UPDATE SULLE TERAPIE FARMACOLOGICHE NELL’INFEZIONE DA HCV Giorgio Barbarini Già responsabile Unità Semplice “Diagnosi e terapia delle Malattie Infettive correlate alla Tossicodipendenza” DIPARTIMENTO MALATTIE INFETTIVE E TROPICALI April 21, 1989 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) 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 Distribution of HCV in the EU Viremic prevalence 0.64% Total viremic pool 3,238,000 New yearly infections 57,900 (plus ~30,000 from immigration) Lancet Gastroenterol Hepatol 2017;2:325-336 The European Union HCV Collaborators: Lancet Gastroenterol Hepatol 2017; 2: 325-36. HCV CHRONIC INFECTION CHRONIC Infection CIRRHOSI HCC HEPATITIS S Asymtomatic Symptomatic COMORBILITA’ ATTRIBUITE AD HCV E GRADO DI ASSOCIAZIONE OMORBILITA’ CVD ESKD Cancer HCV ERADICATION IS ASSOCIATED WITH A SIGNIFICANT REDUCTION IN NON-HEPATIC MORTALITY Lifecycle of the Hepatitis C Virus Release 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 intoreticulum 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!!!! ° Structural and nonstructural proteins contribute to different processes in the viral life cycle 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 Ombitasvir Beclabuvir Simeprevir AL-335 Velpatasvir Vedroprevir Odalasvir ACH-3422 Asunaprevir Radalbuvir Ravidasvir AL-516 Paritaprevir TegobuvirGS- 9669 Grazoprevir Pibrentasvir IDX- 459 Vaniprevir Samatasvir MK- 8876 Sovaprevir Elbasvir TMC-055/r Voxilaprevir Ruzasvir Updated to 2018 April 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 Antivirals Current 100 Peginterferon 2013 2011 90+ 95+ Ribavirin 80 Standard Interferon 2001 70+ 1998 60 55 1991 42 39 40 34 20 16 6 0 IFN IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/ DAA + All–Oral 6 Mos 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. 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 Hepatitis C is an INFECTIOUS Virus: Treatment as Prevention People who Sex between men inJect drugs who are HIV- account for the maJority of new cases Risk of positive increases the risk of of HCV in developed transmission countries[4] from mother contracting HCV[3] Infection in to child is low[2] monogamous heterosexual couples is rare[1] 1. Terrault NA, et al. Hepatology. 2013;57:881-899. 2. Thomas SL, et al. Int J Epidemiol. 1998;27:108-117. 3. Larsen C, et al. PLoS One. 2011;6:1-9. 4. Shepard CW, et al. Lancet Infect Dis. 2005;5:558-567. Contribution of IDU and HCV to the risk of death 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]. Criterio 8: Epatite cronica con fibrosi METAVIR F0-F1 (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]. Criterio 9: Operatori sanitari infetti. Criterio 10: Epatite cronica o cirrosi epatica in paziente con insufficienza renale cronica in trattamento emodialitico. Criterio 11: Epatite cronica nel paziente in lista d'attesa per trapianto di organo solido (non fegato) o di midollo. 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).” EASL 2018 HCV Treatment Guidelines ° Recommendations for treatment-naive patients and patients previously treated with pegIFN/RBV ± SOF or SOF + RBV, ± compensated cirrhosis HCV SOF/VE GLE/PI SOF/VE LDV/SO EBR/GZ OBV/PT Genoty L B L/ VOX F R V/ RTV pe + DSV 1a Yes Yes No* Yes† Yes‡ No 1b Yes Yes No* Yes Yes Yes 2 Yes Yes No* No No No 3 Yesǁ Yes Yes§ No No No 4 Yes Yes No* Yes† Yes# No 5 or 6 Yes Yes No* Yes† No No *Triple combination effective but not needed because double combinations comparably effective. ‡Tx naive or tx experienced without cirrhosis or with compensated cirrhosis and HCV RNA ≤ 800,000 IU/mL. ǁTx naive or tx experienced without cirrhosis. §Tx naive or tx experienced with compensated cirrhosis. #Treatment naive without cirrhosis or with compensated cirrhosis and HCV RNA ≤ 800,000 IU/mL. EASL HCV Guidelines. 2018. In press. Regimi terapeutici IFN-free approvati e rimborsati in Italia per la terapia anti HCV GT Glecaprevir + Pibrentasvir All Sofosbuvir + Velpatasvir (± RBV) All Grazoprevir + Elbasvir (± RBV) 1, 4 Sofosbuvir + Velpatasvir + Voxilaprevir 1 Sofosbuvir + Velpatasvir + Voxilaprevir All 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 Characteristics of PWID Snapshot of PWID Male Single Poor quality of life Limited access to healthcare Homeless or living in temporary accommodation Alcohol consumption (shelters, prison) Use of multiple substances Poorly educated (secondary education or less) HIV and/or HBV coinfection ▪ Psychiatric disorders that are common among PWID include: − Anxiety − Bipolar disorder − Depression − Post-traumatic stress − Schizophrenia Bamvita JM, et al.