ΜΑΚΡΟΦΡΟΝΙΑ ΔΕΔΟΜΕΝΑ ΣΗ ΣΕΛΜΠΙΒΟΤΔΙΝΗ ΣΗ ΘΕΡΑΠΕΙΑ ΣΗ ΦΡΟΝΙΑ ΗΠΑΣΙΣΙΔΑ Β ΗΩΑΝΝΖ. ΔΛΔΤΗΝΗΩΣΖ ΔΠΗΚΟΤΡΟ ΚΑΘΖΓΖΣΖ ΠΑΘΟΛΟΓΗΑ ΠΑΝΔΠΗΣΖΜΗΟΤ ΑΘΖΝΩΝ

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1 ΜΑΚΡΟΦΡΟΝΙΑ ΔΕΔΟΜΕΝΑ ΣΗ ΣΕΛΜΠΙΒΟΤΔΙΝΗ ΣΗ ΘΕΡΑΠΕΙΑ ΣΗ ΦΡΟΝΙΑ ΗΠΑΣΙΣΙΔΑ Β ΗΩΑΝΝΖ. ΔΛΔΤΗΝΗΩΣΖ ΔΠΗΚΟΤΡΟ ΚΑΘΖΓΖΣΖ ΠΑΘΟΛΟΓΗΑ ΠΑΝΔΠΗΣΖΜΗΟΤ ΑΘΖΝΩΝ ΠΑΝΔΛΛΖΝΗΟ ΤΝΔΓΡΗΟ ΓΑΣΡΔΝΣΔΡΟΛΟΓΗΑ ΑΘΖΝΑ 30 ΝΟΔΜΒΡΗΟΤ 2012

2 Δηλώνω ότι έχω σύγκρουση συμφερόντων (conflict of interest) ύμβουλος-διαλέξεις Gilead, Novartis, Roche Φορηγίες: Gilead, Roche

3 ΘΕΡΑΠΕΤΣΙΚΟΙ ΣΟΦΟΙ EASL 2012 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF CHRONIC HBV INFECTION ΑΤΞΖΖ ΔΠΗΒΗΩΖ ΠΟΗΟΣΖΣΑ ΕΩΖ ΑΘΔΝΩΝ Κίρρωζη ήπαηος-τελικού ζηαδίοσ ηπαηική νόζος ΗΚΚ HBV eradication (cccdna, HBV integration) Sustained HBV suppression ΔΜΜΔΟΗ ΓΔΗΚΣΔ Βιοτημική ανηαπόκριζη Ιζηολογική βεληίωζη EASL 2012 HBV CPG, J Hepatol 2012;57:

4 HBV-DNA>2000 IU/ml ALT > UNL Liver disease severity HBV-DNA HBeAg Anti-HBe ALT Inactive carrier* Wong & Lok. Arch Intern Med 2006 EASL 2012 HBV CPG, J Hepatol 2012;57:

Yang et al, NEJM 2002 REVEAL study: Taiwan 1991 1992 11.

5 Yang et al, NEJM 2002 REVEAL study: Taiwan men 30-65y 111 HCC Risk of HCC by HBV status HBsAg+ HBeAg+ RR 60.2 HBsAg+ HBeAg- RR 13.5 HBsAg- RR 1.0

6 ΘΕΡΑΠΕΤΣΙΚΟΙ ΣΟΦΟΙ EASL 2012 CLINICAL PRACTICE GUIDELINES MANAGEMENT OF CHRONIC HBV INFECTION Καηαληκηικά ζημεία (end-points) Sustained off-tx HBsAg loss / antihbs HBeAg (+) / HBeAg (-) Sustained off-tx virological and biochemical response HBeAg (+) HBeAg (-) / antihbe (+) HBeAg (-) Maintained virological remission (long-term NUC Tx) EASL 2012 HBV CPG, J Hepatol 2012;57:

7 Sustained remission HBV Treatment Strategies PEG-IFN HBeAg seroconversion HBV DNA <104 copies/ml Normal ALT Undetectable HBV DNA HBsAg loss Maintained remission Nucleos(t)ide analogue Undetectable HBV DNA by PCR assay Normal ALT HBeAg seroconversion HBsAg loss years

Buster et al, Gastroenterology 2008 Follow-up of PEG-IFN in HBeAg (+) CHB 3 years post-treatment among HBeAg responders 100 90 80 81% n=64 78% n=172

8 Buster et al, Gastroenterology 2008 Follow-up of PEG-IFN in HBeAg (+) CHB 3 years post-treatment among HBeAg responders % n=64 78% n= % 50 45% % 20 11% 10 0 HBeAg negative HBV DNA <10,000 copies/ml HBV DNA <400 copies/ml ALT normal HBsAg negative HBsAg negative overall

9 Rate of HBsAg clearance 230 patients with HBeAg-negative CHB treated Peg-IFN alfa 2a ± LAM All genotypes Genotype 54% % HBsAg seroconversion D 11% 12% 11% 9% 5% 6% 11/ / /230 25/ Follow up (years) 28/ /47 5 Marcellin et al, EASL 2009

10 Παρεληερηθή τορήγεζε Δύζθοια αλεθηή ιόγω αλεπηζύκεηωλ ελεργεηώλ, ορηζκέλες από ασηές απεηιεηηθές γηα ηε δωή Καηά ηε δηάρθεηα ηες ζεραπείας απαηηείηαη ζηελή παραθοιούζεζε Mήνες αγφγής Καηάθλιυη Κόπφζη Άγτος Γριππώδης ζσνδρομή Keeffe EB et al, Clin Gastroenterol Hepatol 2008

11 Πεγκσλιφμένη IFNα NUCs Πλεονεκηήμαηα Σσγκεκριμένη διάρκεια θεραπείας Αποσζία ιικής ανηοτής Υυηλόηερα ποζοζηά οροαναζηροθής HBeAg και HBsAg Ιζτσρή ανηιική δράζη Καλή ανοτή Από ηοσ ζηόμαηος τορήγηζη Μειονεκηήμαηα Μέηρια ανηιική δράζη Μακροτρόνια τορήγηζη Πηφτή ανοτή Υποδόρια τορήγηζη Iική ανηοτή Χαμηλά ποζοζηά οροαναζηροθής HBeAg και HBsAg Νέοι αζθενείρ / HBeAg-pos ALT, HBV-DNA, genotype A Δπιθςμία αζθενούρ Μη ανηιρροπούμενη κίρρφζη Ασηοάνοζα νοζήμαηα Σοβαρή καηάθλιυη-ψύτφζη Βαριά προϋπάρτοσζα καρδιακή νόζος Αρρύθμιζηος ΣΓ Δγκσμοζύνη-Αναπαραγφγική ηλικία Ανοζοκαηαζηολή

12 ΦΡΟΝΙΑ ΗΠΑΣΙΣΙΔΑ Β ΕΠΙΛΟΓΗ ΑΓΩΓΗ NUCs Λακηβοσληίλε (LAM) Αληεθοβίρε (ADV) Εληεθαβίρε (ETV) Τεικπηβοσληίλε (LdT) Τελοθοβίρε (TVF) ΑΣΦΑΛΕΙΑ ΓΕΝΕΤΙΚΟΣ ΦΡΑΓΜΟΣ ΙΣΦΥΣ

Multiple factors are associated with the barrier of resistance Antiviral potency Number of mutations needed to overcome drug suppression Level of exposure to drug Chemical structure Antiviral Drug

13 Multiple factors are associated with the barrier of resistance Antiviral potency Number of mutations needed to overcome drug suppression Level of exposure to drug Chemical structure Antiviral Drug Virus Locarnini S et al. Antivir Ther Locarnini S et al. Antivir Ther Ghany M & Liang TJ. Gastroenterology 2007 Zoulim F et al. Antiviral Res Locarnini S et al. J Hepatol 2003 Zoulim & Locarnini Gastroenterology 2009 Adherence Immune status Prior antiviral exposure Metabolism Body mass Patient Replication fitness and space Persistence of archived mutations as cccdna Pre-existing mutations

14 % PCR w n=1370 CHB log HBV-DNA HBeAg(+) HBeAg(-) Lai CL et al, NEJM 2007

15 % TELBIVUDINE (2 years) p< n=1367 CHB 38 HBeAg(+) HBeAg(-) % p< HBeAg(+) n=588 ALT >x2 UNL 64% Liaw YF et al, Gastroenterology 2009

16 TELBIVUDINE (2 years) % PCR w n=1367 CHB log HBV-DNA HBeAg(+) HBeAg(-) Liaw YF et al, Gastroenterology 2009

17 HBeAg(+) HBV-DNA< 9 log c/ml ALT >x2 UNL TELBIVUDINE (2 years) PCR (-) w.24 45% HBeAg(+) 80% HBeAg(-) HBeAg(-) HBV-DNA< 7 log c/ml Liaw YF et al, Gastroenterology 2009

18 TELBIVUDINE (2 years) HBeAg positive patients EU-like patients (baseline ALT 2 x ULN, HBV DNA <9 log 10 ) (n=80) 71% of telbivudine treated patients achieved PCR negativity at Week 24 (n=57/80) 89% PCR-negative at Week 104 (n=51/57) 81% ALT normal at Week 104 (n=46/57) 52% e-seroconversion at Week 104 (n=25/48) 1.8% Resistance at Week 104 (n=1/57) Zeuzem S et al, J Hepatology 2009

19 Response (%) TELBIVUDINE (3-4 years) HBeAg positive patients % GLOBE Per Protocol Population (n = 213) 86% 79% 81% Year 3 Year % 42% / / / /152 69/186 66/156 PCR negative* ALT norm alization HBeAg seroconversion *Quantification limit 300 copies/ml by COBAS Amplicor. Denominator represents number of patients and laboratory results available for analysis at this time point. Wang Y et al, Hepatology. 2009;50(Suppl):Abstract 482

20 Response (%) TELBIVUDINE (3-4 years) HBeAg positive patients GLOBE Patients Who Were PCR Negative at Week 24 (n = 111) % 92% 83% 88% Year 3 Year % 51% /103 79/86 81/98 73/83 45/99 43/85 PCR negative* ALT norm alization HBeAg seroconversion *Quantification limit 300 copies/ml by COBAS Amplicor. Denominator represents number of patients and laboratory results available for analysis at this time point. Wang Y et al, Hepatology. 2009;50(Suppl):Abstract 482

21 HBeAg Seroconversion Rates at 1 Year In HBeAg+ Patients (NUCs) 1 Lai CL et a, N Engl J Med 2007;357: Chang TT et al, N Engl J Med 2006;354: Heathcote J et al, N Engl J Med 2008;359:

22 Proportion of patients (%) TELBIVUDINE (3-4 years) HBeAg positive patients cumulative HBeAg seroconversion 70 GLOBE Per Protocol Population (n = 213) % 46% 51% 30 24% /213 80/213 97/ /213 Year 1 Year 2 Year 3 Year 4 Cumulative seroconversion: All patients from GLOBE Protocol Population in 2303 who ever had HBeAg seroconversion during 4 years. Missing data was counted as a failure. Wang Y et al, Hepatology. 2009;50(Suppl):Abstract 482

Proportion of patients (%) TELBIVUDINE (3-4 years) HBeAg positive patients cumulative HBeAg seroconversion GLOBE + 015 Per Protocol Population: Patients Who Were PCR Negative* at 24 Weeks (n = 162)

23 Proportion of patients (%) TELBIVUDINE (3-4 years) HBeAg positive patients cumulative HBeAg seroconversion GLOBE Per Protocol Population: Patients Who Were PCR Negative* at 24 Weeks (n = 162) 60% 53% 66% 40% 65/162 85/162 97/ /162 Cumulative seroconversion: All patients from GLOBE +015 per protocol population in 2303 who ever had HBeAg seroconversion during 4 years. Missing data was counted as a failure. Jia J-D et al, APASL 2010

Proportion of patients (%) Durable Off-Treatment HBeAg Seroconversion after 52-120 weeks of follow-up* Study 2303 90% 81% (43/48) (39/48) *Patients who stopped telbivudine due to efficacy (eg,

24 Proportion of patients (%) Durable Off-Treatment HBeAg Seroconversion after weeks of follow-up* Study % 81% (43/48) (39/48) *Patients who stopped telbivudine due to efficacy (eg, HBeAg seroconversion) during the GLOBE and 015 studies. Efficacy endpoints were analyzed using last observation carried forward method (LOCF) to compensate for missing visits. Liaw JF et al, APASL 2010

25 n=162 HBV-DNA (-) Wursthorn et al, Hepatology 2010

26 Wursthorn et al, Hepatology 2010

27 Wursthorn et al, Hepatology log 1log 25% HBsAg loss

29 Published Studies on LDT Immunomodulatory effects 29 Publication type Innate / Adpative Immunity Topics Take-home message on LDT treatment Year Journal Subjects Sample Source size Abstract Innate NK NK cell and predicting VR 2010 AASLD Patients 54 Ning Abstract Innate NK CD244; NKG2A 2010 AASLD Patients 53 Jiang Abstract Innate NK CD APASL Patients 53 Jiang Abstract Innate TLR TLR APASL Patients 34 Gao Paper Bridge IL-21 IL-21 at wk12 predicting HBeAg seoconve 2012 J Hepatol Patients 178 Ma / Hou Abstract Adaptive / Innate NK, Treg NK cell Treg and predicting VR 2011 AASLD Patients 54 Ning Paper Adaptive / Innate Th1 Th2; Th1 Th2 same for macrophages 2010 JVH MHV-infected NA Ning macrophages mice Abstract Adaptive / Innate Th1 Th2 cytokines Th1 Th2 same for macrophages 2008 AASLD MHV-infected NA Ning mice Abstract Adaptive / Innate NK, Treg NKT, Treg 2011 AASLD Patients 53 Jiang Paper Adaptive / Innate Treg, PD-L1, TLR 2 Downregulated Treg, PD-L1 expression on CD4+T cells, serum IL VI Patients 28 Nan Xueping / Bai XF Paper Adaptive T cells response CD4+/CD8+, HBcAg CTL, IFN-γ, TNF-α, IL AR Patients 51 Chen / Li LJ Abstract Adaptive Treg Treg and predicting VR 2010 AASLD Patients 54 Ning Abstract / Poster Adaptive Th17 cell Th17 cells elevation in LDT-treated CRs; and help HBeAg seroconversion 2012 APASL Patients 32 Huang / Hou Paper Adaptive CD8+ T cells Increased CD8+T cell expansion associated 2011 AAC Patients 20 Ma / Hou with LDT treatment Abstract Adaptive TFH cells Play a memory role in liver immune responses 2011 EASL Patients 89 Jiang Paper Adaptive CD127 on CD8+ T CD127 on memory CD8 T cells 2010 VJ Patients 20 Lv / Yang Yida Abstract Adaptive CD8+ T cells CD127 on memory CD8 T cells 2010 AASLD Patients 20 Lv Abstract Adaptive Treg Treg 2009 APASL Patients 36 Pan Paper Adaptive Treg Treg 2008 CJH Patients 36 Pan Paper Adaptive inkt inkt 2011 CEM Patients 29 Shi / Ren Hong Abstract Adaptive Th1 Th2 cytokines Th1 Th APASL Patients 12 Zhang / Ren Hong Abstract Adaptive Treg Treg 2011 AASLD Patients 22 Zhou / Wang YM Paper Adaptive Th1 Th2 cytoki Th1 Th CJH Patients 15 Zhang / Zhang Dazhi Abstract Adaptive PD-1 / PD-L1 PD-1 / PD-L AASLD Patients 137 Xie / Gao Zhiliang Abstract Adaptive PD-1 PD APASL Patients 10 Xie / Gao Zhiliang Paper Adaptive PD-1 PD Hepatology Patients 18 Evans Abstract Adaptive PD-1 PD J Hepatol Patients 18 Evans Abstract Adaptive T cell HBV viral load impact T cell responses 2006 Hepatology Patients 63 Cooksley Abstract Clinical HBeAg seroconve LDT better vs ETV 2009 APASL Patients 80 Ren

30 Effect of telbivudine therapy on the cellular immune response in chronic hepatitis B Zheng Y et al, Mediators Inflamm 2012 Chen Y et al, Antiviral Res 2011;91(1):23-31

31 Effect of telbivudine treatment on the circulating CD4 T-cell subpopulations in chronic hepatitis B patients Zheng Y et al, Mediators Inflamm 2012

32 Effect of telbivudine treatment on the circulating CD4 T-cell subpopulations in chronic hepatitis B patients Zheng Y et al, Mediators Inflamm 2012 IFN-γ : i NKT (decrease PD-1 receptors, CHB) Shi T.D et al, Clinical Experimental Med 2012

33 TELBIVUDINE (2 years) HBeAg negative patients EU-like patients (baseline HBV DNA <7 log 10 ) (n=91) 95% of telbivudine treated patients achieved PCR negativity at Week 24 (n=86/91) 91% PCR-negative at Week 104 (n=78/86) 83% ALT normal at Week 104 (n=57/69) 2% Resistance at Week 104 (n=2/86) Zeuzem S et al, J Hepatology 2009; 51:11-20

34 Proportion of patients (%) % TELBIVUDINE (3-4 years) HBeAg negative patients GLOBE Per Protocol Population 91% 84% 83% Year 3 (n = 186) Year 4 (n = 185) /1 64 PCR negative* 129/ / / / /128 ALT normalization *Quantification limit 300 copies/ml by COBAS Amplicor. 1 patient in per protocol population excluded due to noncompliance. Denominator represents number of patients and laboratory results available for analysis at this time point. Wang Y et al, Hepatology. 2009;50(Suppl):Abstract 482

35 Proportion of patients (%) TELBIVUDINE (3-4 years) HBeAg negative patients GLOBE patients who were PCR negative at week % 86% 84% 90% Year 3 (n = 161) Year 4 (n = 160) / / /130 17/24 126/ / /113 17/22 PCR Negative * ALT normalization *Quantification limit 300 copies/ml by COBAS Amplicor. 1 patient in per protocol population excluded due to noncompliance. Denominator represents number of patients and laboratory results available for analysis at this time point. Wang Y et al, Hepatology. 2009;50(Suppl):Abstract 482

36 Proportion of patients (%) TELBIVUDINE (3-4 years) Genotypic resistance HBeAg positive HBeAg negative 100 Per Protocol Population 100 PCR Negative at Week % HBeAg-neg (24/213) (12/186) Year 3 Year 4 Year 3 Year (17/213) (9/185 ) (4/111) (10/161) (6/111) (4/160 ) * Resistance = viral breakthrough with treatment emergent resistance mutations confirmed by genetic sequencing at week 156. Quantification limit 300 copies/ml by COBAS Amplicor. 1 patient in per protocol population excluded due to noncompliance. Wang Y et al, Hepatology. 2009;50(Suppl):Abstract 482

37 Long Term Telbivudine Therapy with Effective Viral Control Results in Resolution of Liver Fibrosis and Inflammation Achieving Treatment Goals in Patients with CHB Virology, Serological and Biochemical Responses at 5 Years (ITT) HBeAg positive HBeAg negative Total N=43 N=23 N=66 HBV DNA < 300 copies/ml, % (n/m) 100 (43/43) (23/23) 100 ( 66/66) ALT normalization, % (n/m) 85.7 (36/42) 73.7 (14/19) 82.0 (50/61) Cumulative HBeAg loss, % (n/m) 88.4 (38/43) N/A 88.4 (38/43) Cumulative HBeAg seroconversion, % (n/m) 76.7 (33/43) N/A 76.7 (33/43) Cumulative HBsAg loss, % (n/m) 9.3 (4/43) 0 (0/23) 6.1 (4/66) Cumulative HBsAg seroconversion, % (n/m) 7.0 (3/43) 0 (0/23) 4.5 (3/66) Hou J et al, AASLD 2011 (P1446)

TELBIVUDINE (5 years) LIVER HISTOLOGY 120 100 80 60 40 Knodell HAI Score Pt #s Pt #s 1,8 29,8 17 50,9 29 98,2 1 56 10-14 7-9 4-6 0-3 Ishak Score Pt #s 1 1 4 13 24 Pt #s

38 TELBIVUDINE (5 years) LIVER HISTOLOGY Knodell HAI Score Pt #s Pt #s 1,8 29, , , Ishak Score Pt #s Pt #s ,5 15,8 Baseline (57 patients) 2 9 Year 5 (57 patients) Overall Change in Knodell HAI Score 14 Overall Change in Ishak Score Hou J et al, AASLD 2011 (P1446)

39 TELBIVUDINE ΑΥΑΛΕΙΑ 200 telbivudine treated patients 3y cumulative incidence CPK elevation (84.3%) muscle events (5%) 21 months, spont. resolution on Tx 3112 telbivudine treated patients Grade 3-4 CPK elevation 4.37% (year 1) 15.9% (year 4) 74% asymptomatic, transient, recoverable 1.1% persistent (0.15% ME) males aged < 45y HBeAg-neg Zou XJ et al, J Viral Hepat 2011 myopathy / myositis 0.35% (year 1) 0.61% (year 4) Dong Y et al, APASL 2012

40 Ζ ηελμπιβοςδίνη θαίνεηαι να αποηελεί μια αξιόπιζηη επιλογή για ηη θεπαπεςηική ανηιμεηώπιζη ηυν αζθενών με σπόνια ηπαηίηιδα Β HBeAg (+): 67% e-seroconversion (5y) baseline HBV-DNA< 9 log c/ml HBeAg (-): 96% PCR(-) / 80% ALT normal (5y) baseline HBV-DNA< 7 log c/ml Πποβλέτιμο πποθίλ ανηοσήρ (PCR w24) 2.5-3% (4-5y) HBeAg (-) / PCR(-) w24 Αζθάλεια (FDA class B) / αποηελεζμαηικόηηηα κύηζη / αναπαπαγυγική ηλικία

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