Transcript Aucun titre de diapositive - Endo

LEVER AANDOENINGEN
HEPATITES
• AIGUES
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VIRUS A,B,C,D,E
MEDICAMENTS
TOXIQUES
ALCOOL
AUTOIMMUNE
FOIE CARDIAQUE
WILSON
MIGRATION LITHIASE
BUDD CHIARI
METASTASES,LYMPHOME
• CHRONIQUES
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Virus B,C, E?
MEDICAMENTS
ALCOOL
STEATOHEP.DYSMETB
AUTOI
GENETIQUES
BUDD-CHIARI
D
E
VIRUS
HEPATOTROPES
Geelzucht
TRANSMISSION VHA
HAV infection - clinical sequelae
Infection
Incubation
Symptomatic HA
Asymptomatic HA
Protracted HA
Relapsing HA
Fulminant HA
Recovery &
immunity
Death
Recovery &
immunity
HAV endemicity
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
Adapted from CDC
Changing epidemiological patterns
The three major patterns of age-specific prevalence of
anti-HAV Ab
High endemicity
(developing countries)
Prevalence of anti-HAV (%)
100
Intermediate endemicity
50
Low endemicity
(industrialised countries)
0
0
10
20
30
40
Age (years)
: CDC. Hepatitis Surveillance Report No. 51. 1987, 18
50
60
70
PREVENTION HEPATITE A
•
REGLES D’HYGIENE
• PRE-EXPOSITION:vaccin
HAVRIX ou TWINRIX
rechercher anticorps si âge>30 ans
• POST-EXPOSITION:vaccin
HAVRIX si contact récent(1-2
semaines)avec personne
infectée
Clinical-Epidemiologic Correlations
HBV Endemicity
Location
Age of Infection
Mode of
Transmission
Chronicit
y
HCC Risk
High 10-15%
Asia
Sub-Sahara
Africa
Birth
Toddler(bambin)
Perinatal
Horizontal
Likely
High
Low < 2%
N. America
W. Europe
Scandinavia
Early
Adulthood
Percutaneous(IVDUno
socom,horizontal)
Sexual
Rare
Low
Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed February 6, 2006.
Designed by Jules Dienstag, MD
Epidemiology, Prevention, and Treatment of Hepatitis B
Prevalence of Chronic Hepatitis B
~ 2 million Asians
~ 930, 000
Europeans
~ 400,000
South Americans
HBsAg Prevalence
> 8% - High
2-8% - Intermediate
< 2% - Low
~ 350,000
Africans
Immigration numbers summed by continent from 1996-2002
Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis.
Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B
Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed
January 31, 2006.
clinicaloptions.com/hep
Hepatitis B
Sexuele activiteiten
Modes de Transmission
Transmission sexuelle (MST)
Transmission mère-enfant:
dépistage femme enceinte 6ème mois
sérovaccination du nouveau-né
Usage de drogues intraveineuses :
Transmission possible par:
hospitalisations répétées, chirurgie,
examens invasifs, tatouages, piercing,
acupuncture, soins dentaires,
PENSER AU DEPISTAGE +++
Une maladie silencieuse
et potentiellement grave
Guérison (90%)
Hépatite aiguë
Hépatite chronique
(10%)
Cirrhose (20% à 20 ans)
Cancer (20%/5 ans)
INITIAL WORK UP
Three steps of
serological
diagnosis
Infection
1
2
Replication
HBV DNA
HBsAg,
anti-HBc,
Ag HBe/anti-HBe
3
Disease
activity
ALT
FTEST
FSCAN
US, BX
OBJECTIVES OF TREATMENT
• PRIMARY
• Prolonged and sustained annihilation of
HBV replication
• SECONDARY
• HBe seroconversion
• HBs seronversion
• Normalisation of ALT
•
• Improvement of histology including
early cirrhosis
• Prevention of viral transmission
• Prevention of cirrhosis and of
complications of cirrhosis and need for
LTX
Monneja Hepatol 2003,Chen JAMA 2006,Iloeye
GE 2006,Liaw NEJM 2004
only criteria to stop θ
Therapeutic options
Immuno-modulators
IFNpeg
vaccinothérapy
CD8+
HBV
Towards combination therapies ?
Antivirals
Lamivudine
Adefovir
Entecavir
Telbivudine
Tenofovir
Emtricitabine
Clevudine
Valtorcitabine
Elvucitabine
Pradefovir
Hepatitis B:Vaccin
Hépatite C : quelques données
Très gros problème de Santé Publique non pris
en charge par le politique
Prévalence
• 1,1% = 110.000 Belges
• 3% dans le monde
Par rapport au SIDA
• 7 fois plus fréquent
• tue 3 fois plus
• 10 fois plus contagieux
Paucisymptomatique, potentiellement grave
HCV Infection:
Worldwide Prevalence
<1%
1%–2.4%
2.5%–4.9%
5%–10%
>10%
No data available
WHO. Wkly Epidemiol Rec. 2000.
Progression de la fibrose
de la contamination aux complications
Infection VHC
20%
guérison
80% porteurs chroniques
F0
F1
F1
F2
F2
F3
F3
F4
F4
• Age à l ’infection > 40
• Alcool > 50 g/d
• Homme
• Durée de l ’infection
> 20 ans
• Obésité
• Coinfection VHB, VIH
• Tabagisme
cirrhose
• Décompensation 3% / an
• Cancer du foie 3-5% / an
CIRRHOSE DECOMPENSEE OU
« ACLD «
SHP
PPHT
ASCITE / ICTERE
INFECTIONS / PBS
SHR type I et II
THROMBOSE PORTE
HCC
HEPATOK
=> > 50% †
HTP
RISICOFACTOREN
bloed
druggebruikers
Tatoeering,piercing
familie
Opgepast tot persoonlijke toestel !
tatoeering
piercing
VHC - Qui dépister ?
• Avant 1990 :
– TX de sang, produits du sang
– situations à risque de TX : chirurgie lourde, hémorragie,
réanimation, accouchement compliqué, polytrauma
– contact avec sang, actes invasifs avec effraction cutanée,
hémodialyse
• Usage de drogue(s) par voie intraveineuse/nasale
• Risque sexuel : contact avec prostituées,
partenaires sexuels multiples
•  ALT ou asthénie inexpliquée
• Enfants de mère VHC 
• Contact, avec objets par du sang provenant d'une
personne VHC , piercing, aiguille, tatouage, coupeongle familial
Différents stades de la fibrose
4th Annual Clinical Care Options for Hepatitis Symposium
FibroTest:
A Continuous Variable (N = 1270)
FibroTest
Expected
Fibrosis
0.75-1.00
F4
0.73-0.74
F3-F4
0.60
0.59-0.72
F3
0.40
0.49-0.58
F2
0.32-0.48
F1-F2
0.28-0.31
F1
0.22-0.27
F0-F1
0.00-0.21
F0
1.00
FibroTest
0.80
0.20
0.00
0
1
2
3
Fibrosis Stage
Poynard T, et al. Clin Chem. 2004;50:1344-1355.
4
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium
FibroScan
The probe induces an elastic
wave through
the liver
The velocity of the wave is evaluated in a region
located from 2.5 to 6.5 cm below the skin surface
Explored volume
2.5 cm
1 cm 
4 cm
LB: 1/50,000 of the liver
FibroScan: 1/500 of the liver
clinicaloptions.com/hep
ACOUSTIC
RADIATION
FORCE IMPULSE
Buts du traitement
• Eradiquer le virus
• Ralentir l’évolution de la maladie
• Améliorer l’histologie du foie
• Réduire le risque de décompensation hépatique
• Réduire le risque de carcinome hépatique
• Améliorer la qualité de vie
EASL International Consensus Conference on Hepatitis C. J Hepatol 1999;31(Suppl 1)
Ribavirine
PEG-IFN
IFN
RNA
RNA
1ère phase
2ème phase
Lu
Me
Ve
Lu
Lu
4th Pegasys Investigators’ Event
Genotype 2 or 3
Treatment algorithm
• 24 weeks of treatment1
(even for HCV-3 with high viral load2)
• PEGASYS 180µg qw
• COPEGUS 800mg regardless of body weight1
0
24
TREATMENT
24 weeks
HCV RNA Quantitative
48
FOLLOW-UP
24 weeks
HCV RNA Qualitative
1Hadzyannis
SJ. Ann Intern Med 2004, 140(5):346-55.
2Rizetto M. Hepatol 2004, 40(4 S1):252A, Abstract #198.
100%
100%
SVR (%)
4th Pegasys Investigators’ Event
Genotype 2 or 3
Chance for a cure
84%
75%
84%
75%
50%
25%
0%
HCV-2 LVL
HCV-2 HVL
1Rizetto
HCV-3 LVL
HCV-3 HVL
M. Hepatol 2004, 40(4 S1):252A, Abstract #198.
4th Pegasys Investigators’ Event
Genotype 2 or 3
Reimbursement criteria
• Positive HCV RNA
AND
• Genotype 2 or 3
AND
• ALT elevated on 2 occasions
(at least 1 month apart of each other)
• Liver biopsy no longer required !
• Reimbursement for 24 weeks maximum
NEW !
4th Pegasys Investigators’ Event
Genotype 1, 4, 5 or 6
Treatment algorithm
• 48 weeks of treatment1
• PEGASYS 180µg qw
• COPEGUS 1000mg (<75kg) or 1200mg (≥75kg)
0
12
48
TREATMENT
48 weeks
HCV RNA Quantitative
72
FOLLOW-UP
24 weeks
HCV RNA Qualitative
1Hadzyannis
SJ. Ann Intern Med 2004, 140(5):346-55.
Evolutions possibles de l'ARN
sous traitement
ARN
Non-répondeurs
Echappement
Rechute
limite détection
RVS
PEG-IFN/RIBA
0
3
6
12
6
Temps (mois)
PATIENT
Patient:
Adhérence au R/
Médecins généraliste et
spécialiste
Sélection
- Sélection
Soutien
- Soutien
- Education
Education
- Suivi
- PriseSuivi
en charge des
effets secondaires
Prise en charge
Infirmière
INFIRMIERE
SPECIALISEE
MEDECINS
généraliste
Pharmacien
spécialiste
PHARMACIEN(NE)
Potential Targets for Antiviral Intervention in the HCV Life Cycle and
Their Location in the HCV Genome
Manns MP et al. Nat Rev Drug Discovery. 2007;6:991-1000.
New Oral Small Molecule Antivirals in
Development for the Treatment of HCV
Drug name
Drug class
Preclinical Phase I Phase II Phase III
MK-0608 (Merck)
Nucleoside polymerase inhibitor
R7128 (Pharmasset & Roche)
Nucleoside polymerase inhibitor
NIM811 (Novartis)
Cyclophilin inhibitor
ITMN-191 (InterMune & Roche)
Protease inhibitor
X
X
X
MK-7009 (Merck)
Protease inhibitor
X
BI12202 (Boehringer)
Protease inhibitor
X
R1626 (Roche)
Nucleoside polymerase inhibitor
X
DEBIO-025 (Debiopharm)
Cyclophilin inhibitor
X
Celgosivir (Migenix)
-glucosidase inhibitor
X
Telaprevir (Vertex Pharmaceuticals)
Protease inhibitor
X
Boceprevir (Schering-Plough)
Protease inhibitor
X
TMC435350 (Tibotec & Medivir)
Protease inhibitor
X
Adapted from Manns MP et al. Nat Rev Drug Discovery. 2007;6:991-1000.
X
PROVE 1: Telaprevir + PegIFN/RBV in TreatmentNaive HCV GT 1 Patients
• Randomized, placebo-controlled, phase II trial
Wk 12
Wk 24
Wk 48
Placebo + PegIFN alfa-2a 180 g/wk + RBV 1000/1200 mg QD
(n = 75)
Treatment-naive
patients infected
with HCV genotype
1*
(N = 250)
Telaprevir 750 mg every 8 hrs +
PegIFN alfa-2a + RBV
(n = 79)
Telaprevir +
PegIFN alfa-2a + RBV
(n = 79)
Telaprevir +
PegIFN alfa-2a + RBV
(n = 17)
PegIFN alfa-2a + RBV
†
PegIFN alfa-2a + RBV
†
End of
Treatment
End of
Treatment
24-Week
Follow-up
SVR
24-Week
Follow-up
SVR
*Patients received telaprevir 1250-mg loading dose or placebo based on the arm to which they were randomized. †Patients
must achieve undetectable HCV RNA at Wk 4 (< 10 IU/mL) and at last test before stopping therapy at 12 or 24 wks.
EASL 2008 – McHutchinson JG, Abstract 4
PROVE 1: Response Rates (ITT)
Treatment
Week 4
Undetectable*, %
Week 12
Undetectable*,
%
SVR, %
Relapse,%
(N)
PegIFN/RBV 48w
(n=75)
11
45
41
23 (35)
TPV 12w +
PegIFN/RBV 48w
(n=79)
81
80
67
6 (51)
TPV 12w +
PegIFN/RBV 24w
(n=79)
81
68
61
2† (41)
TPV 12w +
PegIFN/RBV 12w
(n=17)
59
71
35
33† (9)
* HCV RNA < 10 IU/L
†Only subjects who met the RVR criterion and stopped at 12 or 24 total weeks of treatment
McHutchison J, et al. EASL 2008. Abstract 4.
SPRINT-1 Final Analysis
RR : relapse rate
VB : viral breakthrough
Total 28 weeks of therapy
DT : discontinuation due
to AE
Total 48 weeks of therapy
75 %
80
67 %
% patients HCV negative
70
55 %
60
56 %
50
38 %
40
30
20
10
0
24%RR
0% VB
8% DT
Control
48 wks
(P/R)
SVR 24
30% RR
7% VB
11% DT
No lead-in and
total 28 wks
(P/R/B)
SVR 24
23% RR
4% VB
15% DT
Lead-in and
total 28 wks
(P/R  P/R/B)
SVR 24
3% RR
5% VB
9% DT
7% RR
12% VB
19% DT
No lead-in and
total 48 wks
(P/R/B)
SVR 24
Kwo request;
et al. EASL
2009
This information is in response to your unsolicited
for MSL
purposes only; not to be copied or distributed.
Lead-in and
total 48 wks
(P/R  P/R/B)
SVR 24
April 23, 2009
HEPATITE E
This information is in response to your unsolicited request; for MSL purposes only; not to be copied or distributed.
April 23, 2009