VHC_Traitement des cas simples et cas compliqués.pdf

13 janv. 2011

VHC
Traitement des cas simples
Traitement des cas compliqués

Thierry Poynard
Vlad Ratziu, Yves Benhamou

http://www.slideshare.net/odeckmyn

LiverCenter

jeudi 13 janvier 2011

13 janv. 2011

Treatment of Acute Hepatitis C:

A la carte from 0 to 1 year

LiverCenter


13 janv. 2011

The Deﬁnition of Acute Hepatitis C

• Exposure to HCV

• Within 4 months

• Anti-HCV seroconversion

• Raised ALTs

• HCVRNA positivity

3


13 janv. 2011

Rationale for Treating Acute HCV

• High risk of chronicity

• Risk of spreading the virus

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

4


13 janv. 2011

Anti-Viral Treatment of Acute HCV

• Randomized controlled trials

• Meta-analysis

• Uncontrolled trials

5


13 janv. 2011

RCTs of IFNα in Acute HCV

4 trials; n=141 All IFN α-2b alone
All patients transfused 12 weeks of treatment
Age 51yrs, 62% males 9-15 months fw-up

• Villadomiu n=28 Hepatology 1992

• Li n=32 China J Int Med 1993

• Lampertico n=48 Hepatology 1994

• Hwang n=23 J Hepatol 1994

6


13 janv. 2011

Meta-Analysis of IFN α-2b RCTs in Acute HCV
Sustained Response (12mo)
Control
% Response Interferon
60

45
P < 0.0001

30

15

0

Normal ALT Negative HCVRNA
Myers R, Cochrane Database Syst Rev 2003

7


13 janv. 2011

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

Hwang 1994 (n=33) OR (95% CI)
Lampertico 1994 (n=48)
Li 1993 (n=32) 4.8 (1.1-22)
TOTAL (n=113) 7.7 (1.6-38)
9.9 (1.5-65)

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

8


13 janv. 2011

IFN-α2b Treatment of Acute Hepatitis C
Uncontrolled Trial (N=44)

• Characteristics: Interferon a-2b for 6 months:
• Young 36 yrs Induction dose: 5MU daily for 4 wks
• Females (57%) Regular dose: 3MU tiw for 20 wks
• Symptomatic (jaundice 68%) Follow-up 24 wks post Rx for viral end-point
• Genotype 1 (68%)

89 days
(30-112)
54 days (15-105)

CONTAMINATION SYMPTOMS TREATMENT

Jackel, N Engl J Med 2001

9


13 janv. 2011

Acute Hepatitis C :
43 patients followed 42 sustained responders normal ALT 1 lost follow up
Tolerance: 1 stop 12 weeks adverse events

IFN 5 M/day
% HCV RNA+ IFN 5 M TIW

100

75

50

25

0
Inclusion 12w 24w 48w

Jaeckel E et al. N Engl J Med 2001


13 janv. 2011

Anti-Viral Treatment of Acute HCV

STRATEGIES

11


13 janv. 2011

Hypothesis:
Early control of viral replication prevents chronicity

• Treat all patients ?

• Treat early ?

• Doses of IFN ?

• Ribavirin ?

• Duration of treatment ?

12


13 janv. 2011

Spontaneous Viral Clearance After
Acute HCV Infection

% VIRAL
TIME PERIOD AUTHOR (N)
CLEARANCE

1985-1991 Alter (n=106) 38*
1993-2000 Gerlach (n=54) 44
1988-1996 Villano (n=43) 14
2000-2001 Hofer (n=12) 67

* No PCR, ALT data only

13


13 janv. 2011

Prevalence of Symptoms According to Outcome
Self limited Chronic

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

14

13 janv. 2011

Predictors of Spontaneous Viral Clearance ...

• IL28b CC genotype

• Younger age (?)

• Females (?)

• White vs. Blacks (?)

• Rare Quasispecies

• Genotype non-1

• ALT useless

• Can normalize despite viral persistence (50%)

15


13 janv. 2011

Early Prediction of HCV Clearance
After Acute Infection ?

Self Limited Chronic

Days after onset of symptoms
Hofer, Hepatology 2003

16


13 janv. 2011

Acute hepatitis C and HIV coinfection

• «People coinfected with HIV and hepatitis C might progress to
chronic liver disease more quickly.

• Several recent reports have documented acute hepatitis C
among men who have sex with men who engage in high risk
sexual practices and often have concomitant genital ulcer
disease.»

Jodie Dionne-Odom, Lancet Infect Dis 2009

17


13 janv. 2011

Proposal: Treatment Restricted to Patients
that Fail to Clear the Virus

• Asymptomatic or

• HCVRNA still detectable 3-4 months after onset of
symptoms

• PEG IFN (± ribavirin) treatment, at least 24 weeks ??

18


13 janv. 2011

Treatment of Chronic Hepatitis C:

A la carte from 0 to 5 years

LiverCenter


13 janv. 2011

Approval of HCV treatments


13 janv. 2011

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 ??


13 janv. 2011

Chronic Hepatitis C

FibroTest ActiTest

Fibroscan if FibroTest
not applicable

Advanced Fibrosis No Advanced Fibrosis
Severe Activity No Severe Activity

FibroTest
Hepatologist
every 2-4 years

GHPS/ HAS for HCV Dec 2007

13 janv. 2011

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

22


13 janv. 2011

Parler l’Hépatan: Dictionnaire actualisé

23


13 janv. 2011


• DAA: Direct-Acting Antiviral therapy: «Anti-viral»

23


13 janv. 2011



• STAT-C: Speciﬁcally Targeted Antiviral Therapy for HCV: «Anti-viral»

23


13 janv. 2011




• Response guided therapy: «A la carte»

23


13 janv. 2011





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

23


13 janv. 2011






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

23


13 janv. 2011







• Lead-in phase: «Première partie»

23


13 janv. 2011








• Pharmaco-Genomic: IL28B genotype

23


13 janv. 2011









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

23


13 janv. 2011









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

• Genotype-1 sub type

23


13 janv. 2011

Menu traitements 2011: Changement d’atmosphère

• Genotype 1: Still Interferon and Ribavirin but:

• SVR >= 70%

• Shorter duration

• Increase side effects

• Resistance

• More expensive

• Frustration for non-Genotype 1

24


13 janv. 2011

Prise en charge de l’Hépatite C en 2011

• Guérir du virus

• Tri-thérapie pour Génotype 1

• Bi-thérapie pour Génotype non-1

• Ne pas mourir de la cirrhose

• Traitement de maintenance

• Transplantation

25


13 janv. 2011


13 janv. 2011

HCV: Actualités thérapeutiques
2 nouveaux traitements pour Génotype 1

• Boceprevir

• Telaprevir

31


13 janv. 2011

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

Kwo, Sprint-1 Lancet 2010

13 janv. 2011

Non responders


13 janv. 2011

Boceprevir: 4-8-24

• Approximately 50% of
patients BOC RGT arm
were eligible for shorter
therapy

• Week 8 is a good timepoint
to assess whether a patient
should receive 28-week or
48-week BOC RGT


13 janv. 2011

PR 4 Week Lead-In as a Predictor of Response

• Lead-in allows real time assessment of patient’s interferon responsiveness vs.
historic response

• 26% (102/393) of RESPOND-2 patients had a < 1 log10 decline in HCV viral
load at week 4

41


13 janv. 2011

SVR by Week 4 PR Lead-In Response


13 janv. 2011

Adverse events


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

13 janv. 2011

HCV: Actualités thérapeutiques
2 nouveaux traitements pour Génotype 1

• Boceprevir

• Telaprevir

47


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

PEG-R 48 Tela 12 Tela 8

100%

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

Jacobson 2010

HCV genotype 1 naive patients: Telaprevir Efﬁcacy
«ILLUMINATE» n=540 750mg x 3

Tela PG 24 Tela PG 48 Overall

100%
92% 88% 75%
72% 50%
25%
0%

Response guided vs ﬁxed duration ?

Sherman 2010

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

PEG-R 48 Telaprevir

90%

Stage METAVIR
86
68%

57 45%

24 23%
31
15 0%
Relapsers
Partial 5
Null

Zeuzem 2010

HCV genotype 1 naive patients: 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

BOCEPREVIR


BOCEPREVIR

Week 4
PEG-Riba (PR)


BOCEPREVIR HCV RNA

Week 4
PEG-Riba (PR)


BOCEPREVIR HCV RNA

Week 4
PEG-Riba (PR) Negative 90% SVR PR


BOCEPREVIR HCV RNA

Week 4

Positive


BOCEPREVIR HCV RNA

Week 4

Positive

Week 8
Boce +PR

Week 24
Boce +PR


BOCEPREVIR HCV RNA

Week 4

Positive

Week 8 Negative
Boce +PR

Negative
Week 24
Boce +PR

Stop
SVR

BOCEPREVIR HCV RNA

Week 4

Positive

Week 8 Negative
Boce +PR

Negative Positive
Week 24
Boce +PR

Stop Stop
SVR Resistance?


BOCEPREVIR HCV RNA

Week 4

Positive

Week 8 Negative Positive
Boce +PR

Negative Positive Negative
Week 24
Boce +PR

Stop Stop Boce+PR
SVR Resistance? Week 48


BOCEPREVIR HCV RNA

Week 4

Positive

Week 8 Negative Positive
Boce +PR

Negative Positive Negative Positive
Week 24
Boce +PR

Stop Stop Boce+PR Stop
SVR Resistance? Week 48 Failure ?


TELAPREVIR


TELAPREVIR

Week 4
Tela + PR


TELAPREVIR HCV RNA

Week 4
Tela + PR


TELAPREVIR HCV RNA

Week 4
Tela + PR

Week 12
Tela + PR

Week 24
PR only


TELAPREVIR HCV RNA

Week 4
Tela + PR Negative

Week 12
Negative
Tela + PR

Week 24 Stop
PR only SVR


TELAPREVIR HCV RNA

Week 4
Tela + PR Negative

Week 12
Negative Positive
Tela + PR

Stop
Week 24 Stop Resistance?

PR only SVR


TELAPREVIR HCV RNA

Week 4
Tela + PR Negative Positive

Week 12
Negative Positive Negative
Tela + PR

Stop PR only
Stop Resistance? Week 48
Week 24
PR only SVR


TELAPREVIR HCV RNA

Week 4
Tela + PR Negative Positive

Week 12
Negative Positive Negative Positive
Tela + PR

Stop PR only Stop
Stop Resistance? Week 48 Failure ?
Week 24
PR only SVR


13 janv. 2011

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

Boceprevir Telaprevir
Lead-in PR 4 weeks No
PegInterferon 2b 2a
PI Dosing 3x 3x 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


13 janv. 2011

ATU


13 janv. 2011

Autorisation Temporaire Utilisation
depuis 3 Janvier 2011

Boceprevir et Telaprevir

www.triton.u707.jussieu/cupic.fr


13 janv. 2011

Population concernée

• Génotype 1

• Cirrhose: biopsie, Fibroscan, Fibrotest, Fibromètre, Hepascore

• Child A

• Non répondeurs «répondeurs nuls exclus» (Leadin phase)

– Rechuteurs

– Répondeurs partiels

(↓ de la virémie > 2 log à S12 et ARN détectable à S24)


13 janv. 2011

Telaprevir (INCIVO)

TPR PR

S0 S12 S48

Telaprevir : 375 mg, 2 cp/8h
Pegasys : 180 µg/semaine
Copegus : 1000 à 1200 mg/j

Règles d’arrêt :
PCR > 100 UI/ml à S4, S8 : arrêt du telaprevir
PCR > 100 UI/ml à S12 : arrêt de tous les traitements
PCR ≥ 25 UI/ml à S24, S36


13 janv. 2011

Boceprevir

PR PBR

S0 S4 S48

Boceprevir 200 mg, 4 cp/8h
ViraferonPeg, 1,5 µg/kg/semaine
Rebetol, 800 à 1400 mg/j

Règles d’arrêt :
PCR détectable à partir de S12 : arrêt de tous les
traitements


13 janv. 2011

CUPIC


13 janv. 2011

CUPIC

Observatoire de l’échec thérapeutique et des résistances
- malades traités par un inhibiteur de protéase (telaprevir ou
boceprevir) et la combinaison interféron pégylé et
ribavirine

- dans le cadre de l’ATU de cohorte génotype 1,
- mono-infectés, cirrhose
- n’ayant pas éradiqué le VHC lors d’un traitement antérieur
par IFN plus ou moins associé à de la ribavirine


13 janv. 2011

Objectif principal

• Evaluer l’efﬁcacité thérapeutique,

• Déﬁnie par l’obtention d’une RVS

(PCR indétectable 24 semaines après l’arrêt du
traitement)


13 janv. 2011

Objectifs secondaires (1)
• Fréquence des résistances au telaprevir et boceprevir

• Impact de la cinétique de la décroissance virale sur la survenue de
l’échec au traitement et de la résistance

• Identiﬁcation et caractérisation génotypique et phénotypique des
variants sélectionnés

• Suivi de l’évolution à 1 an des variants

• Analyse des facteurs prédictifs cliniques et biologiques pré- et per-
thérapeutiques de la réponse virologique et de la survenue de
résistance

• Impact du polymorphisme de l’IL-28B


13 janv. 2011

Objectifs secondaires (2)
• Impact de la concentration résiduelle de telaprevir ou de
boceprevir à S4 sur la réponse virologique à court et long terme

• Observance et son impact sur l’échec et les résistances

• Tolérance et causes d’arrêt prématuré

• Tolérance et efﬁcacité de la trithérapie chez les patients traités
par méthadone ou buprénorphine

• Interactions médicamenteuses éventuelles et impact sur
l’efﬁcacité et la tolérance

• Qualité de vie, avant, pendant et après le traitement


13 janv. 2011

• Effectif : 900

(70 % des 1300 patients de l’ATU)

• Critères d’inclusion : patients de l’ATU

• Critères de non inclusion : aucun


13 janv. 2011

A la Boce ou à la Tela....Previr
A la carte Suisse, ou à l’Américaine ?

71


13 janv. 2011

IDEAL Study Design
HCV 1 Naive to Previous Therapy
PEG-IFN α-2b + ribavirin 800-1400mg/daily
1.5 µg/kg QW (48 wks) N=960

Screening PEG-IFN α-2b + ribavirin 800-1400mg/daily
1.0 µg/kg QW (48 wks) N=960
S*
PEG-IFN α-2a + ribavirin 1000-1200mg/daily
180 µg QW (48 weeks) N=960

Endpoint 48 weeks 24 weeks
Follow-up
S* Stratification: Baseline HCV < vs ≥ 600,000 IU & African American vs non AA
Primary Endpoint: Loss of serum HCV RNA 24 weeks posttreatment

72


13 janv. 2011

IDEAL results n=3,070

PEG 2b 1.5 PEG 2b 1.0 PEG 2a

50

40

30

20

10

0
SVR Relapse Discontinuation AE

82% >= 600.000 IU/mL, 11% F3F4, 19% African American


13 janv. 2011

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


13 janv. 2011

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


13 janv. 2011

Facteurs associès à la réponse au traitement (Genotype 1)

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


13 janv. 2011


Odds Ratio



13 janv. 2011


Odds Ratio
(All <0.0004)



13 janv. 2011


Odds Ratio
(All <0.0004)

IL28B CC genotype vs non-CC 5.2



13 janv. 2011


Odds Ratio
(All <0.0004)


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



13 janv. 2011


Odds Ratio
(All <0.0004)



Caucasien vs Afro-Américain 2.8



13 janv. 2011


Odds Ratio
(All <0.0004)




Fibrose METAVIR F012 vs F34 2.7



13 janv. 2011


Odds Ratio
(All <0.0004)





Hispanique vs Afro-Américain 2.1



13 janv. 2011


Odds Ratio
(All <0.0004)





Hispanique vs Afro-Américain 2.1

Glycémie < 5.6 vs > 5.6 mmol/L 1.7



13 janv. 2011

Facteur prédictifs «indépendants» de réponse virologique

Facteur Naïf 2ème Chance
Baseline 12 Weeks Baseline 12 weeks
Genotype x x x x
Fibrosis stage x x x x
Viral load x x x x
Age (Duration) x
HIV x ? ? ?
Male x
Stéatose, Diabète x ? ?
Ethnicity/IL28 x ? ? ?
ALT elevated x
Previous treatment X

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

76


13 janv. 2011







• Transplantation

78


13 janv. 2011

Traitement à la carte avec PEG-Riba?

• Attention aux faux amis

• G2 et G3

mais

• F2F3F4

• Attention au gras et au sucre

Poynard et al Hepatology 2000, Lancet 2003, Hepatology 2003

79


13 janv. 2011

Results: SVR Genotype 2 and 3
PEG-IFN α-2b 1.5 μg/kg QW α-2b + ribavirin 800-1,400 mg/day

100

75

50

25

0
HCV 2 (n=42) HCV 3 (n=182)

Zeuzem et al, J Hepatol, 2004

80


13 janv. 2011

Results: SVR Genotype 2 and 3
≤ or > 600,000 IU
PEG-IFN α-2b 1.5 μg/kg QW α-2b + ribavirin 800-1,400 mg/day

100

75

50

25

0
G2 ≤ 6 (n=20) G2 > 6 (n=22) G3 ≤ 6 (n=99) G3 > 6 (n=83)

Zeuzem et al, J Hepatol, 2004

81


13 janv. 2011

A la carte regimen with PEG-Riba?

• Longer duration for Genotype 2 and 3 if

• Advanced ﬁbrosis F2F3F4

• Steatosis in genotype 2

• HIV


82


13 janv. 2011

Genotype 2 and 3 patients F2F3F4
treated PEG IFN alfa 2b and ribavirin ﬂat dose

SVR %
78,0

58,5

39,0

19,5

0
PEG IFN-R 48w n=54

83 Zeuzem et al, J Hepatol, 2004


13 janv. 2011

Genotype 2 and 3 patients with bridging ﬁbrosis
treated PEG IFN alfa 2a and ribavirin weight based dose

SVR
100%

75%

50%

25%

0%
PEG IFN-R 24w n=20

Hadziyannis et al Ann Inter Med, 2004

84


13 janv. 2011


SVR
100%

75%

50%

25%

0%
PEG IFN-R 24w n=20 PEG IFN-R 48w n=33


85


13 janv. 2011


SVR

74

56

37

19

0
PEG IFN-R 24w n=20 PEG IFN-R 48w n=33


86


13 janv. 2011

treated PEG IFN alfa 2b and ribavirin weight based dose
14 weeks for VEVR*, 24 weeks for NVEVR

EOT SVR
100

75

50

25

0
EVR PEG IFN-R 14w n=14 NEVR PEG IFN-R 24w n=14

*Undetectable 4,8 W
Dalgart et al Hepatology, 2004

87


13 janv. 2011

A la carte regimen with PEG-Riba for Genotype 2/3 ?

• Shorter duration (2-4 months)

• If PCR negative 4 weeks and no relapse factors:

• HIV,

• Advanced ﬁbrosis,

• Insulin resistance


88


13 janv. 2011

Genotype 2 and 3 patients
treated PEG IFN alfa 2b 1.0 ug/Kg and ribavirin weight based dose
12 weeks for VEVR*, 24 weeks for NVEVR

Standard Variable

80

60

40

20

0
VEVR SVR

*Undetectable 4 W Mangia et al NEJM, 2005

89


Background

90


13 janv. 2011

Impact of Steatosis on SVR (uni and multivariate)

No Steatosis Steatosis

100

75

50

25

G3
G1,4,5,6 0
Fibrosis
G1,4,5,6 HVL+ﬁbrosis

Poynard Hepatology 2003


13 janv. 2011







• Transplantation

92


13 janv. 2011

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

93


13 janv. 2011

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


13 janv. 2011

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


13 janv. 2011

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

96


13 janv. 2011

Fibrosis progression rate per year in patients with Hepatitis C

10

0

-10

-20

-30
IFN-SR IFN-NR Untreated


13 janv. 2011

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


13 janv. 2011

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


13 janv. 2011

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
100


13 janv. 2011

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 2004101


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


13 janv. 2011

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


13 janv. 2011

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


13 janv. 2011

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


13 janv. 2011

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

108


13 janv. 2011

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

Compliance:
• 53% still on treatment,
• 10% lower dose,
• 37% stopped therapy


13 janv. 2011

Poynard, Ratziu, NEJM 2009: Lack of power ?
• The results only show that, as anticipated in the power calculations, therapy
cannot halve the progression rate.

• The number of patients correctly treated with paired biopsies at 3.5 years, needs
to be given and compared to the number needed to demonstrate a reduction by
two of progression with 18 mm biopsies.
• The risk of false negative conclusion seems even higher, as a significant impact on
necrosis and inflammation has been observed.
• Biomarkers to increase the power should have been considered.

• The impact on necroinflammatory lesions and transaminases is good news, as
these endpoints led to approval of interferon in the first place.

• Mortality related to HCV is still growing and the agencies should wait for more trials
before reaching such a conclusion.

111


13 janv. 2011

Lok et al Gastroenterology 2011


13 janv. 2011

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

114


13 janv. 2011

COPILOT – Study Design

PEG-IFN-α2b 0.5 µg/kg/wk
Interferon /
Rebetron /
PEG + RIB
Non-responders
F2-F4
Colchicine 0.6 mg bid

Clinical US
LB, US, q 24 Endoscopy, Endoscopy,
Evaluation
endoscopy q 12 Weeks Weeks LB LB

Baseline 12 weeks 24 weeks 2 years 5 4 years
Jahre

 557 patients enrolled
 Ishak Fibrosis Stage > 3
115


13 janv. 2011

PEG-IFN alfa-2b: effective maintenance for patients with
portal hypertension (PHTN)

No. PHTN PHTN

Colchicine 134 126

Events 8 (6%) 34 (27%)*

PEG-IFN alfa-2b 155 111

Events 12 (7%) 14 (11%)*

*Fishers test, P<0.004: PEG-IFN alfa-2b vs. Colchicine
116


13 janv. 2011

Development of PHTN at year 2
Among patients without PHTN at baseline

Colchicine PEG-IFN alfa 2b

• 92 patients at risk • 95 patients at risk
• 8 varices
• 20 varices • 4 gastropathy

• 4 gastropathy
• Overall 12%*
• 2 patients developed new varices
with bleeding within initial 2 years

• Overall 28%* * p = 0.03

117


13 janv. 2011

Portal pressure Studies on Peg-IFN alfa 2b 0.5mcg/kg

mm Hg 30
Mean 15mmHg
25

20
Mean 8mmHg
15

10

5

0 Baseline 24 weeks
118


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
Subject continue 36 weeks trt
+ 24 weeks follow-up
978 analyzed for SVR*
570 EVR: 341 neg 229 pos
346 non EVR 2 na

Chronic Suppression for
Non-Cirrhotics, n=700
HCV RNA positive at week 12
METAVIR F2 or F3 subjects
PEG-Intron 0.5μg/kg/wk vs. control
Duration: 3 years
385 Randomized*
119



HCV RNA negative at week 12
Subject continue 36 weeks trt
+ 24 weeks follow-up
978 analyzed for SVR*
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*
119



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*
119


13 janv. 2011

Multivariate Regression Analysis
Predictors of Response

• HCV genotype
• G2/3 vs. G1, OR = 4.9; P < 0.0001

• Previous treatment response
• Relapser vs. non-responder, OR = 3.8, P <0.0001
• Baseline METAVIR ﬁbrosis score
• F2 vs. F4, OR = 2.2; P = <.0001 / F3 vs F4, OR = 1.4; P = 0.0183
• Previous treatment
• IFN α + RBV vs. PEG-IFN α + RBV, OR = 2.0, P <0 .0001
• Baseline viral load
• ≤600,000 IU/mL vs. > 600,000 IU/mL, OR = 1.9, P < 0.0001

120


13 janv. 2011

SVR in Prior Non-Responders to Peg-Riba

Peg-IFN α-2 a + b/R,
n = 476

All Patients 0,04

G1 F4 0,04

G1 F3 0,04

G1 F2 0,06

G2/3 F4 0,18

G2/3 F3 0,38

G2/3 F2 0,56

121


13 janv. 2011

SVR in Prior Relapsers to Peg-Riba

Peg-IFN α-2 a + b/R,
n = 344

All Patients 0,32

G1 F4 0,18

G1 F3 0,21

G1 F2 0,32

G2/3 F4 0,51

G2/3 F3 0,62

G2/3 F2 0,61

122


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

F0 F1 F2 F3 F4

Poynard Gastroenterology 2009, J Hepatol 2010


EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40

30
SVR %

20

10

0 All Biopsy n=1459 All FibroTest n=1459



EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40

30
SVR %

27

20

10




EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40

30
SVR %

27
24
20

10




EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40

30
SVR %

27
24
20

16

10




EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40
40

30
SVR %

27
24
20

16

10




EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40
40

30
29
SVR %

27
24
20

16

10




EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40
40

30
29
SVR %

27 27
24
20

16

10




EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40
40

30
29
SVR %

27 27
24
20
20
16

10




EPIC-3 Trial 2009

F0 F1 F2 F3 F4

40
40

30
29
SVR %

27 27
24
20
20
16 15
10




13 janv. 2011

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

Poynard et al AASLD 2009


13 janv. 2011

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 AASLD 2009


13 janv. 2011

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 126


13 janv. 2011

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

13 janv. 2011

Difﬁcult to treat patients

• Adverse events • Cirrhotic • Coinfected HIV

• Aged patients • Anemic • IV drug user

• Uremic • Neutropenic

• Hemophiliac • Thrombopenic

• Thalassemic

128


13 janv. 2011

Difﬁcult physician ?

• Adverse events • Anemic • Coinfected HIV

• Uremic • Neutropenic • IV drug user

• Cirrhotic • Thrombopenic

• Aged patients

129


13 janv. 2011

Difﬁcult physician ?

• Adverse events • Anemic • Coinfected HIV

• Uremic • Neutropenic • IV drug user

• Cirrhotic • Thrombopenic

• Aged patients

Hepatitis C virus-infected patients
report
communication problems with physicians

129


322 Outpatients

Zickmund S, Hepatology 2004 130


322 Outpatients

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



322 Outpatients

with physicians

28%
Physician incompetence
Dx and Tx
(n=91)



322 Outpatients

with physicians

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



322 Outpatients

with physicians

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



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