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. OBJECTIFS DU TRAITEMENT DE
L’HÉPATITE CHRONIQUE B?
- 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

5. OBJECTIFS DU TRAITEMENT
Anti-Hbe Anti-HBs
AgHBe
ADN VHB négatif positif AgHBs positif
négatif négatif
TEMPS

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

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 RÉPONSE
VIRALE IMMUNITAIRE

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

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

12. CHARGE VIRALE ET STADE DE L’HC B
10 10
10 9
10 8
10 7
Hé patite
10 6
chronique
10 5
10 4
AgHBe -
Porteur
10 3
10 2
inactif
10
Martinot et al. J Hepatol 2002

13. COMMENT DISTINGUER LE PORTAGE INACTIF
DE L’HCA AgHBe -
10 10 LE SUIVI +++
10 9
10 8
Hé patite chronique AgHBe -
10 7
10 6
10 5
10 4
10 3 Porteur inactif
10 2
10
1 2 Années 3 4 5
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 2009

15. QUI TRAITER
Guidelines EASL
AgHBe + et AgHBe -
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009

16. QUI TRAITER
Guidelines EASL
AgHBe + et AgHBe -
ADN VHB < 4 log
ALAT = N
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009

17. QUI TRAITER
Guidelines EASL
AgHBe + et AgHBe -
ADN VHB < 4 log
ALAT = N
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009

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

19. QUI TRAITER
Guidelines EASL
AgHBe + et AgHBe -
ADN VHB < 4 log ADN VHB > 4 log
ALAT = N Et/ou ALAT > N
PBH > A1F1
Surveiller Traiter
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009

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
100 90% 88% 93%
80 73% 71%
67%
Negative PCR
60%
60 51%
40%
40
21%
(%)
20
0 ADV 1 LAM 2 ETV 3 LdT 2 TDF 4 ADV 5 LAM 2 ETV 6 LdT 2 TDF 4
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

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
94% 94% 95%
55%
AgHBe + AgHBe -
.
Chan et al. Hepatology 2010 Shouval et al. AASLD 2008

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

29. TENOFOVIR

30. TENOFOVIR
ADN VHB NÉGATIF A 1 et 5 ANS
93%
87%*
73% 65%*
*98%
Per protocol
AgHBe + AgHBe -
.
Marcellin et al. NEJM 2008 Marcellin et al. AASLD 2011

31. Histologie à 5 ans de Traitement
n=348
100%
Ishak Fibrosis Score
90% 6
5
80%
s
4
3
70%
2
60% 1
0
50%
40%
30%
P
o
g
n
a
c
e
r
f
t
i
20%
10%
0
Baselin e Year 1 Year 5
Marcellin et al. AASLD 2011

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

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. THE IMPORTANCE OF HBsAg LOSS
- 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

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

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

39. Cumulative Incidence of HBs
INCIDENCE DE LA NÉGATIVATION DE L’AgHBs
EN FONCTION DE LA SÉROCONVERSION HBe
Seroconversion
1,0
0,8
64%
0,6
p<0,001
0,4
17%
0,2
0,0
0 5 10 15
Tim ( ea )
e Y rs
Moucari et al. J Hepatol 2009

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)
1,0
0,8
Réponse : 64%
0,6
p<.001
0,4
Seroconversion
Non réponse : 17%
0,2
Cumulative Incidence of HBsAg
0,0
0 5 10 15
Tim (Y rs
e ea )
Moucari et al. J Hepatol 2009

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
12
11
9
6
5
0
%
1 an 2 ans 3 ans 4 ans 5 ans
Marcellin et al. NEJM 2004
Marcellin et al. Gastroenterology 2009
Marcellin et al. Hepatology International. In press

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

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

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

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

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

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

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

53. THE ROLE OF HBsAg
QUANTIFICATION

54. HBsAg ACCORDING TO TREATMENT
Weeks
LAM
Median log10 IU/mL
PEG-IFNα-2a
+ LAM
PEG-IFNα-2a
Treatment
Marcellin et al. Hepatology International. In press

55. HBsAg Kinetics: PEG IFN
SVR (+)
HBsAg (Log10 U/ml)
HBV DNA (Log10 copies/ml)
Treatment Moucari et al. Hepatology 2009

56. HBsAg Kinetics: PEG IFN
SVR (-)
HBsAg (Log10 U/ml)
HBV DNA (Log10 copies/ml)
Moucari et al. Hepatology 2009

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

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

59. PEG IFN + LAM
SERUM HBV DNA
On-treatment
7
Mean HBV DNA (log10 cp/mL)
PEG IFN a2a
6 + placebo
5
PEG IFN a2a
+ lamivudine
4
– 4.1 lamivudine
3
– 4.2 0.9 log
– 5.0
2
0 6 12 18 24 30 36 42 48
Study week
Marcellin et al. NEJM 2004

60. PEG IFN + Telbivudine
HBsAg decline baseline to week 24
Time on treatment
Baseline Week 12 Week 24
PEG 42 42 42
LDT 46 46 46
LDT+PEG
16 16 16
Marcellin et al. EASL 2010

61. PEG IFN + Tenofovir
- 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
Marcellin et al. AASLD 2011

62. HBsAg kinetics according to treatment response
Log10 IU/ml
Marcellin et al. AASLD 2011

63. SVR patient with HBsAg loss
Log10 IU/ml
Marcellin et al. AASLD 2011

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