Hepatitis E y VIH - Grupo GEAM · Moluscos Pais HEV-RNA Reference Mejillones Italy 8.1% Donia et...
Transcript of Hepatitis E y VIH - Grupo GEAM · Moluscos Pais HEV-RNA Reference Mejillones Italy 8.1% Donia et...
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Hepatitis E y VIHAntonio Rivero-Juarez
Clinical Virology and Zoonisis Research Group (GC-26)
Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)
Infectious Diseases Unit
Hospital Universitario Reina Sofía de Córdoba
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Conflicto de interés• Payment to my Institution:
• Public Funds: Fundación para la investigación en Salud (FIS)
• Private Funds: AbbVie y ViiV Healthcare
• Payment to me:
• Consultancy: Roche Diagnostics, Gilead, and Bristol Mier Squidd
• Payment for lectures including service on speakers bureaus: Bristol Mier Squidd, ViiV Healtcare,
Janssen Cilag, MSD, y Roche Diagnostics, AbbVie, and Gilead.
• Other relationships/conditions/circumstances:
• I have no personal, business, social or acquaintance relationship with food or livestock enterprises.
• I´m not vegetarian
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Aspectos virológicos
1. Nimgaonkar et al Nature Rev Gastro Hepatol 20182. Debing Y, et al. J Hepatol 2016
Estructura molecular1 Genotipos2
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Principal causa de muerte por hepatitis aguda
20 millones de casos anuales
70.000 muertes anuales
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1980N = 200
1991N = 750
1991N = 119.000
1996N = 300
2006N = 2.700
2010N = 10.000
2015N = 67
1957N = 29.300
1979N = 270
1992N = 79.000
2015N = 10.000
2012N = 170
2004N = 672
2017N = 1874
Hepatitis E largest outbreaks
Rivero-Juarez A
2018N = 957
2017N = 2035
2017N = 1262
1994N = ?
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Aspinall et al Eurosurveillance 2017
Entonces, si no viajo no hay riesgo de infección…
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Aspinall et al Eurosurveillance 2017Adlhoch et al J Virol 2016
Aumento del número de casos en los últimos años
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Agenda
Objetivos
• Epidemiología de la infección por el VHE en pacientes infectados
por el VIH
• Vías de transmisión del VHE: Factores de riesgo
• Diagnóstico de la infección por el VHE
• Tratamiento de la infección por el VHE
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Epidemiología del VHE en pacientes infectados por el VIH¿Es un grupo de riesgo?
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Seroprevalencia VHE en pacientes VIH
France14,7%
Spain18.1%
Italy7.3%
Greece7.3%
Scotland1.04%
England9.4%
Switzerland2.6%
Holland11.7%
Croatia1.1%
Gabon7.1%
Cameroon14.2%
Nigeria30%Ghana
45.3%
USA10.8%
Argentina6.6%
Australia6.3%
Malasya10.3%
Cambodia30%
China44.2%
Poland1%
Germany26%
Rivero-Juarez A
Tanzania8%
Nepal39%
Brasil10.7%
China38%
Etiopia31%
Iran16.9%
Zambia71%
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Jardi et al J Med Virol 2009 IgG = 9%
Mateos-Lindemann et al J Med Virol 2014 IgG = 10,4%
Pineda et al AIDS 2014 IgG = 26%
Incidencia = 19%
Prevalencia e incidencia VHE en pacientes VIH
Riveiro-Barciela et al PLoS One 2014IgG = 9,2%
Rivero-Juarez et al J Infection 2015 IgG = 21%
Incidencia = 7.2 seroconversion /100 patients-year
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Factores de riesgo en pacientes infectados por el VIH
Incidence rate: Rural: 17.4 seroconversion /100 patients-year
Urban: 5.8 seroconversion / 100 patients-years
Rivero-Juarez et al Zoonoses Public Health 2017
Ningún factor asociado conla infección VIH
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¿VIH es un factor de riesgo?
HIV Control
0
20
40
60
80
100
Pre
vale
nce o
f Ig
G p
osit
ive
N = 300 N = 600
38.7%47.3%
p = 0.027
HIV Control
0
20
40
60
80
100
Pre
vale
nce o
f Ig
M p
osit
ive
N = 300 N = 600
3.6% 3.8%
p = 0.85
HIV-infected patient was matched for sex and age with 2 healthy blood donors from thesame area
1. Abravanel et al J Infection 2017
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Subgrupos pacientes con mayor riesgo: HSH
• Population: 636 MSM compared (non-matched) with 288 non MSM healthy donors
• Evaluation: IgG HEV and IgG HAV
Greco et al J Med Virol 2018
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Vías de transmisión del VHELos pacientes VIH se infectan por las mías vías que la población general
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Hewitt P Lancet 2014Mallet V Ann Intern Med 2016
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País Donantes: RNA VHE + Referencia Establecido cribado
Francia
1: 2.218 Gallian Emerg Infec Dis 2014
En consideración1: 1.000 Mansuy Hepatology 2016
1: 744 Gallian et al Transfusion 2017
Alemania
1: 1.200 Vollmer et al J Clin Microbiol 2012
Recomendado en poblaciones especiales.Cribado universal en consideración
1: 4.252 Baylis et al Vox Sang 2012
1: 679 Müller et al Transfus Med Hemother 2015
Italia 1: 1.700 Raffaele EHA 2017 No considerado
Reino Unido
1: 1.365 (Inglaterra)
Hewitt et al Lancet 2014 Universal desde Abril 20171: 2.481 (Escocia)
1: 2.280 (Gales)
Suecia 1: 7.986 Baylis et al Vox Sang 2012 No considerado
Austria 1: 8.416 Fischer et al PLoS One 2015 No considerado
Irlanda 1: 4.997 O´Riordan et al Transfusion 2016 Universal desde Enero 2016
Dinamarca 1: 2.331 Harritshøj et al Transfusion 2016 No recomendado
Holanda1: 2.671 Harritshøj et al Transfusion 2016
En consideración1: 1.289 Hogema et al Transfusion 2016
España
1: 3.333 (Cataluña) Sauleda et al Transfusion 2015
En evaluación1: 17.689 (Norte/Centro) Gonzalez et al Blood Transf 2017
1: 4.720 (Cataluña) Piron et al Blood Transf 2017
1: 2.500 (Euskadi) Unpublished data
Otros países sin estudios de viremia: Suiza (en evaluación), Portugal (En evaluación), Grecia (En evaluación)
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Casos transmisión VHE por transfusiones en Europa
Hewitt P Lancet 2014Mallet V Ann Intern Med 2016
Izopet J et al Emerg Infect Dis 2017Riveiro-Barciela M et al Transfusion 2017
Inglaterra: 18 casos
Francia: 7 casos en trasplantados
Alemania: 1 caso
España: 1 caso
Francia: 1 caso
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Proyecto prospectivo de cribado en Alemania
Octubre 2016
28.981 donantes
Cobas 6800 Roche HEV
30 RNA HEV(1: 966)
3 pacientes con↑ ALT
2 pacientes con viremia > 4m
No HEV
No HEV
No HEV
No HEV
No HEV
No HEV
No HEV
No HEV
ACLF Exitus
Horvatis T et al. EASL 2018 Paris. SAT-331
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Proyecto piloto de cribado en Ciudad Real
Septiembre 2017
6.097 donaciones
RT-PCR: minipools 8
4 RNA HEV(1: 1.519)
Jarilla et al ISBT 2018 Toronto P-466
HEV RNA: 2 X 106 UI/mL
HEV RNA: 4,3 X 104 UI/mL
HEV RNA: 1 X 104 UI/mL
HEV RNA: 2,8 X 104 UI/mL
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Casos documentados de transmisión por trasplante
Lhome S Emerg Infec Dis 2017Protzer U et al Mod Pathol 2014Schlosser B et al J Hepatol 2012
Moal V et al J Med Virol 2013
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Casos documentados de transmisión por trasplante
Lhome S Emerg Infec Dis 2017Protzer U et al Mod Pathol 2014Schlosser B et al J Hepatol 2012
Moal V et al J Med Virol 2013
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Estudio HepE-Tx: HURS
Biopsia tiempo 0
Donante Receptor
Parafina
Extracción RNA(RNeasy FFPE Kit)
RT-PCR(protocolo IMIBIC ORF3)
AnálisisPrevalencia en donantes
Riesgo de transmisiónPrevalencia en receptores
Riesgo causa trasplante
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Órgano trasplantadoN = 105
Órgano ExplantadoN = 105
ARN-VHE en hígado 10
Prevalencia VHE 0.95%0
Estudio HepE-Tx:
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Alimentos principal factor de riesgo
Faber et al Eurosurveillance 2018
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Alimentos principal factor de riesgo
Faber et al Eurosurveillance 2018
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HepEpork Study:
Intensive farming
Extensive farming
Lopez-Lopez et al GeHEP 2017
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Global
0
20
40
60
80
100
% o
f p
igs
HE
V-R
NA
po
sitiv
e
N = 1.037
16.2%(N = 168)
Intensivo Extensivo
0
20
40
60
80
100
Explotación
% o
f p
igs
HE
V-R
NA
po
sitiv
e
N = 679 N = 358
12.1%(N = 82)
24%(N = 86)
p < 0,001
HepEpork Study:
Lopez-Lopez et al GeHEP 2017
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Presencia del VHE en alimentos de origen porcinos
Alimento Pais HEV-RNA Reference
CarneItaly 6% Di Bartolo et al. Emerg Infec Dis 2012
Czech Republic 2.5% Di Bartolo et al. Emerg Infec Dis 2012
Salchicha
Italy 22% Di Bartolo et al. Inter J Food Microb 2015
Spain 6.4% Di Bartolo et al. Emerg Infec Dis 2012
U.K. 9.5% Berto et al. Emerg Infect Dis 2012
Germany 20% Szabo et al. J Food Microbiol 2015
France 30% Pavio et al Emerg Infect Dis 2014
Paté France 17.2% Pavio et al. N Emerg Infect Dis 2015
Hígado
Francia 4% Griergson et al Emerg Infect Dis 2015
Netherlands 6.5% Di Bartolo et al. Inter J Food Microb 2015
Czech Rep 5% Di Bartolo et al. Inter J Food Microb 2015
Italy 6% Di Bartolo et al. Emerg Infec Dis 2012
Spain 3% Di Bartolo et al. Emerg Infec Dis 2012
U.K. 3% Berto et al. Emerg Infect Dis 2012
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HepEboar Study
Rivero-Juarez et al BMC Vet Res 2018
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HepEboar Study
Rivero-Juarez et al BMC Vet Res 2018
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Brote familiar por consumo de jabalí (n = 8)
230.500 copias/gr 155.300 copias/gr
1. Rivero-Juarez Zoonos Publ Health 2017
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Aislamiento en leche materna
Rivero-Juarez Clin Infect Dis 2016
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Leche bovina para consumo
Huang F Hepatology 2016
VHE en vacas Transmisión VHE por leche en modelo animal
Inactivación VHE
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Ausencia del VHE en leche Europea (genotipo 3)
400 granjas testadas
400 muestras de tanque
0%
Baechlein C et al Hepatology 2017
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Hospedadores del VHE
Nimgaonkar Nat Rev Gastro Hepatol 2018
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Aguas residuales factor de riesgo
Faber et al Eurosurveillance 2018
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Repercusión de VHE en aguas residuales riego
Terio V et al Inter J Food Microbiol 2017Brassard J et al Appl Environ Microbiol 2012
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Repercusión de VHE en aguas residuales marinas
?
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Moluscos Pais HEV-RNA Reference
Mejillones
Italy 8.1% Donia et al. J Virol Meth 2012
Finland 0 Diez-Valcarce et al. Food Environ Virol 2012
Spain 6% Diez-Valcarce et al. Food Environ Virol 2012
France 7.4% Grodzki et al. AEM 2014
Spain 14.8 Mesquita et al Food Microbiol 2016
Scotland 85% Song et al J Med Virol 2010
England 92% Crossan et al Emerg Infect Dis 2012
Almejas France 7.6% Grodzki et al. AEM 2014
Berberechos France 12.5% Grodzki et al. AEM 2014
Ostras France 4.5% Grodzki et al. AEM 2014
Presencia del VHE en moluscos
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Manifestaciones clínicas en el paciente VIHExisten algunas peculiaridades
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Manifestaciones clínicas en población general
Faber et al Eurosurveillance 2018
Self-limiting (90%) Complications (10%)
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Descompensaciones hepáticas por VHE
Wang et al EASL 2018 Paris SAT-326
Mortalidad por VHE en cirróticos
Acharya et al J Hepatol 2007
VHE en el paciente cirrótico: descompensaciones
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Causa de fibrosis hepática de origen incierto: VHE crónico
Neukam K et al Clin Infect Dis 2013Huniholm et al Hepatology 2015
Dalton HR et al NEJM 2009
España
EE.UU
Inglaterra
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How often is chronic Hepatitis E infection in HIV infected individuals?• 7 Cases reported worldwide.1-5
1. Dalton et al NEJM 20092. Kaba et al J Med Virol 2011
3. Kenfak-Foguena et al Emerg Infec Dis 20114. Neukam K et al Clin Infect Dis 2013
5. Huniholm et al Hepatology 20156. Rivero-Juarez et al J Infection 2015
0% of chronic HEV infection
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CD4+ count in chronic HEV cases
Reference CD4+ cell count at diagnosis
Time with viremia CD4+ during positive viremia period
Dalton et al [1] < 50 cells/mL 2 years < 200 cells/mL
Kaba et al [2] < 50 cells/mL 10 months < 200 cells/mL
Kenfak-Foguena [3] < 50 cells/mL 13 years < 200 cells/mL
< 100 cells/mL 3 years < 200 cells/mL
Neukam et al [4] < 100 cells/mL 3 years < 200 cells/mL
Cases reported in HIV individuals1. Dalton et al NEJM 2009
2. Kaba et al J Med Virol 20113. Kenfak-Foguena et al Emerg Infec Dis 2011
4. Neukam K et al Clin Infect Dis 2013
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Factors associatted with chronic infection
Kame et al NEJM 2008
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Manifestaciones extra-hepáticas
Pischke S et al J Hepatol 2017
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Alteraciones neurológicas por VHE
Dalton. Nature Neurol. 2016 Pischke S et al J Hepatol 2017
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Follow-up recomendation
GeHep/SEIMC HEV Guidelines 2018
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Hepatitis E reinfection in HIV infected patients
1. Rivero-Juarez et al Clin Infect Dis 2017
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Reinfection in solid organ transplant patients
1. Abravanel JID 2014
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Antibodies concentration Immunosupressed2
IgG > 7 WHO units/mL
1. Zhanh NEJM 20152. Abravanel JID 2014
Immunocompentent1
IgG > 2.5 WHO units/mL
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Tratamiento de la infecciónOpciones terapéuticas escasas
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Algorithm for the treatment of HEV infection
GeHep/SEIMC HEV Guidelines 2018 EASL HEV Guidelines 2018
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How to evaluate SVR?
• Undetactable HEV-RNA 24 weeks after complention of therapy
• In serum
• In faeces
• Positivity in faeces: absence of a response to treatment should be assumed, since
the persistence of HEV-RNA in the faeces, even when absent in the serum, is
associated with HEV recurrence following the interruption of the RBV1
1. Abravanel et al Clin Infect Dis 2015
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HEV positivity in faeces and risk of relapse
1. Abravanel et al Clin Infect Dis 2015
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Rates of SVR
Peters van Ton J Viral Hep 2015
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Sofosbuvir eficaz in vitro…In vitro1
1. Dhao Thi et al Gastroenterol 20162. Van der Valk et al J Hepatol 2017
3. Wang W et al Gastroenterol 2016
…pero in vivo…
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Donnelly M et al Gastroenterol 2017
¿Sofosbuvir + Daclatasvir?
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Conclusiones• La infección por el VHE es frecuente en pacientes infectados por el VIH,
pero no tiene mayor prevalencia que en la población general.
• Las vías de transmisión están principalmente relacionadas con consumo de
alimentos derivados del cerdo
• En pacientes infectados por el VIH inmunodeprimidos el VHE puede
evolucionar a formas crónicas
• Pueden producirse reinfecciones
• Opciones terapéuticas limitadas
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Acknowledge:
Mario FríasIsmael ZafraTeresa BrievaDiego Rodríguez CanoLaura RuizÁngela CamachoFrancisca CuencaIsabel MachucaPedro LópezAntonio MartínezAngeles RisaldeAntonio Rivero
Ignacio García BocanegraDavid CanoSaul JimenezFernando Romero José Carlos Villamandos
Vicente FernandezJuan Luis Millan
Pilar AlberdiUrsula HöfleChristian GortázarFrancisco Ruiz Fons
@Arivejua