at year 5.

13 Αποηειέζκαηα Αλάιπζε ππνζηξνθήο ηεο ίλσζεο ζην 5 ν έηνο (Αζξνηζηηθά απνηειέζκαηα) Σε 641 αζζελείο δηελεξγήζεθαλ αξρηθέο βηνςίεο ήπαηνο (ΑΒΗ), πξηλ ηελ έλαξμε ηεο ζεξαπείαο Τν 76% δελ είραλ θίξξσζε ( Σθόξ ίλσζεο θαηά Ishak <5) ζηελ ΑΒΗ Τν 24% είραλ θίξξσζε ( Σθόξ ίλσζεο θαηά Ishak 5) ζηελ ΑΒΗ Σε 348/641 (54%) αζζελείο ηεο κειέηεο ππήξραλ δεύγε ΑΒΗ θαη βηνςηώλ ζην 5 ν έηνο κε αλάιπζε απνηειεζκάησλ Σε 252 (52%) κε θηξξσηηθνύο αζζελείο ππήξραλ ηα αλσηέξσ δεύγε βηνςηώλ Σε 96 (62%) θηξξσηηθνύο αζζελείο ππήξραλ ηα αλσηέξσ δεύγε βηνςηώλ Τν 71% ησλ 489 αζζελώλ ηεο κειέηεο ζην 5 ν έηνο είραλ δηαζέζηκα απνηειέζκαηα δεπγώλ βηνςηώλ 17/348 (5%) αζζελείο κε δεύγε βηνςηώλ είραλ πξνζζήθε FTC ζηελ TDF 15/252 (6%) κε-θηξξσηηθνί αζζελείο κε δεύγε βηνςηώλ είραλ πξνζζήθε FTC 2/96 (2%) θηξξσηηθνί αζζελείο κε δεύγε βηνςηώλ είραλ πξνζζήθε FTC Marcellin, P, et al. Lancet 2013, in press Το Truvada (TVD = TDF + FTC) και η emtricitabine (FTC) δεν είναι εγκεκριμένα θάρμακα για χρήζη ζηην ΧΗΒ

14 Percentage Knodell necroinflammatory scores at baseline, year 1 and year 5 2A P <0.001 P <0.001 Baseline Year 1 Year 5 Series Series3 7-9 Series2 4-6 Series1 0-3 Progressive reductions in Knodell scores were evident with 8% (27/348) at baseline, this increased to 49% at year 1 and further increased to 80% at year 5 (P <0.001) (278/348) of patients at year 5 having mild to no evidence of necroinflammation (Knodell score 0-3; P <0.001, sign test)

15 Percentage of of Patients s Distribution of Ishak Fibrosis Scores at Baseline, Year 1, and Year 5 P < % 90% 80% 70% 60% 50% 40% 30% 20% 10% Ishak Fibrosis Score Baselin e Year 1 Year 5 344/348 patients had liver biopsy data available at all three time points Percentage of the population with cirrhosis (Ishak Score 5) progressively decreased from 28% at baseline to 8% at Year 5 38% (133/348) had Ishak scores 4 (changes ranging from marked bridging fibrosis to cirrhosis), this declined to 28% and 12% at years 1 and 5 Over time, an increasing proportion of patients had regression of fibrosis as reflected in 63% (219/348) of patients having Ishak scores 2 at year 5 vs 39% baseline &43% at year 1 P <0.001, sign test) Marcellin, P, et al. Lancet 2013, in press

16 Percent Ηistologic response at year 5 as a function of baseline Ishak fibrosis scores 3A. 100 n=10 n=126 n=79 n=37 n=19 n= No Improvement in Histology Histologic Improvement Ishak Fibrosis Score at Baseline Overall, regression of fibrosis was observed in 176/348 (51%) of patients and histologic improvement was seen in 304/348 (87%) of patients at year 5. Furthermore, histologic improvement rates of 91% were observed with Ishak scores >2 at baseline, and patients with the highest liver injury scores showed the greatest degree of improvement P <0.001

17 Percentage of Subjects Impact of Tenofovir DF Treatment on Fibrosis Response at Year 5 100% (n=10) (n=126) (n=79) (n=37) (n=19) (n=77) Year 5 Response 90% 80% Improvement No Change Worsening 70% 60% 50% 40% 30% 20% 10% Baseline Ishak Fibrosis Score 96% (335/348) of patients with paired biopsies either improved ( 1 unit decrease in fibrosis score) or did not change at Year 5 96% (318/331) who did not add FTC either improved or did not change at year 5 98% of patients on TDF treatment had undetectable HBV DNA < 400 copies/ml at Year 5 Marcellin, P, et al. Lancet 2013, in press Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV

18 I-D w0 I-D w240 TDF

19 Overexpression of SMAD7 protects liver from TGFβ/Smad-mediated fibrogenesis G.Germanidis et al in preparation for submission

20 Overexpression of SMAD7 protects liver from TGFβ/Smad-mediated fibrogenesis G.Germanidis et al in preparation for submission

21 BMI Σε πνιππαξαγνληηθή αλάιπζε ν δείθηεο κάδαο ζώκαηνο (BMI) ζηελ έλαξμε ήηαλ αλεμάξηεηα ζπζρεηηδόκελνο κε ηελ ππνζηξνθή ηεο θίξξσζεο (BMI <25 kg/m 2 vs. BMI 25 kg/m 2 ; P=0.0044, odds ratio 7.4 [95% confidence interval, 1.87, 29.41]. Η επίδξαζε ηεο κάδαο ζώκαηνο ζηελ ππνζηξνθή ηεο θίξξσζεο ήηαλ αθόκε πην εκθαλήο όηαλ ε θαηεγνξία ηνπ θπζηνινγηθνύ BMI ζπγθξίζεθε κε ηελ θαηεγνξία ησλ παρπζάξθσλ (BMI 30 kg/m 2 ) (P <0.001, OR = 18.9 [95% CI: 3.57, 99.95]), όπσο θαη απηή ησλ ππέξβαξσλ (BMI 25 to < 30 kg/m 2 ) νκνίσο ζπγθξίζεθε κε απηή ησλ παρπζάξθσλ (P=0.039; OR = 3.9 [95% CI: 1.07, 14.15]).

22 Univariable Logistic Regression in Assessing Factors Associated with Reversal of Cirrhosis Variable Odds Ratio 95% Confidence limit P-value Baseline ALT level - IU/liter (0.996, 1.004) Baseline serum albumin - g/deciliter (0.465, 6.120) Baseline platelet count - per mm (0.998, 1.017) Genotype D (0.405, 2.540) Baseline HBV DNA log 10 - copies/ml (0.677, 1.310) Baseline HBsAg log 10 - IU/ml (0.532, 1.732) Years positive for HBV (0.996, 1.165) Female gender (0.427, 6.327) Age 40 yrs (0.185, 1.675) Asian ethnicity (0.719, 9.987) BMI - kg/m 2 < (2.985, ) < to < 30 Baseline Knodell necroinflammatory score (1.258, ) (0.715, 1.276) Variable Odds Ratio 95% Confidence limit P-value Baseline Ishak fibrosis score (0.773, ) Previous lamivudine use > 12 weeks (0.711, ) Prior Interferon-α use (0.565, 8.054) HBeAg-negative (0.348, 2.440) Initial treatment arm assignment TDF (0.675, 4.277) 0.261

23 Multivariable Logistic Regression Identifying Factors Associated with Reversal of Cirrhosis Variable Level Odds Ratio Estimate BMI (kg/m 2 ) BMI < (normal) BMI 25 to (overweight) Years Positive for HBV Baseline platelet count (/mm3) 95% CI P-value (3.570, ) (1.071, ) < BMI 30 (Obese - Reference) (0.988, 1.177)

24 Multivariable Logistic Regression Identifying Factors Associated with Reversal of Fibrosis Variable Odds Ratio Estimate 95% CI P-value Baseline Ishak fibrosis score Baseline platelet count (/mm 3 ) Baseline HBV DNA (log 10 IU/ml) (4.162, ) < (1.003, 1.015) (0.993, 1.548) 0.058

25 Change from Baseline in Fibrosis Score Change in Ishak Fibrosis Scores at Year 5 for Patients with Cirrhosis at Baseline Change from Baseline in Fibrosis Score n = 15 n = 41 n = 14 n = 1 n = 24 n = 1 96/348 (28%) patients with cirrhosis at baseline (Ishak fibrosis score 5) had paired BL and Year 5 biopsies 74% (n=71) of patients had cirrhosis reversed (Ishak fibrosis score <5) at Year 5, and 73% (n= 70) had decreases of 2 points at Year 5; 58%, (56 patients) experiencing a 3 unit decrease ; 25% (n=24) did not change Of 94 patients who did not add FTC, 73% had cirrhosis reversed; 26% showed no change Marcellin, P, et al. Lancet 2013, in press Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV

26 Σηαηηζηηθή αλάισζε mlocf under the mlocf approach, which included 239 patients with baseline and year 1 biopsies only (missing year 5), and 47 patients with only baseline biopsies (missing both years 1 and 5), the percentage with cirrhosis regression (53%) vs. the percentage of non-cirrhotic patients progressing to cirrhosis (9%) at year 5 remained statistically significant (P <0.001).

27 Study 102 (HBeAg-): Proportion of Patients with HBV DNA <400 copies/ml Long-term evaluation [LTE-TDF] (missing/ addition of FTC = failure) Week 240: TDF-TDF 83% ADV-TDF 84% Overall: 83% On treatment analysis (missing = excluded); TDF-TDF = 99%, ADV-TDF = 99% Marcellin, P, et al. Lancet 2013, in press Marcellin, P, et al. AASLD 2011; Oral #238.

28 Study 103 (HBeAg+): Proportion of Patients with HBV DNA <400 copies/ml Long-term evaluation [LTE-TDF] (missing/ addition of FTC = failure) Week 240: TDF-TDF 64% ADV-TDF 67% Overall: 65% On treatment analysis (missing = excluded); TDF-TDF = 96%, ADV-TDF = 100% Marcellin, P, et al. AASLD 2011; Oral #238. Marcellin, P, et al. Lancet 2013, in press

29 HBeAg Loss and Seroconversion

30 HBsAg Loss in Study 103

31 The Addition of FTC to TDF Between Weeks Did Not Impact Subsequent HBV DNA Decline 57/641 (9%) eligible to add FTC to TDF at/after Week 72 19/57 (33%) remained on TDF monotherapy 38/57 (67%) added FTC to TDF 14/19 (74%) HBV DNA < 400 copies/ml At Week 240/ last visit 24/38 (63%) HBV DNA < 400 copies/ml At Week 240/ last visit All subjects analyzed with >400 copies/ml had no evidence of TDF resistance Marcellin, P, et al. Lancet 2013, in press Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV

32 Summary of Safety During the Open-Label Period TDF (DB TDF) a (N=389) TDF (DB ADV) (N=196) Total TDF (OL Period) (N=585) Adverse events leading to drug discontinuation 8 (2.1%) 0 8 (1.4%) b Deaths 5 (1.3%) 2 (1.0%) 7 (1.2%) c Serious adverse events d 6 (1.5%) 3 (1.5%) 9 (1.5%) e Grade 3 or 4 adverse events d 3 (0.8%) 4 (2%) 7 (1.2%) a. Abbreviations in parentheses refer to initial randomized treatment arm; results are no. patients (%); b. HCC (n=2), septic shock (n=1), abdominal pain (n=1), dizziness/fatigue/attention disturbance (n=1), osteoporosis (n=1), ALT increase (n=1), mild creatinine increase (n=1) [1.3 mg/dl] c. HCC (n=3), cholangiocellular carcinoma of liver (n=1), lung cancer metastasis (n=1), cervical cancer metastasis (n=1), nasopharyngeal carcinoma (n=1); d. Study drug-related AEs only e. ALT increase (n=3), LDH increase (n=1), pancreatitis (n=1), facial spasm (n=1), osteoporosis (n=2), mild renal failure (n=1) [creatinine 1.3 mg/dl, CrCL 75 ml/min] Marcellin, P, et al. Lancet 2013, in press

33 Renal Endpoints During the Open-Label Period TDF (DB TDF) a (N=389) TDF (DB ADV) (N=196) Total TDF (OL Period) (N=585) Confirmed Scr 0.5 mg/dl above Baseline 2 (0.5%) 3 (1.5%) 5 (0.9%) b Confirmed PO 4 <2 mg/dl 4 (1%) 3 (1.5%) 7 (1.2%) c Confirmed CrCL <50 ml/min (C-G) d 0 1 (0.5%) 1 (0.2%) e a. Abbreviations in parenthesis refer to initial randomized treatment arm; results are no. patients (%); b. Three were grade 1 and two were high normal range; c. All were grade 2, transient, and resolved without dose interruption or modification; d. C-G = Cockcroft-Gault; e. 48 ml/min, resolved with dose reduction Marcellin, P, et al. Lancet 2013, in press

34 Ιοιογηθή δηαθσγή ήηαλ ζπάληα θαη ζσζτεηηδόκελε κε Με-ζσκκόρθφζε 4/495 (0.8%) ησλ αζζελώλ, εκθάληζαλ ηνινγηθή δηαθπγή θαηά ην 5 ν έηνο 3 αζζελείο είραλ επηβεβαησκέλε κεζπκκόξθσζε θαηά ηελ πεξίνδν ηεο ηνινγηθήο δηαθπγήο (κε αληρλεύζηκα επίπεδα TFV ζην πιάζκα) Καη νη 4 αζζελείο είραλ επίπεδα HBV DNA εθ λένπ <400 copies/ml θαηά ην 6 ν έηνο Φαηλνηππηθή αλάιπζε έδεημε όηη ηα ζηειέρε ηνπ HBV από όινπο ηνπο αζζελείο θαηά ηελ ηνινγηθή δηαθπγή ήηαλ επαίζζεηα ζηελ ηελνθνβίξε (ηηκέο IC50 <2 ζε ζύγθξηζε κε ηελ αξρηθή) Marcellin, P, et al. Lancet 2013, in press

35 Number of Subjects Summary of Resistance Analyses of Patients Originally Randomized to TDF Through Year (91%) 364 (85%) 348 (82%) 323 (76%) Total Number of Subjects Subjects with Viremia Subjects with Confirmed Resistance (9%) (6%) 13* (3%) 10* (3%) 9* (3%) Year *Includes 7, 5, and 5 subjects on FTC+TDF at Year 3, Year 4, and Year 5 Marcellin, P, et al. Lancet 2013, in press Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV

36 Σσκπεράζκαηα (1) Δπί 5 έηε, ε δηαηεξνύκελε ηνινγηθή ππό ζεξαπεία αληαπόθξηζε ζπζρεηίδεηαη κε ηζηνινγηθή βειηίσζε θαη ππνζηξνθή ηεο επαηηθήο ίλσζεο Σηελ κεγαιύηεξε πξννπηηθή κειέηε αζζελώλ κε ρξόληα επαηίηηδα B κε δηελέξγεηα δηαδνρηθώλ ρξνληθά βηνςηώλ ήπαηνο Τν 96% ησλ αζζελώλ κε δεύγε βηνςηώλ είραλ είηε βειηίσζε,είηε κε επηδείλσζε ηεο ίλσζεο Τν 74% ησλ αζζελώλ κε θίξξσζε ζηελ έλαξμε ηεο ζεξαπείαο, δελ είραλ πιένλ ηζηνινγηθά θίξξσζε ην 5 έηνο Τν 98% ησλ αζζελώλ ππό TDF είρε κε αληρλεύζηκα επίπεδα HBV DNA < 400 copies/ml Η Ινινγηθή θαη ε Βηνρεκηθή αληαπόθξηζε δηαηεξνύληαη ππό ζεξαπεία Η Ινινγηθή αληαπόθξηζε παξακέλεη δηαηεξνύκελε ππό ζεξαπεία επί 5 έηε Η νκαινπνίεζε ηεο ALT παξακέλεη ζηελ πιεηνλόηεηα ησλ αζζελώλ Τν 11% ησλ αζζελώλ είραλ επηβεβαησκέλε απώιεηα ηνπ HBsAg (8% κε νξνκεηαηξνπή) αζξνηζηηθά κε αγσγή επί 5 έηε κε TDF Γελ δηαπηζηώζεθε αληνρή ζηελ TDF αζξνηζηηθά επί 5 έηε Marcellin, P, et al. Lancet 2013, in press

37 Σσκπεράζκαηα (2) Η Αζθάιεηα θαη ε Αλνρή ηεο TDF δηαηεξνύληαη Τν 84% ησλ αζζελώλ πνπ εηζήιζαλ ζηελ αλνηθηή θάζε ηεο κειέηεο, παξέκεηλαλ ζηελ κειέηε έσο ην 5 ν έηνο <1.5% ησλ αζζελώλ δηέθνςαλ ηελ TDF εμαηηίαο κίαο αλεπηζύκεηεο ελέξγεηαο Οη αλεπηζύκεηεο ελέξγεηεο ζηελ Νεθξηθή ιεηηνπξγία ήηαλ ζπάληεο (<1.5%); Μόλνλ 1 αζζελήο δηέθνςε ηελ ζεξαπεία εμαηηίαο κίαο ήπηαο αύμεζεο ηεο ηηκήο ηεο θξεαηηλίλεο νξνύ Γελ ππήξραλ ελδείμεηο απώιεηαο νζηηθήο κάδαο θαηά ηελ δηάξθεηα ελόο έηνπο παξαθνινύζεζεο Marcellin, P, et al. Lancet 2013, in press

38 Back-up

39 ΗΚΚ Σπλνιηθά έγηλε δηάγλσζε ΗΚΚ ζε 12 (2%) αζζελείο αζξνηζηηθά έσο ην 5 ν έηνο 4 ΗΚΚ θαηά ην 1 ν έηνο 11/12 ΗΚΚ ζε αζζελείο πνπ ηπραηνπνηήζεθαλ αξρηθά ζε TDF 6/12 ΗΚΚ επηζπλέβεζαλ ζε αζζελείο κε δηάγλσζε θίξξσζεο ζηελ αξρηθή βηνςία (n=96+56=152) 6/12 ΗΚΚ ζε αζζελείο ρσξίο δηάγλσζε θίξξσζεο ζηελ αξρηθή βηνςία (n=482)

40 Αζζελείς τφρίς θίρρφζε ζηελ αρτηθή βηουία 72% (252/348) ησλ αζζελώλ δελ είραλ θίξξσζε ζηελ αξρηθή βηνςία ( ζθόξ ίλσζεο θαηά Ishak 4) Σην 5 ν έηνο - 54% (135/252) δελ έδεημε θακία αιιαγή, - 42% (105/252) έδεημε βειηίσζε - 5% (12/252) έδεημε επηδείλσζε ζην ζθόξ ηεο ίλσζεο Σε 9/12, αύμεζε ηνπ ζθόξ ηεο ίλσζεο θαηά 1 κνλάδα 3 αζζελείο (1%) εμειίρζεθαλ ζε θίξξσζε ζην 5 ν έηνο

41 Characteristics of Patients with Cirrhosis at Baseline who did and did not have Regression of Cirrhosis at Year 5 (1) Baseline Characteristic No Cirrhosis at Year 5 (N=71) Cirrhosis at Year 5 (N=25) P value Age> 40 years no. (%) 49 (69) 20 (80) Body mass index kg/m ± ± 4.41 <0.001 Body mass index category no. (%) Normal (<25) 29/70 (41) 3/25 (12) <0.001 Overweight ( 25 to <30) 34/70 (49) 12/25 (48) Obese ( 30) 7/70 (10) 10/25 (40) Male sex no. (%) 58 (82) 22 (88) Asian race no. (%) 19 (27) 3 (12) Alanine aminotransferase (ALT) IU/liter 141 ± ± Serum albumin g/deciliter 4.0 ± ± Platelet count per mm 3 188,085 ± 50, ,680 ± 46, Years positive for HBV no. (%) < 4 31 (44) 15 (60) to 6 5 (7) 4 (16) >6 35 (49) 6 (24) HBV genotype no. (%) A 12 (17) 8 (32) B 5 (7) 2 (8) C 11 (15) 1 (4) D 40 (56) 14 (56) E 1 (1) 0 Unable to genotype 2 (3) 0 HBV DNA log 10 - copies/ml 7.4 ± ± HBsAg IU/ml 21,291 ± 43,123 17,344 ± 40, Knodell necroinflammatory score 9 ± ± Ishak fibrosis score no. (%) 5 17 (24) 2 (8) (76) 23 (92)

42 7-9 5 (7) 5 (20) Characteristics of Patients with Cirrhosis at Baseline who did and did not have Regression of Cirrhosis at Year 5 (2) Prior interferon-α use no. (%) 16 (22) 3 (12) Prior lamivudine use for > 12 weeks no. (%) Alcohol comsumption history no. (%) 16 (22) 2 (8) Current use 15 (21) 5 (20) Past use only 26 (37) 10 (40) Never used 30 (42) 10 (40) History of diabetes mellitus no. (%) 1 (1) 6 (24) History of hyperlipidemia no. (%) 2 (3) 1 (4) On Treatment Characteristic HBV DNA < 400 copies/ml - no./n (%) 69/69 (100) 24/24 (100) - Normal ALT level no./n (%) 59/68 (87) 14/24 (58) Change from baseline in serum albumin g/deciliter 0.2 ± ± Change from baseline in platelet count per mm 3 28,300 ± 42,400 34,400 ± 50, HBsAg loss no./n (%) 1/69 (1) 0/24 (0) Change from baseline to week 12 in HBsAg IU/ml -4,848 ± 19, ± 7, HBeAg loss no. (%) 12/23 (52) 6/7 (86) Change from baseline in Knodell necroinflammatory score Change from week 48 in Knodell necroinflammatory score Knodell necroinflammatory score category at year 5 no. (%) -5.6 ± ± ± ± (83) 13 (52) (10) 7 (28)

43 Characteristics of Patients with and without Liver Biopsy Data at Year 5 Baseline Characteristic Non-Missing at Year 5 (N=348) Missing at Year 5 (N=293) P value Age> 40 years no. (%) 191 (55) 132 (45) Body mass index > 26 no. (%) 135 (39) 106 (36) Male sex no. (%) 276 (79) 197 (67) <0.001 Asian race no. (%) 88 (25) 101 (34) Alanine aminotransferase IU/liter 146 ± ± Serum albumin g/deciliter 4.2± ± Platelet count per mm 3 207,000 ± 54, ,200 ± 58, Years positive for HBV no. (%) < (41) 110 (39) to 6 35 (10) 30 (10) >6 168 (49) 145 (51) HBV genotype no. (%) A 70 (20) 33 (11) <0.001 B 34 (10) 40 (14) C 44 (13) 68 (23) D 182 (52) 133 (45) E 4 (1) 8 (3) F 5 (1) 4 (1) Other 9 (3) 7 (2) HBV DNA log 10 - copies/ml 7.5 ± ± HBsAg IU/ml** 28,587 ± 49,861 35,895 ± 55, Knodell necroinflammatory score 8 ± ±

44 HBeAg loss no. (%) 57/115 (50) 24/50 (48) Characteristics of Patients with and without Liver Biopsy Data at Year 5 Baseline Characteristic Ishak fibrosis score no. (%) Non-Missing at Year 5 (N=348) Missing at Year 5 (N=293) P value (0.3) (3) 10 (3) (36) 122 (43) 3 79 (23) 74 (26) 4 37 (11) 23 (8) 5 19 (5) 10 (3) 6 77 (22) 46 (16) Prior interferon-α use no. (%) 72 (21) 36 (12) Prior lamivudine use for > 12 weeks no. (%) 54 (15) 21 (7) On Treatment Characteristic HBV DNA < 400 copies/ml - no./n (%) 330/334 (99) 132/136 (97) Normal alanine aminotransferase level no./n (%) Change from baseline in serum albumin g/deciliter 274/337 (81) 110/134 (82) ± ± Change from baseline in platelet count per mm 3 23,500 ± 41,700 21,100 ± 40, HBsAg loss no./n (%) 6/338 (2) 5/136 (4) Change from baseline to Week 12 in HBsAg IU/ml -8,267 ± 27,189-14,312 ± 33,

45 Summary of efficacy results at year 5 Summary of Efficacy Results at Year 5 HBeAg+ Patients HBeAg- Patients TDF-TDF ADV-TDF Overall TDF-TDF ADV-TDF Overall ALT Normalized ALT a,b 69% (71/103) 80% (53/66) 73% (124/169) 85% (155/183) 86% (81/94) 85% (236/277) Mean ± SD (U/L) 42 ± ± ± ± ± ± 16 HBV DNA < 400 copies/ml c (intent-to-treat) 64% (103/162) 66% (57/86) 65% (160/248) 83% (192/232) 84% (99/118) 83% (291/350) < 400 copies/ml b (on treatment) 96% (106/111) 100% (64/64) 97% (170/175) 99% (193/195) 99% (99/100) 99% (292/295) < 169 copies/ml c (intent-to-treat) 63% (102/162) 66% (57/86) 64% (159/248) 82% (191/233) 84% (99/118) 83% (290/351)

46 Serology HBeAg loss b 50% (52/104) 48% (29/61) 49% (81/165) na d na na HBeAg seroconversion b 40% (41/103) 41% (25/61) 40% (66/164) na na na HBsAg Loss e,f 11% (6.7, 17.0) 8% (4.1, 16.9) 10% (6.8, 14.7) g HBsAg Seroconversion e 8% (4.4, 13.6) 8% (4.1, 17.0) 8% (5.1, 12.5) Histology Histologic improvement b,h,i 88% (67/76) 90% (43/48) 89% (110/124) 87% (131/150) 85% (63/74) 87% (194/224) a Biochemically evaluable dataset (ALT>ULN at baseline); b Observed analysis (missing=excluded; addition of FTC included); c LTE-TDF (missing=failure; add FTC=failure); d na = not applicable; e KM = Kaplan-Meier analysis (%, 95% CI); f N=23 patients; 1 patient had transient confirmed HBsAg loss but became HBsAg+ again 24 weeks after seroconversion; g One HBeAg-negative patient had confirmed HBsAg loss at week 240 (year 5); h Defined as reduction in Knodell necroinflammation score of 2 points with no worsening of fibrosis i Overall, results at year 5 for patients who did not add FTC (N=331) showed 88% with histologic improvement

47 Response to TDF Treatment at Year 5 Response HBeAg-positive Patients (N = 266) HBeAg-negative Patients (N=375) Normalized alanine aminotransferase level 124/169 (73) 236/277 (85) no./total no. (%)* HBV DNA < 400 copies/ml no./total no. (%) Intention to treat analysis 160/248 (65) 291/350(83) On-treatment analysis 170/175 (97) 292/295 (99) HBeAg loss no./total no. (%) 81/165 (49) - HBeAg seroconversion no./total no. (%) 66/164 (40) - HBsAg loss % (95% confidence interval) 10 (6.8, 14.7) - HBsAg seroconversion % (95% confidence interval) 8 (5.1, 12.5) -

48 Efficacy Summary 102 (eag-) Year 3 Year (eag+) 102 (eag-) 103 (eag+) HBV DNA <400 c/ml 1 87% 71% 83% 65% HBV DNA <400 c/ml 2 99% 93% 99% 97% ALT normalization 2 84% 74% 85% 73% HBeAg loss (seroconversion) 2 na 3 34% (26%) HBsAg loss (seroconversion) 4 0 9% (7%) na n=1 (Week 240) 50% (40%) 11% (9%) 1 LTE-TDF (modified ITT) analysis; 2 On-treatment (observed data; M=E); 3 na = not applicable; 4 KM% Marcellin, P, et al. Lancet 2013, in press

49 Adverse Events and Laboratory Abnormalities Reported During the Open-Label Study Phase Variable, n (%) TDF-TDF* (n = 389) ADV-TDF (n = 196) Total TDF (N = 585) Adverse events Any treatment-emergent adverse event related to study drug Grade 3 or 4 adverse event related to study drug 61 (16) 30 (15) 91 (16) 3 (1) 4 (2) 7 (1) Serious adverse event related to study drug 6 (2) 3 (2) 9 (2) Deaths 5 (1) 2 (1) 7 (1) Adverse event leading to discontinuation of study drug 8 (2) 0 8 (1) Laboratory abnormalities Serum creatinine 0.5 mg/dl above baseline value 2 (1) 3 (2) 5 (1) Serum phosphorus < 2 mg/dl 4 (1) 3 (2) 7 (1) Creatinine clearance < 50 ml/min 0 1 (1) 1 (0.2)

50 Bone Mineral Density Results (Year 4 to Year 5) No significant changes were observed in mean (SD) BMD results from year 4 to year 5 for hip and lumbar spine No consistent trends were observed in T score (see Table) or Z score (data not shown) category shifts between year 4 and year 5 Year 4 to 5 shifts in T scores a Hip Spine normal osteopenia 3 patients 7 patients osteopenia normal 2 patients 8 patients osteopenia osteoporosis 0 patients 1 patient osteoporosis osteopenia 0 patients 2 patients a. T Score ranges: normal > -1, osteopenia -1 to -2.5, osteoporosis < -2.5; pooled data (N=266 hip; N=276 spine) Marcellin, P, et al. Lancet 2013, in press

51 Virology Analysis Plan for Studies 102 & 103 Genotyping (HBV pol / RT) All patients: at baseline yearly if HBV DNA 400 copies/ml at discontinuation if HBV DNA 400 cp/ml Phenotyping (HBV pol / RT) All patients with: conserved site changes in pol/rt virologic breakthrough polymorphic site changes (> 1 patient) Marcellin, P, et al. Lancet 2013, in press

52 A Small Percentage of Patients (12/495, 2.4%) Qualified for Resistance Surveillance During Year 5 Study 102 (HBeAg ) Study 103 (HBeAg+) TDF-TDF ADV-TDF TDF-TDF ADV-TDF Total Patients entering Year Patients with HBV DNA >400 cp/ml during Year TDF Monotherapy FTC/TDF Combination Therapy Confirmed Virologic Breakthrough During Year Marcellin, P, et al. Lancet 2013, in press Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV

53 Number of Subjects No Patient with Persistent Viremia During Year 5 Analysis TDF Subjects with Persistent Viremia (Never had HBV DNA <400 cp/ml) N=426 N=384 N=366 N=348 N=323 All persistent viremia subjects had no evidence of TDF resistance Marcellin, P, et al. Lancet 2013, in press

54 HBV DNA (log 10 copies/ml) HBV DNA (log 10 copies/ml) ALT (U/L) HBV DNA (log 10 copies/ml) ALT (U/L) ALT (U/L) HBV DNA (log 10 copies/ml) ALT (U/L) DNA Profiles of Virologic Breakthrough Patients Patient A Patient B TDF Unable to Genotype 400 copies/ml WT FTC/TDF WT HBV DNA ALT Weeks HBV DNA ALT 400 copies/ml TDF rtr51k rts325p/s Weeks ADV 400 copies/ml TDF rtt212k/t WT Patient C WT FTC/TDF HBV DNA ALT rtr138k rtk168n rtt212k rta214v Weeks HBV DNA ALT 400 copies/ml Patient D TDF WT Weeks Patients B, C, and D were non-adherent to study medication at the time of virologic breakthrough Marcellin, P, et al. Lancet 2013, in press Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV