Πέτρος Καραγιάννης Καθηγητής Μικροβιολογίας / Μοριακής Ιολογίας, Ιατρική Σχολή, Πανεπιστήμιο Λευκωσίας. Νέες Εξελίξεις στη Θεραπεία της Χρόνιας Ηπατίτιδας Γ

5. Νέες Εξελίξεις στη Θεραπεία
της Χρόνιας Ηπατίτιδας Γ
Πέτρος Καραγιάννης
Καθηγητής Μικροβιολογίας/ Μοριακής Ιολογίας
Ιατρική Σχολή, Πανεπιστήμιο Λευκωσίας

6. Targeted Antiviral therapy for hepatitis C
virus infection
By
P. Karayiannis

7. HEPATITIS C VIRION STRUCTURE:
LIPO-VIRAL PARTICLE
Envelope
Core
Electron micrograph
RNA
ApoB
ApoE
VLDL

8. HEPATITIS C VIRUS GENOME ORGANISATION
Moradpour et al, 2007;5:453-463
SIGNAL PEPTIDEPEPTIDASE
SIGNAL PEPTIDASE
VIRALLY ENCODED PROTEASES
GLYCOSYLATION SITES

9. LIFE CYCLE OF HEPATITIS C VIRUS: POTENTIAL TARGETS
FOR THERAPEUTIC INTERVENTION
ATTACHMENT
UPTAKE
CORE RELEASE
UNCOATING
TRANSLATION
RNA
REPLICATION
ASSEMBLY
TRANSPORT
RELEASE
Pawlotsky, Hepatology 2006;43:S207-20

10. BartenschlagerR et al, J Hepatol2010;53:583-5
REPLICATION CYCLE OF HCV: TARGETS FOR ANTIVIRALS
Cytoplasm
Lumen
ER Membrane
Golgi
Antibodies
Inhibitors
Small Molecules
siRNAs,
Miravirsen
PIs
NIs
NNIs
HTAs

11. Bode etal, Biol. Chem.,Vol. 390,pp. 1013–1032
REPLICATION MACHINERY: MEMBRANOUS WEB

12. HOST TARGETING AGENTS

13. Jopling et al, Viruses 2010;2:1382-1393
miR122 binding sites and inhibition
of its action
Miravirsen
Translation

14. INHIBITORS:POTENTIAL NS3 SERINE
PROTEASE/HELICASE
TARGETS AND RESISTANCE
MUTATIONSHELICASE
PROTEASE
RNA
binding
NTPasesite
Membrane
binding
domain
Zinc
Catalytic site
NH2
Inhibitor
BILN-20611,2 Telaprevir2,3,7
(VX-950)
SCH-64 Boceprevir
(SCH-5030345)
ITMN-1916
A156V/T
R155Q
D168A/V/Y
A156S/V/T A156V/T
R109K
A156S/T
T54A
V170A
A156S/V
Q41R, F43S,
S138T, D168A,
S489L,
V23A (NS4A)
NA V36A/M
T54A
R155K/T
A156S/V/T
NA V36A/M, T54A,
R155K/Q/T/M,
A156S,
V170A/T,
F43C/S
NA
InvivoInvitro

15. DAAs and HTAs IN CLINICAL TRIALS
RIBBON MODEL OF THE HCV POLYMERASE
Active site with bound inhibitor and non-nucleoside
inhibitor (NNI) sites 1 to 4. Palm, thumb and fingers
coloured red, green and blue, respectively.
DRUGS FOR FUTURE TREATMENT
OF CHRONIC HCV INFECTION
Welsch etal, Gut 2012;61:36-46.
Sofosbuvir (Sovaldi)

16. HepatitisC virus genome and viral proteins targeted byDAAs
Shinazi et al, Liver Int 2014;34 Suppl 1:69-78

17. Phase III trials with telaprevir in interferon-naive (ADVANCE and ILLUMINATE)
and interferon-experienced patients (REALIZE)
Soriano V et al. J. Antimicrob. Chemother. 2011;66:1673-1686
Jacobsonet al, NEJM 2011;364:2405-16
Shermanet al, NEJM 2011;365:2417-28
Zeuzemet al, NEJM 2011;364:2417-28

18. Phase III trials with boceprevir in interferon-naive (SPRINT-2) and interferon-
experienced patients (RESPOND-2).
Soriano V et al. J. Antimicrob. Chemother.
2011;66:1673-1686
Poordad et al, NEJM 2011;364:1195-206
Bacon et al, NEJM 2011;364:1207-17

19. 0
20
40
60
80
100
IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12 m Peg-IFN 12m Peg-IFN/RBV 12m Peg-IFN/RBV/DAA
SVR(%)
2001
1998
2011
Standard
Interferon
+ Ribavirin
Peginterferon
1991
+ DAAs
Milestones in Therapy of CHC:
Average SVR Rates from Clinical Trials
Adapted from US Food and Drug Administration,
Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.
6%
16%
34%
42% 39%
55%
70+%
2014
???

20. Non-nucleos(t)idic
DAAs undergoing
Clinical trials
Welzelet al, J Hepatol 2014;61:S98-107

21. Not All Direct-ActingAntivirals Have the Same
Properties
Characteristic
Protease
Inhibitor*
Protease
Inhibitor**
NS5A
Inhibitor
Nuc
Polymerase
Inhibitor
Non-Nuc
Polymerase
Inhibitor
Resistance
profile
Pangenotypic
efficacy
Antiviral potency
Adverse events
Good profile Average profile Least favorable profile
*First generation. **Second generation.
Feld JJ, CCO Hepatitis

22. Alexopoulou &Karayiannis, Ann Gastroenterol 2015;51:1-11
Resistance Mutations induced by DAAs When Used as Monotherapy

23. Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Design & Results
0 12 24Week
Sofosbuvir + PEG + RBVN=327 SVR12
Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

24. Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Results
Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
91 87
0
20
40
60
80
100
Non-black Black
PatientswithSVR12(%)
248/273
47/54
Race and Cirrhosis status

25. JacobsonIM, et al. Lancet. 2014;384:403-13.
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1Trial: SVR12
N=130 Placebo
+ PEG + RBV
Simeprevir
+ PEG + RBV
N= 264 PEG + RBV PEG + RBV
PEG + RBV
Randomized 2:1;
stratified on IL28B and
HCV1 subtype
Week 0 12 4824 36
80
50
0
20
40
60
80
100
Simeprevir+ PEG + RBV PEG + RBV
Patients(%)withSVR12
210/264
Response-GuidedTherapy:
Patients with HCV RNA <25 IU/ml at week 4
and <15 IU/ml at week 12 completed
treatment after 24 weeks.
65/130

26. Jacobson IM, et al. Lancet. 2014;384:403-13.
71
90
49 52
0
20
40
60
80
100
1a 1b
Patients(%)withSVR12
HCV Genotype
Simeprevir + PEG +RBV PEG + RBV
SVR12 by HCV Genotype 1 Subtype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1Trial: Results
105/147 36/74 105/117 29/56

27. Jacobson IM, et al. Lancet. 2014;384:403-13.
52
85
53
44
0
20
40
60
80
100
1a (with baseline Q80K) 1a (without baseline Q80K)
Patients(%)withSVR12
HCV Genotype
Simeprevir + PEG + RBV PEG + RBV
QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1Trial: Results
Abbreviations: PEG = Peginterferon RBV = Ribavirin
31/60 16/30 73/86 19/43

28. Source:JacobsonIM,et al. Lancet.2014;384:403-13.
94
76
65
78
42
24
0
20
40
60
80
100
CC CT TT
Patients(%)withSVR12
Simeprevir + PEG + RBV PEG + RBV
QUEST 1: SVR12 by Host IL28B Genotype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1Trial: Results
72/77 29/37 114/50 32/76 24/37 4/17

29. Jacobson IM, et al. Lancet. 2014;384:403-13.
83
78
5860
26 29
0
20
40
60
80
100
F0-F2 F3 F4 (Cirrhosis)
Patients(%)withSVR12
Metavir Fibrosis Score
Simeprevir + PEG + RBV PEG + RBV
QUEST 1: SVR12 by Liver Fibrosis (Metavir Score)
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1Trial: Results
152/183 54/90 36/46 6/23 18/31 5/17

30. Simeprevir in Treatment Experienced Genotype 1 HCV
ASPIRE Trial: Results
ASPIRE: SVR 24, by Treatment Regimen
Zeuzem S, et al. Gastroenterol. 2014;146:430-41.
70
66
61
67
72
80
23
0
20
40
60
80
100
SMV 12 wks
PR 48 wks
SMV 24 wks
PR 48 wks
SMV 48 wks
PR 48 wks
SMV 12 wks
PR 48 wks
SMV 24 wks
PR 48 wks
SMV 48 wks
PR 48 wks
Placebo
PR 48 wks
PatientswithSVR24(%)
46/66
Simeprevir100 mg
43/65 40/66 44/66 49/68 52/65 15/66
Simeprevir150 mg Placebo

31. Simeprevir in Treatment Experienced Genotype 1 HCV
ASPIRE Trial: Results
ASPIRE: SVR 24, by Prior Treatment Response
Zeuzem S, et al. Gastroenterol. 2014;146:430-41.
46/66 43/65 40/66 44/66 49/68 52/65 15/66
37
9
19
85
57
46
85
75
51
0
20
40
60
80
100
Relapser Partial Responder Null Responder
PatientswithSVR24(%)
Placebo + PEG/RBV SMV 100 mg + PEG/RBV SMV 150 mg + PEG/RBV

32. Simeprevir in Treatment Experienced Genotype 1 HCV
ASPIRE Trial: Results
ASPIRE: SVR 24, by Prior Treatment Response and GT 1 Subtype
Zeuzem S, et al. Gastroenterol. 2014;146:430-41.
46/66 43/65 40/66 44/66 49/68 52/65 15/66
33
40
13
7
0
33
82
89
39
68
33
56
85 84
56
88
42
58
0
20
40
60
80
100
1a 1b 1a 1b 1a 1b
PatientswithSVR24(%)
Placebo + PEG/RBV Simeprevir100 mg + PEG/RBV Simprevir150 mg + PEG/RBV
Relapser PartialResponder NullResponder

33. Pawlotsky, Gastroenterology 2014;146:1176-92
SVR12 in genotype 2 and 3 patients on Sofosbuvir+RBV treatment
A. Treatmentnaïve and experienced,GT 2
B. Treatmentnaïve and experienced,GT 2, cirrhotics vs non-cirrhotices
C. Treatmentnaïve,GT 3, cirrhotics vs non-corrhotics
D. Treatmentexperienced,GT3, cirrhotics vs non-cirrhotics

34. Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.
Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3
GT1 Treatment-Naïve & Experienced 12 Week Rx: Results
100 100
90
95
0
20
40
60
80
100
DCV + SOF DCV + SOF + RBV DCV + SOF DCV + SOF + RBV
PatientswithSVR12(%)
Treatment-Naïve:GT 1a or 1b Treatment-Experienced: GT 1a or 1b
DCV = daclatasvir;SOF = sofosbuvir;RBV = ribavirin
41/41 41/41 19/21 19/20

35. IFN-free trials for Genotype 1 naïve patients

36. IFN-free trials for Genotype 1 treatment experienced patients

37. IFN-free trials for non-Genotype 1 naïve patients

38. Characteristicsneeded for future DAAs

39. Summary
• First-generation PIs have now been replaced
– SMV + P/R x 24 weeks – issue with Q80K in GT1a
– SOF + P/R x 12 weeks in GT1
• IFN will hang around for a short while. . .
– IFN-free therapy coming soon for GT1
• Challenges
– GT1a vs GT1b
– One size fits all vs GT1b regimens
– GT3 may still need IFN, at least for now
• Drawback
– Expensive treatments

40. Η ομιλία σε φιλμάκι
Ομιλία Πέτρου Καραγιάννη
http://www.biosyn-oelmek.org/
Ιστοσελίδα Συνδέσμου Βιολόγων ΟΕΛΜΕΚ
http://www.biosyn-oelmek.org/?page_id=352
facebook Βιολόγων
https://www.facebook.com/groups/670297819664373/1088887251138759
/?comment_id=1089101171117367&ref=notif¬if_t=like
στο youtube
https://www.youtube.com/watch?v=buBkpqHA5bI#t=137