1. 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 Feb 24;142:83-122

2. 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 Feb 24;142:83-122

3. 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 Feb 24;142:83-122

4. 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 Feb 24;142:83-122

5. 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 Feb 24;142:83-122

6. 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 Feb 24;142:83-122

7. HCV Drug name : Boceprevir
Date approved : May 2011
Efficacy of PegIFNa/RBV for 4 weeks 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 Feb 24;142:83-122

8. 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 Feb 24;142:83-122

9. Efficacy of 1125 mg telaprevir BID plus PegIFNa/RBV
HCV Drug name : Telaprevir
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 Feb 24;142:83-122

10. 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.
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 Feb 24;142:83-122

11. HCV Drug name : Sofosbuvir
Date approved : Dec. 2013
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 Feb 24;142:83-122

12. Efficacy of 400 mg sofosbuvir QD + ribavirin for 12 weeks.
HCV Drug name : Sofosbuvir
Date approved : Dec. 2013
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 Feb 24;142:83-122

13. HCV Drug name : Sofosbuvir
Date approved : Dec. 2013
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 Feb 24;142:83-122

14. 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 Feb 24;142:83-122

15. Efficacy of 150 mg simeprevir plus 400 mg
HCV Drug name : Simeprevir
Date approved : NOV. 2013
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 Feb 24;142:83-122

16. HCV Drug name : Simeprevir
Date approved : NOV. 2013
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 Feb 24;142:83-122

17. HCV Drug name : Simeprevir
Date approved : NOV. 2013
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 Feb 24;142:83-122

18. 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 Feb 24;142:83-122

19. 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
Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res Feb 24;142:83-122

20. HCV Drug name : Ledipasvir
Date approved : Oct. 2014
Efficacy of 90 mg ledipasvir 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 Feb 24;142:83-122

21. 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
Dasabuvir
FDA-approved compound
Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res Feb 24;142:83-122

22. HCV Drug name : Dasabuvir
Date approved : Dec. 2014
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 Feb 24;142:83-122

23. HCV Drug name : Dasabuvir
Date approved : Dec. 2014
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 Feb 24;142:83-122

24. HCV Drug name : Dasabuvir
Date approved : Dec. 2014
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 Feb 24;142:83-122

25. 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
Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res Feb 24;142:83-122

26. Efficacy of Technivie™ with or without ribavirin for 12 weeks.
HCV Drug name : Technivie™
Date approved : July 2015
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 Feb 24;142:83-122

27. 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 Feb 24;142:83-122

28. HCV Drug name : Daclatasvir
Date approved : July 2015
Efficacy of 60 mg daclatasvir 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 Feb 24;142:83-122

29. 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 Feb 24;142:83-122

30. HCV Drug name : Zepatier™
Date approved : Jan 2016
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 Feb 24;142:83-122

31. 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 Feb 24;142:83-122

32. HCV Drug name : Epclusa®
（Sofosbuvir + velpatasvir）
Date approved : June 2016
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 Feb 24;142:83-122

33. 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 Feb 24;142:83-122

34. 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 Feb 24;142:83-122
Please contact us: Guangdi Li Erik De Clercq
Thank you for your attention !