Du 2012 tp traitement hcv

26 janv. 2012

VHC
Traitement des cas simples
Traitement des cas compliqués

Thierry Poynard

http://www.slideshare.net/odeckmyn

LiverCenter

jeudi 26 janvier 2012

26 janv. 2012

Treatment of Acute Hepatitis C:

A la carte from 0 to 1 year

LiverCenter


26 janv. 2012

The Deﬁnition of Acute Hepatitis C

• Exposure to HCV

• Within 4 months

• Anti-HCV seroconversion

• Raised ALTs

• HCV RNA positivity

3


26 janv. 2012

Rationale for Treating Acute HCV

• High risk (75%) of chronicity

• Risk of spreading the virus

• Chances for better cure (no ﬁbrosis, recovery of immune response)

4


26 janv. 2012

Predictors of Spontaneous Viral Clearance ...

• No HIV

• IL-28B CC genotype

• Inducible Protein10

• Younger age (?)

• Females (?)

• White vs. Blacks (?)

• Rare Quasispecies ?

• Genotype non-1 ?

• ALT useless: can normalize despite viral persistence (50%)

5


26 janv. 2012

Prevalence of Symptoms According to Outcome
Spontaneous Clearance Persistence HCV

100
87 % 87 %
P=0.02 P=0.002
75
59 %
47 %
50

25

0
Jaundice Flu-like symptoms
OR 4.9 (1.3-19) OR 7.8 (2.2-29)
Gerlach, Gastroenterology 2003

6

29 Acute HCV: Initial RNA, viral kinetics, IL-28B
and spontaneous clearance

Liui Hepatology 2012

120 Acute HCV: Inducible Protein10, IL-28B
and spontaneous clearance

Beinhardt Gastroenterology 2012

26 janv. 2012

Acute hepatitis C and HIV coinfection

• Patients coinfected HIV-HCV more rapid ﬁbrosis progresssion

• High risk acute hepatitis C in HIV infected patients

• Men who have sex with men

• High risk sexual practices

• Concomitant genital ulcer disease

Jodie Dionne-Odom, Lancet Infect Dis 2009

9


26 janv. 2012

Anti-Viral Treatment of Acute HCV

Interferon based

10


26 janv. 2012

Meta-Analysis of IFN α-2b RCTs in Acute HCV
Sustained Viral Response

OR (95% CI)
Hwang 1994 (n=33)
4.8 (1.1-22)
Lampertico 1994 (n=48)
7.7 (1.6-38)
Li 1993 (n=32)
9.9 (1.5-65)
TOTAL (n=113) 6.8 (2.6-17.5) *
0.1 1.0 10 100
Favours Control Favours IFN *P<0.0001
Myers R, Cochrane Database Syst Rev 2003

11


26 janv. 2012

Acute HCV: 12 studies PEG-Interferon in mono-infected

Grebely, Nat Rev Gastroenterol Hepatol 2011

26 janv. 2012

Acute HCV: 10 studies PEG-Interferon in HIV-co-infected


26 janv. 2012

Anti-Viral Treatment of Acute HCV

STRATEGIES

14


26 janv. 2012

Hypothesis:
Early control of viral replication prevents chronicity

• Treat all patients ?

• Treat early ?

• Doses of PEG-IFN ?

• Ribavirin ?

• Duration of treatment ?

15


26 janv. 2012

Proposed algorithm for the treatment of acute HCV infection

CC


26 janv. 2012

Acute Hepatitis C

Viral load baseline

Viral load 4 week

Decrease < 2 Log Decrease ≥ 2 Log

Viral load 12 week

Treatment
Detectable Undetectable
PEG-Riba

«Poynard Opinion» 2012

26 janv. 2012

Treatment of Chronic Hepatitis C:

A la carte from 0 to 5 years

LiverCenter


26 janv. 2012

Approval of HCV treatments


26 janv. 2012

Approval of HCV treatments

Date Endpoint Treatment Approval Reference

1991 ALT Interferon Davis NEJM

Poynard Lancet
1998 SVR Interferon Ribavirin McHutchison NEJM

Manns NEJM,
2001 SVR PEG Interferon Ribavirin Fried NEJM

PEG Interferon Ribavirin, Zeuzem, Bacon
2011 SVR Jacobson, Sherman
Boceprevir, Telaprevir

2015 ? SVR Xprevir+Yprevir ??


26 janv. 2012

Sustained Virologic Response (SVR): HCV RNA negative

SVR %
100

75

50

25
PEG-R Previr
PEG-R
0 IFN-R
IFN 48w
IFN 24w
Control

G 1-4-5-6 G 2-3

20


26 janv. 2012

NS5A inhibitor BMS-790052 + NS3 protease inhibitor BMS-650032
in 9 HCV genotype 1b-infected null responders

1a et B52 ?

21 Chayama Hepatology 2012

26 janv. 2012

NS5A inhibitor BMS-790052 + NS3 protease inhibitor BMS-650032
in 11 HCV genotype 1a (n=9) and 1b (n=2) null responders

1a et B52 ?

Daclatasvir
BMS-790052
HCV NS5A replication complex inhibitor

Asunaprevir BMS-650032
HCV NS3 protease inhibitor

22 Lok NEJM 2012

26 janv. 2012

Quadri Therapy: PEG-Riba + BMS-790052 + BMS-650032
in 10 HCV genotype 1a (n=9) and 1b (n=1) null responders

Daclatasvir
BMS-790052
HCV NS5A replication inhibitor

Asunaprevir BMS-650032
HCV NS3 protease inhibitor

23 Lok NEJM 2012

26 janv. 2012

Parler l’Hépatan: Dictionnaire actualisé

24


26 janv. 2012


• DAA: Direct-Acting Antiviral therapy: PI, Inhibiteur protéase

24


26 janv. 2012



• STAT-C: Speciﬁcally Targeted Antiviral Therapy for HCV:

24


26 janv. 2012




• Response guided therapy: «A la carte»

24


26 janv. 2012





• RVR: undetectable HCV RNA at week 4; EVR: undetectable HCV RNA at week 12

24


26 janv. 2012






• eRVR, extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12);

24


26 janv. 2012







• Lead-in phase: «Phase initiale de bithérapie»

24


26 janv. 2012








• Pharmaco-Genomic: IL28B genotype

24


26 janv. 2012









• Resistance, genetic barrier, ﬁtness, virologic stopping rule, virologic breakthrough

24


26 janv. 2012









• Resistance, genetic barrier, ﬁtness, virologic stopping rule, virologic breakthrough

• Genotype-1 sous type 1b meilleur réponse ?

24


26 janv. 2012

Menu traitements 2012: Changement d’atmosphère

• Genotype 1: Toujours Interferon et Ribavirine mais:

• SVR >= 70%

• Plus court

• Plus d’effets indésirables

• Risque de résistance

• Plus cher de 6 à 60.000 €

• Frustration pour les non-Genotype 1 non-répondeurs

25


26 janv. 2012

Prise en charge de l’Hépatite C en 2012

• Guérir du virus

• Tri-thérapie pour Génotype 1

• Bi-thérapie pour Génotype non-1

• Ne pas mourir de la cirrhose

• Traitement de maintenance

• Transplantation

26


26 janv. 2012

Key Factors for Considering Treatment Candidacy for
Protease Inhibitor-Based Therapy

Factor Role

Genotype  Boceprevir and telaprevir licensed only for genotype 1

Fibrosis stage  Independent response factor

 Treatment-naive
Treatment  Previous relapsers
experience  Partial responders
 Previous null responders

27


26 janv. 2012

Challenges to Categorizing Previous Therapy Response

• Lack of detailed records

• Lack of standardized deﬁnitions of response

• Lack of patient evaluation at key time points on pervious therapy

• Potential lapses in patient memory

• Differentiation of previous partial response vs null response

• Many clinics unable to characterize exact log10 decline in HCV RNA levels at
key time points

28


26 janv. 2012

Genotype 1: NS3/4A Protease Inhibitor

• Boceprevir (Victrelis™)

• Telaprevir (Incivek®, Incivo® )

29


26 janv. 2012

Boceprevir and Telaprevir pivotal Phase-3 Clinical Trials

• Boceprevir plus pegIFN/RBV

• SPRINT-2: treatment-naive patients: Poordad, NEJM 2011

• RESPOND-2: treatment-experienced patients, Bacon NEJM 2011

• Telaprevir plus pegIFN/RBV

• ADVANCE: treatment-naive patients Jacobson NEJM 2011

• ILLUMINATE: treatment-naive patients Sherman NEJM 2011

• REALIZE: treatment-experienced patients Zeuzem NEJM 2011

30


26 janv. 2012


26 janv. 2012

Boceprevir Phase 2: Efﬁcacy naive genotype1
n=520 Lead-in phase: for 4w responders to PEG-Riba

Kwo, Sprint-1 Lancet 2010

26 janv. 2012

Naive


Boceprevir Naive patients
«Sprint-2» Non Black n= 938 Black n=150

PEG-R 48 BOC RGT BOC/PR48

70%
67 68
53%
53

SVR
40 35%
42
18%
23
0%
Non Back
Black

Poordad NEJM 2011

SPRINT-2 Subanalysis:
Response to 4-Wk PegIFN/RBV Lead-in

•Response to 4-wk lead-in phase with •When 4-wk lead-in phase included
pegIFN/RBV strongest predictor of SVR in as continuous variable, IL28B
multivariate analysis (OR: 9.0; P < .001) genotype no longer signiﬁcantly
predictive of SVR

90%
79 81
68%

SVR
38 51 45%
28
23%
2
0%
< 1 log10 decline in HCV RNA
≥ 1 log10 decline in HCV RNA

PEG-R 48 BOC RGT BOC 48

Poordad NEJM 2011

HCV genotype 1 naive patients: 12 week Telaprevir Efﬁcacy
«Advance» n=1095 750mg x 3

PEG-R 48 Tela 12 Tela 8

100%

75%
75%
69% 50%
44%
25%
0%

Jacobson NEJM 2011

HCV genotype 1 naive patients: Telaprevir efﬁcacy in extended rapid
virological responder (eRVR) 4w and 12w negative PCR
«ILLUMINATE» n=540 750mg x 3

Tela12 PEG-R 24 Tela12 PEG-R 48 Tela12 PEG-R 48 non eRVR

100%
92%
88% 75%

64% 50%
25%
0%

24 weeks is OK

Sherman NEJM 2011

26 janv. 2012

Non responders


Previously relapsers, partial-responders: Boceprevir
«Respond-2» n= 403


80%
75 60%
69

SVR
52 40%
40

29 20%

7 0%
Partial
Relapser

Bacon NEJM 2011



70%
66 68 68
53%

SVR
44 35%

23 18%

13 0%
F0-2
F3-4

Bacon NEJM 2011



80%

Stage METAVIR
77
64 66 60%

40%

35 20%
24
0%
No Cirrhosis 0
Cirrhosis

For both boceprevir and telaprevir, ﬁxed duration therapy rather
than response-guided approach in cirrhotics

Bacon NEJM 2011

Genotype 1 Previously non-responders: Telaprevir
«Realize» n=662

PEG-R 48 Telaprevir

90%
88
68%

SVR
54 45%

24 23%
33
15 0%
Relapsers
Partial 5
Null

Zeuzem NEJM 2011

Genotype 1 Previously non-responders: Telaprevir
«Realize» n=662

PEG-R 48 Telaprevir

86 85 84 90%
72
68%
56

SVR
32 45%
34 41
13 39
13 18 20 23%

0 0%
F0-1 F2-3 F4 6 10 14
F0-1 F2-3 0
F4
F0-1 F2-3 F4

Relapser Partial Null

Zeuzem NEJM 2011

26 janv. 2012

Boceprevir, Telaprevir

Recommendations

46


Menu à la carte....of European Drug Agency

(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission


Victrelis® 200 mg gélules 2!
Mentions obligatoires complètes – Juillet 2011 Vic/mlc-1107-1!

!
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-*#.-&/&0-!1#*!.0-&*2+*30!&-!*.$#6.*.0&!

EVALUATION*
(Taux d’ARN-VHC†)
A la A la semaine ACTION
semaine de de
traitement 8 traitement 24
Patients non Durée du traitement = 28 semaines
préalablement (C! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
traités &-! *.$#6.*.0&! 1&0,#0-! F!
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A! %#! 2.0! ,&! %#! 9&/#.0&! HO!
7P!HO?C
Durée du traitement = 48
semainesQ
(C! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
&-! *.$#6.*.0&! 1&0,#0-! F!
9&/#.0&9G!1'.9!
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&-! *.$#6.*.0&! &-! #**N-&*! %&!
-*#.-&/&0-!A!%#!2.0!,&!P!FOC!
Patient en Durée du traitement = 48 semaines!
échec à un B0,+-&4-#$%&! B0,+-&4-#$%& (C! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
précédent &-! *.$#6.*.0&! 1&0,#0-! F!
traitement 9&/#.0&9G!1'.9!
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&-! *.$#6.*.0&! &-! #**N-&*! %&!
-*#.-&/&0-!A!%#!2.0!,&!P!FOC!
*Règles d’arrêt de traitement :
:! P.! %&! 1#-.&0-! #! '0! -#'V! ,W#4.,&! *.$30'4%+.5'&! ,'! 6.*'9! ,&! %W<+1#-.-&! X! 7D8Y:MZX?!
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!
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Q
X&! 94<+/#! 0W#! +-+! -&9-+! 5'&! 4<&@! %&9! 1#-.&0-9! *+130,&'*9! %&0-9! &0! +4<&4! A! '0!
1*+4+,&0-!-*#.-&/&0-!7X2C!I*31*.+-+9!1<#*/#43,=0#/.5'&9?C !
!



Victrelis® 200 mg gélules 2!
Mentions obligatoires complètes – Juillet 2011 Vic/mlc-1107-1!

!
"#$%&#'!(!
)'*+&!,'!-*#.-&/&0-!#,#1-+&!&0!2304-.30!,&!%#!4.0+-.5'&!6.*#%&!1*+434&!78&91309&:;'.,&,!"<&*#1=>!
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-*#.-&/&0-!1#*!.0-&*2+*30!&-!*.$#6.*.0&!

EVALUATION*

12 Menus with
(Taux d’ARN-VHC†)
A la A la semaine ACTION
semaine de de
traitement 8 traitement 24
Patients non Durée du traitement = 28 semaines

«Amuses bouche
préalablement (C! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
traités &-! *.$#6.*.0&! 1&0,#0-! F!
9&/#.0&9G!1'.9!
HC! I3'*9'.6*&! #6&4! %&9! -*3.9!
B0,+-&4-#$%&! B0,+-&4-#$%&
/+,.4#/&0-9! 71&E.0-&*2+*30!

Entrées
#%2#! &-! *.$#6.*.0&! JI8K! L!
M.4-*&%.9?!&-!#**N-&*!%&!-*#.-&/&0-!
A! %#! 2.0! ,&! %#! 9&/#.0&! HO!
7P!HO?C
Durée du traitement = 48
semainesQ

Plats
(C! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
&-! *.$#6.*.0&! 1&0,#0-! F!
9&/#.0&9G!1'.9!
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Desserts
R'95'SA!%#!2.0!,&!P!TUG!1'.9!
TC! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
&-! *.$#6.*.0&! &-! #**N-&*! %&!
-*#.-&/&0-!A!%#!2.0!,&!P!FOC!
Patient en Durée du traitement = 48 semaines!

Digestifs»
échec à un B0,+-&4-#$%&! B0,+-&4-#$%& (C! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
précédent &-! *.$#6.*.0&! 1&0,#0-! F!
traitement 9&/#.0&9G!1'.9!
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TC! D,/.0.9-*&*! 1&E.0-&*2+*30! #%2#!
&-! *.$#6.*.0&! &-! #**N-&*! %&!
-*#.-&/&0-!A!%#!2.0!,&!P!FOC!
*Règles d’arrêt de traitement :
:! P.! %&! 1#-.&0-! #! '0! -#'V! ,W#4.,&! *.$30'4%+.5'&! ,'! 6.*'9! ,&! %W<+1#-.-&! X! 7D8Y:MZX?!
9'1+*.&'*!3'!+E#%!A!([[!B>/%!A!P!(H]!#**N-&*!%#!-*.-<+*#1.&C!
:!P.!%&!1#-.&0-!#!'0!D8Y:MZX!,+-&4-#$%&!4302.*/+!A!P!HF]!#**N-&*!%#!-*.-<+*#1.&C!
!
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834<&!X^_DP!"#5/#0!HC[G!#6&4!'0&!%./.-&!,&!,+-&4-.30!A!`GT!B>/%!&-!'0&!%./.-&!,&!
5'#0-.2.4#-.30!A!Ha!B>/%C!
Q
X&! 94<+/#! 0W#! +-+! -&9-+! 5'&! 4<&@! %&9! 1#-.&0-9! *+130,&'*9! %&0-9! &0! +4<&4! A! '0!
1*+4+,&0-!-*#.-&/&0-!7X2C!I*31*.+-+9!1<#*/#43,=0#/.5'&9?C !
!



1.00 _

0.75 _
Severe

0.50 _ Moderate

0.25 _
Minimal
0.00 _

FibroTest

An interactive guide for HCV

Direct Anti-viral Acting therapy


for iPad for Desktop (PC + Mac)


TELAPREVIR Guide
According to proﬁle: One simple, interactive tool
Patient previously not-treated or relapsers, not cirrhotic



TELAPREVIR Guide
According to proﬁle: One simple, interactive tool
Patients cirrhotics, previously non-responders



26 janv. 2012

Adverse events


Drug Class Contraindicated with Contraindicated with
Boceprevir Telaprevir
Alpha 1-adrenoreceptor Alfuzosin Alfuzosin
antagonist

Anticonvulsants Carbamazepine, phenobarbital, N/A
phenytoin
Antimycobacterials Rifampin Rifampin

Ergot derivatives Dihydroergotamine, ergonovine, Dihydroergotamine, ergonovine,
ergotamine, methylergonovine ergotamine, methylergonovine

GI motility agents Cisapride Cisapride

Herbal products Hypericum perforatum (St John’s Hypericum perforatum
wort)
HMG CoA reductase inhibitors Lovastatin, simvastatin Atorvastatin, lovastatin,
simvastatin
Oral contraceptives Drospirenone N/A

Neuroleptic Pimozide Pimozide

PDE5 inhibitor Sildenafil or tadalafil when used for Sildenafil or tadalafil when used
treatment of pulmonary arterial for treatment of pulmonary
hypertension arterial hypertension

Sedatives/hypnotics Triazolam; orally administered Orally administered midazolam,
midazolam triazolam


26 janv. 2012

Boceprevir-Related Adverse Events in Clinical Trials

 Most notable adverse events occurring more frequently with boceprevir plus
pegIFN/RBV vs pegIFN/RBV alone

– Anemia, neutropenia, and dysgeusia

Boceprevir + PegIFN/
Adverse Event, % PegIFN/RBV
RBV

Treatment-naive patients (n = 1225) (n = 467)
 Anemia 50 30
 Neutropenia 25 19
 Dysgeusia 35 16

Treatment-experienced patients (n = 323) (n = 80)
 Anemia 45 20
 Dysgeusia 44 11

Boceprevir [package insert]. May 2011.
55


26 janv. 2012

Telaprevir-Related Adverse Events in Clinical Trials

 Most notable adverse events occurring more frequently with telaprevir vs
pegIFN/RBV alone

– Rash, anemia, and anorectal symptoms

Telaprevir + PegIFN/RBV PegIFN/RBV
Adverse Event, %
(n = 1797) (n = 493)

Rash 56 34
Anemia 36 17
Anorectal symptoms 29 7

56 Telaprevir [package insert]. 2011.


26 janv. 2012

Telaprevir-Related Adverse Events:
Management of Rash

 Telaprevir-related rash
– Primarily eczematous
– Resolves with discontinuation of therapy
– Typically observed within ﬁrst 4 wks of treatment but can occur at any time during therapy

Rash Severity Deﬁnition

Grade 1 Mild, localized skin eruption

Grade 2 Diffuse skin eruption involving ≤ 50% of body surface area

Severe, generalized skin eruption involving > 50% of body
surfacegeneralized skin eruption involving > 50% of body surface area, or
Severe, area, or Rash with bullae, vesicles, mucous membrane
Grade33
Grade rash with substantial systemic signs/
ulceration, target lesions, purpura, or with epidermal
detachment, general symptoms
57


Boceprevir adverse events:
SPRINT-1 n=520 Genotype 1

PEG-R PEG-R Boceprevir

60%

Adverse events
55
45%

34 30%

27 15%

0%
Anemia 9
Dysgeusia

Zeuzem 2010

Telaprevir adverse events
«Advance» n=1095 750mg x 3

PEG-R 48 Tela 12 Tela 8

8%

Adverse events
7,7%
6,9% 6%
4%
3,6%
2%
0%

Telaprevir 12 stopped in: 0.8% Anemia, 1.4% Rash

Jacobson 2010

26 janv. 2012

Boceprevir vs Telaprevir: 25-30% +SVR vs PegRiba

Boceprevir Telaprevir
Lead-in PR 4 weeks No
PegInterferon 2a or 2b 2a or 2b
PI Dosing 3x4 tablets meal 3x2 tablets fatty meal
Duration PI 24-44 after 4w 12w PRI 12-36w PR
Response Guided W8 eRVR w4-12
Short treatment % 44 % 58 %
SVR % 63-66% 69-75%
Relapse % 9 % 9 %
Adverse events Anemia dysgueusia Rash, anemia, prurit,
nauea

PEG 2b 1.5 ug/kg/w 2a 180 ug Riba 800-1400 mg


26 janv. 2012

Treatment of Chronic Hepatitis C

STRATEGIES

62


26 janv. 2012

IL28B CC génotype vs non-CC: réponse au traitement
1,628 HCV Genotype 1 IDEAL study

Ge et al Nature 2009, Thomson et al, 2010


26 janv. 2012

IL28B CC génotype vs non-CC: réponse au traitement
1,628 HCV Genotype 1 IDEAL study

!

Ge et al Nature 2009, Thomson et al, 2010


26 janv. 2012

Facteurs associès à la réponse au traitement PEG-Riba
Genotype 1

Ge et al Nature 2009, Thomson et al, Gastro 2010


26 janv. 2012

Genotype 1

Odds Ratio



26 janv. 2012

Genotype 1

Odds Ratio
(All <0.0004)



26 janv. 2012

Genotype 1

Odds Ratio
(All <0.0004)

IL28B CC genotype vs non-CC 5.2



26 janv. 2012

Genotype 1

Odds Ratio
(All <0.0004)


Charge virale ≤ 600,000 vs > 600,000 IU/mL 3.1



26 janv. 2012

Genotype 1

Odds Ratio
(All <0.0004)



Caucasien vs Afro-Américain 2.8



26 janv. 2012

Genotype 1

Odds Ratio
(All <0.0004)




Fibrose METAVIR F012 vs F34 2.7



26 janv. 2012

Genotype 1

Odds Ratio
(All <0.0004)





Hispanique vs Afro-Américain 2.1



26 janv. 2012

Genotype 1

Odds Ratio
(All <0.0004)





Hispanique vs Afro-Américain 2.1

Glycémie < 5.6 vs > 5.6 mmol/L 1.7



26 janv. 2012

At week 4
Factors of response (SVR) to PEG-Riba-Boceprevir

Odds Ratio n = 912
(All <0.004)

Response 4W > Log1 2.3

Viral load baseline ≤ 400,000 vs > 400,000 IU/mL 6.3

HCV 1 Subtype 1b vs 1a 1.8

Age <40 vs >40 1.7

BMI <25 vs 25-30 vs >30 2.1

Poordad EASL 2011 Submitted 2011


26 janv. 2012

Facteur prédictifs «indépendants» de réponse virologique

Facteur PEG-Riba DAA
Genotype 2-3 (1b vs 1a ?) x x
Fibrosis stage F0F1/F2/F3/F4 x x
Viral load: baseline/W4/W8/W12.. x x
Age (Duration) x
HIV negative x
Female x
No Steatosis, Diabetes x
Ethnicity/IL28 CC CT x x
ALT elevated ActiTest x
Previous treatment/response x x

Poynard Lancet 2007, Poynard Gastroenterology 2009, Ge Nature 2009, Thompson Gastroenterology 2010

66


Background

67


26 janv. 2012

Impact of Steatosis on SVR (uni and multivariate)

No Steatosis Steatosis

100

75

50

25

G3
G2
G 1456
High viral 0
Fibrosis
G1456 HVL
G1456 VL F234

Poynard Hepatology 2003


HCV Geno-FibroTest Ref #123456

Internal reference : TEST
http://www.biopredictive.com/

Patient Biomarkers Hepatitis C
Birth date 1935-09-22 Sample date 2009-05-06 HCV Viral Load 250000
Sex Female Alpha2 3.12 g/l HCV Genotype Genotype 2
Macroglobulin
IL28B Genotype C/C
Apolipoprotein A1 1.82 g/l
Bilirubin 13.00 Ämol/l
Haptoglobin 1.18 g/l
Gamma GT 149.00 IU/l
ALT 47.00 IU/l

Tests results
FibroTest ActiTest HCV Geno-FibroTest
FibroTest assesses the ActiTest assesses activity Chance of sustained
fibrosis of the liver (inflammation in chronic virological response.
viral hepatitis C or B)

Score: 0.72 Score: 0.41 Score: 0.14
(F3) (A1-A2) (SVR ++)
F3: advanced fibrosis A1-A2: minimal activity SVR ++: very good
response

Precautions of use and interpretability
Å The reliability of results is dependent on compliance with the preanalytical and analytical conditions recommended by BioPredictive.
Å The Tests have to be deferred for: acute hemolysis, acute hepatitis, acute inflammation, extra hepatic cholestasis.
Å The advice of a specialist should be sought for interpretation in chronic hemolysis and Gilbert's syndrome.
Å The Test interpretation is not validated in liver transplant patients.
Å Isolated extreme values of one of the components should lead to caution in interpreting the results.
Å In case of discordance between a biopsy result and a Test, it is recommended to seek the advice of a specialist. The causes of these discordances could be due to a flaw of the Test or to a flaw
in the biopsy: i.e. a liver biopsy has a 33% variability rate for one fibrosis stage
Å FibroTest is interpretable for chronic hepatitis B and C, alcoholic and non alcoholic steatosis.
Å ActiTest is interpretable for chronic hepatitis B and C.
Å HCV Geno-FibroTest is interpretable when FibroTest is interpretable and when the IL28b genotype is interpretable. C/C : good response, C/T : intermediate response, T/T : poor response.


26 janv. 2012

Geno-FibroTest:
Sustained Virologic Response (SVR) to PEG-Riba

• Independent Factors (OR; P value)
100%

• Genotype 2/3 (5.7 <0.0001)
75%

• IL28B CC (4.8 <0.0001)
SVR

50%
94%
• FibroTest low (4.2 0.03)
61%
25%
44%
• ActiTest high (3.9 0.03)
19%
0% 0-0.25 0.25-0.50 0.50-0.75 0.75-1
• Viral load <5.8 Log (1.9 0.03)
HCV-GenoFibroTest Score

Costa CRHG 2011


26 janv. 2012

Geno-FibroTest:
Sustained Virologic Response (SVR) to PEG-Riba

Independent Factors Algorithm
100% • Genotype Virus 2/3/5...

75%
• IL28B CC/CT/TT

• FibroTest 0.0/1.0

SVR
50%
• ActiTest high 1.0/0.0
25%
• Viral load
1 20
0 40 60
0-0.20
0.25-0.50
0.50-0.75
80
0.75-1 100
0% • Steatosis
Sans titre 2

HCV-GenoFibroTest Score • Female

9 factors = 512 combinations • Age

• 4 weeks VL..
From 3 months to 24 months


26 janv. 2012

Chronic Hepatitis C

FibroTest ActiTest

Applicability

No (2%) Yes (98%)

F2F3F4 Advanced ﬁbrosis
FibroScan or A2A3 Advanced activity

No FibroTest ActiTest
Hepatologist Every 2-4 year

«Poynard’s Opinion» 2012

26 janv. 2012

Chronic Hepatitis C

Hepatologist

Genotype

Genotype 1 Genotype 2/3/4/5/6

3-24 months
Need Lead In Phase Accept dermato AE
according to response factors
No DAA possible Need short treatment

Boceprevir Telaprevir PEG-Riba

«Poynard’s Opinion» 2012

FibroTest screening is a cost-effective alternative to liver biopsy

«Considering screening-based strategies using triple therapy
(Telaprevir), FibroTest Only is cost-effective:

Incremental Cost-Effectiveness Ratios (ICER):

$21,200/QALY for men

$26,100/QALY for women»

Liu et al, PlosOne Dec 2011

26 janv. 2012

Prise en charge de l’Hépatite C en 2012

• Guérir du virus

• Tri-thérapie pour Génotype 1

• Bi-thérapie pour Génotype non-1

• Ne pas mourir de la cirrhose

• Traitement de maintenance pour non-répondeurs Tri (G1) ou Bi (non-1)

• Transplantation

76


26 janv. 2012

Traitement à la carte avec PEG-Riba?

• Ne pas baisser les bras : maladie virale et ﬁbrosante

• Traitement anti-ﬁbrosant

• On peut vivre avec le virus

• On peut mourir sans le virus

Poynard et al, Lancet 2003

77


26 janv. 2012

Progression de la ﬁbrose chez les patients VHC avec doubles
biopsies, traités ou non par IFN 24-48 semaines

F METAVIR
102 contrôles
4

3
91 “non répondeurs” ALT 3 mo
2

1
94 “répondeurs” ALT 3mo
0
0 10 20 30 40 Années
Sobesky et al, Gastroenterology 1999


26 janv. 2012

Incidence (per year) of Cirrhosis in patients with Chronic hepatitis C:
2 Randomized trials

Reinforced 3MU TIW 6 mo

15

10
p=0.14 p=0.004

5

0
Poynard Degos

Poynard T, N Engl J Med 1995 Degos F, J Hepatol 1998


26 janv. 2012

Histologic improvement of ﬁbrosis in patients with hepatitis C
who have sustained response to interferon therapy

• 593 patients 2 biopsies

• 106 Untreated patients 4.8 years

• 304 IFN virologic non-responders 3.2 years

• 183 IFN virologic responders 3.2 years

Y Shiratori, Ann Int Med 2000

80


26 janv. 2012

Fibrosis progression rate per year in patients with Hepatitis C

10

0

-10

-20

-30
IFN-SR IFN-NR Untreated


26 janv. 2012

Four pivotal International RCTs SPRI
Poynard et al, McHutchison et al, Lindsay et al, Manns et al

4,493 Patients
4 Trials
Naive HCV patients

3,010 Patients with paired biopsies
One pathologist
One virologist

Poynard et al Gastroenterology, 2002


26 janv. 2012

Fibrosis progression rate per year
in F2-F3-F4 with paired biopsies and duration of infection
Before After

0,2
0,1 0,14 0,14
0
0,00 -0,59
-0,1
-0,2
-0,3 P<0.001
-0,4
-0,5

NR (n=679) SVRs (n=210)

Titre de catégorie


26 janv. 2012

FibroTest: Estimates anti-ﬁbrotic impact

Baseline EOF
FibroTest
1,0
-10% -31%
0,8 0,71
0,64 0,68
0,6
0,47
0,4

0,2

0
F234 NR n=110 F234 SVR n=65
Poynard et al Hepatology, 2003
84


26 janv. 2012

Reversal of cirrhosis in 75 (49%) of patients

F0
F1
153 F2
F3
78 F4

First
Second

Poynard et al Gastroenterology 2002, Pol et al Hum Pathol 2004, Camma et al Hepatology 2004 85


Impact of treatment on FibroTest n=817
1.00

F METAVIR difference
0.75
-3
-2
Fibrotest

0.50 -1
0
1
2
0.25 3

Baseline Follow-up
0.00

Poynard et al Hepatology, 2003


26 janv. 2012

Disappearance of cirrhosis: signiﬁcant factors

No more cirrhosis n=75 Persistent cirrhosis n=78

100
89
100

80

45 47 60
33
45
15 40
Reinforced regimen 23 20
Sustained response

Age 0
Activity grade A0A1 after

Multivariate analysis P=0.02


26 janv. 2012

Reversibility of Cirrhosis

F3 Regression Pararameters (Repair Complex)
Delicate perforated septa

Isolated thick collagen ﬁbers
Delicate periportal ﬁbrosis spikes

Portal tracts, Hepatic Vein remnants
Prolapsed Hepatocytes, Inside Portal tracts or
splitting septa, minute regenerative nodules,
aberrant parenchymal veins.

F4

Wanless, Arch Pathol Lab Med 2000


10 Years Later, Right Lobe


26 janv. 2012

Beware of hepatocellular carcinoma
in sustained virological responders
previously F3 or F4


26 janv. 2012

Maintenance therapy trials

HALT-C COPILOT EPIC3

Patients Ishak 4-6 Ishak 3 – 6 Metavir 2 –4

N 1000 800 2200 (3 studies)

End-point Fibrosis/Clinical Fibrosis /Clinical Fibrosis/Clinical

PEG-IFN α−2a PegIntron®
Initial Tx. None
+riba 800 mg + Rebetol® WBD

PEG-IFN α−2a PegIntron® PegIntron®
Maintenance Tx.
90 μg 0.5 μg/kg 0.5 μg/kg
Maintenance Control Placebo Colchicine Observation
Treatment
3.5 4 3-5
Duration (years)
Recruitment
Complete Mid-point Analysis Complete
Status

92


26 janv. 2012

HALT-C: Peg 2a 90 mcg/w 3.5 years

Compliance:
• 53% still on treatment,
• 10% lower dose,
• 37% stopped therapy
Poynard, Ratziu, NEJM 2009: Lack of power ?


26 janv. 2012

HALT-C: Effective on Hepatocellular carcinoma ?

Lok Gastroenterology 2011


26 janv. 2012

Maintenance therapy trials

HALT-C COPILOT EPIC3

Patients Ishak 4-6 Ishak 3 – 6 Metavir 2 –4

N 1000 800 2200 (3 studies)

End-point Fibrosis/Clinical Fibrosis /Clinical Fibrosis/Clinical

PEG-IFN α−2a PegIntron®
Initial Tx. None
+riba 800 mg + Rebetol® WBD

PEG-IFN α−2a PegIntron® PegIntron®
Maintenance Tx.
90 μg 0.5 μg/kg 0.5 μg/kg
Maintenance Control Placebo Colchicine Observation
Treatment
3.5 4 3-5
Duration (years)
Recruitment
Complete Mid-point Analysis Complete
Status

97


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