Στην Ελλάδα τα διαγνωσμένα περιστατικά εκτιμώνται σε 42% των συνολικών.

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1 Σε εκτιμώνται οι άνθρωποι παγκοσμίως που πεθαίνουν κάθε χρόνο από ασθένειες του ήπατος σχετικές με την ηπατίτιδα Β. Περίπου 292 εκατομμύρια άνθρωποι εκτιμάται ότι ζουν με τον ιό της ηπατίτιδας Β (HBV) παγκοσμίως, αλλά μόνο ένας στους 20 (ποσοστό 5%) έχει κάνει θεραπεία, σύμφωνα με την πιο ολοκληρωμένη μέχρι σήμερα διεθνή ανάλυση για την εξάπλωση της νόσου. Εννέα στους δέκα δεν ξέρουν καν ότι έχουν τον ιό, επειδή δεν έχουν διαγνωσθεί. Στην Ελλάδα τα διαγνωσμένα περιστατικά εκτιμώνται σε 42% των συνολικών. Ακόμη και σε ανεπτυγμένες χώρες, τα ποσοστά των μη διαγνωσμένων είναι υψηλά: στις ΗΠΑ οι δύο στους τρεις με τον ιό και στη Βρετανία οι τέσσερις στους πέντε. World Health Organization. Global hepatitis report, Geneva. 2017: 1-68 «The Lancet Gastroenterology & Hepatology» 2017

2 Στην Ευρώπη, τα ποσοστά όσων έχουν κάνει θεραπεία, εμφανίζουν μεγάλες αποκλίσεις από το 3% στο Βέλγιο ως το 95% στη Φινλανδία, ενώ στην Ελλάδα είναι 51%, δηλαδή οι μισοί σε σχέση με όσους θα έπρεπε. Στην Ελλάδα, το 2016 είχαν διαγνωσθεί με ηπατίτιδα Β συνολικά άνθρωποι και οι ήταν νέα περιστατικά εκείνου του έτους. Περίπου οι μισοί (45.600) πληρούν τις προϋποθέσεις για θεραπεία, αλλά μόνο οι έχουν λάβει την κατάλληλη θεραπεία κατά του ιού HBV. Στη χώρα μας ο επιπολασμός της νόσου (δηλαδή ο αριθμός των περιστατικών που ήδη υπάρχουν στον πληθυσμό) εκτιμάται σε περίπου 2,3% των κατοίκων έναντι 3,9% παγκοσμίως. «The Lancet Gastroenterology & Hepatology» 2017

3 Πρόοδοι στη θεραπεία της ηπατίτιδας Β. Τι άλλαξε σε σχέση με το παρελθόν Γεράσιμος Μπαλταγιάννης Επίκουρος Καθηγητής Γαστρεντερολογίας Ιατρική Σχολή Πανεπιστήμιο Ιωαννίνων

4 Ποια είναι τα δεδομένα που μας πείθουν ότι πρέπει να θεραπεύουμε τη χρόνια ηπατίτιδα Β;;

5 Cumulative Incidence of Liver Cirrhosis REVEAL: Επίπεδα HBV DNA και κίνδυνος ανάπτυξης κίρρωσης Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC in untreated, HBsAg-positive individuals in Taiwan (N = 3582) Baseline HBV DNA Level (copies/ml) 1 million (36.2%) 100, ,999 10,000-99, < 300 (4.5% ) Follow-up (Yrs) Iloeje UH, et al. Gastroenterology. 2006;130:

6 Cumulative Incidence of HCC (%) REVEAL: Επίπεδα HBV DNA και κίνδυνος Prospective study in same REVEAL cohort (N = 3653) ανάπτυξης ΗΚΚ Baseline HBV DNA (copies/ml) 1 million(14.9%) 100, ,999 10,000-99, < 300(1.3%) Follow-up (Yrs) Increased HCC incidence with increasing DNA levels (P <.001) HCC can occur in the absence of cirrhosis Chen CJ, et al. JAMA. 2006;295:65-73.

7 Sex-Adjusted HCC Mortality Rate Ratio Ελάττωση στην θνησιμότητα από ΗΚΚ εξαιτίας της εφαρμογής του εθνικού προγράμματος θεραπείας της ιογενούς ηπατίτιδας στην Ταιβάν Pts receiving treatment for chronic hepatitis after start of program in 2003 in Taiwan: 157,570 (HBV) and 61,823 (HCV) Reduced rate of HCC mortality in all age cohorts by 5-8 yrs after introduction of national therapy program * 0.92* 0.88* *P <.01 vs P <.005 vs Age Group (Yrs) Chiang CJ, et al. Hepatology. 2015;61:

8 LT-Free Survival (%) Η θεραπεία του HBV ελαττώνει την πιθανότητα μεταμόσχευσης ήπατος Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 707) Treated,* responder (n = 245) Treated,* nonresponder (n = 178) Untreated (n = 284) 20 Bonferroni-adjusted P < Antiviral therapy improved transplant-free Mos survival over 5 yrs (P =.0098 vs untreated) *Treated predominantly with lamivudine (n = 203) or entecavir (n = 198). Jang JW, et al. Hepatology. 2015;61:

9 Κρατήστε το ιολογικό φορτίο (HBVDNA) όσο χαμηλά.μπορείτε και για όσο χρονικό διάστημα είναι εφικτό!!!!

10 ΟΛΙΚΗ ΑΝΤΑΠΟΚΡΙΣΗ Απώλεια του HBsAg Βελτίωση της επιβίωσης Στόχοι Θεραπείας στην χρόνια HBV Απώλεια του HBeAg ή ορομετατροπή Απώλεια του cccdna λοίμωξη Φυσιολογική ALT Βελτίωση της ιστολογικής εικόνας ( ίνωση) Μη ανίχνευση του HBV DNA στον ορό Keeffe et al., Clinical Gastroenterology and Hepatology 2004; 2: Conjeevaram HS. J Hepatol. 2003;38:S90-S103 EASL 2017

11 Νέα τελικά σημεία που ορίζουν την θεραπεία της ηπατίτιδας Β Μερική θεραπεία(ιϊκή καταστολή) με ανιχνεύσιμο HBsAg και σταθερά μη ανιχνεύσιμο HBV DNA στον ορό μετά ολοκλήρωση της θεραπείας.(virus suppression) Use of Current and New Endpoints in the Evaluation of Experimental Hepatitis B Therapeutics Timothy M. Block,1 Stephen Locarnini,2 Brian J. McMahon,3 Barbara Rehermann,4 and Marion G. Peters5 : Clinical Infectious Diseases 2017;64(9): LOK ET AL. HEPATOLOGY, Vol. 66, No. 4, 2017

12 Διάφοροι ορισμοί θεραπείας της HBV λοίμωξης

13 Γιατί η λειτουργική-τυπική(functional) θεραπεία της HBV λοίμωξης είναι σημαντική;;

14 Στόχος.. Κατάσταση ανενεργού φορέα HBV DNA: > 10 6 IU/mL HBeAg/anti-HBe status Ορόσημο 1: Start of HBV DNA decline HBeAg+, anti-hbe- Ορόσημο 2: HBeAg/anti-HBe seroconversion Ορόσημο 3: HBV DNA undetectable Ορόσημο 4: HBsAg loss Ορόσημο 5: cccdna clearance HBeAg-, anti-hbe+ Αυτή είναι η κατάσταση όπου θα θέλαμε οι ασθενείς μας να είναι HBV DNA: undetectable HBV DNA < 2000 IU/mL for reduced progression risk HBsAg status HBsAg+ HBsAg- ALT level Immune Tolerance Immune Clearance Inactive Carrier State Functional Cure Immune control Terrault. Hepatology. 2018;67:1560.

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16 <1000IU/ml EASL 2017

17 5 HBVDNA<200 IU/ml Οροθετική (anti-hbcag+) Απώλεια HBsAg κατά τη διάρκεια της χρόνιας HBV Απώλεια HBsAg μετά οξεία HBV λοίμωξη Οροαρνητική (antihbsag -& antihbcag-) Πρωταρχικά λανθάνουσα Προοδευτική απώλεια αντισωμάτων Λοίμωξη με HBV που φέρει μεταλλάξεις στο γονίδιο S Τα επίπεδα του HBVDNA είναι παρόμοια με την φανερή λοίμωξη

18 Ποιοι ασθενείς πρέπει να υποβάλλονται σε θεραπεία και πότε;

19 Ενδείξεις Θεραπείας Όλοι οι ασθενείς με HBeAg + ή - χρόνια ηπατίτιδα Β ( HBVDNA>2000 IU/ml, ALT>ULN και ή τουλάχιστον μέτρια ηπατική νέκρωση-φλεγμονή ή ίνωση). Ασθενείς με HBVDNA>20000 IU/ml και ALT>2xULN (χρόνια ηπατίτιδα Β) ανεξάρτητα από το βαθμό ίνωσης. Ασθενείς με HBeAg + χρόνια HBV λοίμωξη ( ALT φυσιολογική και υψηλά επίπεδα HBVDNA), αν είναι μεγαλύτεροι από 30 ετών, ανεξάρτητα από την σοβαρότητα της ηπατικής βιοψίας. Ασθενείς με HBeAg - χρόνια HBV λοίμωξη και οικογενειακό ιστορικό ΗΚΚ ή κίρρωσης και εξωηπατικές εκδηλώσεις, ακόμη και αν απουσιάζουν τα κριτήρια θεραπείας. Ασθενείς με αντιρροπούμενη ή μη αντιρροπούμενη κίρρωση ( με ανιχνεύσιμα επίπεδα HBVDNA και ανεξάρτητα από τα επίπεδα ALT) EASL 2017

20 Ενδείξεις Θεραπείας ή προφύλαξης στη χρόνια ηπατίτιδα Β στην κλινική πράξη 17 Jiannis Vlachogiannakos George V. Papatheodoridis Liver International. 2018

21 < Περίληψη συστάσεων της AASLD για την πρόληψη και θεραπεία ενεργοποίησης της HBV λοίμωξης κατά τη διάρκεια ανοσοκατασταλτικής θεραπείας Pattullo V: Clinical and Molecular Hepatology 2016

22 2018 AASLD Guidance: Monitor vs Treat in HBeAg-Positive Patients Noncirrhotic HBeAg-Positive Patients With CHB ALT ULN* HBV DNA > 20,000 IU/mL Monitor ALT, HBV DNA every 3-6 mos Monitor HBeAg every 6-12 mos ALT > ULN but < 2 x ULN* ALT 2 x ULN* HBV DNA > 20,000 IU/mL Treat *The upper limit of normal (ULN) for ALT in healthy adults is U/L for men and U/L for women in AASLD guidance. The ULN of 35 U/L for men and 25 U/L for women is recommended to guide treatment. HBV DNA > 20,000 IU/mL Exclude other causes of ALT elevation Treat if ALT elevation persists, especially if > 40 yrs of age Evaluate fibrosis/inflammation Treat if F2 or A3 HBV DNA ,000 IU/mL Exclude other causes of ALT elevation Treat if ALT elevation persists, especially if > 40 yrs of age Evaluate fibrosis/inflammation Treat if F2 or A3 Additional note if HBV DNA ,000 IU/mL (which may represent seroconversion) Monitor HBV DNA every 1-3 mos Treat if HBV DNA > 2000 IU/mL persists for > 6 mos Terrault. Hepatology. 2018;67:

23 2018 AASLD Guidance: Monitor vs Treat in HBeAg-Negative Patients Noncirrhotic HBeAg-Negative Patients With CHB ALT ULN* HBV DNA 2000 IU/mL Monitor ALT, HBV DNA every 3 mos for 1 yr, then every 6 mos HBV DNA < 2000 IU/mL Monitor ALT, HBV DNA every 3 mos for 1 yr, then every 6-12 mos Monitor HBsAg annually *The upper limit of normal (ULN) for ALT in healthy adults is U/L for men and U/L for women in AASLD guidance. The ULN of 35 U/L for men and 25 U/L for women is recommended to guide treatment. ALT > ULN but < 2 x ULN* Any Detectable HBV DNA Exclude other causes of ALT elevation Treat if ALT elevation persists, especially if > 40 yrs of age Evaluate fibrosis/inflammation Treat if F2 or A3 ALT 2 x ULN* HBV DNA 2000 IU/mL Treat HBV DNA < 2000 IU/mL Exclude other causes of ALT elevation Treat if ALT elevation persists, especially if > 40 yrs of age Evaluate fibrosis/inflammation Treat if F2 or A3 Terrault. Hepatology. 2018;67:

24 2018 AASLD Guidance: Cirrhosis HBsAg-Positive Patients With CHB Decompensated Cirrhosis Compensated Cirrhosis Any HBV DNA Any ALT HBV DNA < 2000 IU/mL Any ALT HBV DNA > 2000 IU/mL Any ALT Treat with ETV or TDF TAF may be considered Monitor closely for AEs Refer for consideration of liver transplantation if no stabilization PegIFN contraindicated owing to safety concerns Treat with ETV, TAF, or TDF If treatment not offered, monitor HBV DNA every 3-6 mos Treat for HBV DNA elevation and/or clinical decompensation PegIFN is not contraindicated, but NA therapy considered safer Treat with ETV, TAF, or TDF based on criteria for HBeAg+ and HBeAginfected patients Terrault. Hepatology. 2018;67:

25 2018 AASLD Guidance: Ποιοι Monitoring ασθενείς πρέπει of να CHB υποβάλλονται Patients σε τακτική Not on παρακολούθηση Antiviral Therapy ( δεν έχουν απόλυτη ένδειξη θεραπείας); Definition of Population Recommended Monitoring for Population Immune-Tolerant CHB Inactive CHB Resolved CHB HBeAg positive, high HBV DNA ALT: every 3-6 mos If ALT level rises to > ULN, evaluate ALT and HBV DNA more frequently HBeAg status: every 6-12 mos Treat if HBeAg+ with HBV DNA > 20,000 IU/mL for 3-6 mos and ALT > 2 x ULN HBeAg negative, normal ALT, low HBV DNA ALT and HBV DNA: every 3 mos for first yr, then every 6-12 mos If ALT level rises to > ULN, evaluate ALT and HBV DNA more frequently HBsAg: annually HBsAg loss ALT and HBV DNA monitoring no longer required HCC surveillance Continue if individual has cirrhosis, a first-degree family member with HCC, or a long duration of infection Liver biopsy or noninvasive assessment of fibrosis Consider with slight, persistent ALT elevation, particularly if > 40 yrs of age and infected for long duration Terrault. Hepatology. 2018;67:

26 Οι τρέχουσες και διαθέσιμες θεραπείες για την χρόνια ηπατίτιδα Β δεν μπορούν να εξαφανίσουν τον ιό.

27 Ποια είναι τα εμπόδια για τη θεραπεία του HBV; Programmed cell death protein 1(PD-1) Υψηλό ιϊκό φορτίο CTLA-4 PD-1 CD8+ T-cells B-cells Ασθενής ανοσολογική απάντηση Cytotoxic T- lymphocyteassociated protein 4 (CTLA-4) Persistence of cccdna

28 Γιατί οι υπάρχουσες θεραπευτικές επιλογές δεν οδηγούν σε πλήρη θεραπεία;;;

29 Structural maintenance of chromosomes 5 and 6 (Smc5/6) can silence cccdna double stranded linear DNA (dsldna) rcdna HBV regulatory protein X (HBx) hijacks the Cullin 4- ROC1 RING E3 ubiquitin ligase (CRL4) complexes by binding to damage-specific DNA-binding protein 1 (DDB1) to target Smc5/6 for ubiquitination Smc5/6 is consequently degraded by the proteasome, and cccdna can then be transcribed. Kazuma Sekiba et al:world J Gastroenterol 2018 June 7; 24(21):

30 Ποια είναι η πρώτη θεραπευτική επιλογή σας ;

31 Εγκεκριμένες θεραπείες: Interferon discovered 1990 PMEA anti-hbv activity discovered TC anti-hbv and anti-hiv activity discovered 1998 Entecavir anti-hbv activity discovered 2001 Telbivudine anti-hbv activity discovered Tenofovir Alafenamide for the Treatment of Chronic HBV Infection Buti M et al.lancet Gastroenterol Hepatol 2016 Sep Interferon alfa-2b approved for HBV 1998 Lamivudine (3TC) approved as first nucleoside analogue for HBV 2002 Adefovir dipivoxil (PMEA prodrug) approved for HBV 2005 peginterferon alfa-2a approved for HBV 2006 entecavir approved for HBV 2008 telbivudine approved for HBV TAF tenofovir approved for HBV

32 2018 AASLD Guidance: επιλογές θεραπείας Treatment Preferred Notes Entecavir Yes High potency, high genetic barrier to resistance TAF Yes High potency, high genetic barrier to resistance TDF Yes High potency, high genetic barrier to resistance PegIFN Yes Less safe in patients with cirrhosis, contraindicated in patients with decompensated cirrhosis Adefovir No Low genetic barrier to resistance Lamivudine No Low genetic barrier to resistance Telbivudine No Low genetic barrier to resistance Terrault. Hepatology. 2018;67: EASL. J Hepatol. 2017;67:370.

33 Ο μηχανισμός δράσης των εγκεκριμένων φαρμάκων Entry Virion Secretion ER hntcp DNA+ Positive Strand Synthesis Nucleos(t)ide analogue reverse transcriptase inhibitors ETV, TAF, TDF HBV DNA Integration cccdna Formation rcdna Nucleus DNA- Encapsidation & Reverse Transcription Viral Protein Secretion cccdna pgrna HBeAg PegIFN Hepatocyte Immunomodulators Transcription pgrna AAA AAA AAA mrna Translation AAA ER HBsAg CD8+ T-Cells Effect Through IFN-γ or Cytotoxicity NK Cells CD4+ T-cells Innate Immunity B-Cells Other Cells Adaptive Immunity Zoulim. Cold Spring Harb Perspect Med. 2015;5:a

34 PegIFN VS. ORAL THERAPY IN HBeAg-NEGATIVE CHB PATIENTS Mauro Viganò1 and Pietro Lampertico2* 1 Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy; 2CRC A. M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy One year of PegIFNα achieves a persistent suppression of viral replication with alanine aminotransferase (ALT) normalisation in nearly 20% of HBeAg-negative patients, ultimately leading to HBsAg loss in approximately 30% of them during long-term off-treatment follow-up.

35 12/63(19.04) G. Baltayiannis et al. Alim. Pharm. Ther 2006

36 2018 AASLD Guidance: Efficacy of First-line Antiviral Therapies in Treatment-Naive Adults With CHB Outcomes From Separate Studies (Not Head to Head) HBeAg positive PegIFN* ETV TAF TDF HBV DNA suppression, % (IU/mL) (< ,000) 61 (< IU/mL) 73 (< 29) 76 (< 60) HBeAg loss, % HBeAg seroconversion, % Normalization ALT, % HBsAg loss, % HBeAg negative HBV DNA suppression, % (IU/mL) 43 (< 4000) (< 50-60) 90 (< 29) 93 (< 60) Normalization ALT, % HBsAg loss,% < 1 0 *Assessed 6 mos after completion of 12 mos of therapy. Assessed after 3 yrs of continuous therapy. Assessed after 2 yrs of continuous therapy. HBV DNA < ,000 IU/mL for pegifn; < 60 IU/mL for ETV and TDF; < 29 IU/mL for TAF. HBV DNA < 20,000 IU/mL for pegifn; < 60 IU/mL for ETV and TDF; < 29 IU/mL for TAF. ALT normalization defined by laboratory normal rather than < 35 U/L for men and 25 U/L for women. Terrault. Hepatology. 2018;67:

37 Επιλογή θεραπείας HBV για ηλικιωμένους ασθενείς και / ή ασθενείς με οστική ή νεφρική νόσο Indications for using (ETV or TAF) over TDF: Aged > 60 yrs Bone disease Chronic steroids or other meds that affect bone History of fragility fracture Osteoporosis Renal abnormalities egfr < 60 ml/min/1.73 m 2 Albuminuria > 30 mg or moderate proteinuria Low phosphate (< 2.5 mg/dl) Hemodialysis When to prioritize TAF over ETV: Previous nucleoside exposure Lamivudine with or without adefovir resistance HIV/HBV coinfection No dose adjustment for CrCl 15 ml/min When to prioritize ETV over TAF: If less expensive (generic available) Dosing guidelines for CrCl < 15 ml/min Terrault. Hepatology. 2018;67:1560. EASL. J Hepatol. 2017;67:370.

38 Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. Papatheodoridis GV 1, Dalekos GN 2, Yurdaydin C 3, Buti M 4, Goulis J 5, Arends P 6, Sypsa V 7, Manolakopoulos S 8, Mangia G 9, Gatselis N 2, Keskın O 3, Savvidou S 5, Hansen BE 6, Papaioannou C 8, Galanis K 2, Idilman R 3, Colombo M 9, Esteban R 4, Janssen HL 10, Lampertico P 9. Author information Abstract BACKGROUND/AIMS: The risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB) treated with entecavir (ETV) or tenofovir (TDF) is unclear. We evaluated the incidence and predictors of HCC and the accuracy of existing HCC risk scores in Caucasian CHB patients receiving ETV/TDF. METHODS: This large, multicenter, retrospective cohort study included 1666 adult Caucasian CHB patients under ETV/TDF for 39 months. CHB without cirrhosis, compensated and decompensated cirrhosis were present in 67%, 39% and 3% of patients. The predictability of baseline parameters and three risk scores (GAG-HCC, CU-HCC and REACH-B) developed in Asians was assessed. RESULTS: The cumulative probability of HCC was 1.3%, 3.4% and 8.7% at year-1, year-3 and year-5 after ETV/TDF onset. Older age and lower platelets were strong independent HCC predictors in the total population and in the subgroups of cirrhotic and noncirrhotic patients, while liver disease severity was an independent HCC predictor in the total population and the cirrhotics. GAG-HCC, CU-HCC and REACH-B risk scores were associated with HCC development only in the univariable but not in the multivariable analyses and offered poor to modest predictability. CONCLUSIONS: HCC can still develop in Caucasian CHB patients treated with ETV/TDF. Besides the well known predictors of HCC, such as older age, male gender and more advanced liver disease, lower platelets represent an independent factor of higher HCC risk. The applicability and predictability of HCC risk scores developed in Asians are poor or modest in Caucasian CHB patients, for whom different risk scores are required. J Hepatol Sep 4

39 Πότε θα σταματήσετε την θεραπεία;

40 Patients (%) FINITE: Stopping Long-term TDF in HBeAg-Negative CHB Noncirrhotic patients with HBeAg-negative CHB who had received TDF for 4 yrs with HBV DNA suppression for 3.5 yrs and were randomized to stop TDF (n = 21) BL Wks Patients off therapy, n Off therapy with HBV DNA > 2000 IU/mL and/or ALT ULN Off therapy with HBV DNA < 2000 IU/mL and ALT ULN Restarting therapy with HBV DNA < 2000 IU/mL and ALT ULN 19% (4/21) achieved HBsAg loss at Wk % (13/21) remained off therapy at Wk 144 Berg. J Hepatol. 2017;67:918.

41 Typical Course After Withdrawal of NA Therapy in HBeAg-Negative CHB Potential Outcome Predictors Age, time to undetectable HBV DNA, duration of viral suppression under NA, HBsAg levels at BL and NA cessation, type of NA (TDF vs ETV), HBV DNA levels during reactivation phase, retreatment strategy, and HBV genotype Treatment Phase (> 3 yrs) Lag Phase (< 1-12 mos) Reactivation Phase (~ 3 mos) Consolidation Phase (~ 12 mos) Long-term Outcome Categories Nucleos(t)ide analogue Risk of severe flare? HBV DNA ALT CHB requiring retreatment (~ 40%) Indeterminate state not fulfilling immediate retreatment criteria (~ 10% to 20%) Sustained virologic response or healthy carrier state ± HBsAg level decline (~ 20% to 30%) Limit of HBV DNA detection HBsAg loss (~ 20% after 2-3 yrs of follow-up) Time Lampertico. Hepatology. 2018;68:397.

42 Διακοπή των ΝΑs Τα NAs μπορούν να διακοπούν μετά την απώλεια του HBsAg με ή χωρίς ορομετατροπή (anti-hbs) Τα NAs μπορούν να διακοπούν σε μη κιρρωτικούς HBeAg + ασθενείς που παρουσιάζουν σταθερή HBeAg ορομετατροπή και μη ανιχνεύσιμο HBVDNA και που συμπλήρωσαν τουλάχιστον 12 μήνες θεραπείας. Πολύ στενή παρακολούθηση μετά είναι αναγκαία. Επίσης τα ΝΑs μπορούν να διακοπούν σε επιλεγμένους μη κιρρωτικους HBeAg ασθενείς που παρουσιάζουν μακροχρόνια (> 3 χρόνια) ιολογική ανταπόκριση αν έχουν απόλυτα, πολύ στενή παρακολούθηση EASL 2017

43

44 Εξελίξεις Νεότερα δεδομένα 2019 ( στη θεραπεία της χρόνιας ηπατίτιδας Β)

45 Τι θα φέρει το μέλλον στη θεραπεία της ηπατίτιδας Β.. G Baltayiannis and P.Karayiannis J V Hepatitis 2014

46 HBV life cycle. HSPG: heparin sulfate proteoglycan; NTCP: sodium/taurocholate cotransporting polypeptide; cccdna: covalently closed circular DNA; pdsdna: partially double stranded DNA; POL-II: cellular polymerase II; RT: viral reverse transcriptase; pgrna: pregenomic RNA; pres/srna: Surface messanger RNA; XRNA: X messanger RNA; HBV: hepatitis B virus; HBc: capsid; HBs: surface protein.

47 Major HBV therapeutic targets. HSPG: heparin sulfate proteoglycan; NTCP: sodium/taurocholate cotransporting polypeptide; cccdna: covalently closed circular DNA; pdsdna: partially double stranded DNA; POL-II: cellular polymerase II; RT: viral reverse transcriptase; pgrna: pregenomic RNA; pres/srna: Surface messanger RNA; XRNA: X messanger RNA; HBV: hepatitis B virus; HBc: capsid; HBs: surface protein.

48 Νέοι στόχοι για τον HBV: NTCP Entry Virion Secretion ER hntcp DNA+ Positive Strand Synthesis HBV DNA Integration cccdna Formation rcdna Nucleus DNA- Encapsidation & Reverse Transcription Viral Protein Secretion cccdna pgrna Bulevirtide Entry inhibitors HBeAg Hepatocyte Transcription pgrna AAA AAA AAA mrna Translation AAA ER HBsAg CD4+ T-Cells CD8+ T-Cells Effect Through IFN-γ or Cytotoxicity NK Cells Innate Immunity B-Cells Other Cells Adaptive Immunity Zoulim. Cold Spring Harb Perspect Med. 2015;5:a

49 MYR203: Bulevirtide for Chronic HBV/HDV Coinfection Bulevirtide: investigational NTCP inhibitor that targets parenchymal liver cells with strong inhibitory potential against HBV/HDV coinfection Final analysis of multicenter, open-label phase II trial Wk 48 Patients positive for serum HDV RNA, anti-hdag ( 6 mos), HBsAg; HBeAg positive or negative; ALT ULN but 10 x ULN; no HCV or HIV coinfection (N = 60) PegIFN (n = 15) Bulevirtide 2 mg + PegIFN (n = 15) Bulevirtide 5 mg + PegIFN (n = 15) Bulevirtide 2 mg (n = 15) All patients followed through Wk 72 Wedemeyer. EASL Abstr GS-13.

50 Patients (%) Patients (%) Patients (%) MYR203: Antiviral Activity of Bulevirtide Undetectable HDV RNA ALT Normalization HBsAg Response* n/n = 0 P =.0209 P = / 15 9/ 15 6/ 15 2/ / 15 4/ n/n = 0 4/ 15 4/ 15 7/ 15 10/ 15 Wk 48 Wk 72 Wk 48 Wk 72 Wk 48 Wk 72 1/ 15 7/ 15 5/ 15 3/ n/n = 0 0 7/ 15 3/ / 15 2/ 15 0 PegIFN Bulevirtide 2 mg + pegifn Bulevirtide 5 mg + pegifn Bulevirtide 2 mg *Either HBsAg undetectability or 1 log IU/mL reduction. Includes HBsAg loss in 26.7% of patients. Wedemeyer. EASL Abstr GS-13.

51 Νέοι στόχοι για τον HBV: Συναρμολόγηση καψιδίου Entry Virion Secretion ER hntcp DNA+ Positive Strand Synthesis Core inhibitors ABI-H0731 HBV DNA Integration cccdna Formation rcdna Nucleus DNA- Encapsidation & Reverse Transcription Viral Protein Secretion cccdna pgrna HBeAg Hepatocyte Transcription pgrna AAA AAA AAA mrna Translation AAA ER HBsAg CD4+ T-Cells CD8+ T-Cells Effect Through IFN-γ or Cytotoxicity NK Cells Innate Immunity B-Cells Other Cells Adaptive Immunity Zoulim. Cold Spring Harb Perspect Med. 2015;5:a

52 Studies 201/202: ABI-H0731 for Treatment-Naive and Virologically Suppressed Patients With CHB ABI-H0731: investigational HBV core inhibitor Interim analysis of 2 double-blind, placebo-controlled phase IIa trials CHB patients virologically suppressed on SoC NAs; HBsAg > 400 IU/mL if HBeAg+ or > 100 IU/mL if HBeAg-; Metavir F0-2 (N = 73) Study 201 Study 202 Randomized 3:2 NA + ABI-H mg NA + Placebo Primary endpoint: Wk 24 log 10 decline in HBsAg or HBeAg Wk 24 Tx-naive patients with HBeAg+ CHB, HBV DNA > 10 5 IU/mL, Metavir F0-2 (N = 25) Randomized 1:1 ETV + ABI-H mg ETV + Placebo Primary endpoint: Wk 12 and 24 log 10 decline in HBV DNA Wk 24 Ma. EASL Abstr LB-06.

53 HBV DNA Reduction (log 10 IU/mL) Studies 201/202: Primary Endpoints Outcome at Wk 24, % (n/n) Undetectable HBV DNA HBV RNA < 200 copies/ml HBeAg 0.5 log 10 decline HBsAg 0.5 log 10 decline Study 201: Virologic Outcomes NA + ABI-H0731 NA + Placebo 83 (5/6) 0 (0/4) 50 (3/6) 0 (0/3) 17 (1/6) 0 (0/3) 0 (0/6) 0 (0/4) * Study 202: HBV DNA Decline n = 12 n = 12 ETV + ABI-H0731 ETV + placebo n = 6 n = Treatment Wk *P <.05 or better. * * Ma. EASL Abstr LB-06.

54 Αναστολείς του πυρηνικού αντιγόνου ελαττώνουν τους δείκτες τα επίπεδα του cccdna που εκφράζουν

55 Νέοι βιοδείκτες απαιτούνται : Iϊκά (HBV) αντιγόνα και σωματίδια που απαντώνται στον ορό

56 HBVRNA (pgrna) σε ιϊκά σωμάτια που κυκλοφορούν στον ορό

57 Νέοι ορολογικοί δείκτες της HBV λοίμωξης HBcrAg [1-4] Comprising HBeAg, HBcAg, and a core-related protein (p22cr) found in virion-like particles without HBV DNA Products of the precore/core gene, share identical sequence of 149 amino acids May reflect cccdna levels HBV RNA [5] Serum HBV RNA may be a marker of antiviral efficacy No standardized assays yet exist Correlations with HBV DNA, cccdna, and other markers are not consistent 1. Wong. Liver Int. 2017;37: Hadziyannis. Genes (Basel). 2018;9: Wong. J Clin Microbiol. 2007;45: Kimura. J Biol Chem. 2005;280: Liu. Hepatology. 2018;[Epub].

58 Νέοι στόχοι για τον HBV: μετάφραση Entry hntcp HBV DNA Integration cccdna Formation rcdna Nucleus cccdna Hepatocyte Transcription pgrna AAA AAA AAA mrna AAA CD4+ T-Cells CD8+ T-Cells Effect Through IFN-γ or Cytotoxicity B-Cells Adaptive Immunity DNA+ DNA- pgrna Translation Virion Secretion ER Positive Strand Synthesis Encapsidation & Reverse Transcription Viral Protein Secretion HBeAg ER HBsAg NK Cells Innate Immunity Other Cells Inhibition of protein translation by sirna JNJ-3989 Zoulim. Cold Spring Harb Perspect Med. 2015;5:a

59 AROHBV1001: JNJ-3989 for Patients With CHB JNJ-3989 (formerly ARO-HBV): 2 hepatocyte-targeted RNAi molecules that interfere with cccdna, integration-derived transcripts Interim analysis of open-label CHB cohorts from phase II trial (N = 40) Patients received 3 subcutaneous JNJ-3989 doses; if NA naive, started NA treatment at Day 1; if experienced, continued baseline NA Characteristic* C2b C3b C4b C5b C8 C9 C6 C7 C10 C11 Dose, mg Frequency Q4W Q4W Q4W Q4W Q4W Q4W Q2W QW QW QW HBeAg +/-, n 1/3 0/4 1/3 1/3 4/0 4/0 0/4 1/3 1/3 0/4 NA experienced, n *N = 4 in each cohort. Yuen. EASL Abstr PS-080. Gane. AASLD Abstr LB-25. NCT

60 Log HBsAg Δ From Day 1 Log HBsAg Δ From Day 1 AROHBV1001: HBsAg Reduction With JNJ Monthly Dosing 0 Weekly or Every-Other-Wk Dosing Dose Mos Mos 100 mg Q4W x 3 (C2b) 200 mg Q4W x 3 (C3b) 300 mg Q4W x 3 (C4b) 400 mg Q4W x 3 (C5b) 300 mg Q4W x 3 (C8) 300 mg Q4W x 3 (C9) 100 mg Q2W x 3 (C6) 100 mg QW x 3 (C7) 200 mg QW x 3 (C10) 300 mg QW x 3 (C11) Yuen. EASL Abstr PS-080.

61 Νέοι στόχοι για τον HBV: HBsAg REP 2139, REP 2165 HBsAg release inhibitor Entry hntcp HBV DNA Integration cccdna Formation rcdna Nucleus cccdna Hepatocyte Transcription pgrna AAA AAA AAA mrna AAA CD4+ T-Cells CD8+ T-Cells Effect Through IFN-γ or Cytotoxicity B-Cells Adaptive Immunity DNA+ DNA- pgrna Translation Virion Secretion ER Positive Strand Synthesis Encapsidation & Reverse Transcription Viral Protein Secretion HBeAg ER HBsAg NK Cells Innate Immunity Other Cells Zoulim. Cold Spring Harb Perspect Med. 2015;5:a

62 REP 401: First-line NAPs for HBeAg-Negative CHB REP 2139: investigational NAP(nucleic acid polymers) that prevents assembly/release of subviral particles from integrated HBV DNA or cccdna, blocks replenishment of circulating HBsAg Open-label, randomized phase II trial Patients received REP 2139 or, if showing poor HBsAg response to TDF + pegifn in Wks 24-48, were rescued with REP 2165 (amenable to high-frequency dosing) Tx-naive patients with HBeAg(-) CHB, HBsAg > 1000 IU/mL, HBV DNA > 10,000 IU/mL, no cirrhosis (N = 40) TDF (n = 20) TDF (n = 20) Wk 24 Wk 48 Wk 72 Wk 96 NAP 250 mg IV QW + TDF + PegIFN α-2a (n = 20) TDF + PegIFN α-2a (n = 20) NAP 250 mg IV QW + TDF + PegIFN α-2a (n = 20) Bazinet. Global Hepatitis Summit Abstr O-018. NCT

63 REP 401: Antiviral Activity of First-line NAP Treatment HBsAg Anti-HBs HBV DNA HBsAg decline o < 1 log 10 : 4/40 o > 1 log 10 but < 1 IU/mL: 8/40 HBsAg < 1 IU/mL: 28/40 HBsAg loss: 24/40 Anti-HBs levels markedly increased when pegifn added, but only in those whose HBsAg decreased to < 1 IU/mL TDF-associated decreases in HBV DNA not affected during therapy Bazinet. Global Hepatitis Summit Abstr O-018.

64 Lenvervimab, a mab against HBsAg, can induce sustained HBsAg loss in a chronic hepatitis B mouse model BACKGROUND & AIMS Sustained loss of HBsAg is regarded as a marker for functional cure in HBV As HBsAg is known to suppress HBV immune responses, this study hypothesized that HBsAg removal could result in immune response restoration METHODS Therapeutic potential of surrogate lenvervimab (slenvervimab) was evaluated in an HDI-based CHB mouse model RESULTS Sustained HBsAg loss for 6 months was observed after end of slenvervimab treatment in 5/12 mice (41.7%) HBV replication and HBcAg+ hepatocytes barely detectable >1 log reduction in copy number of injected DNA (paav-hbv1.2*) was observed and at a level comparable to self-limited mice IHC showed lymphocyte infiltration and structural changes of hepatocytes, resembling ballooning degeneration Upregulation of inflammatory markers, such as Cox-2, interleukin-1β and prostaglandin E2 Statistically meaningful mild moderate increase in ALT Existence of protective immunity was confirmed by further challenge experiments to the HBsAg loss mice 60% showed immunity vs. 0% of HBsAg-persistent mice *Acts as a template for HBV replication as cccdna does in natural infection. Kim J-H, et al. ILC 2019; PS-077

65 Lenvervimab, a mab against HBsAg, can induce sustained HBsAg loss in a chronic hepatitis B mouse model FIGURE Lenvervimab treatment Functional cure Chronic hepatitis B: Immune balance Immune response restored Immune cells HBsAg Lenvervimab Chronic hepatitis B again: Balance restored CONCLUSIONS Removal of HBsAg by Lenvervimab resulted in restoration of HBV immune responses. Sustained HBsAg loss was achieved by elimination of HBV+ hepatocytes. This study provides proof of concept for Ab-based therapies for CHB functional cure Kim J-H, et al. ILC 2019; PS-077

66 Νέοι στόχοι για τον HBV: RIG-I Entry Virion Secretion ER hntcp DNA+ Positive Strand Synthesis HBV DNA Integration cccdna Formation rcdna Nucleus DNA- Encapsidation & Reverse Transcription Viral Protein Secretion cccdna pgrna HBeAg Hepatocyte (Retinoid Acid Inducible gene) RIG-I agonist (eg, Immunomodulators inarigivir) Transcription pgrna AAA AAA AAA mrna Translation AAA ER HBsAg CD4+ T-Cells CD8+ T-Cells Effect Through IFN-γ or Cytotoxicity NK Cells Innate Immunity B-Cells Other Cells Adaptive Immunity IFN Zoulim. Cold Spring Harb Perspect Med. 2015;5:a

67 ACHIEVE: First-line Inarigivir for Patients With CHB Inarigivir: investigational RIG-I agonist that induces IFN production, suppresses viral replication by countering interaction of HBV pol with pgrna Final analysis of dose escalation cohorts from phase II trial (Wks 1-24) Wk 12 HBsAg+ without treatment for > 6 mos; HBV DNA > 2000 IU/mL if HBeAgor > 20,000 IU/mL if HBeAg+; ALT > ULN to < 150 IU/mL; FibroScan < 8 kpa (N = 80) Inarigivir 25, 50, 100, or 200 mg QD (n = 64) Placebo (n = 16) All patients switched to TDF 300 mg QD through Wk 24 Yuen. EASL Abstr GS-12.

68 HBV DNA Δ (log 10 ) ACHIEVE: HBV DNA Decline With Inarigivir 2 HBeAg-Positive Patients 2 HBeAg-Negative Patients * * * * * -8 *P <.01 vs placebo. -8 *P <.01 vs placebo. Wks 0-12 Inarigivir Wks TDF 300 mg QD Wks 0-12 Inarigivir Wks TDF 300 mg QD Yuen. EASL Abstr GS-12.

69 Νέοι στόχοι για τον HBV: cccdna Entry hntcp HBV DNA Integration cccdna Formation rcdna Nucleus cccdna Hepatocyte Transcription pgrna AAA AAA AAA mrna AAA CD4+ T-Cells CD8+ T-Cells Effect Through IFN-γ or Cytotoxicity B-Cells Adaptive Immunity DNA+ DNA- pgrna Translation Virion Secretion ER Positive Strand Synthesis Encapsidation & Reverse Transcription Viral Protein Secretion HBeAg ER HBsAg NK Cells Innate Immunity Other Cells cccdna silencing ZFNs, TALENs, CRISPR/Cas9 Zoulim. Cold Spring Harb Perspect Med. 2015;5:a

70 Μέθοδοι για να ελαττωθεί ή εξαφανιστεί το cccdna Pharmacological (small molecules) Immune control cccdna Gene therapy (nucleases) Enhance host factors Lok. Hepatology. 2017;66:1296. Asadi. CP Allergy and Immunology. 2018;1:001.

71 A first-in-class orally available HBV cccdna destabilizer ccc_r08 achieved sustainable HBsAg and cccdna reduction in the HBV circle mouse model BACKGROUND & AIMS Persistence of cccdna is a major barrier to cure in CHB patients with existing therapies Aim: To evaluate the effect of a novel small molecule ccc_r08 on the level of pre-existing cccdna both in vitro and in vivo METHODS HBV-infected primary human hepatocytes (PHH) were used for evaluating antiviral activities in vitro ccc_r08 was orally administered in HBV circle mouse model* to study its in vivo efficacy Levels of HBV DNA, HBsAg, HBeAg, pgrna, and cccdna were measured RESULTS HBV-infected PHH Potent inhibition of HBV DNA, HBsAg, HBeAg, and pre-existing cccdna No effect on mitochondrial DNA level and cytotoxicity HBV circle mice Levels of serum HBV DNA, pgrna, HBsAg, HBeAg reduced significantly Sustained during the off-treatment period Levels of cccdna in the liver of ccc_r08 treated mice were < LLOQ ETV had no such effect on cccdna level in this model *Yan Z, et al. HBV circle: A novel tool to investigate hepatitis B virus covalently closed circular DNA. J Hepatol 2017;66: Wang L, et al. ILC 2019; PS-074

72 L o g 1 0 ( c o p i e s / u l ) A first-in-class orally available HBV cccdna destabilizer ccc_r08 achieved sustainable HBsAg and cccdna reduction in the HBV circle mouse model FIGURE HBV circle mouse model: serum levels of HBsAg, HBeAg, and HBV DNA and cccdna levels in the liver Treatment End HBsAg Treatment End HBeAg Treatment End HBV DNA L o g 1 0 ( I U / m l s e r u m ) L L O Q L o g 1 0 ( N C U / m l s e r u m ) L L O Q Vehicle ccc_r08 20 mg/kg BID D a y s p o s t 1 s t d o s e D a y s p o s t 1 s t d o s e Liver cccdna level LLOQ CONCLUSIONS A novel small molecule ccc_r08 can sustainably reduce serum HBsAg and liver cccdna levels in the HBV circle mouse model Vehicle ccc_r08 20 mg/kg BID Wang L, et al. ILC 2019; PS-074

73 HDV co-infection modifies the immunoproteasome profile of HBV infected hepatocytes leading to increased CD8 T-cell recognition BACKGROUND & AIMS Immunological therapy with engineered virus-specific T cells might eradicate HBV/HDV-infected hepatocytes; impact of HDV on the T-cell recognition is unknown Aim: To analyze how HDV modifies HBV antigen presentation to CD8 T cells and test the antiviral efficacy of engineered T cells in HBV/HDV co-infected humanized chimeric mice METHODS HBV CD8 T-cell epitope:mhc complexes were measured concomitantly with Primeflow HDV RNA specific probes on PHH infected with HBV alone or HBV/HDV Antibodies and CD8 T cells specific for either core or envelope HLA-A0201 restricted HBV epitopes Differentially expressed genes during HDV infection characterized using Nanostring technology In vivo adoptive T-cell transfer to HBV/HDV co-infected mice* repopulated with HLA-A02- matched PHH HBV-specific TCR T cells were engineered using TCR mrna electroporation on T cells of healthy and HDV chronically infected subjects *Adoptive transfer of T cells engineered with TCR specific for envelope/a0201 complexes into HBV/HDV co-infected human liver chimeric mice (upa-scid/beige/il2rg-/- [USG]). Tham CYL, et al. ILC 2019; PS-079

74 HDV co-infection modifies the immunoproteasome profile of HBV infected hepatocytes leading to increased CD8 T-cell recognition RESULTS (Cont.) 2 Ενισχυμένη HBV Env183-ειδική CD8 Τ κυτταρική αναγνώριση και ενεργοποίηση στόχων HBV / HDV 1 Οι επίτοποι Τ-κυττάρων HBV CD8 δεν αναστέλλονται από μόλυνση με ΗDV, με τον Env183 επίτοπο να ενισχύεται σημαντικά 3 Η εισαγωγή HBV Env183-ειδικών Τ κυττάρων σε εξανθρωπισμένους ποντικούς HBV / HDV μειώνει ταχέως την ιαιμία HDV και HBV Humanized mice co-infected with HBV and HDV H D V v ire m ia x fo ld c h a n g e (c o p ie s p e r m l) in lo g T c e ll in fu s io n H B V / H D V c o n t r o l H B V / H D V + T c e lls B L CONCLUSION The ability of HDV to activate immunoproteasome activity in HBV-infected hepatocytes and boost the presentation of envelope-derived HBV epitopes support the therapeutic use of HBV envelope-specific TCR engineered T cells in HBV/HDV co-infection Tham CYL, et al. ILC 2019; PS-079

75 Η ενεργοποίηση των Τ κυττάρων απαιτεί 3 σήματα Ανασταλτικά σήματα οδηγούν σε εξουθένωσηεξάντληση των Τ κυττάρων

76 PD-1 inhibitors: Exampl es of drugs that target PD-1 include: Pembrolizumab (Keytruda) Nivolumab (Opdivo) Cemiplimab (Libtayo) Drugs that target CTLA-4 Ipilimumab (Yervoy) PD-L1 inhibitors: Examples of drugs that target PD-L1 include: Atezolizumab (Tecentriq) Avelumab (Bavencio) Durvalumab (Imfinzi)

77 Antonio Bertoletti1,2 and Nina Le Bert1,2 1 Emerging Infectious Diseases Program, Duke-NUS Medical School and 2 Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, A*STAR, Singapore Gut and Liver, Vol. 12, No. 5, September 2018, pp

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