Marcellin p ttvhb2015final- du 2015

1. TRAITEMENT
DE L’HÉPATITE B
Patrick Marcellin

2. L’HÉPATITE B EN FRANCE
- 0,7% (300.000) porteurs chroniques*
- 3ème cause de cirrhose et CHC
- Mortalité: 1500/an**
- < 150 000 dépistés
- 15 000 traités
- 1500 nouveaux traités par an
* InVS 2005 ** INSERM CépiDC, FPRH, AFEF, InVS
Marcellin et al. J Hepatol 2008

3. POURQUOI TRAITER?

4. - Arrêter la multiplication virale
- Diminuer l’activité de l ’hépatite chronique
- Arrêter l’évolution de la fibrose (régression?)
- Prévenir l’évolution vers la cirrhose
- Prévenir les complications
- Prévenir le CHC
- Prévenir la mortalité
OBJECTIFS DU TRAITEMENT DE
L’HÉPATITE CHRONIQUE B?

5. TEMPS
AgHBeAgHBe
négatifnégatifADN VHBADN VHB
négatifnégatif
Anti-HbeAnti-Hbe
positifpositif AgHBsAgHBs
négatifnégatif
Anti-HBsAnti-HBs
positifpositif
OBJECTIFS DU TRAITEMENT

6. ADN VHB
négatif
Seroconversion
HBe
Seroconversion
HBs
1
3 2
SEROCONVERSION HBs:
LE CHAMPION DES CRITÈRES

7. QUI TRAITER

8. COMMENT OPTIMISER LE TRAITEMENT DE
L’HÉPATITE CHRONIQUE B?
-Traiter les malades qui en ont besoin
(risque de complications)
- Traiter les malades qui ont de bonnes
chances de répondre

9. HEPATITE CHRONIQUE B =
MULTIPLICATION VIRALE/RÉPONSE
IMMUNITAIRE
MULTIPLICATION
VIRALE
RÉPONSE
IMMUNITAIRE

10. PHASE DE TOLÉRANCE IMMUNITAIRE
= MAUVAISE RÉPONSE
ADN VHB > 7 log ALAT < N
AgHBe + PBH = A1F1
MULTIPLICATION
VIRALE
RÉPONSE
IMMUNITAIRE

11. PHASE DE RÉACTION IMMUNITAIRE
= BONNE RÉPONSE
ADN VHB < 7 log ALAT > N
AgHBe +/- PBH > A1F1
MULTIPLICATION
VIRALE
RÉPONSE
IMMUNITAIRE

12. 10
102
103
104
105
106
107
108
109
1010
Hé patite
chronique
AgHBe -
Porteur
inactif
Martinot et al. J Hepatol 2002
CHARGE VIRALE ET STADE DE L’HC B

13. 10
102
103
104
105
106
107
108
109
1010
1 2 3 4Années
Hé patite chronique AgHBe -
Porteur inactif
5
COMMENT DISTINGUER LE PORTAGE INACTIF
DE L’HCA AgHBe -
LE SUIVI +++
Asselah et al. GCB 2005

14. QUI TRAITER
Guidelines EASL
1. Indications semblables pour
HC AgHBe + ou AgHBe -
2. Indication dépend de:
- ADN VHB
- ALAT
- PBH
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2012

15. AgHBe + et AgHBe -
QUI TRAITER
Guidelines EASL
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2012

16. AgHBe + et AgHBe -
QUI TRAITER
Guidelines EASL
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2012
ADN VHB < 4 log
ALAT = N

17. AgHBe + et AgHBe -
QUI TRAITER
Guidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2012
ADN VHB < 4 log
ALAT = N

18. AgHBe + et AgHBe -
QUI TRAITER
Guidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009
ADN VHB < 4 log
ALAT = N
ADN VHB > 4 log
et/ou ALAT > N
PBH > A1/F1

19. AgHBe + et AgHBe -
QUI TRAITER
Guidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2012
ADN VHB < 4 log
ALAT = N
ADN VHB > 4 log
Et/ou ALAT > N
PBH > A1F1
Traiter

20. COMMENT TRAITER

21. TREATMENT OF CHRONIC
HEPATITIS B
Two Strategies
- Analogues: pure antivirals
maintained response
- Interferon: antiviral + immune modulator
sustained response

22. NUCs vs IFN
NUCs IFN
- Finite duration - +
- Sustained response - +
- No resistance +/- +
- Oral administration + -
- Good tolerance + -
- Low cost - +?

23. RESULTS WITH ANALOGUES

24. VIROLOGICAL RESPONSE AT 1 YEAR
HBeAg-positive HBeAg-negative
LAM2
ADV1 ETV3
LdT2
TDF4
LAM2
ADV5
ETV6
LdT2
TDF4
21%
51%
40%
71%
67%
90%
60%
88%
73%
93%
0
20
40
60
80
100
1. Marcellin et al. N Engl J Med. 2003 2. Lai et al. N Engl J Med. 2007
3. Chang et al. N Engl J Med. 2006 4. Marcellin et al. N Engl J Med. 2008
5. Hadziyannis et al. N Engl J Med. 2003 6. Lai et al. N Engl J Med. 2006
NegativePCR
(%)

25. ANALOGUES REGISTERED FOR THE
TREATMENT OF CHRONIC HEPATITIS B
- Lamivudine -
- Adefovir -
- Telbivudine +
- Entecavir +++
- Tenofovir
+++

26. ENTECAVIR

27. ENTECAVIR
ADN VHB NÉGATIF A 1 et 3-5
ANS
.
55%
94%
AgHBe + AgHBe -
Chan et al. Hepatology 2010
95%94%

28. 0
20
40
60
100
80
ENTECAVIR DANS L’HC AgHBe +
ADN VHB négatif
1 an 2 ans 3 ans
55%
85% 90%
Chan et al. Hepatology 2010
4 ans
91%
N=146 N=140 N=134 N=112
5 ans
94%
N=94

29. TENOFOVIR

30. TENOFOVIR
ADN VHB NÉGATIF A 1 et 5 ANS
.
73%
93%
AgHBe + AgHBe -
Marcellin et al. NEJM 2008 Marcellin et al. Lancet 2013
87%*
65%*
*98%
Per protocol

31. Histologie à 5 ans de Traitement
n=348
Baselin e Year 1 Year 5
0
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PercentageofPatients
Ishak Fibrosis Score
6
5
4
3
2
1
0
Marcellin et al. Lancet 2013

32. Cumulative incidence of HBV
resistance
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
24%
38%
49%
67%
70%
0%
4%
22%
3%
11%
18%
29%
0%
LAM ADV ETV LdT TDF
1.2% 1.2%0.2% 1.2% 0%
Year 1
Year 2
Year 3
Year 4
Year 5
0% 0% 0% 0%

33. NO CORRELATION BETWEEN ANTIVIRAL
POTENCY AND HBs SEROCONVERSION*
HBV DNA HBs
decrease (log) loss
- Lamivudine 5.0 0%
- Adefovir 4.0 0%
- Entecavir 7.0 2%**
- Telbivudine 6.5 0%
- Tenofovir 5.5 3%**
* One year ** Only in HBeAg-

34. TREATMENT OF CHRONIC HEPATITIS B
WITH ANALOGUES: LIMITATIONS
- HBV DNA must be undetectable to prevent
resistance
- HBe seroconversion inconstant despite
virological response
- Risk of resistance on the long term?
- Tolerance on the long term?
- Importance of compliance
- When to stop?
- HBsAg loss rare

35. WHY HBsAg IS THE MAIN
OBJECTIVE OF THERAPY

36. - Ultimate goal of therapy
- Closest to cure
- Not HBV eradication but associated with
improved prognosis
Marcellin et al. Annals Intern Med 1990
Loriot et al. Hepatology 1992
THE IMPORTANCE OF HBsAg LOSS

37. HBsAg AND THE RISK OF HCC
HBsAg HBeAg ALT Relative Risk
-- -- normal 1
-- -- elevated 5
+ -- normal 10
+ -- elevated 30
+ + normal 60
+ + elevated 110
Yang et al. NEJM 2002
11,893 men in Taiwan

38. No HBsAg
loss
20
40
60
80
100
Survival(%)
HBsAg
loss
P<0.001
309 cirrhotics with a mean follow-up of 6 years
Fattovich et al. Am J Gastroenterology 1998
Time (years)
1 2 3 4 5 6 7
HBsAg Loss is Associated with Improved
Survival

39. INCIDENCE DE LA NÉGATIVATION DE L’AgHBs
EN FONCTION DE LA SÉROCONVERSION HBe
Moucari et al. J Hepatol 2009
0 5 10 15
Time (Years)
0,0
0,2
0,4
0,6
0,8
1,0
CumulativeIncidenceofHBs
Seroconversion
64%
17%
p<0,001

40. EVOLUTION (10 ans)
APRÈS TRAITEMENT IFN
AgHBs+ AgHBs-
• CHC : 6 0
• Ascite : 5 0
• Hemorhagie: 0 0
• Transplantation: 0 0
• Mortalité (CHC): 4 0
Moucari et al. J Hepatol 2009

41. RESULTS WITH INTERFERON

42. INCIDENCE OF HBsAg LOSS ACCORDING TO
RESPONSE TO IFN (HBe seroconversion)
Moucari et al. J Hepatol 2009
0 5 10 15
Time (Years)
0,0
0,2
0,4
0,6
0,8
1,0
CumulativeIncidenceofHBs
Seroconversion
Réponse : 64%
Non réponse : 17%
p<.001

43. OUTCOME (10 years) AFTER IFN THERAPY
HBsAg+ HBsAg-
• HCC : 6 0
• Ascitis : 5 0
• Hemorhage: 0 0
• Transplantation: 0 0
• Mortality (HCC): 4 0
Moucari et al. J Hepatol 2009

44. PEG IFN
HBeAg negative CHB

45. HBsAg LOSS after PEG IFN ± LAM
1 an 2 ans 3 ans 4 ans
%
5
6
9
11
0
Marcellin et al. NEJM 2004
Marcellin et al. Gastroenterology 2009
Marcellin et al. Hepatology International. In press
12
5 ans

46. HBsAg LOSS
1 an 2 ans 3 ans 4 ans
%
5
6
9
11
0
Marcellin et al. NEJM 2004
Marcellin et al. Gastroenterology 2009
Marcellin et al. APASL 2009
12
5 ans
64% of the
patients HBV DNA
negative

47. HBeAg + or HBeAg -
HOW TO TREAT
EASL Guidelines
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009

48. HBeAg + or HBeAg -
HOW TO TREAT
EASL Guidelines
• 2 million IU
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009
PEG IFN
HBV DNA < 7 log (copies)*
ALT > 3N

49. HBeAg + or HBeAg -
HOW TO TREAT
EASL Guidelines
• 2 million IU
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009
PEG IFN
HBV DNA < 7 log (copies)*
ALT > 3N
HBV DNA < 1 log at S12

50. HBeAg + or HBeAg -
ANALOGUE
Entecavir or Tenofovir
or Telbivudine
HOW TO TREAT
EASL Guidelines
• 2 million IU
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009
PEG IFN
HBV DNA < 7 log (copies)*
ALT > 3N
HBV DNA < 1 log at S12

51. HBeAg + or HBeAg -
ANALOGUE
Entecavir or Tenofovir
or Telbivudine
HOW TO TREAT
EASL Guidelines
• 2 million IU
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009
PEG IFN
HBV DNA < 7 log (copies)*
ALT > 3N
HBV DNA < 1 log at S12

52. HBeAg + or HBeAg -
ANALOGUE
Entecavir or Tenofovir
or Telbivudine
If HBV DNA + at S24-48
Change analogue
HOW TO TREAT
EASL Guidelines
• 2 million IU
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009
PEG IFN
HBV DNA < 7 log (copies)*
ALT < 3N
HBV DNA < 1 log at S12

53. THE ROLE OF HBsAg
QUANTIFICATION

54. HBsAg ACCORDING TO TREATMENT
Treatment
Weeks
LAM
PEG-IFNα-2a
PEG-IFNα-2a
+ LAM
Medianlog10IU/mL
Marcellin et al. Hepatology International 2012

55. HBVDNA(Log10copies/ml)
HBsAg(Log10U/ml)
Treatment
HBsAg Kinetics: PEG IFN
SVR (+)
Moucari et al. Hepatology 2009

56. HBVDNA(Log10copies/ml)
HBsAg(Log10U/ml)
HBsAg Kinetics: PEG IFN SVR (-)
Moucari et al. Hepatology 2009

57. Quantification of HBsAg: “Stopping Rule”
Early Serological Response = 0.5 log at W12
48 Patients
treated with
PEG IFN a2a
ESR -
PPV = 89 %
NPV = 90 %
Moucari et al. Hepatology 2009
ESR +
SVR
Sustained VirologicalResponse

58. PEG IFN + NUC
THE FUTURE OF THERAPY FOR HBV

59. PEG IFN + LAM
SERUM HBV DNA
Study week
On-treatment
MeanHBVDNA(log10cp/mL)
2
3
4
5
6
7
0 6 12 18 24 30 36 42 48
PEG IFN a2a
+ placebo
lamivudine
+ lamivudine
PEG IFN a2a
– 4.1
– 5.0
– 4.2
Marcellin et al. NEJM 2004
0.9 log

60. PEG IFN + Telbivudine
HBsAg decline baseline to week 24
Baseline
42
46
16
Week 12
42
46
16
Week 24
42
46
16
PEG
LDT
LDT+PEG
Time on treatment
Marcellin et al. Antiviral Therapy 2013

61. - 36 patients
- 8 (22%) with HBsAg drop > 0.5 log at 24 weeks
- All with SVR
- 4 (11%) HBsAg negative at 24 weeks post-TX
PEG IFN + Tenofovir
Marcellin et al. AASLD 2013

62. Log10 IU/ml
HBsAg kinetics according to treatment response
Marcellin et al. AASLD 2013

63. SVR patient with HBsAg loss
Log10 IU/ml
Marcellin et al. AASLD 2013

64. Conclusion
La quantification de l’AgHBs a une forte VPN:
- AgHBs à J0 > 3000 UI: 89%
- AgHBs diminué de moins de 0,5 log à S24: 86%
Ces résultats suggèrent qu’il est possible de
sélectionner les bons répondeurs avant
traitement et de considérer un arrêt à S24.

65. PERSPECTIVAS
L’AVENIR?

66. PERSPECTIVAS
Traitement individualisé