Farmaci anti-HIV e anti-HCV: Dalla ricerca Farmacologica allaccesso - PowerPoint PPT Presentation

Farmaci anti-HIV e anti-HCV: Dalla ricerca Farmacologica all’accesso in clinica Milano, 19 Novembre 2013 Burden of illness dell’epatite C, stato dell’arte della terapia Alessio Aghemo, MD, PhD U.O. Gastroenterologia ed Epatologia Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Università degli Studi di Milano

Current Prevalence of HCV Infection In Different European Countries Esteban JI et al J Hepatol 2008;48:148-162

Epidemiology of Hepatitis C In Europe Northern Europe: Prevalence: 0.1%-1.0% Central Europe: Prevalence: 0.2%-1.2% Southern Europe ( Italy , Spain, Greece, Southern France): Prevalence: 2.5% - 3.5% Spread of infection: 1) initial epidemic (> 50 years ago): iatrogenic nature 2) ongoing epidemic: IDU-related

Natural History of hepatitis C Decompens. Decompens. Liver cancer Death , , steatosis, Fe. (Modified by Lauer and Walker NEJM 2001;345:41-52)

The Burden of Hepatitis C in Italy • The cause of death in at least 10,000 persons each year • The single etiologic agent in half the patients with cirrhosis • The single etiologic agent in more than half the patients with a liver cancer • The indication for liver transplantation in half the patients with ESLD • Each year 67,460 patients with cirrhosis or HCC hospitalized for 11 days on average, 50% HCV (SIS) • Each year 220 million € spent to treat chronic infection with HCV

General Strategy of Hepatitis C Therapy • Goal of therapy To prevent complications of HCV infection, which is principally achieved by eradication of HCV. • The optimal treatment Peg-interferon alpha and Ribavirin, dose and duration of therapy depending on HCV genotype and early virological response. • End-point of therapy Infection is considered eradicated when there is a (Surrogate?) sustained virologic response (SVR) defined as the absence of HCV-RNA by a sensitive PCR assay at the end of treatment and 6 months later. Strader DB et al, Hepatology. 2004;39:1147-71 AASLD Practice Guidelines

Mortality in Patients With Chronic Hepatitis C Infection: A Nationwide Cohort Study Denmark: 5.4 million. 0.3% HCV;1996-2005:13,005 HCV identified; 6,292 included (37% cleared HCV) Liver related death in chronic HCV vs cleared HCV: SDHR: 2.42, 95% CI: 1.51-3.88 HCV HCV HCV HCV Omland et al, J Hepatol 2010;53:36-42

Survival Outcomes in Patients with Advanced Hepatic Fibrosis Due to HCV Van der Meer JAMA 2012;308:2584-93

Rates of Cirrhosis Regression According to the METAVIR Scoring System 100 Metavir 80 F4 TIENTS (%) F3 60 15 15 NUMBER OF PAT F2 F2 F1 40 F0 14 20 Cirrhosis Regression in 7 23 (61%) Patients 38 2 0 PRE-TREATMENT POST-TREATMENT D’Ambrosio R et al Hepatology 2012, 56(2):532-43

Extrahepatic Clinical Benefits of a SVR in Patients with Chronic Hepatitis C Clinical Event Number/Total Patients Reference SVR (+) SVR (-) Diabetes 26/1167 (2.2%) 117/1175 (9.9%) Arase et al 2009 Malignant lymphoma 0/2161 (0%) 25/1048 (12.6%) Kawamura et al 2007 Improved Neurocognitive 8/8 100% 0/6 0% Byrnes et al 2012 Functions* * Improved Brain Metabolism: basal ganglia Cho/Cr and ml/Cr ratios

Antiviral Treatment For HCV Is Associated With Improved Renal And Cardiovascular Outcomes In Diabetic Patients End-stage renal disease (3 cohorts) Ischemic stroke (3 cohorts) Hsu et al, Hepatology in press

SVR to IFN- α Is Associated with Improved Outcome in HCV Related Cirrhosis: A Retrospective Study in Italy Strata No. Patients Person-yrs No. Event Rate/100 Person- Rate Ratio yrs (95% CI) (95% CI) Liver-related complications Non-SVR 759 5,703 107 1.88 (1.54-2.27) n.a. SVR 124 1,061 0 0 (0-0.35) HCC non-SVR 759 5,805 122 2.10 (1.75-2.51) 3.12 (1.42-6.86) SVR 124 1,055 7 0.66 (0.27-1.87) Liver-related mortality non-SVR 728 5,781 83 1.44 (0.14-1.78) 7.59 (1.84-31.29) SVR 120 1,019 2 0.19 (0.02-0.71) Non liver-related mortality non-SVR 759 6,004 31 0.52 (0.35-0.73) 1.28 (0.44-3.68) SVR 124 1,077 4 0.37 (0.1-0.96) Bruno S et al Hepatology 2007;45:579-587

A Key Period For the Treatment of HCV (+)RNA 2. release and 3. IRES mediated uncoating translation 1. Binding and 4. polyprotein internalisation processing 6. replication 7. assembly and release (+)RNA (-)RNA Endoplasmic reticulum 5. membraneous web formation adapted from Moradpour et al., Nat Rev Microbiol 2007;5:453-63 Aghemo A et al, Nat Rev Gastroenterol Hepatol 2010 ;7(9):485-94

The First Class of Protease Inhibitors p7 NS4 C E1 E2 NS3 NS5A NS5B NS2 A B The NS3 serine protease and a cofactor NS4A allow for post-translational cleavage and proteolysis of the polyprotein to release NS5A Linear covalent peptidomimetic inhibitors of the NS3/4A complex Telaprevir Boceprevir O O O O H N NH 2 O H N H N HN H N N HN N N O N O O O H O O N

New DAAs for anti-HCV Treatment NS3 1° wave Resistance Can’t be used as monotherapy, require PegIFN and Rbv profile Pan-genotypic Effective only against HCV-1 genotype efficacy Efficacy Low SVR rates in some patients groups Adverse events Poor safety in patients with advanced disease Good Average Unfavorable

When Overall Antiviral Activity is Inadequate Resistant Variants May Be Selected Anti Anti- -HCV HCV drug e.g. drug e.g. NS3/4A NS3/4A Viral Load Viral Load protease inhibitor protease inhibitor HCV RNA V HCV RNA V HCV RNA HCV RNA detection limit detection limit Virus sensitive to small molecule Virus sensitive to small molecule Time Time Virus resistant to protease inhibitor Virus resistant to protease inhibitor

The Crucial Role of PegIFN and Rbv as The Backbone of DAAs PegIFNalfa PegIFNalfa Anti Anti- -HCV HCV drug e.g. drug e.g. NS3/4A NS3/4A protease inhibitor protease inhibitor Viral Load Viral Load Ribavirin Ribavirin HCV RNA V HCV RNA V HCV RNA HCV RNA detection limit detection limit Virus sensitive to small molecule Virus sensitive to small molecule Time Time Virus resistant to protease inhibitor Virus resistant to protease inhibitor

Chance for Cure in HCV 1: Dual vs. Triple Therapy A Systematic Review Patients Dual Triple ∆ Pts # SVR Pts # SVR Previously untreated 1545 39% 1634 68.5% <2-fold Relapsers/Partial Resp. 539 26% 719 73% 3-fold Nonresponders 255 7.5% 386 44% 6-fold Jurchis AR et al. EASL 2012, Poster 1123 (S442)

Telaprevir & Boceprevir in Cirrhotic Naïve Patients Boceprevir Boceprevir Telaprevir Telaprevir 100 78 80 67 62 (%) 60 52 SVR ( 40 20 226/290 45/73 211/313 22/42 0 F0/F2 F3/F4 F0/F2 F3/F4 Jacobson IM, et al. NEJM 2011,364:2405-16 Poordad F, et al. N Engl J Med 2011;364:1195–206

SVR Rates in Treatment Experienced Patients According to Previous Response Telaprevir Telaprevir Boceprevir Boceprevir REALIZE REALIZE RESPOND-2 RESPOND-2 100 Relapsers Relapsers 86% Partial 80 Partial Responders Responders 72% 72% 60 SVR (%) Null 57% Responders 46% 40 31% 20 0 Bacon BR et al. N Engl J Med 2011;364:1207–17 Zeuzem S . et al. NEJM 2011;364:2417-28

SVR by Fibrosis Stage and Prior Response to Peg-IFN/RBV Prior Prior partial Prior null relapsers responders responders 100 86% 85% 80 72% 60 %) SVR (% 42% 41% 40 25% 20 144/167 101/119 34/47 21/50 24/59 22/88 0 F0/F2 F3/F4 F0/F2 F0/F2 F3/F4 F3/F4 Zeuzem S, et al. J Hepatol 2011;54(Suppl. 1):S3

Anaemia & Rash Adverse Events: The Telaprevir EAP Grade 1: Hb 10.0 – 10.9 g/dL; decrease 2.5 – 3.4 g/dL e of patients (%) Grade 2: Hb 9.0 – 9.9 g/dL; decrease 3.5 – 4.4 g/dL Grade 3: Hb 7.0 – 8.9 g/dL; decrease >4.5 g/dL Grade 4: Hb <7.0 g/dL Percentage 59% 42% Colombo M et al, Gut in press

CUPIC baseline characteristics: F4 treatment-experienced patients TVR CUPIC 1 REALIZE F4 2 BOC CUPIC 1 RESPOND 2 3 (BOC44/PR48) Baseline characteristic, % F0–F4 N=292 N=169* N=205 N=161 Male 68 75 68 70 Mean/median age, years (range) 57.2 (27–83) 54 (24–68) 56.9 (34–81) 52.3 F4 100 100 100 14 HCV genotype 1 subtype 1a 34 57 40 60 1b 54 42 50 38 HCV RNA ≥800,000 IU/mL 62 89 131 (64) 88 Hb level, g/dL (range) 14.6 ( 9.0 –19.7) 15.6 ( 12.3 –18.9) 14.8 ( 9.7 –18.4) - Platelets, /mm 3 (range) 88% >150,000 167,000 152,000 146,000 ( 18,000 –604,000) ( 33,900 –346,000) ( 88,000 –425,000) Serum albumin, g/L (range) 40.1 ( 20.7 –52.0) - 40.4 ( 27.0 –50.3) - Total bilirubin, µmol/L (range) 15.4 (4.0– 73.5 ) - 15.0 (4.0– 78.0 ) - Esophageal varices 33 excluded 40 - Exclusion criteria REALIZE 33 - 29 - RESPOND 2 46 40 1. Hézode C, et al. J Hepatol. 2013;59:434–41 2. Pol S, et al. AASLD 2011; Abstract 31 *All arms (TVR arms + control arm) 3. Bacon B, et al. N Engl J Med 2011;364:1207–17

CUPIC Week 60 analysis: safety overview TVR CUPIC BOC CUPIC Outcomes, % N=299 N=205 Serious adverse event 53.8 44.3 Premature discontinuations 23.8 17.5 due to serious adverse events Death, n (%) 8 (2.7) 3 (1.4) Infections (grade 3/4) 9.7 2.4 EPO use 57.0 62.6 Transfusion 17.7 11.8 RBV dose reduction 27.8 23.6 Hézode C, et al. Unpublished data