Du2013poynardtraitementhcv 130118061904-phpapp01

18 janv. 2013

VHC
Traitement des cas simples

Thierry Poynard

LiverCenter

vendredi 18 janvier 13

18 janv. 2013

Treatment of Acute Hepatitis C:

A la carte from 0 to 1 year

LiverCenter


18 janv. 2013

The Deﬁnition of Acute Hepatitis C

• Exposure to HCV

• Within 4 months

• Anti-HCV seroconversion

• Raised ALTs

• HCV RNA positivity

3


18 janv. 2013

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


18 janv. 2013

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


18 janv. 2013

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

18 janv. 2013

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


18 janv. 2013

Anti-Viral Treatment of Acute HCV

Interferon based

10


18 janv. 2013

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


18 janv. 2013

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

Grebely, Nat Rev Gastroenterol Hepatol 2011

18 janv. 2013

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


18 janv. 2013

Anti-Viral Treatment of Acute HCV

STRATEGIES

14


18 janv. 2013

Hypothesis:
Early control of viral replication prevents chronicity

• Treat all patients ?

• Treat early ?

• Doses of PEG-IFN ?

• Ribavirin ?

• Duration of treatment ?

15


18 janv. 2013

Proposed algorithm for the treatment of acute HCV infection

CC


18 janv. 2013

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

18 janv. 2013

Treatment of Chronic Hepatitis C:

A la carte from 0 to 5 years

LiverCenter


18 janv. 2013

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, Jacobson,
2011 SVR Sherman, NEJM
Boceprevir, Telaprevir

2014 ? SVR X-vir + Y-vir ?


18 janv. 2013

Sustained Virologic Response (SVR): HCV RNA negative

SVR %
100

75

50

25
PEG-R-B/T-Previr
PEG-R
IFN-R
0 IFN 48w
IFN 24w
Control

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

20


Hépatite C : virus et marqueurs

Maturation des protéines virales
Boce/Tela-‐Previr
NS3 ARN
polymérase
dépendante
de

Hélicase l’ARN
Cytosol
Autoprotéase
Cana
ionique Protéase NS5A
Capside (viroporine)

Cofacteur
NS3
Protéine
d’ancrage
Glycoprotéines

membranaire
d’enveloppe

Lumière
du
RE

Moradpour
et
al.,
Nat
Rev
Microbiol
2007,
102(1):
63-‐74.


18 janv. 2013

Prise en charge de l’Hépatite C en 2013

• Guérir du virus

• Tri-thérapie pour Génotype 1

• Bi-thérapie pour Génotype non-1

• Ne pas mourir de la cirrhose

• Traitement de maintenancetr

• ATU avec traitements en phase 3

• Transplantation

22


18 janv. 2013

Chronic Hepatitis C

Hepatologist

Genotype

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

Boceprevir Telaprevir PEG-Riba

«Poynard’s Opinion» 2013

18 janv. 2013

Chronic Hepatitis C

Hepatologist

Genotype


3-24 months
according to response factors

PEG-Riba


18 janv. 2013

Chronic Hepatitis C

Hepatologist

Genotype


Boceprevir Telaprevir


18 janv. 2013

Genotype 1: NS3/4A Protease Inhibitor

• Boceprevir (Victrelis™)

• Telaprevir (Incivek®, Incivo® )

26


18 janv. 2013

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


18 janv. 2013

Menu traitements 2013: Changement d’atmosphère

• Genotype 1: Toujours Interferon et Ribavirine mais:

• SVR >= 70%

• Plus court

• Plus d’effets indésirables

• Risque de résistance

• Plus cher de 30 à 60.000 €

• Frustration pour les non-Genotype 1 non-répondeurs

28


18 janv. 2013

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

29


18 janv. 2013

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


18 janv. 2013

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

Kwo, Sprint-1 Lancet 2010

18 janv. 2013

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

18 janv. 2013

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

18 janv. 2013

Boceprevir, Telaprevir

Recommendations

43


Menu à la carte....of European Drug Agency
Victrelis® 200 mg gélules 2
Mentions obligatoires complètes – Juillet 2011 Vic/mlc-1107-1

Tableau 1
Durée du traitement adaptée en fonction de la cinétique virale précoce (Response-Guided Therapy/
RGT) chez les patients non cirrhotiques non préalablement traités ou en échec à un précédent
traitement par interféron et ribavirine

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 1. Administrer peginterféron alfa
traités et ribavirine pendant 4
semaines, puis
2. Poursuivre avec les trois
Indétectable Indétectable
médicaments (peginterféron

Entrées
alfa et ribavirine [PR] +
Victrelis) et arrêter le traitement
à la fin de la semaine 28
(S 28).
Durée du traitement = 48
semaines‡

Plats
1. Administrer peginterféron alfa
et ribavirine pendant 4
semaines, puis
Détectable Indétectable 2. Poursuivre avec les trois
médicaments (PR + Victrelis)

Desserts
jusqu’à la fin de S 36, puis
et ribavirine et arrêter le
traitement à la fin de S 48.
Patient en Durée du traitement = 48 semaines

Digestifs»
échec à un Indétectable Indétectable 1. Administrer peginterféron alfa
précédent et ribavirine pendant 4
traitement semaines, puis
2. Poursuivre avec les trois
médicaments (PR + Victrelis)
jusqu’à la fin de la semaine 36,
Détectable Indétectable puis
et ribavirine et arrêter le
traitement à la fin de S 48.
*Règles d’arrêt de traitement :
- Si le patient a un taux d'acide ribonucléique du virus de l'hépatite C (ARN-VHC)
supérieur ou égal à 100 UI/ml à S 12; arrêter la trithérapie.
- Si le patient a un ARN-VHC détectable confirmé à S 24; arrêter la trithérapie.
†
Dans les essais cliniques, l'ARN-VHC plasmatique a été mesuré par méthode
Roche COBAS Taqman 2.0, avec une limite de détection à 9,3 UI/ml et une limite de
quantification à 25 UI/ml.
‡
Ce schéma n'a été testé que chez les patients répondeurs lents en échec à un
précédent traitement (Cf. Propriétés pharmacodynamiques).

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


18 janv. 2013

http://www.daa-guide.com/register/


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)


What is it ?

• A tablet and desktop application

• To help prescribers

• prescribing

• explaining to patients

• training their staff

« Everything to ease DAA treatments »



Modus Operandi

• At baseline:
• Prescriber gets the application on line (iPad or Desktop PC Mac)
• Enter data defining baseline profile
• Previous treatment, previous response, chosen Direct Active Antiviral
• Fibrosis stage : Biopsy, FibroTest or Fibroscan
• A each visit
• Clinician enter ALT and viral load
• The application automatically produces for each profile
• Corresponding approved treatment
• Interactive road map
• Simple tools for followup: calendar, graphics, table



Demonstration



Login



Main Screen

My patients

Add patient



Add a patient

Only main data

- Gender, birth date, genotype 1a ou 1b, weight
- DAA Treatment (Boceprevir or Telaprevir)
-Treatment start date

Proﬁle
- Previously not-treated not-cirrhotic ?
- Previously treated not null-responder (≧2Log W12)?
- Cirrhosis ?
- Previously null-responder (<2Log W12) ?



That’s all !

adding a patient is that easy....



According to proﬁle
One simple, interactive tool

Patient previously not-treated non-cirrhotic



6 pages per patient
Services:



Proﬁle Page



With FibroTest number->
automatic input
Page Fibrosis



FibroTest Tab

Auto download

Based on optional FibroTest ID, application downloaded all
informations regarding the patient’s diagnostic :
- Fibrosis stage
- Activity grade
- IL28B proﬁle



Calendar Page

Integration
Outlook/iCal

Simple



Page Feuille de Route

«You are here»

Shorter than there..



Graphic follow-up
Treatment

ALT

Viral Load



18 janv. 2013

Summary

DAA treatment apparently complex but in fact «à la carte»

• Adapted to various proﬁles:

• From rapid responder with minimal ﬁbrosis

• To cirrhosis previously non-responder

64


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



18 janv. 2013

Adverse events


Drug Class Contraindicated with Contraindicated with
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


18 janv. 2013

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.
69


18 janv. 2013

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

70 Telaprevir [package insert]. 2011.


18 janv. 2013

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
71


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

18 janv. 2013

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

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


18 janv. 2013

Treatment of Chronic Hepatitis C

STRATEGIES

76


18 janv. 2013

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


A variant upstream of IFNL3 (IL28B) creating a new interferon gene
IFNL4 is associated with impaired clearance of hepatitis C virus
Prokuna, Nature Genetics 2013


18 janv. 2013

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

Odds Ratio
(All <0.0004)

IL28B CC genotype vs non-CC 5.2

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

Caucasien vs Afro-Américain 2.8

Fibrose METAVIR F012 vs F34 2.7

Hispanique vs Afro-Américain 2.1

Glycémie < 5.6 vs > 5.6 mmol/L 1.7

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


18 janv. 2013

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


18 janv. 2013

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

81


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 µmol/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
• The reliability of results is dependent on compliance with the preanalytical and analytical conditions recommended by BioPredictive.
• The Tests have to be deferred for: acute hemolysis, acute hepatitis, acute inflammation, extra hepatic cholestasis.
• The advice of a specialist should be sought for interpretation in chronic hemolysis and Gilbert's syndrome.
• The Test interpretation is not validated in liver transplant patients.
• Isolated extreme values of one of the components should lead to caution in interpreting the results.
• 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
• FibroTest is interpretable for chronic hepatitis B and C, alcoholic and non alcoholic steatosis.
• ActiTest is interpretable for chronic hepatitis B and C.
• 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.


18 janv. 2013

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


18 janv. 2013

Chronic Hepatitis C

FibroTest ActiTest

Applicability

No (2%) Yes (98%)

F2F3F4 Advanced ﬁbrosis
FibroScan or AixPlorer or A2A3 Advanced activity

No FibroTest ActiTest
Hepatologist Every 2-4 year


18 janv. 2013

Chronic Hepatitis C

Hepatologist

Genotype


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

Boceprevir Telaprevir PEG-Riba


18 janv. 2013

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 2011
86


18 janv. 2013

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

2
91 “non répondeurs” ALT 3 mo

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


18 janv. 2013

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


18 janv. 2013

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


18 janv. 2013

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
Poynard et al Gastroenterology, 2002


18 janv. 2013

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
91


18 janv. 2013

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 92


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


18 janv. 2013

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


18 janv. 2013

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


18 janv. 2013

Survie sans complications du VHC

n = 933
NS

SVR n=4
3 HCC
1 Cholangiocarcinome
Tous F4 avant
2 F2 après


18 janv. 2013

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

99


EPIC 3 Program Design
Non-Responder Trial: N=2200
CHC with ﬁbrosis (F2, F3 or F4 METAVIR)
who failed to respond any IFN alfa/alpha + Ribavirin
PEG-Intron 1.5 μg/kg/wk + Rebetol 800-1400mg/d
N=3136 screened*, 1843 treated* 1369 analyzed for EVR *

HCV RNA negative at week 12 METAVIR F4 CHC subjects
Subject continue 36 weeks trt Non-responder to any
+ 24 weeks follow-up IFN alfa/alpha + Ribavirin
978 analyzed for SVR* DIRECT ENROLLERS
570 EVR: 341 neg 229 pos
346 non EVR 2 na

Chronic Suppression for Chronic Suppression
Non-Cirrhotics, n=700 for Cirrhotics, n=1000
HCV RNA positive at week 12 HCV RNA positive at week 12
METAVIR F2 or F3 subjects METAVIR F4 subjects
PEG-Intron 0.5μg/kg/wk vs. control PEG-Intron 0.5μg/kg/wk vs. control
Duration: 3 years Max duration: 5 years
385 Randomized* 404 Randomized*
100


18 janv. 2013

Multivariate Regression Analysis P < 0.0001
Predictors of Response: 23% SVR second chance

• HCV genotype G2/3 vs. G1

• Previous response: Relapser vs. non-responder

• Baseline METAVIR ﬁbrosis score F2/F3/F4

• Previous IFN treatment (PEG or not)

• Baseline viral load

Poynard Gastroenterology 2009, J Hepatol 2010

101


Prognostic value of FibroTest
in 1,459 HCV virological non responders
EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40
40

30
29
SVR %

27 27
24
20
20
16 15
10

0 All Biopsy n=1459 All FibroTest n=1459

Poynard Gastroenterology 2009, J Hepatol 2011


18 janv. 2013

HCV EPIC3 PEG interferon maintenance
in Cirrhotic patients n=441: Improvement FibroTest/ActiTest (Actitest)

PEG2b (n=222) Controls (n=219)

P=0.006 P=0.29 P=0.0006 20

Improvement %
16

12

8

4

1 Grade 0
1 Stage Either

Bruix, Poynard et al Gastroenterology 2011


18 janv. 2013

HCV EPIC3 randomized PegInterferon maintenance in
358 F2/F3 patients: impact on FibroTest
PEG2b (n=174) Controls (n=184)

P=0.31 P=0.05 P=0.003

Difference FibroTest
0,100

0,070 0,05

0,040 0,03
0,02

0,010

-0,020 -0,003 -0,004
-0,01

-0,050
1 year 2 years 3 years

Poynard et al J Hepatol 2012


18 janv. 2013

Maintenance therapy with Ribavirin alone
Interferon
Follow-up
Ribavirin Tx

120 P=0.06 n=32
100

80 Sustained R
ALT
Ribavirin
IU/L 60 Placebo

40

20

0
Baseline EOT 12 months 18 months

Hoofnagle et al Hepatology, 2003 105


18 janv. 2013

Improvement of Activity Grade (HAI) with Ribavirin
16 Ribavirin 1.0-1.2 vs 16 patients placebo non viral responders

Activity Grade Ribavirin
Placebo
10 P=0.02
8

6

4

2

0
M0 M18

Hoofnagle et al, Hepatology 2003

322 Outpatients

131 (41%) of patients
report poor communication
with physicians

28% 23%
9%
Physician incompetence Feelings of Misdiagnosis
Stigmatized by Physician
Dx and Tx Abandoned
(n=29)
(n=91) (n=74)

Zickmund S, Hepatology 2004 107


18 janv. 2013

Time course of side effects

Hematologic side effects
Severity

Flu-like Fatigue
symptoms

Depressive/anxiety
symptoms

0 1 2 3 4 5 6 7 8 9 10 11 12

IFN-Riba Treatment (Weeks)
108


Time Course of Treatment-Associated
Psychiatric Adverse Effects

100

80
Incidence/Severity

Depression
60
Anxiety
40 FaPgue

20
Inﬂuenza-‐like

symptoms
0
0 1 2 3 4
Months

Dan,
J
Hepatol.
2006;

Constant

J
Clin
Psychiatry.
2005


18 janv. 2013

Effect of Adherence on SVR
PEG-IFN α-2b 1.5 μg/kg QW α-2b + ribavirin 800-1,400 mg/day

Adherent ≥80% of both drugs (n=35/146)
Not Adherent <80% of one or both drugs (n=7/21)

0,97
0,84
0,71 0,76

HCV 2
HCV 3

Zeuzem et al, J Hepatol, 2004

110


Hépatite C : virus et marqueurs

Maturation des protéines virales
NS3 ARN
polymérase
dépendante
de

Hélicase l’ARN
Cytosol
Autoprotéase
Cana
ionique Protéase NS5A
Capside (viroporine)

Cofacteur
NS3
Protéine
d’ancrage
Glycoprotéines

membranaire
d’enveloppe

Lumière
du
RE

Moradpour
et
al.,
Nat
Rev
Microbiol
2007,
102(1):
63-‐74.


GS-Sofosbuvir

BMS-791325

ATU
?
ABT-333

BMS-Daclatasvir
BI-207127
GS-5885

ABT-267 BMS-Asunaprevir BI-Faldaprevir J-Simeprevir
ABT-450


Phase
3
HCV:
BMS
Results
2013
• Daclatasvir
+
Asunaprevir
+
PEG-‐IFN
+
Riba
• G1/G4
NR
• Daclatasvir
+
Asunaprevir

• 2
Japanese:
1
NR/ineligible;
1
vs
Telaprevir
Results
2014
• Daclatasvir
+
Asunaprevir:
G1
Naïve/NR
• Daclatasvir
+
PEG-‐IFN
+
Riba:
G1
naive
• Daclatasvir
+
PegIFN-‐lambda:
G1b
Naïve/Relapser
Results
2015:
(IFN-‐Ribavirin-‐Ritonavir)
Free
start
2014
• Daclatasvir
+
Asunaprevir
+
BMS-‐791325


18 janv. 2013

Daclatasvir + Asunaprevir
in 9 HCV genotype 1b-infected null responders

1a et
Daclatasvir ?

115 Chayama Hepatology 2012

18 janv. 2013

Daclatasvir + Asunaprevir
in 11 HCV genotype 1a (n=9) and 1b (n=2) null responders

1a et Daclatasvir ?

116 Lok NEJM 2012

18 janv. 2013

Quadri Therapy: PEG-Riba + Daclatasvir + Asunaprevir
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

117 Lok NEJM 2012

Phase
3
HCV:
Gilead
Results
2013
• Sofosbuvir
+
Ribavirin
– G2/G3
no
alternaMve:
3
trials
12-‐16W
• SVR12=

93%/61%
vs
0%
(Placebo)
• Sofosbuvir
+
Ribavirin
+
PEG-‐IFN
– G1/G4/G5/G6
naïve
12W
Results
2014

One
Pill
• Sofosbuvir

+
NS5A
inhibitor
GS-‐5885
– G1
:
No
calendar


18 janv. 2013

NEJM 2013:

119


Phase
3
HCV:
AbboY
Results
2013
• ABT-‐450
+
Ritonavir
+
ABT-‐267
+
ABT-‐333
In
G1
(Naïve/NR)

97%/93%
phase
2

– Non-‐F4:
12W
with
and
without
Ribavirin
– F4:
12-‐24W
with
Ribavirin


18 janv. 2013

NEJM 2013
A: ABT-333 + Ribavirin + 250 mg ABT-450/ + 100 mg Ritonavir
B/C: ABT-333 + Ribavirin + 100 mg ABT-450/ + 100 mg Ritonavir

Naive

Naive

Null/
Partial

121


Pre-‐Phase
3
HCV:
Boehringer
Results
2014
• Faldaprevir

(BI
201335)
+
BI
207127
+
Ribavirin
G1
including
F4


Phase
3
HCV:
Medivir
Janssen
Results
2014?
• Simeprevir

(TMC435)
+
Ribavirin
+
PEG-‐IFN
12W
All
genotypes
?
Naïve/NR


18 janv. 2013

2 dernières questions

• Faut il faire attendre des malades, pour les traitements sans IFN ?

• Peut-on utiliser Boceprevir ou Telaprevir pour des génotypes
non-1 ?

124


18 janv. 2013

Réponses (1)
Faut il faire attendre des malades, pour les traitements sans IFN ?

• Oui si F0-F1 ou F2 stables protocole «IFN Free»

• Non si

• F2 rapid ﬁbroseur

• F3/F4

• Traiter par ATU ou

• Plus forte dose PEG-Riba si 4 Semaines <1Log + Boce-Tela

• Si toujours PCR positif 8S: maintenance PEG-Riba a dose supportable

125


18 janv. 2013

Réponses (2)
Peut-on utiliser Boceprevir ou Telaprevir pour des génotypes non-1 ?

• Boceprevir: non

• Telaprevir: cas par cas

• G2 grave OUI

• G4 peut-être...

126


18 janv. 2013

Telaprevir: Genotype 2 yes, Genotype 3 no

127 Foster Gastro 2011

18 janv. 2013

Telaprevir/PEG-Riba efﬁcacy according to genotype
(Log VL decrease)

1/8 (15%) patient genotype 4 was PCR negative at day 5
Benhamou EASL 2009

128


18 janv. 2013

Résumé:
Traitement hépatite C en 2013
• Intensifier dépistage

• Simplifier bilan initial et suivi: biomarqueurs validés

• Traiter « à la carte »: pharmaco-génomique

• Genotype 1a, IL28b, Fibrose, Activité, Poids, Stéatose,

• ATU si fibrose avancée et non-répondeur

• Tolérance clinico-biologique, résistance

• Ne pas oublier l’efficacité non virologique:

• Freiner la progression de la Fibrose

• Surveiller les F2F3F4 «Guéris virologiques»

129


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