1. 25 janv. 2010
VHC
Traitement des cas simples
Traitement des cas compliqués
Thierry Poynard
Vlad Ratziu, Yves Benhamou
LiverCenter
lundi 25 janvier 2010 1

2. 25 janv. 2010
Treatment of Acute Hepatitis C:
A la carte from 0 to 1 year
LiverCenter
lundi 25 janvier 2010 2

3. 25 janv. 2010
The Definition of Acute Hepatitis C
• Exposure to HCV
• Within 4 months
• Anti-HCV seroconversion
• Raised ALTs
• HCVRNA positivity
3
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4. 25 janv. 2010
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
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5. 25 janv. 2010
Anti-Viral Treatment of Acute HCV
• Randomized controlled trials
• Meta-analysis
• Uncontrolled trials
5
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6. 25 janv. 2010
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
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7. 25 janv. 2010
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
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8. 25 janv. 2010
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
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9. 25 janv. 2010
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
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10. 25 janv. 2010
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
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11. 25 janv. 2010
Anti-Viral Treatment of Acute HCV
STRATEGIES
11
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12. 25 janv. 2010
Hypothesis:
Early control of viral replication prevents chronicity
• Treat all patients ?
• Treat early ?
• Doses of IFN ?
• Ribavirin ?
• Duration of treatment ?
12
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13. 25 janv. 2010
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
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14. 25 janv. 2010
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
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15. 25 janv. 2010
Predictors of Spontaneous Viral Clearance ...
• Younger age (?)
• Females (?)
• White vs. Blacks (?)
• Rare Quasispecies
• Genotype non-1
• ALT useless
• Can normalize despite viral persistence (50%)
15
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16. 25 janv. 2010
Early Prediction of HCV Clearance
After Acute Infection ?
Self Limited Chronic
Days after onset of symptoms
Hofer, Hepatology 2003
16
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17. 25 janv. 2010
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
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18. 25 janv. 2010
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
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19. 25 janv. 2010
Treatment of Chronic Hepatitis C:
A la carte from 0 to 5 years
LiverCenter
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20. 25 janv. 2010
Prise en charge de l’Hépatite C en 2010
• Améliorer le dépistage
• Simplifier le bilan
• Améliorer le traitement
• A la carte
• Ne pas baisser les bras
20
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21. 25 janv. 2010
Chronic Hepatitis B or C
FibroTest ActiTest
Fibroscan if FibroTest
not applicable
Advanced Fibrosis No Advanced Fibrosis
Severe Activity No Severe Activity
FibroTest
Hepatologist
every 2-4 years
HAS for HCV Dec 2007
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22. 25 janv. 2010
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,
2011 ? SVR ??
Boceprevir, Telaprevir ??
2015 ? SVR Xprevir+Yprevir ??
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23. 25 janv. 2010
HCV Treatment: % Sustained Virological Response
99
100 88
80
80 73
60 48
40 35
40
20 15
20 5
1 1
0
ol
ir
w
w
-R
-R
v
24
48
tr
G
re
N
on
PE
-P
IF
N
N
C
IF
IF
R
P-
G 1-4-5-6 G 2-3
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24. 25 janv. 2010
Factors associated with SVR in HCV
• Genotype
• Viral load
• Fibrosis stage
• Age (Duration)
• HIV
• Male
• BMI,Steatosis,Diabetes
• Ethnicity, IL-28
Poynard et al Lancet 2003, Gastroenterology 2009
24
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25. 25 janv. 2010
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 ? ? ?
Previous treatment X
Poynard Lancet 2007, Poynard Gastroenterology 2009, Ge Nature 2009,
25
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26. 25 janv. 2010
IL28B CC génotype vs non-CC: réponse au traitement
1,628 HCV Genotype 1 IDEAL study
!
Ge et al Nature 2009, Thomson et al, submitted
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27. 25 janv. 2010
Facteurs associès à la réponse au traitement (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, submitted
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28. 25 janv. 2010
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
28
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29. 25 janv. 2010
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
29
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30. 25 janv. 2010
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
30
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31. 25 janv. 2010
A la carte regimen with PEG-Riba?
• Longer duration for Genotype 2 and 3 if
• Advanced fibrosis F2F3F4
• Steatosis in genotype 2
• HIV
Poynard et al Hepatology 2000, Lancet 2003, Hepatology 2003
31
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32. 25 janv. 2010
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
32 Zeuzem et al, J Hepatol, 2004
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33. 25 janv. 2010
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
33
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34. 25 janv. 2010
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 PEG IFN-R 48w n=33
Hadziyannis et al Ann Inter Med, 2004
34
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35. 25 janv. 2010
Genotype 2 and 3 patients with bridging fibrosis
treated PEG IFN alfa 2a and ribavirin weight based dose
SVR
74
56
37
19
0
PEG IFN-R 24w n=20 PEG IFN-R 48w n=33
Hadziyannis et al Ann Inter Med, 2004
35
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36. 25 janv. 2010
Genotype 2 and 3 patients with bridging fibrosis
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
36
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37. 25 janv. 2010
A la carte regimen with PEG-Riba?
• Shorter duration (2-4 months)
• For Genotype 2 and 3, if no relapse factors
Poynard et al Hepatology 2000, Lancet 2003, Hepatology 2003
37
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38. 25 janv. 2010
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
38
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39. 25 janv. 2010
Traitement à la carte avec PEG-Riba?
N=96 patients naïfs consécutifs: facteurs de risque de rechute
• Plus d’un facteur de risque
84%
• Génotype 1,4,5,6
58%
• Charge virale >= 800,000 IU/ml 38%
• Age >40 ans 66%
• Sexe masculin 60%
• Fibrose avancée: F2, F3, F4
34%
Poynard et al Hepatology 2000, D’Arondel JVH 2006
39
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40. 25 janv. 2010
Traitement à la carte PEG-Riba
D’Arondel JVH 2006
40
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41. Background
41
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42. 25 janv. 2010
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
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43. 25 janv. 2010
A la carte suisse, ou à l’américaine ?
43
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44. 25 janv. 2010
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
44
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45. 25 janv. 2010
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
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46. 25 janv. 2010
Prediction of Sustained Response
based on Week 12 HCV-RNA
174 patients treated PEG2b 1.5 Riba
90
90
60
30
26
0
0
PCR+ <2log drop n=31 PCR+ >=2 log n=23 PCR- n=120
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47. 25 janv. 2010
Treatment à la Carte 2009
RBV >10.6 mg/kg/d
PEG IFN 1.5 µg/kg QW
Quantitative viral load at 4/12 weeks
Negative or >2-log decrease <2-log decrease
PCR at 12/24 weeks
Negative Positive
Count favorable factors: Stop at 12 weeks ?
genotype 2/3, viral load <1 MIU mL Discuss slow responder
F0–F1 (FibroTest), BMI <27 PEG IFN for fibrosis prevention
if progression is rapid
<3 3 or 4
favorable factors favorable factors
IL28 in 2010 ??
Stop at 48 weeks Stop at 12/24 weeks
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48. 25 janv. 2010
Prise en charge de l’Hépatite C en 2010
• Améliorer le dépistage
• Simplifier le bilan
• Améliorer le traitement
• A la carte, surtout si cas compliqués
• Ne pas baisser les bras
48
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49. 25 janv. 2010
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
49
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50. 25 janv. 2010
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
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51. 25 janv. 2010
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
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52. 25 janv. 2010
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
52
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53. 25 janv. 2010
Fibrosis progression rate per year in patients with Hepatitis C
10
0
-10
-20
-30
IFN-SR IFN-NR Untreated
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54. 25 janv. 2010
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
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55. 25 janv. 2010
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
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56. 25 janv. 2010
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
56
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57. 25 janv. 2010
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 57
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58. 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
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59. 25 janv. 2010
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
Poynard et al Gastroenterology, 2002
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60. 25 janv. 2010
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
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61. lundi 25 janvier 2010 61

62. 10 Years Later, Right Lobe
lundi 25 janvier 2010 62

63. 25 janv. 2010
Beware of hepatocellular carcinoma
in sustained virological responders
previously F3 or F4
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64. 25 janv. 2010
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
64
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65. lundi 25 janvier 2010 65

66. 25 janv. 2010
HALT-C: Peg 2a 90 mcg/w 3.5 years
Compliance:
• 53% still on treatment,
• 10% lower dose,
• 37% stopped therapy
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67. 25 janv. 2010
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.
67
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68. 25 janv. 2010
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
68
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69. 25 janv. 2010
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
69
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70. 25 janv. 2010
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
70
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71. 25 janv. 2010
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
71
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72. 25 janv. 2010
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
72
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73. 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*
73
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74. 25 janv. 2010
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
74
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75. 25 janv. 2010
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
75
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76. 25 janv. 2010
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
76
lundi 25 janvier 2010 76

77. Prognostic value of FibroTest
in 1,459 HCV virological non responders
EPIC-3 Trial 2009
F0 F1 F2 F3 F4
80
75
60 63 65 61 60
57
SVR %
52
48
40
40
27 29 27
20 24
20
16 15
0
All Biopsy n=1459 EVR Biopsy n=506 All FibroTest n=1459 EVR FibroTest n=506
Poynard Gastroenterology 2009, AASLD 2009
lundi 25 janvier 2010 77

78. 25 janv. 2010
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 78
lundi 25 janvier 2010 78

79. 25 janv. 2010
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
lundi 25 janvier 2010 79

80. 25 janv. 2010
Attention: optimiste mais pas trop: nouvelles molécules,
Molécules en Développement
bénéfice/risque attente ? toujours besoin PEG-Riba
• ITMN-191 (Intermune/Roche) • TMC435350 (Medivir/ • Telaprevir (Vertex)
Protease •! MK-7009 (Merck) Tibotec) • Boceprevir
•! BI 201335 (Schering Plough)
Inhibitors (Boehringer Ingelheim)
• GS-9190 (Gilead) • R7128 (Pharmasset/Roche)
• BMS-790052 (BMS)
Polymerase •! PF-00868554 (Pfizer)
Inhibitors •! ANA598 (Anadys)
•! BILB 1941 (Boehringer
Ingelheim)
• Bavituximab (Peregrine) • DEBIO-025 (Debiopharm)
Novel • NIM811 (Novartis)
Mechanisms • Nitazoxanide (Romark)
of Action • Celgosivir (Migenix)
Phase 1 Phase 2 Phase 3
4
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81. 25 janv. 2010
Difficult to treat patients
• Adverse events • Cirrhotic • Coinfected HIV
• Aged patients • Anemic • IV drug user
• Uremic • Neutropenic
• Hemophiliac • Thrombopenic
• Thalassemic
81
lundi 25 janvier 2010 81

82. 25 janv. 2010
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
82
lundi 25 janvier 2010 82

83. 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 83
lundi 25 janvier 2010 83

84. 25 janv. 2010
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)
84
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85. 25 janv. 2010
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
85
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86. 25 janv. 2010
Dose Modifications / Discontinuations
Rebetol > 10.6 mg/kg
Peg2b 1.5 ug/Kg IntronA 3MU
Discontinuations
Due to AE’s 14% 12%
Dose Modification 49% 33%
Anemia 12% 14%
Neutropenia 21% 8%
lundi 25 janvier 2010 86

87. 25 janv. 2010
Neutrophils
Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6
Mean Neutrophil Counts x 10 9/l
5
4
3
2
1
0
0 2 4 6 8 12 18 24 30 36 42 48 4 12 24
Treatment Week Follow-up Week
lundi 25 janvier 2010 87

88. 25 janv. 2010
Hemoglobin
Mean Hemoglobin Concentration g/dl
Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6
17,0
16,3
15,6
14,9
14,2
13,5
12,8
12,1
11,4
10,7
10,0
0 2 4 6 8 12 18 24 30 36 42 48 4 12 24
Treatment Week Follow-up Week
lundi 25 janvier 2010 88

89. 25 janv. 2010
Platelets
Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6
Mean Platelet Counts x 10 6/l
250
200
150
100
50
0
0 2 4 6 8 12 18 24 30 36 42 48 4 12 24
Treatment Week Follow-up Week
lundi 25 janvier 2010 89

90. 25 janv. 2010
Difficult to treat patients
• Adverse events • Cirrhotic • Coinfected HIV
• Aged patients • Anemic • IV drug user
• Uremic • Neutropenic
• Hemophiliac • Thrombopenic
• Thalassemic
90
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91. Large Scale Studies (Boston 2004)
32,527 patients: Fibrotest-Actitest-HCV-FibroSURE
and ALT
ALT 50 IU/L: 65 years+ n=3,084
for F2F3F4 Se=60% NPV 42% (prevalence 73%)
for Cirrhosis Se=69% NPV 75% (prevalence 40%)
91
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92. 25 janv. 2010
HCV treatment in aged patients n=166
65-80 yrs >80 yrs
Number of treated patients 162 4
Number of treatments 275 4
Type of treatment
-IFN alone 143 0
-IFN-Ribavirin 42 1
-PEGinterferon alone 11 0
-PEG Ribavirin 16 2
-Ribavirin alone 30 0
-Other 33 1
Interruption of treatment 55 (20 %) 0
Thabut et al AJG 2006
92
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93. 25 janv. 2010
Sustained Virological Response
in aged patients n=166
Genotype 1 Genotype 2 Genotype 3 Other Total
Classic IFN 4/79 0/10 1/2 5/52 10/143 (7 %)
Ribavirin 1/16 0/1 0/0 1/13 2/30 (7 %)
PEG alone 0/6 0/0 0/0 0/4 0 /10
IFN-Ribavirin 3/28 3/5 0/0 1/9 7 /42 (16 %)
PEGIFN-
5/12 1/1 1/2 2/5 9/19 (45%)
Ribavirin
Thabut et al AJG 2006 93
lundi 25 janvier 2010 93

94. 25 janv. 2010
Difficult to treat patients
• Adverse events • Cirrhotic • Coinfected HIV
• Aged patients • Anemic • IV drug user
• Uremic • Neutropenic
• Hemophiliac • Thrombopenic
• Thalassemic
94
lundi 25 janvier 2010 94

95. 25 janv. 2010
Renal Diseases
• Renal insufficiency
• Hemodialysis
• Renal transplantation
95
lundi 25 janvier 2010 95

96. 25 janv. 2010
Renal insufficiency
• IFN, PEG-IFN:
• Same dose or slightly reduced
• Ribavirin:
• Adjusted plasma concentration ?,
• 10-15 micromol/L ?
• Start 200mg per week
• Range 170-300 mg/day
• EPO: 20,000-30,000 UI/week
96
lundi 25 janvier 2010 96

97. 25 janv. 2010
Kinetics of PEG-IFN 2a in renal failure
Group 1: Cl >100 (n=5)
6.0
Group 2: 100 < Cl >80 (n=4)
PEGASYS® Conc. [ng/mL]
5.0 Group 3: 80 < Cl >60 (n=5)
Group 4: 60 < Cl >40 (n=6)
4.0
Group 5: 40 < Cl >20 (n=3)
3.0
2.0
1.0
0.0
0 48 96 144 192 240 288 336 384 432 480528
Time [h] Martin et al. AASLD 2000.
97
lundi 25 janvier 2010 97

98. 25 janv. 2010
Renal Diseases
• Renal insufficiency
• Hemodialysis
• Renal transplantation
98
lundi 25 janvier 2010 98

99. 25 janv. 2010
Interferon alfa for HCV infection in hemodialyzed
• INF alfa is feasible in dialysis patients
• Poorly tolerated
• discontinuation: 20-40%;
• reduction: 60%
• Efficient: at least as efficient than in the general population
(pharmacokinetic of INF)
• Frequent histological improvement
99
lundi 25 janvier 2010 99

100. 25 janv. 2010
Ribavirin in Hemodialyzed
• Warning Hemolysis +++
• Increased risk despite the absence of variation of the level of serum ribavirin
• Long duration of the risk; accumulation of metabolites in erythrocytes
• Particularly with aziathioprine
• Low doses of ribavirin
• 200 mg after each dialysis
• 200 daily
• Increased doses of EPO
Thervet et al. Transplantation 1994 Thevenot et al. JVH 1997
100
lundi 25 janvier 2010 100

101. 25 janv. 2010
Renal Diseases
• Renal insufficiency
• Hemodialysis
• Renal transplantation
101
lundi 25 janvier 2010 101

102. 25 janv. 2010
Summary
Treatment options in HCV patients with Renal disorders
• No Transplantation scheduled: As in non uremic:
• F0F1: Follow-up FibroTest /12mo or biopsy /3y
• F1-F2: FibroTest /6mo or biopsy /y
• F2F3F4: Treatment A la Carte
• Transplantation scheduled:
• Treatment A la Carte as soon as possible
• Double transplantation in F4 non-responders
• Transplanted:
• F0F1: Follow-up FibroTest /12mo or biopsy /3y
• F1-F2: FibroTest /6mo or biopsy /y
• F2F3F4:
– Ribavirin
– Liver Transplantation in F4 non-responders
102
lundi 25 janvier 2010 102

103. 25 janv. 2010
Difficult to treat patients
• Adverse events • Cirrhotic • Coinfected HIV
• Aged patients • Anemic • IV drug user
• Uremic • Neutropenic
• Hemophiliac • Thrombopenic
• Thalassemic
103
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104. 25 janv. 2010
Hemophiliac Patients
• Massively contaminated,
• Coinfection HIV,
• Same natural history,
• Biopsy worse cost-benefit rate
• Same treatments, including transplantation
• Same results than in non-hemophiliacs
104
lundi 25 janvier 2010 104

105. 25 janv. 2010
Thalassemic Patients
• Massively contaminated,
• Progression of fibrosis
• Iron overload
• Insulin-resistance
• Same treatments, including bone marrow transplantation
• Blood transfusion sometimes needed
105
lundi 25 janvier 2010 105

106. 25 janv. 2010
Anemic Patients
• Ribavirin dose dependent reversible hemolytic anemia
• Erythropoietin (epoetin alfa)
• 40,000 U/week vs standard
• Hemoglobin drop: 0.3 g vs 2.9 g/dL
• 900 vs 700 mg/day ribavirin
• When to start ?
– Anemic at baseline <11g Hb?
– During treatment if <11g Hb ?
106
lundi 25 janvier 2010 106

107. AFSSAPS
lundi 25 janvier 2010 107

108. 25 janv. 2010
Neutropenic Patients
• Granulocyte colony-stimulating factor (G-CSF)
• Potentiates effect of EPO
• 300 microG SC 1-3 / week
• Maintain Neutrophils >750/mm3
• Adverse events
– Skin rash
– Vasculatis
– Bone pain, myalgia
– Thrombocytopenia, splenomegaly
– Leukemoid reaction
– Exacerbation of psoriasis
108
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109. 25 janv. 2010
Thrombopenic Patients
• Problematic in cirrhotic patients
• Severe thrombopenia exceptional in non cirrhotic
• Thrombopoietin
109
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110. 25 janv. 2010
Elthrombopag: 4 weeks impact + 12 weeks PEG-Riba
74 HCV Cirrhosis 20,000-70,000 platelets
>100,000 /mm3 week 4
100% 95%
75% 79%
75%
50%
25%
0%
0%
0%
Placebo 30mg 50mg 75mg
McHutchison NEJM 2007
lundi 25 janvier 2010 110

111. 25 janv. 2010
Elthrombopag: 4 weeks impact + 12 weeks PEG-Riba
74 HCV Cirrhosis 20,000-70,000 platelets
Completed HCV treatment week 12
100%
75%
65%
53%
50%
36%
25%
6%
0%
Placebo 30mg 50mg 75mg
McHutchison NEJM 2007
lundi 25 janvier 2010 111

112. 25 janv. 2010
Elthrombopag: Adverse events
• Headache
• Thrombosis
112
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113. 25 janv. 2010
Traitement hépatite C 2010
• Intensifier dépistage
• Simplifier bilan initial et suivi
• Traiter « à la carte »:
• Fibrose, Poids, Stéatose, Age
• Tolérance
• Efficacité non virologique:
• Freiner la progression de la Fibrose
113
lundi 25 janvier 2010 113