L’UTILIZZO DEI DAAs NEI CONSUMATORI DI SOSTANZE : EFFICACIA E SICUREZZA Giorgio Barbarini Già responsabile Unità Semplice “Diagnosi e terapia delle Malattie Infettive correlate alla Tossicodipendenza” DIPARTIMENTO MALATTIE INFETTIVE E TROPICALI Disclosures I have received funding in the past 2 years for membership of Advisory Boards, for membership of speaker panels and for support for travel to conferences from the following companies: Abbvie Gilead Sciences April 21, 1989 Seroprevalence of Hepatitis C: 150 to 200 Million Worldwide Eastern Europe 10 M Western Pacific 60 M United States Western Europe 5M 5 M Southeast Asia Highest Prevalence: 30-35 M Egypt-4M Americas (45% adults >40y) 12-15 M Africa 30-40M Australia .2 M 1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28. 2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44. 3. Fontanet A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html Hepatitis C is the silent global epidemic of the 21st Century 2015 • ~72 million people with viraemic HCV • ~8.1 million people with HCV-related liver cirrhosis • ~261,000 people with HCV-related HCC • ~7000 HCV-related liver transplants • ~370,000 HCV liver-related deaths Viraemic prevalence 0.0–<0.6% 0.6–<0.8% 0.8–<1.3% 1.3–<2.9% 2.9–<6.7% Blach S, et al. Lancet Gastroenterol Hepatol 2017;2:161–76; The Polaris Observatory. Hepatitis C. Available at: http://polarisobservatory.org/polaris/hepC.htm (accessed April 2017) The Lancet Global Health – 23 October, 2017 • Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review. Louisa Degenhardt et al. • 179 of 206 countries or territories report IDU (31 new compared to 2008) • 15.6 million PWID worldwide – 17.8% HIV+ ( 2.77 million people ) – 52.3% HCV+ (8.2 million people) – 9% Hepatitis B surface antigen (HBsAg)+ – 83% mainly opioids – 33% mainly stimulants – 58% history of incarceration Proportion of HCV disease burden attributable to injecting drug use 1990 2013 Mean DALYs 1990 Population Mean DALYs Population attributable 2013 attributable factor factor Western 376,000 44% 705,000 64% Europe Eastern 73,000 32% 605,000 68% Europe Global 2,095,000 23% 7,046,000 38% Degenhardt L, et al. Lancet Infect Dis 2016;16:1385–98 © 2016 The Authors. Published by Elsevier Ltd. Lifecycle of the Hepatitis C Virus DifferentlyEntry from HIV and HBV: • HCV replication occursAssembly only in cytoplasm Golgi complex Fusion and Viral RNA uncoating • replication Endoplasmic Viral genome is no archived reticuluminto the NS5B genome ofNS5A infectedReplication cells NS3-NS4A complex ° Nonstructural proteins play RNA a key role in the replication NS4B and assembly of new virions Translation Processing This makes HCV curable!!!! 1. Asselah and Marcellin. Liver Int. 2011;31(suppl 1):68; 2. Scheel and Rice. Nat Med. 2013;19:837. Manns, von Hahn, Nat Rev Drug Discov 2013 Glecaprevir Sofosbuvir Telaprevir Ledipasvir Dasabuvir Boceprevir Daclatasvir Uprifosbuvir Beclabuvir Simeprevir Ombitasvir AL-335 Velpatasvir Vedroprevir ACH-3422 Odalasvir Asunaprevir Radalbuvir Ravidasvir AL-516 Paritaprevir TegobuvirGS- 9669 Grazoprevir Pibrentasvir IDX- 459 MK- 8876 Vaniprevir Samatasvir Sovaprevir Elbasvir TMC-055/r Voxilaprevir Ruzasvir Updated to 2018 September Nearly Everyone With HCV Can Now Be Treated Successfully • Very high SVR rates; therapies highly tolerable • All-oral therapy for almost every pt • Treatment generally just 12 wks All-Oral Direct- Therapy Acting Antiviral Current 100 Peginterferon 2013 s 90+ 98+ Standard Ribaviri 2011 80 Interferon n 2001 70+ 1998 60 55 1991 42 39 40 34 20 16 6 0 IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/ DAA + All–Oral IFN 6Mos 12 6 Mos 12 Mos 12 Mos RBV RBV + RBV ± DAA± Mos 12 Mos DAA PegIFN RBV Goals obtained by achieving Sustained Virological Response (SVR) ≈ cure • Reduce necroinflammation • Stop fibrosis progression • Prevent cirrhosis & complications • Prevent hepatocellular carcinoma • Reduce extra-hepatic manifestations • Increase survival • No AE Eradicate the virus (HCV clearance) Adapted by Schinazi & Asselah. From HCV to HBV cure. Liver Int. 2017;37 S1:73-80. Global Call for HCV Elimination Vision: “A world where viral hepatitis transmission is stopped and everyone has access to safe, affordable, and effective treatment and care” 2020 target: 3 million HCV infections treated Feasible by scaling up 6 key interventions to high coverage: Hepatitis B vaccination (including birth dose) Safe injection practices and safe blood 2030 Targets Harm reduction for injecting drug users 90% Diagnosed Safer sex (including condom promotion) 80% Treated Hepatitis B treatment 65% Reduced Mortality Hepatitis C cure WHO. Towards the elimination of hepatitis B and C by 2030. Draft WHO Global Hepatitis Strategy, 2016-2021. Potential benefits of treatment in PWID : Societal benefits and Individual benefits • Target therapy to those at greatest risk of transmitting infection (younger injectors or newer initiates to injecting) Grebely J, Dore GJ. Antiviral Res 2014;104:62–72 Treatment of HCV in PWID PWID populations included in clinical trials with DAAs Lifetime PWID OST OST and ongoing drug use Ongoing drug use ▪ PWID populations included in clinical trials with DAAs − Patients on OST (Phase 2 AbbVie trial; ION-1, 2 and 3, ASTRAL-1, 2 and 3) − Patients on stable OST, ongoing injection use permitted (C-EDGE CO-STAR) − Patients on and not on OST with ongoing injection use (SIMPLIFY) Lalezari J, et al. J Hepatol 2015;63:364–9; Grebely J, et al. Clin Infect Dis 2016;63:1405–11; Grebely J, et al. Clin Infect Dis 2016;63:1479–81; Dore G, et al. Ann Intern Med 2016;165:625–34; DAA: direct-acting antiviral agent; OST: opioid substitution therapy; Grebely J, et al. EASL 2017; Poster #FRI234 PWID: people who inject drugs Clinical Symptoms and Well-Being of OST Patients after SOF–Based Regimens: DHC-R ‡ Real-World Impact of SVR12 on PROs and Clinical Symptoms in OST Patients: DHC-R Clinical Symptoms 1230 24 19 19 No OST: 10 Baseline 8 Week 24 8 7 OST: 6 Baseline 6t 4 4 4 4 Week 24 Percen 4 3 2 2 22 22 22 2 2 2 2 2 1 1 1 1 1 0 0 00 0 0 00 0 0 0 0 0 00 00 0 0 0 00 0 0 0 0 In OST patients, a number of clinical symptoms had decreased compared to baseline, including fatigue, abdominal pain, and depression/depressive mood 26 Christensen S, INHSU 2017, Poster #92 German Hepatitis C – Registry (DHC-R) ‡ Real-World Effectiveness of SOF-Based Regimens in Patients with OST SVR rate by alcohol consumption (ITT) P=0.215 P=1.000 P=0.123 P=0.013 P=0.004 93 100 90 88 91 8892 88 84 85 82 ° High SVR rates were achieved in 80 OST and Non-OST patients 60 ° Alcohol consumption had no SVR (%) SVR 40 impact on SVR12 rates 20 380 42 45 14 335 28 2834 225 3225 267 421 50 53 16 368 34 3055 255 3488 305 0 Yes >40 g/day/men ≤40 g/day/men No Total >30g/day women ≤ 30g/day women SVR rate by cannabis consumption (ITT) P=0.420 P=0.016 P=0.004 93 100 88 8892 88 83 80 ° SVR rates were comparable in 60 patients with and without OST 40 ° Cannabis consumption had no SVR (%) SVR 20 82 34 3142 233 3325 267 impact on SVR12 rates 93 41 3394 264 3488 305 0 Yes No Total SOF-based therapies resulted in high SVR rates in OST and Non-OST patients. Consumption of alcohol and cannabis had no impact on SVR12 27 Günther, INHSU 2017, Poster #91 TraP HepC: 2-Yr Results From HCV Treatment as Prevention in PWID in Iceland ° Dramatic reduction in community viral load and HCV incidence between 2015-2017 at National Addiction Hospital – 53% reduction in new HCV infections – 72% reduction in HCV PCR positivity among PWID from 43% to 12% SVR12, % Treated Pts (N P = 518) Current IVD use 87 .0033 (last 6 mos) Tyrffingsson T, et al. EASL 2018. Abstract PS-095. Not currently 95 using IVD Homeless 74 .0005 Not homeless 94 Epatite C. Lorenzin: "Nuovi farmaci per tutti, nessuna selezione dei pazienti. Piano nazionale per eradicare la malattia : 80.000 trattati l’anno x 3 anni (1.500.000 E in bilancio).” Criteri AIFA da marzo 2017 Criterio 1: Pazienti con cirrosi in classe di Child A o B e/o con HCC con risposta completa a terapie resettive chirurgiche o loco-regionali non candidabili a trapianto epatico nei quali la malattia epatica sia determinante per la prognosi. Criterio 2: Epatite ricorrente HCV-RNA positiva del fegato trapiantato in paziente stabile clinicamente e con livelli ottimali di immunosoppressione. Criterio 3: Epatite cronica con gravi manifestazioni extra-epatiche HCV-correlate (sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative a cellule B, insufficienza renale). Criterio 4: Epatite cronica con fibrosi METAVIR F3 (o corrispondente Ishack). Criterio 5: In lista per trapianto di fegato con cirrosi MELD <25 e/o con HCC all'interno dei criteri di Milano con la possibilità di una attesa in lista di almeno 2 mesi. Criterio 6: Epatite cronica dopo trapianto di organo solido (non fegato) o di midollo in paziente stabile clinicamente e con livelli ottimali di immunosoppressione. Criterio 7: Epatite cronica con fibrosi METAVIR F2 (o corrispondente Ishack) e/o comorbilità a rischio di progressione del danno epatico [coinfezione HBV, coinfezione HIV, malattie croniche di fegato non virali, diabete mellito in trattamento farmacologico, obesità (body mass index ≥30 kg/m2), emoglobinopatie e coagulopatie congenite].