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Optimizing Current Therapies & Future Perspectives for HCV Etienne Bouchaud Pr Tarik Asselah (MD, PhD) Service d’Hépatologie & INSERM UMR 1149, Hôpital Beaujon, Clichy, France. Disclosures – Advisory Board/Speaker Bureau member and investigator for: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and Roche We still have a dream (back to 2011) Martin Luther King J (1963, Washington) Where we go : The Future (back to 2011) Ten Commandments for the Magic Drug 1 HIGH EFFICACY 2 LOW RESISTANCE (high genetic barrier) 3 PAN-GENOTYPIC ACTIVITY 7 SHORT DURATION 8 FAVORABLE SAFETY PROFILE 9 ONCE A DAY (Good pharmacokinetic) 10 ORAL REGIMEN (IFN free) 11 FEW DRUG-DRUG INTERRACTION 12 AVAILABLE FOR (ELD), CIRRHOSIS and HIV-HCV 19 LOW PRICE (access program) HCV ERADICATION WORLWIDE Asselah et al. Direct acting antivirals for the treatment of chronic hepatitis C: One pill a day for tomorrow. Liver Int 2012;32 Suppl 1:88-102. The goal of this lecture will be to summarize results obtained with recently approved oral DAAs combinations for HCV treatment to discuss future perspectives. Optimizing Current Therapies & Future Perspectives for HCV Introduction (Direct-Acting Antivirals) Recently approved treatment – Ledipasvir/Sofosbuvir – Paritaprevir/Ombitasvir/Dasabuvir – Optimization (simplification) Available soon - Grazoprevir/elbasvir - Velpatasvir/Ledipasvir - AbbVie 2nd Generation Perspectives – Shorten treatment duration – Future Challenges (ELD, RAVs, DDI….) Direct-acting antivirals (DAAs) 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease RNA Capsid glycoproteins RNA helicase Cofactors polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors « …previr » « ….asvir » « …..buvir » Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir Velpatasvir (GS-5816) Sofosbuvir Dasabuvir Paritaprevir Ombitasvir MK 3682 GS-9669 ABT 493 ABT 530 ACH-3422 MK-8876 Grazoprevir Elbasvir ALS-335 GS-9857 MK-8408 Sovaprevir Samatasvir ACH-2684 Odalasvir (ACH-3102) Asselah et al. Liver Int 2016. Direct-Acting Antivirals: Mode of Action Nucleotide Non- NS5A Protease NS5B nucleoside replication inhibitors inhibitors NS5B complex inhibitors inhibitors Gilead Sofosbuvir GS-9669 Ledipasvir GS-9857 Velpatasvir AbbVie Dasabuvir Ombitasvir Paritaprevir/r ABT-530 ABT-493 Merck MK-3682 MK-8876 Elbasvir Boceprevir (MSD) MK-8408 Grazoprevir Samatasvir Janssen/ ACH-3422 Odalasvir Simeprevir Achilleon AL-335 (ACH-3102) Sovaprevir Optimizing Current Therapies & Future Perspectives for HCV Introduction (Direct-Acting Antivirals) Recently approved treatment – Ledipasvir/Sofosbuvir – Paritaprevir/Ombitasvir/Dasabuvir – Optimization (simplification) Available soon - Grazoprevir/elbasvir - Velpatasvir/Ledipasvir - AbbVie 2nd Generation Perspectives – Shorten treatment duration – Future Challenges Sofosbuvir/ledipasvir LDV/SOF LDV/SOF+RBV 99 97 98 99 94 93 96 94 96 99 99 100 80 ) % 60 ( 2 1 R 40 V S 20 210/ 211/ 212/ 215/ 202/ 201/ 208/ 102/ 107/ 108/ 110/ 213* 217 217 217 215 216 216 109 111 109 111 0 12 Weeks 24 Weeks 8 Weeks 12 Weeks 12 Weeks 24 Weeks ION-1 ION-3 ION-2 GT 1 treatment-naïve GT 1 treatment-naïve GT 1 treatment-experienced including cirrhotics non-cirrhotic including cirrhotics and PI failures Afdhal et al. N Engl J Med 2014; 370: 1889–98. Afdhal et al. N Engl J Med 2014; 370: 1483–93. Kowdley et al. N Engl J Med 2014; 370: 1879–88. Sofosbuvir/ledipasvir Treatment Status Cirrhosis Status Duration (Wks) ITT SVR 8 94.0% Non-Cirrhotic 12 95.4% Treatment Naïve 12 94.1% Cirrhotic 24 93.9% 12 95.4% Non-Cirrhotic Treatment 24 98.9% Experienced 12 86.4% Cirrhotic 24 100.0% Gilead Sciences Ltd. Harvoni (ledipasvir/sofosbuvir), Summary of Product Characteristics, November 2014. Paritaprevir/Ombitasvir/Dasabuvir GT1a-infected, non-cirrhotic patients GT1b-infected, non-cirrhotic patients SAPPHIRE-I, -II, PEARL-IV SAPPHIRE-I, -II, PEARL-II, -III 3D + RBV 3D 100 100 100 100 100 100 100 96 96 94 95 100 80 80 ) ) % 60 % 60 ( ( 2 2 1 1 R R V 40 V 40 S S 20 20 n 569 403 47 36 83 n 301 210 33 26 32 N 593 420 50 36 87 N 301 210 33 26 32 0 0 Overall Naive Relapse Prior Prior null Overall Naive Relapse Prior Prior null partial partial Everson et al. Hepatology 2014; 60 S: 239–240A. Colombo et al. Hepatology 2014; 60 S: 1131A. Paritaprevir/Ombitasvir/Dasabuvir GT1a-infected, cirrhotic patients GT1b-infected, cirrhotic patients TURQUOISE-II TURQUOISE-II 12 weeks 24 weeks 100 100 100 99 100 100 100 100 100 100 100 100 100 100 95 92 95 93 93 89 86 80 80 80 ) ) % % ( 60 ( 60 2 2 1 1 R R V V S 40 S 40 20 20 n 124 115 61 53 14 13 11 10 40 39 n 67 51 22 18 14 10 6 3 25 20 N 140 121 66 56 15 13 11 10 50 42 N 68 51 22 18 14 10 7 3 25 20 0 0 Overall Naive Relapse Prior Prior null Overall Naive Relapse Prior Prior null partial partial Everson et al. Hepatology 2014; 60 S: 239–240A. Colombo et al. Hepatology 2014; 60 S: 1131A. Genotype 1: High SVR rates for treatment-naïve patients in clinical trials These studies are not head-to-head comparison Pearl-IV ION-1 ION-3 Pearl-III Optimist-1 Study-040 Sapphire-1 120% with RBV without RBV 99% 99% 99% 99% P<0.006 100% 100% 100% 97% 98% 95% 95% 95% 100% 94%93% 90% P<0.05 85% 80% 60% 40% 20% 0% 214 217 217 217 215 216 216 209 210 202 420 115 103 41 41 14 15 3D, peritaprevir/ritonavir + ombitasvir + dasabuvir; ASV, asunaprevir; DCV, daclatasvir; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response. Afdhal N, et al. N Engl J Med 2014;370:1483–1493, Kowdley KV et al. N Engl J Med 2014; 370: 1879-88, Ferenci P et al. N Engl J Med 2014; 370: 1983-92, Feld JJ. N Engl J Med 2014; 370: 1594-1603, Everson GT et al. AASLD 2014: abst 53, Kwo P et al. EASL 2015: abst LB 14, Sulkowski et al. N Engl J Med 2014;370:211–21. Optimization, Simplification Sofosbuvir/Ledipasvir : Shortening treatment durations Patients Population Treatment Duration Genotype 1, Sofosbuvir/Ledipasvir 8 weeks without cirrhosis Optimization, Simplification Sofosbuvir/Ledipasvir : Shortening treatment durations Patients Population Treatment Duration Genotype 1, Sofosbuvir/Ledipasvir 8 weeks without cirrhosis Genotype 4, Sofosbuvir/Ledipasvir 8 weeks without cirrhosis Asselah et al. Liver Int 2016. Optimization, Simplification Paritaprevir based regimen : Shortening treatment duration or avoiding ribavirin Patients Population Treatment Duration Genotype 1b, Viekira Pak; (Viekirax + Exviera) 8 weeks without cirrhosis Genotype 1b, Viekira Pak; (Viekirax + Exviera) 12 weeks with compensated cirrhosis Optimization, Simplification Paritaprevir based regimen : Shortening treatment duration or avoiding ribavirin Patients Population Treatment Duration Genotype 1b, Viekira Pak; (Viekirax + Exviera) 8 weeks without cirrhosis Genotype 1b, Viekira Pak; (Viekirax + Exviera) 12 weeks with compensated cirrhosis Genotype 4, Viekirax (Technivie) 12 weeks without cirrhosis Genotype 4, Viekirax + ribavirine 12 weeks with compensated cirrhosis Asselah et al. Liver Int 2016. Optimizing Current Therapies & Future Perspectives for HCV Introduction (Direct-Acting Antivirals) Recently approved treatment – Ledipasvir/Sofosbuvir – Paritaprevir/Ombitasvir/Dasabuvir – Optimization (simplification) Available soon - Grazoprevir/elbasvir - Velpatasvir/Ledipasvir - AbbVie 2nd Generation Perspectives – Shorten treatment duration – Future Challenges (ELD, RAVs, DDI….) Grazoprevir/elbasvir GT-1,4, 6 compensated cirrhotic patients (402) Treatment Naive Treatment Experienced 97.8 93.9 100 100 90.3 88.9 91.4 75 % , s t 50 n e ti a P 25 135 28 48 74 46 49 138 31 54 81 49 49 0 12 weeks 12 weeks 16 or 18 weeks Jacobson I et al. AASLD 2015, Abs. 42 Grazoprevir/elbasvir Chronic Kidney Disease (CKD) stage 4/5 GZR/EBR 12 weeks 99% 94% 100 ) % ( 75 , s t n e 50 t a P 25 115/116 115/122 0 Modified Full Analysis Set Full Analysis Set Roth et al. Lancet, 2015 Grazoprevir/elbasvir People Who Inject Drugs (PWID) 95% 92% 99% 100% 80% 100% 75% % , s t n 50% e i t a P 25% 299/316 144/157 129/131 18/18 8/10 0% All Patients GT1a GT1b GT4 GT6 Zeuzem et al. Ann Intern Med 2015; 163: 1–13. Velpatasvir/Sofosbuvir SOF/VEL SOF+RBV SOF/VEL + RBV 99 98 100 100 100 99 100 97 94 95 94 86 80 83 80 ) % ( 60 2 1 R V 40 S 20 618/ 323/ 104/ 116/ 34/ 41/ 133/ 124/ 264/ 221/ 75/ 82/ 77/ 624 328 104 116 35 41 134 132 277 275 90 87 90 0 Overall GT 1 GT 2 GT 4 GT 5 GT 6 12 Weeks 12 24 12 Weeks 24 Weeks 12 Weeks Weeks Weeks ASTRAL-1 ASTRAL-2 ASTRAL-3 ASTRAL-4 (GT 1, 2, 4‒6) (GT 2) (GT 3) (GT 1‒6 CTP-B Cirrhosis) Feld et al. N Engl J Med 2015. Foster et al. N Engl J Med 2015. ABT-493/ABT-530 GT-1 GT-2 GT-3 97 100 96 100 100 93 93 94 83 100 100 100 ) 80 ) 80 ) 80 % % % ( ( ( s s s t t t n n n e 60 e 60 e 60 ti ti ti a a a p p p , , , 2 2 2 1 1 1 40 40 40 R R R V V V S S S 20 20 20 38 40 24 24 25 28 28 29 25 39 40 25 24 25 29 30 30 28 0 0 0 ABT-493 200 mg 200 mg 300 mg 200 mg 200 mg 300 mg 200 mg 200 mg 200 mg ABT-530 40 mg 120 mg 120 mg 120 mg 120 mg 120 mg 120 mg 120 mg 40 mg RBV 1000-1200 mg RBV Poordad F et al.
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    Recent advances in clinical practice Hepatitis C virus treatment in the real world: optimising treatment and access to therapies 1 2 3 4 Editor’s choice Fabien Zoulim, T Jake Liang, Alexander L Gerbes, Alessio Aghemo, Scan to access more 5,6,7,8 9 10 11 free content Sylvie Deuffic-Burban, Geoffrey Dusheiko, Michael W Fried, Stanislas Pol, Jürgen Kurt Rockstroh,12 Norah A Terrault,13 Stefan Wiktor14 For numbered affiliations see ABSTRACT treatments—how can we improve access to diagno- end of article. Chronic HCV infections represent a major worldwide sis and treatment for those patients who need them Correspondence to public health problem and are responsible for a large most? Professor Fabien Zoulim, proportion of liver related deaths, mostly because of Gut brought together some of the leading global Université Lyon 1, Cancer HCV-associated hepatocellular carcinoma and cirrhosis. experts in HCV to discuss these questions and Research Center of Lyon The treatment of HCV has undergone a rapid and point a way forward. The round table, held during (CRCL), INSERM U1052, spectacular revolution. In the past 5 years, the launch of the European Association for the Study of the Hospices Civils de Lyon 69003, ’ France; direct acting antiviral drugs has seen sustained Liver s International Liver Congress 2015, brought [email protected] virological response rates reach 90% and above for clarity to some of these issues and looked into the many patient groups. The new treatments are effective, future pipeline of HCV treatment. This article aims Received 21 July 2015 well tolerated, allow for shorter treatment regimens and to summarise that shared knowledge.
  • Direct-Acting Antivirals with Excellent Efficacy and Favourable Safety, Represent a Unique Opportunity to Achieve HCV Elimination

    Direct-Acting Antivirals with Excellent Efficacy and Favourable Safety, Represent a Unique Opportunity to Achieve HCV Elimination

    The French and European Approach Towards Hepatitis C Virus Elimination HEPDART 2017 USA December 3rd, 2017 Tarik Asselah (MD, PhD) Professor of Medicine Hepatology, Chief INSERM UMR 1149, Hôpital Beaujon, Clichy, France. Disclosures • Employee of Paris Public University Hospitals (AP-H P, Beaujon’s Hospital) and University of Paris • Principal investigator for research grants : Funds paid to Hospital (AP-HP) • Consultant, expert and speaker for: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp Dohme, Roche. • Grants from : ANR, CNRS , INSERM , University of Paris, ANRS 2 The French and European Approach Towards Hepatitis C Virus Elimination The goal of this lecture will be to present the situation of HCV in Europe and in France. Direct-acting antivirals with excellent efficacy and favourable safety, represent a unique opportunity to achieve HCV elimination. We will discuss the European & French approach towards Hepatitis Programs and to identify models to achieve Elimination. The French and European Approach Towards Hepatitis C Virus Elimination 1 Great Drugs (Direct-acting antivirals) 2 Epidemiology : Europe & France 3 HCV management : Europe & France 4 Remaining Challenges 5 Take home messages Direct-acting antivirals : a Revolution 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease RNA Capsid glycoproteins RNA helicase Cofactors polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors « …previr » « ….asvir » « …..buvir » Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir Velpatasvir (GS-5816) Sofosbuvir Dasabuvir Paritaprevir Ombitasvir MK 3682 GS-9669 Glecaprevir Pibrentasvir ACH-3422 MK-8876 Grazoprevir Elbasvir ALS-335 Voxilaprevir MK-8408 Sovaprevir Samatasvir ACH-2684 Odalasvir (ACH-3102) Asselah et al.
  • A Randomized, Double-Blind, Multiple-Dose Study of the Pan-Genotypic NS5A Inhibitor Samatasvir in Patients Infected with Hepatitis C Virus Genotype 1, 2, 3 Or 4

    A Randomized, Double-Blind, Multiple-Dose Study of the Pan-Genotypic NS5A Inhibitor Samatasvir in Patients Infected with Hepatitis C Virus Genotype 1, 2, 3 Or 4

    Accepted Manuscript A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4 Bradley Vince, John M. Hill, Eric J. Lawitz, William O’Riordan, Lynn R. Webster, Daniel M. Gruener, Ricky S. Mofsen, Abel Murillo, Eileen Donovan, Jie Chen, Joseph F. McCarville, John Z. Sullivan-Bólyai, Douglas Mayers, Xiao-Jian Zhou PII: S0168-8278(14)00014-2 DOI: http://dx.doi.org/10.1016/j.jhep.2014.01.003 Reference: JHEPAT 4997 To appear in: Journal of Hepatology Received Date: 8 October 2013 Revised Date: 29 December 2013 Accepted Date: 6 January 2014 Please cite this article as: Vince, B., Hill, J.M., Lawitz, E.J., O’Riordan, W., Webster, L.R., Gruener, D.M., Mofsen, R.S., Murillo, A., Donovan, E., Chen, J., McCarville, J.F., Sullivan-Bólyai, J.Z., Mayers, D., Zhou, X-J., A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep. 2014.01.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.