Treatment hcv du 2015 poynard

1. 22 janv. 2015
LiverCenter
Treatment of Hepatitis C
!
VHC
Traitement des cas “simples”
Thierry Poynard
!
!
!

2. 22 janv. 2015
LiverCenter
Traitement Hépatite Aiguë C:
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Identifier les cas

3. 22 janv. 2015
3
The Definition of Acute Hepatitis C
• Exposure to HCV
• Within 4 months
• Anti-HCV seroconversion
• Raised ALTs
• HCV RNA positivity

4. 22 janv. 2015
4
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)

5. 22 janv. 2015
5
Predictors of Spontaneous Viral Clearance ...
• No HIV
• IL-28B CC genotype
• Inducible Protein10
• Younger age (?)
• Females (?)
• White vs. Blacks (?)
• Genotype non-1 ?
• ALT useless: can normalize despite viral persistence (50%)

6. 22 janv. 2015
6
Prevalence of Symptoms According to Natural Outcome
0
25
50
75
100
Clearance HCV Persistence HCV
Jaundice Flu-like symptoms
87 %
59 %
87 %
47 %
P=0.02 P=0.002
Gerlach, Gastroenterology 2003

7. 29 Acute HCV: Initial RNA, viral kinetics, IL-28B
and spontaneous clearance
Liui Hepatology 2012

8. 120 Acute HCV: Inducible Protein10, IL-28B
and spontaneous clearance
Beinhardt Gastroenterology 2012

9. 22 janv. 2015
Acute HCV : prediction of spontaneous clearance
No 100% predictive values of IL28B, IP10
!
Viral kinetics: “100%” predictive value
9

10. 22 janv. 2015
10
Acute hepatitis C and HIV coinfection
• Patients coinfected HIV-HCV more rapid fibrosis progression
• 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

11. 22 janv. 2015
Anti-Viral Treatment of Acute HCV
Direct Acting Antivirals
11

12. 22 janv. 2015
12
Meta-Analysis of IFN α-2b RCTs in Acute HCV
Sustained Viral Response
Myers R, Cochrane Database Syst Rev 2003
*P<0.0001
Hwang 1994 (n=33)
Lampertico 1994 (n=48)
Li 1993 (n=32)
!
TOTAL (n=113)
1.0 100100.1
!
!
4.8 (1.1-22)
7.7 (1.6-38)
9.9 (1.5-65)
6.8 (2.6-17.5) *
Favours IFNFavours Control
OR (95% CI)

13. Boesecke J Vir Hep 2015

15. 22 janv. 2015
15
Anti-Viral Treatment of Acute HCV
STRATEGIES

16. 22 janv. 2015
16
Hypothesis:
Early control of viral replication prevents chronicity
• Treat all patients ?
• Treat early ?
• Which DAA ?
• Price
• Concomitant interaction with antiretroviral therapy in HIV (p450)
• Duration of treatment ? HIV=non-HIV in chronic hepatitis C

17. Boesecke J Vir Hep 2015
< 2log10

18. «Poynard Opinion» 2015, Sulkowski J Hepatol 2014
Acute Hepatitis C
Treatment 4-12W
Sofosbuvir-Ledispasvir
Sofosbuvir-Daclatasvir
Cheaper DAA
Viral load 4 week
Viral load 12 week
Detectable Undetectable
Viral load baseline
Decrease < 2 Log Decrease ≥ 2 Log
Peg-Riba if no money

19. 22 janv. 2015
LiverCenter
Treatment of Chronic Hepatitis C:
!
Approved DAA

20. 22 janv. 2015
Date Endpoint Treatment approval Reference
1991 ALT Interferon Davis, NEJM
1998 SVR Interferon Ribavirin
Poynard, Lancet
McHutchison, NEJM
2001 SVR PEG Interferon Ribavirin
Manns, NEJM
Fried, NEJM
2011 SVR
PEG Interferon Ribavirin,
Boceprevir, Telaprevir
Zeuzem, Bacon, Jacobson,
Sherman, NEJM
Approval of HCV treatments

21. 22 janv. 2015
Date Endpoint Treatment Approval Reference
2013 SVR Sofosbuvir, Ribavirin, PEG Lawitz, NEJM
2013 SVR Sofosbuvir, Ribavirin, Lawitz, Jacobson, NEJM
2014 SVR Sofosbuvir , Daclatasvir Sulkovski, NEJM
2014 SVR Sofosbuvir, Ledispasvir Afdahl, Kowdley, NEJM
2014 SVR
Sofosbuvir , Simeprevir,
Ribavirin
Lawitz, Lancet
2014 SVR
Ombitasvir, Dasabuvir,
Paritaprevir, Ritonavir, ribavirin
Poordad, Feld, NEJM
Approval of HCV treatments

22. 22 janv. 2015
Sustained Virologic Response (SVR): HCV RNA negative
G 1-4-5-6 G 2-3
SVR %
22

23. Feenney BMJ 2014

24. 22 janv. 2015
Daclatasvir + Asunaprevir
in 9 HCV genotype 1b-infected null responders
Chayama Hepatology 201224
1a et
Daclatasvir ?

26. Ombitasvir, paritaprevir, ritonavir fixed dose combination tablets
copackaged with
dasabuvir tablets for use with or without ribavirin

28. 0%
25%
50%
75%
100%
0-Prevalence 1-Screening 2-Evaluation 3-Treatment 4-No Virus 5-No Fibrosis
5
15
20
30
60
100
50
90
100100100100
Ideal Observed
5 barriers
for total cure in chronic hepatitis C
Fibrosis Stage
Motivation patient
Duration treatment
Fibrosis Stage
Detection Cancer
in previous F3F4

29. 22 janv. 2015
LiverCenter
Limitations of approved DAA

30. 22 janv. 2015
Limitation Sofo/Sime Sofo/Dacla Sofo/Ledi Viekira/Riba
Efficacy G3, cirrhosis G3, cirrhosis G3, cirrhosis G3, cirrhosis
Adverse
events
Cutaneous, Interaction,
headache, fatigue
headache, fatigue headache, fatigue
Interaction, itching, fatigue,
nausea, trouble sleeping
Pills 2 2 1 4-6
Duration 12w 12-24w 8-24w 12-24w
France Sofo 13667€/4w ? <16000 €/4w ?
US 56000$/4W ? ? 94500 $/12w 83319 $/12w
Limitations of Approved DAA

31. (c) BioPredictive 2012 - All Rights Reserved - No reproduction without written permission(c) BioPredictive 2012 - All Rights Reserved - No reproduction without written permission
Connect to the website/application
!
Just reach :
http://app.fibrotest.com/

34. Worse scenario
BUG si Intolerant RIBA

35. Best scenario

36. Intermediate scenario

37. AASLD less choices than EASL

38. 22 janv. 2015
Facteur indépendants de moindre réponse virologique
Facteur PEG-Riba DAA-1 DAA-2
Genotype: 3, 1a x x x
Fibrosis stage F3/F4 x x x
Immuno Supression x x x
Viral load: D0/W4/W8/W12. x x ?
Previous response x x ?
No Steatosis, Diabetes x ?
Ethnicity/IL28 CC CT x x ?
Male x ?
Age (Duration) x
38
Poynard Lancet 2007, Poynard Gastroenterology 2009, Ge Nature 2009, Thompson Gastroenterology 2010, Lawitz NEJM 2013

41. 22 janv. 2015
Sofosbuvir-Riba 12 weeks
Cirrhosis limitations in Genotype 2 and 3
Lawitz NEJM 2013

42. 22 janv. 2015
Sofosbuvir-Riba 24 weeks
Limitations in Cirrhosis G3 previously non-responders
Valence AASLD 2013

43. 22 janv. 2015
43
Treatment of Chronic Hepatitis C
STRATEGIES

46. !
49
572
396
€
“prix
catalogue”
!
100.000
€
par
pa0ent

48. 22 janv. 2015
«Poynard’s Opinion» Janvier 2015
Genotype, Marqueur Fibrose
Chronic Hepatitis C
treated or not
Sofo-Dacla
Sofo-Sime
Genotype 4Genotype 1-5-6
Sofo-LediSofo-Dacla
Sofo-Riba
24w
Sofo-Riba
12w
Genotype 3Genotype 2

49. 22 janv. 2015
49
Treatment of Chronic Hepatitis C
En Résumé

50. 22 janv. 2015
50
Menus traitements 2015: Bons mais Chers
• Plus d’Interferon, rarement Ribavirine
• SVR >= 90%
• Plus court 6-24w
• Peu d’effets indésirables
• Plus cher: 1000 € /j

51. 22 janv. 2015
51
Prise en charge de l’Hépatite C en 2015
• Guérir du virus:
• Ne pas mourir de la cirrhose:
• Si SVR surveiller fibrose et dépister cancer / 6 mois
• Si aggravation (SVR ou pas) transplantation