TRAITEMENT DE L’HÉPATITE B Patrick Marcellin
TRAITEMENT
DE L’HÉPATITE B
Patrick Marcellin
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, InVSMarcellin et al. J Hepatol 2008
POURQUOI TRAITER?
- 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?
TEMPS
AgHBeAgHBenégatifnégatifADN VHBADN VHB
négatifnégatif
Anti-HbeAnti-Hbepositifpositif AgHBsAgHBs
négatifnégatif
Anti-HBsAnti-HBspositifpositif
OBJECTIFS DU TRAITEMENT
ADN VHBnégatif
SeroconversionHBe
SeroconversionHBs
13 2
SEROCONVERSION HBs:LE CHAMPION DES CRITÈRES
QUI TRAITER
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
HEPATITE CHRONIQUE B =MULTIPLICATION VIRALE/RÉPONSE
IMMUNITAIRE
MULTIPLICATION
VIRALE
RÉPONSE
IMMUNITAIRE
PHASE DE TOLÉRANCE IMMUNITAIRE= MAUVAISE RÉPONSE
ADN VHB > 7 log ALAT < N AgHBe + PBH = A1F1
MULTIPLICATION
VIRALE
RÉPONSE
IMMUNITAIRE
PHASE DE RÉACTION IMMUNITAIRE= BONNE RÉPONSE
ADN VHB < 7 log ALAT > N AgHBe +/- PBH > A1F1
MULTIPLICATION
VIRALERÉPONSE
IMMUNITAIRE
10102
103
104
105
106
107
108
109
1010
Hé patitechroniqueAgHBe -
Porteurinactif
Martinot et al. J Hepatol 2002
CHARGE VIRALE ET STADE DE L’HC B
10102
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
QUI TRAITERGuidelines 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
AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
ADN VHB < 4 logALAT = N
AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
ADN VHB < 4 logALAT = N
AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
ADN VHB < 4 logALAT = N
ADN VHB > 4 loget/ou ALAT > N
PBH > A1/F1
AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
ADN VHB < 4 logALAT = N
ADN VHB > 4 logEt/ou ALAT > N
PBH > A1F1
Traiter
COMMENT TRAITER
TREATMENT OF CHRONIC HEPATITIS B
Two Strategies
- Analogues: pure antivirals maintained response
- Interferon: antiviral + immune modulator sustained response
NUCs vs IFN
NUCs IFN
- Finite duration - +
- Sustained response - +
- No resistance +/- +
- Oral administration + -- Good tolerance + -
- Low cost - +?
RESULTS WITH ANALOGUES
VIROLOGICAL RESPONSE AT 1 YEAR
HBeAg-positive HBeAg-negative
LAM2ADV1 ETV3 LdT2 TDF4 LAM2ADV5 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. 20085. Hadziyannis et al. N Engl J Med. 2003 6. Lai et al. N Engl J Med. 2006
Ne
ga
tive
PC
R
(%)
ANALOGUES REGISTERED FOR THE TREATMENT OF CHRONIC HEPATITIS B
- Lamivudine -- Adefovir -- Telbivudine + - Entecavir +++- Tenofovir+++
ENTECAVIR
ENTECAVIR ADN VHB NÉGATIF A 1 et 3-5
ANS
.
55%
94%
AgHBe + AgHBe -
Chan et al. Hepatology 2010 Shouval et al. AASLD 2008
95%94%
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
TENOFOVIR
TENOFOVIR ADN VHB NÉGATIF A 1 et 5 ANS
.
73%
93%
AgHBe + AgHBe -
Marcellin et al. NEJM 2008 Marcellin et al. AASLD 2011
87%*
65%*
*98%Per protocol
Histologie à 5 ans de Traitementn=348
Baselin e Year 1 Year 5
0
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Percentage of Patients
Ishak Fibrosis Score
6543210
Marcellin et al. AASLD 2011
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 1Year 2Year 3Year 4Year 5
0% 0% 0% 0%
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-positive patients
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
WHY HBsAg IS THE MAIN
OBJECTIVE OF THERAPY
- Ultimate goal of therapy
- Closest to cure
- Not HBV eradication but associated with improved prognosis
Marcellin et al. Annals Intern Med 1990Loriot et al. Hepatology 1992
THE IMPORTANCE OF HBsAg LOSS
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
No HBsAgloss
20
40
60
80
100
Su
rviv
al (
%)
HBsAgloss
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
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
Cu
mu
lativ
e In
cid
en
ce o
f H
BsA
g
Sero
co
nversio
n
64%
17%
p<0,001
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
RESULTS WITH INTERFERON
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
Cumulative Incidence of HBsAg
Seroconversion
Réponse : 64%
Non réponse : 17%
p<.001
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
PEG IFN
HBeAg negative CHB
HBsAg LOSS after PEG IFN ± LAM
1 an 2 ans 3 ans 4 ans %
5 6
911
0
Marcellin et al. NEJM 2004Marcellin et al. Gastroenterology 2009 Marcellin et al. Hepatology International. In press
12
5 ans
HBsAg LOSS
1 an 2 ans 3 ans 4 ans %
5 6
911
0
Marcellin et al. NEJM 2004Marcellin et al. Gastroenterology 2009 Marcellin et al. APASL 2009
12
5 ans
64% of the patients HBV DNAnegative
HBeAg + or HBeAg -
HOW TO TREATEASL Guidelines
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
HBeAg + or HBeAg -
HOW TO TREATEASL 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
HBeAg + or HBeAg -
HOW TO TREATEASL 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
HBeAg + or HBeAg -
ANALOGUEEntecavir or Tenofoviror Telbivudine
HOW TO TREATEASL 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
HBeAg + or HBeAg -
ANALOGUEEntecavir or Tenofoviror Telbivudine
HOW TO TREATEASL 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
HBeAg + or HBeAg -
ANALOGUEEntecavir or Tenofoviror Telbivudine
If HBV DNA + at S24-48Change analogue
HOW TO TREATEASL 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
THE ROLE OF HBsAg QUANTIFICATION
HBsAg ACCORDING TO TREATMENT
Treatment
Weeks
LAM
PEG-IFNα-2a
PEG-IFNα-2a + LAM
Med
ian
log
10 I
U/m
L
Marcellin et al. Hepatology International. In press
HB
V D
NA
(L
og
10 c
op
ies/
ml)
HB
sAg
(Lo
g10 U
/ml)
Treatment
HBsAg Kinetics: PEG IFNSVR (+)
Moucari et al. Hepatology 2009
HB
V D
NA
(L
og
10 c
op
ies/
ml)
HB
sAg
(Lo
g10 U
/ml)
Treatment
HBsAg Kinetics: PEG IFNSVR (-)
Moucari et al. Hepatology 2009
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 +
SVRSustained Virological
response
PEG IFN + NUC
THE FUTURE OF THERAPY
FOR HBV
PEG IFN + LAMSERUM HBV DNA
Study week
On-treatment
Mea
n H
BV
DN
A (
log
10 c
p/m
L)
2
3
4
5
6
7
0 6 12 18 24 30 36 42 48
PEG IFN a2a+ placebo
lamivudine
+ lamivudinePEG IFN a2a
– 4.1
– 5.0
– 4.2
Marcellin et al. NEJM 2004
0.9 log
PEG IFN + TelbivudineHBsAg decline baseline to week 24
Baseline424616
Week 12424616
Week 24424616
PEGLDTLDT+PEG
Time on treatment
Marcellin et al. EASL 2010
- 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 2011
Log10 IU/ml
HBsAg kinetics according to treatment response
Marcellin et al. AASLD 2011
SVR patient with HBsAg loss
Log10 IU/ml
Marcellin et al. AASLD 2011
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.
PERSPECTIVASL’AVENIR?
PERSPECTIVAS
Traitement individualisé