Guangdi Li, Erik De Clercq Current therapy for chronic hepatitis C: The role of direct-acting antivirals Guangdi Li, Erik De Clercq Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Our Highlights Interferon-based regimens were replaced by interferon-free regimens; Genotype-specific drugs evolved to drugs for all HCV genotypes; Therapies based upon multiple pills per day were simplified to a single pill per day; Drug potency increased from moderate (~60%) to high (>90%) levels of sustained virologic responses; Treatment durations were shortened from 48 to 12 or 8 weeks; Therapies could be administered orally regardless of prior treatment history and cirrhotic status. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Non-structural proteins HCV genome structure 5’ UTR 3’ UTR Core E1 E2 p7 NS2 NS3 NS4B NS5A NS5B NS4A 192 1 384 747 810 1027 1658 1712 1973 2421 3011 Structural proteins Non-structural proteins Three drug targets NS4A NS5A NS5B NS3 Simeprevir Daclatasvir Beclabuvir Sofosbuvir Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV drug combinations NS3/4A inhibitor Booster NS5B inhibitor Viekira PakTM ZepatierTM Epclusa® TechnivieTM Boceprevir Telaprevir Paritaprevir Grazoprevir Simeprevir Daclatasvir Ledipasvir Ombitasvir Elbasvir Velpatasvir Sofosbuvir Dasabuvir Ritonavir Vaniprevir Asunaprevir Harvoni® PegIFNα/RBV Voxilaprevir Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

FDA-approved HCV drugs Victrelis® and Incivek® were discontinued. Except for Technivie™, all the HCV therapies above could be applied to patients with cirrhosis. Sunvepra and Vanihep approved in Japan are not listed Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Boceprevir Mechanism of drug action Boceprevir can inhibit the enzymatic activity of NS3/4A. Njoroge et al., 2008 Author and date Primary ketoamide 4 Boceprevir Initial compound FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 www.virusface.com

HCV Drug name : Boceprevir Date approved : May 2011 www.virusface.com Efficacy of PegIFNa/RBV for 4 weeks + 200 mg boceprevir TID plus PegIFNa/RBV for 44 weeks Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Telaprevir Mechanism of drug action Telaprevir can inhibit the enzymatic activity of NS3/4A. Kwong et al., 2011 Author and date Telaprevir Tetraaldehyde peptide Initial compound FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 www.virusface.com

Efficacy of 1125 mg telaprevir BID plus PegIFNa/RBV HCV Drug name : Telaprevir www.virusface.com Date approved : May 2011 Efficacy of 1125 mg telaprevir BID plus PegIFNa/RBV for 12w + PegIFNa/RBV for 12w or 36w Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Sofosbuvir Mechanism of drug action Sofosbuvir binds to the catalytic site of NS5B and competes with incoming nucleoside triphosphates to interrupt the RNA synthesis. www.virusface.com 2’-F, 2’-C-methyluridine 5’-phosphoramidate Sofia et al., 2010 Author and date Sofosbuvir 2’-F, 2’-C-methylcytidine Initial compound FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Sofosbuvir Date approved : Dec. 2013 www.virusface.com Efficacy of 400 mg sofosbuvir QD + PegIFNa/RBV for 12w. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Efficacy of 400 mg sofosbuvir QD + ribavirin for 12 weeks. HCV Drug name : Sofosbuvir Date approved : Dec. 2013 www.virusface.com Efficacy of 400 mg sofosbuvir QD + ribavirin for 12 weeks. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Sofosbuvir Date approved : Dec. 2013 www.virusface.com Efficacy of 400 mg sofosbuvir QD + ribavirin for 24 weeks. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name :Simeprevir Mechanism of drug action Simeprevir can inhibit the enzymatic activity of NS3/4A. Rosenquist et al., 2014 Author and date Simeprevir Early Medivir peptidic inhibitor Initial compound FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 www.virusface.com

Efficacy of 150 mg simeprevir plus 400 mg HCV Drug name : Simeprevir Date approved : NOV. 2013 www.virusface.com Efficacy of 150 mg simeprevir plus 400 mg sofosbuvir QD for 12w. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Simeprevir Date approved : NOV. 2013 www.virusface.com Efficacy of 150 mg simeprevir QD plus PegIFNa/RBV for 12w þ PegIFNa/RBV for 12w. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Simeprevir Date approved : NOV. 2013 www.virusface.com Efficacy of 150 mg simeprevir QD plus PegIFNa/RBV for 12w + PegIFNa/RBV for 36w. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Compound 30 Ledipasvir HCV Drug name : Ledipasvir Link et al., 2014 Mechanism of drug action NS5A inhibitors (ledipasvir) not only block HCV RNA synthesis at the stage of membranous web biogenesis but also impair viral assembly by inhibiting the delivery of HCV genomes to assembly sites Link et al., 2014 Author and date Compound 30 Ledipasvir Initial compound FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 www.virusface.com

Efficacy of 90 mg ledipasvir +400 mg sofosbuvir , QD for 12 weeks. HCV Drug name : Ledipasvir Efficacy of 90 mg ledipasvir +400 mg sofosbuvir , QD for 12 weeks. Date approved : Oct. 2014 www.virusface.com Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Ledipasvir Date approved : Oct. 2014 www.virusface.com Efficacy of 90 mg ledipasvir + 400 mg sofosbuvir QD for 24 weeks , or with ribavirin for 12 weeks in phase 2 and 3 clinical trials. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Mechanism of drug action HCV Drug name : Dasabuvir Mechanism of drug action Non-nucleotide inhibitors (e.g. dasabuvir) bind to the allosteric binding pockets outside the NS5B catalytic site based on the non-competitive mechanisms of action that inhibit the RNA synthesis Liu et al., 2012 Author and date www.virusface.com Dasabuvir FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Dasabuvir Date approved : Dec. 2014 www.virusface.com Efficacy of 12.5 mg ombitasvir + 75 mg paritaprevir + 50 mg ritonavir fixed-dose two pills QD plus 250 mg dasabuvir BID for 12w Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Dasabuvir Date approved : Dec. 2014 www.virusface.com Efficacy of 12.5 mg ombitasvir + 75 mg paritaprevir + 50 mg ritonavir fixed-dose two pills QD plus 250 mg dasabuvir BID plus ribavirin for 12w Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Dasabuvir Date approved : Dec. 2014 www.virusface.com Efficacy of 12.5 mg ombitasvir + 75 mg paritaprevir + 50 mg ritonavir fixed-dose two pills QD plus 250 mg dasabuvir BID plus ribavirin for 24w. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name :Technivie™ （Ombitasvir + paritaprevir + ritonavir） Mechanism of drug action Technivie™ is the first FDA-approved therapy solely against the GT4 infections. (DeGoey et al., 2014) Author and date N-phenylpyrrolidine inhibitors Ombitasvir FDA-approved compound Initial compound Paritaprevir ritonavir www.virusface.com Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Efficacy of Technivie™ with or without ribavirin for 12 weeks. HCV Drug name : Technivie™ Date approved : July 2015 www.virusface.com Efficacy of Technivie™ with or without ribavirin for 12 weeks. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Daclatasvir Mechanism of drug action NS5A inhibitors (Daclatasvir) not only block HCV RNA synthesis at the stage of membranous web biogenesis but also impair viral assembly by inhibiting the delivery of HCV genomes to assembly sites Belema and Meanwell, 2014 Author and date Daclatasvir Iminothiazolidinone 7 FDA-approved compound Initial compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 www.virusface.com

HCV Drug name : Daclatasvir Date approved : July 2015 www.virusface.com Efficacy of 60 mg daclatasvir + 400 mg sofosbuvir QD with or without ribavirin for 12 weeks. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Mechanism of drug action HCV Drug name : Zepatier™ （ Elbasvir+ grazoprevir ） Mechanism of drug action Zepatier™ against HCV genotype 1 or 4 infections Harper et al,2012 , Liverton et al. 2008 Author and date Compound 3 Grazoprevir (MK-5172) Coburn et al., 2013 Author and date MK-4882 Elbasvir (MK-8742) Initial compound FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 www.virusface.com

HCV Drug name : Zepatier™ Date approved : Jan 2016 www.virusface.com Efficacy of Zepatier™ with or without ribavirin in phase 2 and 3 clinical trials. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

HCV Drug name : Epclusa® （Sofosbuvir + velpatasvir） Mechanism of drug action Epclusa® is the first pan-genotypic therapy approved for the treatment of all HCV genotypes except genotype 7. Velpatasvir (GS-5816) 2’-F, 2’-C-methyluridine 5’-phosphoramidate Sofia et al., 2010 Author and date Sofosbuvir 2’-F, 2’-C-methylcytidine Initial compound FDA-approved compound Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 www.virusface.com

HCV Drug name : Epclusa® （Sofosbuvir + velpatasvir） Date approved : June 2016 www.virusface.com Efficacy of Epclusa® in phase 2 and 3 clinical trials. Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Summary of potent HCV inhibitors explored between 2011 and 2016 Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122

Thank you for your attention ! Please cite our article: Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res. 2017 Feb 24;142:83-122 Please contact us: Guangdi Li (liguangdi.research@gmail.com) Erik De Clercq (erik.declercq@kuleuven.be) Thank you for your attention !