NUOVE OPPORTUNITÀ TERAPEUTICHE IN EPATITE DA HCV FRANCESCO ARCADU U.O. MEDICINA GENERALE E GASTROENTEROLOGIA P.O. SAN FRANCESCO ASL 3 - NUORO

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1 NUOVE OPPORTUNITÀ TERAPEUTICHE IN EPATITE DA HCV FRANCESCO ARCADU U.O. MEDICINA GENERALE E GASTROENTEROLOGIA P.O. SAN FRANCESCO ASL 3 - NUORO

2 Why Treat Chronic Hepatitis C THE DISEASE Common, chronic, and potentially progressive Complications are becoming more common Liver failure, HCC THE TREATMENT Viral cure, or SVR, is achievable SVR associated with histologic improvement and gradual regression of fibrosis SVR reduces risk for liver failure and HCC, improves survival Kanwal F et al. Gastroenterology 2011; 140: Maylin et al. Gastroenterology 2008, 3:821-9 Asselah et al. Liver Int. 2015;35 S1:56-64

3 SVR 24 = SVR 12 = Cure The primary goal of HCV therapy is to cure the infection A sustained virological response - SVR - is defined as undetectable HCV RNA 12 weeks (SVR12) or 24 weeks (SVR 24) after treatment completion The infection is cured in more than 99% of patients who achieve an SVR Swain MG, et al.. Gastroenterology 2010;139: Martinot-Peignoux et al.. Hepatology 2010;51:

4 SVR Associated With Reduced 5-Yr Risk of Death and HCC in All Populations SVR on IFN-based therapy was associated with substantial benefit vs no SVR 62% to 84% reduction in all-cause mortality 90% reduction in liver transplantatio 68% to 79% reduction in HCC 5-Yr Risk of All Cause Death by SVR SVR No SVR 5-Yr Risk of HCC by SVR Analysis included survival data from pts followed for average of 5 yrs Hill AM, et al. AASLD Abstract 44

5 Risposta alla terapia anti HCV (fino al 2013) RISPOSTA VIROLOGICA SOSTENUTA (SVR) Terapia basata su IFN/RBV e nel GT1 anche sui DAA di 1^ generazione (Telaprevir/Boceprovir)

6 SVR % The evolution of CHC therapy Virologic eradication is the goal 100 HCV therapeutic timeline PegIFN DAAs Standard IFN 1991 RBV IFN 6 mos IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos PegIFN/ RBV/ DAA DAA ± DAA ± RBV ± PegIFN Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, Adapted MD. from the US Foof and Drug Administration, Antiviral Drugs Advisory Cmmitee Meeting, , Silver Spring, MD

7 BF, maschio, 58 anni HCV prevalence, diagnosis and treatment rates in 2013 Dore G et al. J Viral Hepatitis 2014

8 BF, maschio, 58 anni Gaps in the achievement of effectiveness of HCV treatment in national VA practice Kramer et al, Journal of Hepatology 2012; 56:

9 PWID have a high willingness to receive HCV treatment PWID LIVING WITH HCV INFECTION

10 PWID have a high willingness to receive HCV treatment 80% OF PWID ARE WILLING TO RECEIVE HCV TREATMENT PWID LIVING WITH HCV INFECTION Doab A, Clinical Infectious Diseases Fischer B, et al. Presse Med Strathdee S, et al Clinical Infectious Diseases Grebely J, et al. Drug and Alcohol Dependence Alavi M, et al. Clinical Infectious Diseases 2013.

11 Treatment uptake among PWID is still low. 80% OF PWID ARE WILLING TO RECEIVE HCV TREATMENT 1-2% are treated each year PWID LIVING WITH HCV INFECTION Grebely J. J Viral Hepatitis Mehta S. J Community Health Iversen J, J Viral Hepatitis Alavi M. Liver International. 2014

12 The HCV Care Cascade Less than 10% of people with HCV have been cured Diagnosi Accesso Terapia SVR Should improve with IFN-free therapy but long way to go Yehia BR, Schranz AJ, Umscheid CA, Lo Re V III (2014) The Treatment Cascade for Chronic Hepatitis C Virus Infection in the United States: A Systematic Review and Meta-Analysis. PLoS ONE 9(7): e doi: /journal.pone

13 Efficacious treatments do not work if not given.. SVR in individuals SVR in the population Need for reinforcing HCV screening and access to therapy to amplify the control of the disease Thomas, DL Lancet 2010 Oct 30;376(9751):1441-2

14 Quanti HCV cronicamente infetti in Italia? 63 out of 353 Centers throughout Italy parteciped 33,433 patients were involved, 56% genotype 1 Combining these figure with NHS registries of HCV disease identification (016) the predicted number of known HCV patients are: 250,000 Monoinfected attending liver centers 30,000 HIV co-infected attending ID centres 25,000 Inmates 70,000 Under the care of GPs and legal migrants Overall 350,000 * Documento GdL Epatite C - AIFA-MinSal-ISS-SIMIT-AISF-EPAC-CNT Aprile 2014

15 Scenario 2014.quanti pazienti da trattare? * urgenti * entro 18 mesi * Documento GdL Epatite C - AIFA-MinSal-ISS-SIMIT-AISF-EPAC-CNT Aprile 2014

16 Con quali costi? * urgenti * entro 18 mesi * Documento GdL Epatite C - AIFA-MinSal-ISS-SIMIT-AISF-EPAC-CNT Aprile 2014

17 EASL & AASLD-IDSA Recommendations Indications to treatment All treatment-naïve and -experienced patients with compensated disease due to HCV should be considered for therapy (A1) Treatment is recommended for patients with chronic HCV infection (IA)

18 Treatment Benefits All Pts All Clinical Practice Guidelines emphasizes the potential benefits of and recommends treatment for all pts with HCV infection URGENT TREATMENT INITIATION RECOMMENDED FOR: Advanced fibrosis (Metavir F3) Compensated cirrhosis (Metavir F4) Liver transplantation Severe extrahepatic HCV

19 Treatment Benefits All Pts REDUCED HCV TRANSMISSION EXPECTED WITH TREATMENT OF: Women wishing to become pregnant Long-term hemodyalisis pts MSM with high-risk sexual practices Injection drug users Incarcerated persons

20 Requirements for HCV regimen Extremely high efficacy (>95%) Tolerability - IFN free Minimal toxicity High barrier to resistance Once daily oral dosing Pangenotypic No drug drug interactions Short duration (4-6 weeks) Affordable

21 Direct-Acting Antivirals (DAA) Farmaci che interferiscono su processi specifici nel ciclo di replicazione del virus attraverso una diretta interazione con una proteina virale o acido nucleico

22 HCV genome and polyprotein potential drug targets Protease Inhibitors.PREVIR Telaprevir Boceprevir Simeprevir Asunaprevir ABT Ritonavir Paritaprevir Sovaprevir Ombitasvir NS5A Inhibitors.ASVIR Daclatasvir Ledipasvir ABT-267 GS-5816 ACH-3102 Samatasvir MK-8742 GSK Polymerase Inhibitors.UVIR Schinazi R, Halfon P, Marcellin P, Asselah T. Liver Int 2014; 34 S1:69-78

23 Direct-Acting Antiviral Agents (DAAs) - Key Characteristics C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3 /4A Inhibitors (Protease inhibitor PI) High potency Limited genotypic coverage Low barrier to resistance Boc and Tel Simeprevir Paritaprevir NS5B Nucleos(t)ide Inhibitors (NI) Intermediate potency Pangenotypic coverage High barrier to resistance Sofosbuvir NS5A Inhibitors High potency Multi-genotypic coverage Low barrier to resistance Ledipasvir Ombitasvir Daclatasvir NS5B Non Nucleoside Inhibitors (NNI) Intermediate potency Limited genotypic coverage Low barrier to resistance Dasabuvir NS= Nonstructural Proteins

24 Agents and Regimens

25 HCV guidelines, recommendations & anti HCV drugs approval by International agencies EMA APPROVAL Sovaldi Olysio Daklinza Harvoni Viekirax Exviera EASL guidelines WHO guidelines EACS guidelines Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec AASLD recommendations 1 EASL recommendations AASLD recommendations 2 FDA APPROVAL Sovaldi & Olysio Harvoni Viekira Pack

26 Anti HCV drugs approval by International agencies European Medicines Agency (EMA) authorisations Sofosbuvir (Sovaldi ) 16/01/2014 Simeprevir (Olysio ) 14/05/2014 Daclatasvir (Daklinza ) 22/08/2014 Ledipasvir/Sofosbuvir (Harvoni ) 26/09/2014 Ombitasvir /Paritaprevir/Ritonavir (Viekirax ) 21/11/2014 Dasabuvir (Exviera ) 21/11/2014 Agenzia Italiana del Farmaco (AIFA) authorisations Sofosbuvir (Sovaldi ) 30/09/2014 Simeprevir (Olysio ) 23/02/2015

27 Comunicato n febbraio 2015 Epatite C: accordo AIFA e Gilead Sciences per la rimborsabilità di Harvoni Ufficio Stampa Agenzia Italiana del Farmaco - Dott.ssa Arianna Gasparini Tel ufficiostampaaifa@aifa.gov.it a.gasparini@aifa.gov.it

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29 Priorità in base all'urgenza clinica 7 criteri di eleggibilità AIFA Pazienti con cirrosi in classe di Child A o B e/o con HCC con risposta completa a terapie resettive chirurgiche o locoregionali non candidabili a trapianto epatico nei quali la malattia epatica sia determinante per la prognosi Recidiva di epatite dopo trapianto di fegato con fibrosi METAVIR 2 (o corrispondente Ishack) o fibrosante colestatica Epatite cronica con gravi manifestazioni extra-epatiche HCV correlate (sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative a cellule B) Criterio 1 Criterio 2 Criterio 3 Epatite cronica con fibrosi METAVIR F3 (o corrispondente Ishack) Criterio 4 In lista per trapianto di fegato con cirrosi MELD Criterio 5 Epatite cronica dopo trapianto di organo solido (non fegato) o di midollo con fibrosi METAVIR 2 (o corrispondente Ishack) Epatite cronica con fibrosi METAVIR F0-F2 (o corrispondente Ishack) (solo per Simeprevir) Criterio 6 Criterio 7

30 Regimens with the best cost/benefit Categorie Gt1 e 4 Gt2 Gt3 Cirrotici Child A/B controind. a P/R Non Responder SIM + SOF ± RBV SIM + SOF ± RBV SOF + RBV SOF + RBV SOF + RBV (24 w) oppure SOF + DACLA (compassionevole) Pazienti non cirrotici* appartenenti ai criteri 2,3,6 SOF + RBV + Peg-IFN oppure SIM + SOF ± RBV SOF + RBV SOF + RBV + Peg-IFN * Si ritiene che il criterio 4 non comprenda pazienti con diagnosi clinica di cirrosi

31 FDA-Approved All-Oral Regimens for GT1 *Not recommended per AASLD/IDSA guidance. 8-wk course can be considered in pts without cirrhosis with pretreatment HCV RNA < 6 million IU/mL. 12-wk course may be considered for some patients based on previous treatment history.

32 All-Oral Regimens for Other Populations *Up to 48 wks or until transplantation, whichever occurs first. Not FDA approved but recommended in AASLD/IDSA guidance. 24 wks of SOF/LDV if anemia or RBV intolerance; 24 wks of SOF/LDV + RBV (600 mg/day with increasing dose if tolerated) if prior SOF failure.

33 SVR rates >90% in genotype 1

34 AASLD/IDSA HCV Guidelines

35 Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: results SVR 12 by Regimen Duration and Treatment Experience 11/14 14/14 10/17 13/15 Treatment Naive Treatment Experienced Source: Ruane P, et al. 49 th EASL. April 2014: Abstract P1243

36 Liver Int Jan;35 Suppl 1:27-34 Optimal therapy in genotype 4 chronic hepatitis C: finally cured? Abdel-Razek W, Waked I. SVR 12 by Regimen Duration and Treatment Experience IFN-free combinations with paritaprevirombitasvir, SOF-ledipasvir, or DCVasunaprevir (ASV)-beclabuvir (BMS ) for 12 weeks or less with close to 100% cure rates will soon become the optimal therapy 11/14 14/14 10/17 13/15 Optimal therapy for patients with hepatitis C virus (HCV) genotype 4 (HCV- 4) infection is changing rapidly, and the possibility of a total cure is near.

37 Genotype 3 HCV: still difficult to treat? GT1, 4-6 GT2 GT3 Treatment naïve Treatment experienced Treatment naïve Treatment experienced I pazienti con cirrosi avevano significativamente meno probabilità di raggiungere SVR rispetto ai pazienti non cirrotici per tutti i genotipi studiati, e in particolare per il genotipo 3 Mangia A. et al AASLD 2013 Abstract 1115

38 Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3 ELECTRON 2: Results SOF-Experienced CTP Class B Treatment Naive SVR 12, by GT and Treatment Regimen Gane EJ, et al. 49 th EASL. 2014: Abstract O6

39 A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3 infected patients with cirrhosis is underway HEPATOLOGY 2015;00:

40 Patients With Compensated or Decompensated Cirrhosis are Candidates for IFN-free Regimens Phase 2 clinical trials with IFN-free regimens including cirrhotic patients. Afdhal N et al, EASL OC #68

41 Difficult to Treat Patients: Decompensated Cirrhosis and portal hypertension Phase 3 clinical trials with IFN-free regimens including cirrhotic patients. Afdhal N et al, EASL OC #68

42 Ledipasvir-Sofosbuvir + Ribavirin in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis): Preliminary Study Results 45/52 42/47 26/30 24/27 19/22 18/20 Treatment Naïve and Treatment Experienced Flamm SL, al. 65 th AASLD. 2014: Abstract 239

43 Therapeutic approaches of HCV infection in cirrhosis decompensated, in waiting list & after LT Flamm SL, al. 65 th AASLD. 2014: Abstract 239. Afdhal N, et al. ILC 2014, Abstract #O68

44 Feedback from the real-world: do HCV cure rates in real-life patient cohorts hold what clinical trials promised? HCV-TARGET & TRIO Data from two large observational databases demonstrate that: IFN-free regimens dominate the treatment landscape SOF-based regimens are effective in real-world settings Safety demonstrated in non-cirrhotic and cirrhotic patients Jensen D, et al. AASLD Abstract 45. Dieterich D, et al. AASLD Abstract 46

45 .in summary, after 2015 Source: Liver Int 2014 Blackwell

46 Where do we go from here??

47 Mild Severe Decomp HCV chronic disease spectrum Currently treated

48 IFN-free DAA will expand the pool of treatable patients We must strive to obtain appropriate and effective treatment for all patients Mild Severe Decomp HCV chronic disease spectrum The future treatment By enrolling new patients at the extreme of the spectrum By enforcing need for mass screening for HCV WHO. Guidelines on the screening, care and treatment of persons with hepatitis C infection. April 2014

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