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
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
10. PHASE DE TOLÉRANCE IMMUNITAIRE
= MAUVAISE RÉPONSE
ADN VHB > 7 log
AgHBe +
MULTIPLICATION
VIRALE
ALAT < N
PBH = A1F1
RÉPONSE
IMMUNITAIRE
11. PHASE DE RÉACTION IMMUNITAIRE
= BONNE RÉPONSE
ADN VHB < 7 log
AgHBe +/MULTIPLICATION
VIRALE
ALAT > N
PBH > A1F1
RÉPONSE
IMMUNITAIRE
12. CHARGE VIRALE ET STADE DE L’HC B
10 10
10 9
10 8
10 7
10 6
10 5
10 4
10 3
10 2
10
Hé patite
chronique
AgHBe Porteur
inactif
Martinot et al. J Hepatol 2002
13. COMMENT DISTINGUER LE PORTAGE INACTIF
DE L’HCA AgHBe LE SUIVI +++
10 10
10 9
10 8
10 7
10 6
10 5
10 4
10 3
10 2
10
Hé patite chronique AgHBe -
Porteur inactif
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 2012
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 2012
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 2012
18. QUI TRAITER
Guidelines EASL
AgHBe + et AgHBe -
ADN VHB < 4 log
ALAT = N
ADN VHB > 4 log
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
ALAT = N
Surveiller
ADN VHB > 4 log
Et/ou ALAT > N
PBH > A1F1
Traiter
EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2012
30. TENOFOVIR
ADN VHB NÉGATIF A 1 et 5 ANS
93%
73%
87%*
65%*
*98%
Per protocol
AgHBe +
AgHBe -
.
Marcellin et al. NEJM 2008
Marcellin et al. Lancet 2013
31. Histologie à 5 ans de Traitement
n=348
100%
Ishak Fibrosis Score
6
5
4
3
2
1
0
s
90%
80%
70%
60%
50%
40%
i
f
o
g
a
t
n
c
r
e
P
30%
20%
10%
0
Baselin e
Year 1
Marcellin et al. Lancet 2013
Year 5
32. Cumulative incidence of HBV
resistance
100%
Year 1
Year 2
Year 3
Year 4
Year 5
90%
80%
70%
67%
70%
60%
49%
50%
40%
30%
38%
29%
24%
11%
10%
0%
22%
18%
20%
0%
LAM
3%
0.2% 1.2% 1.2% 1.2%
ADV
ETV
4%
0% 0% 0% 0% 0%
LdT
TDF
33. NO CORRELATION BETWEEN ANTIVIRAL
POTENCY AND HBs SEROCONVERSION*
HBV DNA
decrease (log)
- Lamivudine
- Adefovir
- Entecavir
- Telbivudine
- Tenofovir
* One year
5.0
4.0
7.0
6.5
5.5
** Only in HBeAg-
HBs
loss
0%
0%
2%**
0%
3%**
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
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
normal
elevated
normal
elevated
normal
elevated
Relative Risk
1
5
10
30
60
110
Yang et al. NEJM 2002
38. HBsAg Loss is Associated with Improved
Survival
309 cirrhotics with a mean follow-up of 6 years
Survival (%)
100
80
60
HBsAg
loss
No HBsAg
loss
P<0.001
40
20
2
1 (years)3
Time
4
5
6
7
Fattovich et al. Am J Gastroenterology 1998
39. Cumulative Incidence of HBs
Seroconversion
INCIDENCE DE LA NÉGATIVATION DE L’AgHBs
EN FONCTION DE LA SÉROCONVERSION HBe
1
,0
0
,8
64%
0
,6
p<0,001
0
,4
17%
0
,2
0
,0
0
5
1
0
1
5
T
im ( ea )
e Y rs
Moucari et al. J Hepatol 2009
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
0
,2
Non réponse : 17%
Cumulative Incidence of HBsAg
0
,0
0
5
1
0
1
5
T
im (Y rs
e
ea )
Moucari et al. J Hepatol 2009
45. HBsAg LOSS after PEG IFN ± LAM
11
12
9
%
5
0
6
1 an
2 ans
3 ans
Marcellin et al. NEJM 2004
Marcellin et al. Gastroenterology 2009
Marcellin et al. Hepatology International. In press
4 ans
5 ans
46. HBsAg LOSS
64% of the
patients HBV DNA
negative
12
11
9
%
5
0
6
1 an
2 ans
Marcellin et al. NEJM 2004
Marcellin et al. Gastroenterology 2009
Marcellin et al. APASL 2009
3 ans
4 ans
5 ans
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)*
ALT > 3N
Entecavir or Tenofovir
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)*
ALT > 3N
Entecavir or Tenofovir
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)*
ALT < 3N
Entecavir or Tenofovir
or Telbivudine
HBV DNA < 1 log at S12
If HBV DNA + at S24-48
Change analogue
• 2 million IU
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B.
J Hepatol 2009
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
traitement et de considérer un arrêt à S24.
avant
Marcellin P et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive
chronic hepatitis B. N Engl J Med. 2003;348:808−816.
Lai CL et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl
J Med. 2007;357:2576−2588.
Chang TT et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic
hepatitis B. N Engl J Med. 2006;354:1001−1010.
Heathcote J et al. A randomized, double blind, comparison of tenofovir DF (TDF)
versus adefovir diprivoxil (ADV) for the treatment of HBeAg positive chronic hepatitis
B (CHB): study GS-US-174−0103. Hepatology. 2007;46(4 suppl 1):861A (Abstract
LB6).
Hadziyannis S et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-
negative chronic hepatitis B. N Engl J Med. 2003;348:800−807.
Lai CL et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic
hepatitis B. N Engl J Med. 2006;354:1011−1020.
Marcellin P et al. A randomized, double blind, comparison of tenofovir DF (TDF)
versus adefovir diprivoxil (ADV) for the treatment of HBeAg negative chronic hepatitis
B (CHB): study GS-US-174-0102. Hepatology. 2007;46(4 suppl 1):290A−291A
(Abstract LB2).
Therapeutic Response
HBV DNA suppressed to ≤ 5 log10, with ALT normalized OR HBeAg loss
Therapeutic Response
HBV DNA suppressed to ≤ 5 log10, with ALT normalized OR HBeAg loss
Patients were selected for HBsAg analysis, who reached week 24 of study
There were no significant differences between the 3 treatment arms
