Marcellin tt vhb final

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