marcellin p tt vhb 2014 final
DESCRIPTION
TRANSCRIPT
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TRAITEMENT
DE L’HÉPATITE B
Patrick Marcellin
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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
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POURQUOI TRAITER?
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- 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?
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TEMPS
AgHBeAgHBenégatifnégatifADN VHBADN VHB
négatifnégatif
Anti-HbeAnti-Hbepositifpositif AgHBsAgHBs
négatifnégatif
Anti-HBsAnti-HBspositifpositif
OBJECTIFS DU TRAITEMENT
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ADN VHBnégatif
SeroconversionHBe
SeroconversionHBs
13 2
SEROCONVERSION HBs:LE CHAMPION DES CRITÈRES
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QUI TRAITER
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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
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HEPATITE CHRONIQUE B =MULTIPLICATION VIRALE/RÉPONSE
IMMUNITAIRE
MULTIPLICATION
VIRALE
RÉPONSE
IMMUNITAIRE
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PHASE DE TOLÉRANCE IMMUNITAIRE= MAUVAISE RÉPONSE
ADN VHB > 7 log ALAT < N AgHBe + PBH = A1F1
MULTIPLICATION
VIRALE
RÉPONSE
IMMUNITAIRE
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PHASE DE RÉACTION IMMUNITAIRE= BONNE RÉPONSE
ADN VHB < 7 log ALAT > N AgHBe +/- PBH > A1F1
MULTIPLICATION
VIRALERÉPONSE
IMMUNITAIRE
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10102
103
104
105
106
107
108
109
1010
HépatitechroniqueAgHBe -
Porteurinactif
Martinot et al. J Hepatol 2002
CHARGE VIRALE ET STADE DE L’HC B
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10102
103
104
105
106
107
108
109
1010
1 2 3 4Années
Hépatite chronique AgHBe -
Porteur inactif
5
COMMENT DISTINGUER LE PORTAGE INACTIF DE L’HCA AgHBe -
LE SUIVI +++
Asselah et al. GCB 2005
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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 2012
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AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2012
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AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2012
ADN VHB < 4 logALAT = N
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AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2012
ADN VHB < 4 logALAT = N
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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
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AgHBe + et AgHBe -
QUI TRAITERGuidelines EASL
Surveiller
EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2012
ADN VHB < 4 logALAT = N
ADN VHB > 4 logEt/ou ALAT > N
PBH > A1F1
Traiter
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COMMENT TRAITER
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TREATMENT OF CHRONIC HEPATITIS B
Two Strategies
- Analogues: pure antivirals maintained response
- Interferon: antiviral + immune modulator sustained response
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NUCs vs IFN
NUCs IFN
- Finite duration - +
- Sustained response - +
- No resistance +/- +
- Oral administration + -
- Good tolerance + -
- Low cost - +?
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RESULTS WITH ANALOGUES
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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. 2008
5. Hadziyannis et al. N Engl J Med. 2003 6. Lai et al. N Engl J Med. 2006
Ne
gat
ive
PC
R (
%)
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ANALOGUES REGISTERED FOR THE TREATMENT OF CHRONIC HEPATITIS B
- Lamivudine -- Adefovir -- Telbivudine + - Entecavir +++- Tenofovir +++
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ENTECAVIR
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ENTECAVIR ADN VHB NÉGATIF A 1 et 3-5
ANS
.
55%
94%
AgHBe + AgHBe -
Chan et al. Hepatology 2010
95%94%
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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
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TENOFOVIR
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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
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Histologie à 5 ans de Traitementn=348
Baselin e Year 1 Year 5
0
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Perc
en
tag
e o
f P
ati
en
ts
Ishak Fibrosis Score
6543210
Marcellin et al. Lancet 2013
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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%
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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
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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
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WHY HBsAg IS THE MAIN
OBJECTIVE OF THERAPY
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- 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
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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
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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
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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
lative In
cid
en
ce o
f H
BsA
g
Sero
co
nversio
n
64%
17%
p<0,001
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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
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RESULTS WITH INTERFERON
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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
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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
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PEG IFN
HBeAg negative CHB
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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
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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
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HBeAg + or HBeAg -
HOW TO TREATEASL Guidelines
• EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009
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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
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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
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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
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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
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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
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THE ROLE OF HBsAg QUANTIFICATION
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HBsAg ACCORDING TO TREATMENT
Treatment
Weeks
LAM
PEG-IFN-2a
PEG-IFN-2a + LAM
Med
ian
lo
g10
IU
/mL
Marcellin et al. Hepatology International 2012
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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
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HB
V D
NA
(L
og
10 c
op
ies/
ml)
HB
sAg
(Lo
g10 U
/ml)
HBsAg Kinetics: PEG IFN SVR (-)
Moucari et al. Hepatology 2009
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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 VirologicalResponse
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PEG IFN + NUC
THE FUTURE OF THERAPY FOR HBV
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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
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PEG IFN + TelbivudineHBsAg decline baseline to week 24
Baseline424616
Week 12424616
Week 24424616
PEGLDTLDT+PEG
Time on treatment
Marcellin et al. Antiviral Therapy 2013
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- 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
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Log10 IU/ml
HBsAg kinetics according to treatment response
Marcellin et al. AASLD 2013
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SVR patient with HBsAg loss
Log10 IU/ml
Marcellin et al. AASLD 2013
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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.
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PERSPECTIVASL’AVENIR?
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PERSPECTIVAS
Traitement individualisé
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