Yamashita, T. et al. Proc.Natl.Acad.Sci.USA 106

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Yamashita, T. et al. Proc.Natl.Acad.Sci.USA 106
Yamashita, T. et al. Proc.Natl.Acad.Sci.USA 106: 12986-12991!
VHE: l’omniprésence d’un
nouveau virus
Vincent Mallet, MD, PhD
CHU Cochin, Université Paris Descartes,
APHP, Inserm
Hépatite aiguë chez un immunodéprimé
Quel Bilan?
Hépatite aiguë chez un immunodéprimé
Quel Bilan?
IgM anti-VHA, AgHBs (PCR VHB), PCR VHC (anti-VHC), PCR CMV
(sérologie), PCR EBV (sérologie), PCR HSV, PCR VHE (sérologie),
Hépatite autoimmune (HAI), Maladie de Wilson, Echographie doppler
hépatique
Caucasien né en 1965
Prednisone, 5 mg/d
Tacrolimus, 10 mg/d
Azathioprine, 75 mg/d
Greffe rein-pancreas
ATG, CTS
Caucasien né en 1965
Prednisone, 5 mg/d
Tacrolimus, 10 mg/d
Azathioprine, 75 mg/d
Greffe rein-pancreas
ATG, CTS
Caucasien né en 1965
Prednisone, 5 mg/d
Tacrolimus, 10 mg/d
Azathioprine, 75 mg/d
Greffe rein-pancreas
ATG, CTS
Mycophenolate mofetil, 500 mg/d
Mycophenolate mofetil, 500 mg/d
Prednisone, 5 mg/d
Tacrolimus, 10 mg/d
Azathioprine, 75 mg/d
Greffe rein-pancreas
ATG, CTS
Mycophenolate mofetil, 500 mg/d
Prednisone, 5 mg/d
Tacrolimus, 10 mg/d
Azathioprine, 75 mg/d
Greffe rein-pancreas
ATG, CTS
Metavir A2F3
Mycophenolate mofetil, 500 mg/d
Prednisone, 5 mg/d
Tacrolimus, 10 mg/d
Azathioprine, 75 mg/d
Greffe rein-pancreas
ATG, CTS
Ribavirin, 12 mg/kg/d
Metavir A2F3
43 pa&ents dans 12 centres français Age — ans, médiane (Q1, Q3)
52 (42-59)
Sexe — H, n (%)
32
ALAT — UI , médiane (Q1,Q3)
114 (85-164)
Greffe
43 (100%)
Rénale
27 (63%)
Hépatique
8 (19%)
Cardiaque
5 (12%)
Autre (Poumon, rein-pancréas)
3 (6%)
Fibrose hépatique — F3-F4, n (%)
5 (12%)
Génotype — 3, n (%)
3 (100%)
Dose de ribavirine (mg/kg)
10 (7,7-13)
Durée de traitement — semaines,
médiane (Q1, Q3)
12 (12, 12)
Mallet, Kamar, AFEF 2012 Réponse virologique
40% des pa6ents ont développé une anémie sous traitement ayant nécessité soit une baisse de la ribavirine, un ajout d’EPO ou une transfusion) 100
HEV RNA < LOD (sérum)
90
80
70
60
50
40
30
20
10
0
S0
S4
EOT
FUP S12
FUP S24
LDD: Limite de détection (400 copies/ml); EOT: fin de traitement; FUP: suivi
Mallet, Kamar, AFEF 2012 HEV — Milestones
• Balayan MS et al. Intervirology 1983: First observation of viral particles
• Reyes RG et al. Science 1990: Molecular cloning and sequencing of HEV
• Yarbough PO et al. J Virol 1991: First serological test
• Arankalle VA et al. Proc Natl Acad Sci USA 1994: HEV, major ET-hepatitis
• Meng XJ et al. Proc Natl Acad Sci USA 1997: HEV, zoonosis
• Kamar N et al. N Engl J Med. 2008: Chronic HEV
• Yamashita et al. Proc Natl Acad Sci USA 2009: Cristal structure
• Mallet et al. Ann Intern Med 2010: Ribavirin for HEV
• Zhu FC et al. Lancet 2010: Phase 3 trial on recombinant HEV vaccine
Characteristics
HAV
HEV
Family Picornaviridae
Hepeviridae
Genus
hepatovirus
hepevirus
Diameter (nm)
27 - 32
27 - 34
Genome
1 RNA+ strand
1 RNA+ strand
Nucleotides
7474
7200
Replication
Cytoplasm
Cytoplasm
Serotypes, n
1
1
Genotypes, n
6
5
Evidence for an animal reservoir Animals
Countries
Seroprevalence
Genotypes
Worldwide
30-80 %
3-4
Japan, France, Deutschland,
Italia, Spain, Hungary
5-42 %
3-4
Japan, Hungary
2,6 %
3-4
China
57 %
Rabbit
India, Brazil, USA
50-80 %
Rat
Japan
8,3 %
3-4
Horse
China, Egypt
13-16,3 %
Cat
Japan, Spain
11,1-33 %
Dog
Brazil, China
7-17,8 %
Cheep
China, Spain
1,9 %
Goat
China, Spain
0,6-24 %
Bovine
Brazil, China, India
1,42-6,9 %
Chicken
USA, Australia, Hungary
20-30 %
Avian
China
12,8 %
Avian
Swine
Wild boars
Deer
Rabbit
Rat
Mongoose
Duck
Source N. Pavio!
http://www.cdc.gov/hepatitis/HEV/HEVfaq.htm; (January 17, 2011, date last accessed).!
Methods of transmission
Highly endemic areas
Endemic areas
?
Genotypes 3, 4
Genotypes 1, 2
G3 G3 G3 G1 G4 G2 G1 G3 G2 G1 Human HEV!
Geographic Distribution of Genotypes!
Diagnosis of HEV
• Detection of anti-HEV antibodies
– Early (IgM) : Sensitivity 82-90%, specificity 99.5-100%
(Legrand-Abravanel Clin Vaccine Immunol 2009)
– Late (IgG) : Low sensitivity, especially in
immunocompromised (Kamar N Engl J Med 2008)
• PCR on ORF 2 in blood, stool, #
liver… (Mansuy J Clin Virol 2009)
189 bp product
28
MeT
5 NCR
ORF 3
ORF 1
Cap
Y
Pro
P
X
Hel
RdRp
ORF 2
3 NCR
An
Chronic HEV infection • Immunocompromised patients
o Transplant recipients
o People living with HIV
o Chemotherapy (lymphoma)
• After HEV infection, the rate of chronicity ranges
from 40-60% in solid organ recipients
• HEV clearance is possible after immune
restoration or reduction of immune suppressive
regimen
• Mild antiviral efficiency of Interferon #
(risk of graft rejection)
Dalton HR et al. N Engl J Med 2008; Kamar N et al. N Engl J Med 2008; Kamar N et al. Transplantation 2010;
Kamar N et al. Clin Infect Dis 2010
Pischke S, 2012 Pischke S, 2012 Key messages on HEV
• First cause of acute hepatitis worldwide • Emerging autochtonous infectious disease • New cause of chronic liver disease • HEV should always be searched in the setting of acute/
chronic unexplained liver disease • Use PCR
• Ribavirin is a treatment of HEV
• Les transfusions sanguines peuvent transmettre le VHE
Yamashita, T. et al. Proc.Natl.Acad.Sci.USA 106: 12986-12991!