Terapie attuali. Eradicazione di HCV e nuove prospettive:

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1 Eradicazione di HCV e nuove prospettive: Terapie attuali Luisa Pasulo U.S.C. Gastroenterologia Epatologia e Trapiantologia Ospedale Papa Giovanni XXIII - Bergamo

2 From Infection to liver disease Infezione acuta 1 Infezione cronica Years 1. Adapted from Metzner KJ. Future Virol. 2006;1:377-91

3 Ideal HCV Therapy: getting there? Potent Efficacy across all patient populations High barrier to Resistance COst reduction All genotypes Availability: Cirrhosis, HIV HCV, etc. Ideal HCV treatment GOAL = ERADICATION Short treatment Duration Minimal drug interaction Optimal tolerability All oral PharmaCokinetic (low pill burden)

4 SVR Rate (%) SVR Rates for Approved Therapies in HCV GT 1 TN or TE Years are not to scale IFN 6 or 12 mo IFN+RBV 6 mo IFN+RBV 12 mo PEG 2a/b+RBV 12 mo BOC+PEG +RBV 6-12 mo TVR+PEG +RBV 6-12 mo SMV+PEG +RBV 6-12 mo SOF+PEG +RBV 3 mo LDV/SOF 2-6 mo 1 pooled data from ION-1, ION-2, and ION-3 Jeffers L, et al. Hepatology 2004; 39: ; Conjeevaram H, et al. Gastroenterology 2006; 131: ; Muir A, et al. N Engl J Med 2004; 350: ; McHutchison J, et al. Gastroenterology 2000; 119: ; Poordad F, et al. N Engl J Med 2011; 364: ; Bacon B, et al. N Engl J Med 2011; 364: ; Jacobson I, et al. N Engl J Med 2011; 364: ; Zeuzem S, et al. N Engl J Med 2011; 364: ; Manns M, et al. Lancet 2014; 384: ; Jacobson I, et al. Lancet 2014; 384: ; Lawitz E, et al. N Engl J Med 2013; 368: ; Afdhal N, et al. N Engl J Med 2014; 370: ; Afdhal N, et al. N Engl J Med 2014; 370: ; Kowdley K, et al. N Engl J Med 2014; 370:

5 Treated/cured patients represent only a small proportion of diagnosed ones North CS, et al. Gen Hosp Psych 2013;35:122 8.

6 IFN free DAA will expand the pool of treatable patients Mild Severe Decomp HCV chronic disease spectrum Currently treated We must strive to obtain appropriate and effective treatment for all patients

7 Requirements for HCV Therapy SVR > 90% Toxicity Must haves Tolerability Short duration High barrier to resistance Helpful One size fits all: pangenotypic No drug drug interactions Low pill burden Nice bonus

8 DAA classes and subclasses: antiviral potency and resistance barrier according to HCV genotype Drug Class Subclass 1 b 1a Protease inhibitors NS5a Inhibitor 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Simeprevir Paritaprevir/r 2nd Generation Grazoprevir ABT st Generation Daclatasvir Ledipasvir Ombitasvir Elbasvir 2 nd Generation GS 5816 ABT 530 NN Polymerase Inhibitors Dasabuvir Nucleos/tides Polymerase inhibitors 2 nd Generation : Sofosbuvir High Moderate Low Very low

9 DAA classes and subclasses: antiviral potency and resistance barrier according to HCV genotype Drug Class Subclass 1 b 1a Protease inhibitors NS5a Inhibitor 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Simeprevir Paritaprevir/r 2nd Generation Grazoprevir ABT st Generation Daclatasvir Ledipasvir Ombitasvir Elbasvir 2 nd Generation GS 5816 ABT 530 NN Polymerase Inhibitors Dasabuvir Nucleos/tides Polymerase inhibitors 2 nd Generation : Sofosbuvir High Moderate Low Very low

10 DAA classes and subclasses: antiviral potency and resistance barrier according to HCV genotype Drug Class Subclass 1 b 1a Protease inhibitors NS5a Inhibitor 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Simeprevir Paritaprevir/r 2nd Generation Grazoprevir ABT st Generation Daclatasvir Ledipasvir Ombitasvir Elbasvir 2 nd Generation GS 5816 ABT 530 NN Polymerase Inhibitors Dasabuvir Nucleos/tides Polymerase inhibitors 2 nd Generation : Sofosbuvir High Moderate Low Very low

11 IFN-free Combination Regimens: Two Possible Options Backbone Drug: Nucleotide NS5B Inhibitor Non-NUC-based Combinations PI NS5A PI NUC NNI NS5A NUC PI NNI NS5A RBV

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13 LDV/SOF Phase 3 Program (ION-1, ION-2, ION-3) Afdhal N et al. Engl J Med May 15;370(20): Afdhal N et al. N Engl J Med Apr 17;370(16): Kowdley KW et al. N Engl J Med May 15;370(20): Wk 0 Wk 8 Wk 12 Wk 24 LDV/SOF + RBV SVR 99 % ION-1 ION-2 LDV/SOF LDV/SOF + RBV % % LDV/SOF % ION-3 LDV/SOF + RBV LDV/SOF ION-1 treatment naïve: N = 865 ION-2 treatment experienced: N = 440 ION-3 treatment naïve: N = % 94% N=1952 total patients

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15 PER CHI?

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17 Cat 1 COME SCEGLIERE? IN BASE A: INTERAZIONI FARMACOLOICHE TOLLERABILITA? FUNZIONE RENALE FUNZIONE EPATICA?

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19 Pharmacokinetics of DAA in Hepatic Impairment Graded According to CTP Score Gambato M. et al, Journal of Hepatology 2014; 61: S

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23 Clinical Outcomes Cirrhosis regression Slowing progression of PH

24 Number of Patients (%) Cirrhosis Regression in HCV(+) patients achieving SVR «Regression» of cirrhosis: Over 60% Hepatology. 2012;56: Prima di SVR *Median interval between pre and post-treatment liver biopsies was 79 months Dopo SVR Metavir Score* F4 F3 F2 F1

25 Hepatology. 2012;56: Cirrhosis! Less fibrosis.. but still Cirrhosis!

26 The impact of SVR on Esophageal Varices Cumulative incidence of esophageal varices in 149 IFN ± RBV-treated patients with compensated HCVinduced (stage 1) cirrhosis according to response to therapy Bruno S, et al. Hepatology 2010

27 Clinical Outcomes Delay/prevent HCC

28 Eradication of HCV and HCC Development: RISK of HCC following SVR N=530 van der Meer AJ, et al. JAMA. 2012; 308(24):

29 Prevent Decompensation Clinical Outcomes Delay Liver-Related Death

30 Flamm, AASLD, 2014, Oral #239 LDV+SOF+RBV in G1/G4 HCV patients with decompensated cirrhosis CPT B CPT C 12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)* (+10) 36% not improved 35% not improved 2 4 n=5 n=5 n=2 n= *Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk.

31 Eradication of HCV: What about CURE??? Point of NO RETURN????

32 Cat 3 Cat 4 Cat 6 DA SEGNALARE Stessi schemi terapeutici della cat 1 ma con durata max di 12 sett. Per gnt 3 tp ottimale anche:

33 Clinical Outcomes Extrahepatic Benefit????

34 HCV complications Negro F, J Hepatol 2014

35 Antiviral Treatment and Extrahepatic Outcomes in HCV Hsu et al, Gut 2015; 64: End Stage Renal Disease Acute Coronary Syndrome p=0,001 p=0,027 Ischemic Stroke Autoimmune Diseases p=0,001 p= ns

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38 Clinical Outcomes Prevent Viral Recurrence After OLT

39 Post-Transplant HCV Recurrence in patients in whom HCV RNA was non detectable for 28 days prior to transplant NB: stop therapy at OLT!!! No Recurrence (69%) Recurrence (31%) No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days OLT transforms a suboptimal treatment for HCV cirrhosis in excellent strategy!! *Wilcoxon rank sum test. Curry AASLD Days with HCV RNA Continuously TND Prior to Liver Transplant

40 HCV Cirrhosis Natural History: can we modify it? Cirrhosis regression Slowing progression of PH SVR: Clinical Outcomes Prevent Decompensation Delay Liver-Related Death Delay/prevent HCC Prevent Viral Recurrence After OLT Prevent (Improve) Extrahepatic disorders

41 Cat 2 STESSI SCHEMI TERAPEUTICI DELLA CAT 1 in base ai genotipi DA SEGNALARE.

42 Cat 7 GENOTIPI 1 o 4 SIM + PEG+ RIBA

43 SOF/LED + RIBA 12 sett o SOF+DAC + RIBA 12 sett o SOF/LED 24 sett o SOF+DAC 24 sett FARMACI SENZA CROSS-REAZIONE

44 Summary of Key Points Clinical Impact of SVR Benchmark of SVR: > 90% Moving into IFN-free regimens SVR impact is greater when treating Non-cirrhotcs Point of no return!! (High MELD) Key points in selection of appropriate schedule: Genotype (Drug combination) Prior Experience (?) Fibrosis (Treatment duration, Ribavirin) Toxicity (Drug-Drug, Bilirubin, Decompensated disease)

45 Thank You for Your Attention