11 ς 2015 3 28 ομ 2 πέτρος καραγιάννης ηπατίτιδα

Νέες Εξελίξεις στη Θεραπεία της Χρόνιας Ηπατίτιδας Γ

Πέτρος Καραγιάννης Καθηγητής Μικροβιολογίας / Μοριακής Ιολογίας

Ιατρική Σχολή, Πανεπιστήμιο Λευκωσίας

Targeted Antiviral therapy for hepatitis C

virus infection

By

P. Karayiannis

HEPATITIS C VIRION STRUCTURE:

LIPO-VIRAL PARTICLE

Envelope

Core Electron micrograph

RNA

ApoB

ApoE

VLDL

HEPATITIS C VIRUS GENOME ORGANISATION

Moradpour et al, 2007;5:453-463

SIGNAL PEPTIDE PEPTIDASE

SIGNAL PEPTIDASE

VIRALLY ENCODED PROTEASES

GLYCOSYLATION SITES

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

Bartenschlager R et al, J Hepatol 2010;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

http://www.sciencedirect.com/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6W7C-506RMR2-C&_image=B6W7C-506RMR2-C-3&_ba=&_user=217827&_coverDate=09/30/2010&_rdoc=1&_fmt=full&_orig=search&_cdi=6623&_pii=S0168827810004745&view=c&_isHiQual=Y&_acct=C000011279&_version=1&_urlVersion=0&_userid=217827&md5=c15b2c41df413ae30849aab087213394

Bode et al, Biol. Chem., Vol. 390, pp. 1013–1032

REPLICATION MACHINERY: MEMBRANOUS WEB

http://www.reference-global.com/action/showImage?doi=10.1515/BC.2009.118&iName=master.img-003.jpg&type=master

HOST TARGETING AGENTS

Jopling et al, Viruses 2010;2:1382-1393

miR122 binding sites and inhibition

of its action

Miravirsen

Translation

http://genomebiology.com/2010/11/1/201/figure/F1?highres=y

INHIBITORS: POTENTIAL NS3 SERINE PROTEASE/HELICASE

TARGETS AND RESISTANCE MUTATIONS HELICASE

PROTEASE

RNA binding

NTPase site

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

In v

ivo

In v

itro

http://bmc.ub.uni-potsdam.de/1472-6807-5-1/F2high.htm

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 et al, Gut 2012;61:36-46.

Sofosbuvir (Sovaldi)

Hepatitis C virus genome and viral proteins targeted by DAAs

Shinazi et al, Liver Int 2014;34 Suppl 1:69-78

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

Jacobson et al, NEJM 2011;364:2405-16 Sherman et al, NEJM 2011;365:2417-28 Zeuzem et al, NEJM 2011;364:2417-28

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

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

SV

R (

%)

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 ???

Non-nucleos(t)idic DAAs undergoing

Clinical trials

Welzel et al, J Hepatol 2014;61:S98-107

Not All Direct-Acting Antivirals 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

Alexopoulou & Karayiannis, Ann Gastroenterol 2015;51:1-11

Resistance Mutations induced by DAAs When Used as Monotherapy

Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6

NEUTRINO Trial: Design & Results 0 12 24 Week

Sofosbuvir + PEG + RBV N=327 SVR12

Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

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

Pa

tie

nts

wit

h S

VR

12

(%

)

248/273

47/54

Race and Cirrhosis status

Jacobson IM, et al. Lancet. 2014;384:403-13.

Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: 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 48 24 36

80

50

0

20

40

60

80

100

Simeprevir + PEG + RBV PEG + RBV

Pa

tie

nts

(%

) w

ith

SV

R 1

2

210/264

Response-Guided Therapy: Patients with HCV RNA <25 IU/ml at week 4

and <15 IU/ml at week 12 completed

treatment after 24 weeks.

65/130


71

90

49 52

0

20

40

60

80

100

1a 1b

Pa

tie

nts

(%

) w

ith

SV

R 1

2

HCV Genotype

Simeprevir + PEG +RBV PEG + RBV

SVR12 by HCV Genotype 1 Subtype

Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results

105/147 36/74 105/117 29/56


52

85

53

44

0

20

40

60

80

100

1a (with baseline Q80K) 1a (without baseline Q80K)

Pa

tie

nts

(%

) w

ith

SV

R 1

2

HCV Genotype


QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status


Abbreviations: PEG = Peginterferon RBV = Ribavirin

31/60 16/30 73/86 19/43

Source: Jacobson IM, et al. Lancet. 2014;384:403-13.

94

76

65

78

42

24

0

20

40

60

80

100

CC CT TT

Pa

tie

nts

(%

) w

ith

SV

R 1

2


QUEST 1: SVR12 by Host IL28B Genotype


72/77 29/37 114/50 32/76 24/37 4/17


83 78

58 60

26 29

0

20

40

60

80

100

F0-F2 F3 F4 (Cirrhosis)

Pa

tie

nts

(%

) w

ith

SV

R 1

2

Metavir Fibrosis Score


QUEST 1: SVR12 by Liver Fibrosis (Metavir Score)


152/183 54/90 36/46 6/23 18/31 5/17

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






Placebo PR 48 wks

Pa

tie

nts

wit

h S

VR

24

(%

)

46/66

Simeprevir 100 mg

43/65 40/66 44/66 49/68 52/65 15/66

Simeprevir 150 mg Placebo


ASPIRE: SVR 24, by Prior Treatment Response


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

Pa

tie

nts

wit

h S

VR

24

(%

)

Placebo + PEG/RBV SMV 100 mg + PEG/RBV SMV 150 mg + PEG/RBV


ASPIRE: SVR 24, by Prior Treatment Response and GT 1 Subtype


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

Pa

tie

nts

wit

h S

VR

24

(%

)

Placebo + PEG/RBV Simeprevir 100 mg + PEG/RBV Simprevir 150 mg + PEG/RBV

Relapser Partial Responder Null Responder

Pawlotsky, Gastroenterology 2014;146:1176-92

SVR12 in genotype 2 and 3 patients on Sofosbuvir+RBV treatment

A. Treatment naïve and experienced, GT 2

B. Treatment naïve and experienced, GT 2, cirrhotics vs non-cirrhotices C. Treatment naïve, GT 3, cirrhotics vs non-corrhotics D. Treatment experienced, GT3, cirrhotics vs non-cirrhotics

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

Pati

en

ts w

ith

SV

R12 (

%)

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

IFN-free trials for Genotype 1 naïve patients

IFN-free trials for Genotype 1 treatment experienced patients

IFN-free trials for non-Genotype 1 naïve patients

Characteristics needed for future DAAs

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

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

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11 ς 2015 3 28 ομ 2 πέτρος καραγιάννης ηπατίτιδα

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