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Direct-Acting Antivirals 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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