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TRAITEMENT DE L’HÉPATITE B Patrick Marcellin

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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

Hé patitechroniqueAgHBe -

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

Hé patite 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 2009

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AgHBe + et AgHBe -

QUI TRAITERGuidelines EASL

EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009

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AgHBe + et AgHBe -

QUI TRAITERGuidelines EASL

EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009

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

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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 2009

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. 20085. Hadziyannis et al. N Engl J Med. 2003 6. Lai et al. N Engl J Med. 2006

Ne

ga

tive

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 Shouval et al. AASLD 2008

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. AASLD 2011

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%

Percentage of Patients

Ishak Fibrosis Score

6543210

Marcellin et al. AASLD 2011

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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

lativ

e 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-IFNα-2a

PEG-IFNα-2a + LAM

Med

ian

log

10 I

U/m

L

Marcellin et al. Hepatology International. In press

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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)

Treatment

HBsAg Kinetics: PEG IFNSVR (-)

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 Virological

response

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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. EASL 2010

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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 2011

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Log10 IU/ml

HBsAg kinetics according to treatment response

Marcellin et al. AASLD 2011

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SVR patient with HBsAg loss

Log10 IU/ml

Marcellin et al. AASLD 2011

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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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