management of hepatitis e virus infection...
TRANSCRIPT
Management of Hepatitis E Virus
Infection
Masterclass 2019
Prof.Dr.R.A. de Man
Department of Gastroenterology and
Hepatology
Erasmus MC, Rotterdam, Netherlands
Disclosure R.A. de Man
Disclosure speaker
Post-graduate teaching: Virology International,
Gilead, Falk.
All references to drugs used for HEV are “off-label”
indications.
Teaching goals • Understand epidemiology of Hepatitis E
• Be able to define population at risk and
use correct diagnostic work-up
• To understand the different clinical
presentations of HEV infection
• Be able to use a management algoritm for
treatment
▪
HEV is a zoonotic disease
Four Genotypes Hepatitis E infect humans
with regional restriction
Two types of clinical presentation
Endemic HEV infection
Genotype 1,2
• Outbreaks > 50 people
• Explains 30-70% acute
hepatitis in these regions
• Young healthy people
• Severe disease in
pregnancy
• Travel related disease in
the Netherlands
Sporadic HEV infection
Genotype 3, 4
• Sporadic cases
• Older males
• Pre-existing disease
• Alcohol consumption or
NASH
• No severe disease in
pregnancy
van der Poel WH, et al. - Curr Opin Virol 2014;4:91–6
Factor Odds ratio Attributable
fraction
Raw pork meat 3,0 48%
Working with pigs 3,1 2%
Working with septic
tanc
6,9 1%
Pre-existing liver
disease
3,8
Immunosuppressive
drugs
2,5
Ppi medication 2,3
Diabetes 2,1
Case control study Netherlands 2015-2017
N= 376, 23% n=85 admitted to hospital
Tulen et al;J Infection 2019;xxx.
HEV infection has seasonal variationreported cases 2007-2017 the Netherlands
Thermostability HEV
• Input: faeces or commercialy available raw pork liver
• 56 °C for 30-60 minutes (medium rare)--→alive
• 60 °C 60 minutes (medium rare)----------→ alive
• 70 °C 10 minutes (well done)--------------→ no detectable
virus
▪ Emerson SU J Infect Dis 2005;192:930-3
▪ Tanakada T J Gen Virol 2007;88:903-11
▪ Feagins AR Int J Food Microbiol 2008;123:32-37
Consequences: Life style changes
• “Voor transplantatiepatiënten kan hepatitis E wel schadelijk
zijn. Daarom adviseert het RIVM mensen die een
transplantatie hebben ondergaan geen producten te eten
waar varkenslever in zit die niet goed is door gegaard. Het
gaat om leverworst en paté. De reden is dat hierdoor
mogelijk een besmetting met het hepatitis E-virus kan
worden overgedragen. Bij mensen die
afweeronderdrukkende medicijnen slikken is er een grote
kans dat zo'n besmetting chronisch wordt en leidt tot
leverproblemen.”
http://www.rivm.nl/Onderwerpen/H/Hepatitis_E
Hepatitis E virus is a re-emerging
infectious disease • “Seroprevalence :
• Overall ↓ until 2011 (Germany and the Netherlands)
• ↑ young (largely unexposed) adults
• ↑ HEV RNA positive blood donations in the Netherlands
• Oct 2012 – Mar 2013 1:2742
• Apr 2014 – Sep 2014 1:611
Hogema BM, Transfusion 2014; Wenzel JJ, Hepatol 2014, Zaaijer HL, Hepatol 2015
HEV incidence among healthy blood donors
0
20
40
60
80
100
120
140
160
180
NL 2014 GERMANY2012
FRANCE2014
uk 2014 NL 2013 USA 2015
HEV PCR (+) DONORS/100.000
Hewitt Lancet 2014;Volmer J Clin Microbiol 2012;
Gallian EID 2014;Stromer Transfusion 2015; Hogema Transfusion 2014
HEV Infection versus HEV induced disease
Kamer N,Lancet 2012
Hepatitis E Virus
Immunocompetent Immunosuppressed
Silent infection, clearance
Symptomatichepatitis E
Acute liverfailure
Life-threatening
Chronichepatitis E
Courses of hepatitis E
Immunosuppression
Does unexplained Hepatitis equals HEV infection ?
• Dutch general hospital based population with elevated ALT
• Inclusion period 10/2007 – 9/2008
• All tested negative for A,B,C
• 139 samples
• 23 samples ELISA HEV IgG and/or IgM(+)
• 16/23 confirmed in immunoblot IgM(+)
• 16/139--→ 11,5 % diagnosis HEV was made.
• Median ALT 132 IU/l (range 35-2278 IU/l)
van Wijngaarden NTvG 2010;154:A1865
Does unexplained Hepatitis equals HEV infection ?
• Dutch academic hospital based population with elevated
ALT and test requisition: CMV, EBV, HAV
• Inclusion period 1/2011 – 10/2012
• Exclusion of immune compromised patients
• 90 samples tested by Wantai assay and HEV PCR
• 2% acute HEV genotype 3, pcr confirmed
• One pregnant woman (only pcr positive)
• One alcoholic male with diabetes
Tholen AT,et al;Plos One:2016;11(2):1-6
Clinical presentation
• Acute HEV infection
• Acute on chronic HEV infection
• HEV coinciding with extrahepatic manifestations
• (Chronic HEV in immune competent patients)
• Chronic HEV in immune compromised patients
Flow diagram for diagnosis of acute hepatitis E virus infection
Nassim Kamar et al. Clin. Microbiol. Rev. 2014;27:116-138
Clinical presentation in acute HEV gt-3
• Sporadic cases in predominantly older males
• Pre-existing disease (alcohol, DILI, NASH)
• No severe disease in pregnancy
Patient characteristics: Age and gender
HEV pcr neg
Koot et al. J Clin Virology 2015
Acute on chronic liver failure
hospital admissions UK/Toulouse
• Inclusion: Admission for decompensated liver disease
• All tested for HEV PCR
• Cases: n= 11/343 (3.2%) UK 1,2 % Toulouse 7,9%
• All NASH or alcoholic liver disease
• 3/11 (27%) died within 6 months
• No difference in mortality between HEV(+) and
HEV(neg)
Blasco-Perrin H AP&T 2015;42:574-581
Acute on chronic liver failure
hospital admissions New Delhi India
• Inclusion: four groups
• Cirrhosis (n= 107):
• rapid decompensation; chronic dec.; stable disease
• healthy blood bank controls (n=200)
• HEV PCR controls 4,5%;cirrhosis 28%
• 12 months mortality in cirrhosis 70% vs. 30%
• Multivariate analysis: HEV infection, Child Pugh score,
renal failure and sepsis.
Kumar J Hepatol 2007;46:387-94.
One year survival in patients with liver cirrhosis
after HEV infection in New Delhi
HEV in India kills in Child B and C liver disease
Definition of risk groups chronic
HEV infection
• Solid organ transplantation (SOT), 60-80% after
acute infection.
• Bone Marrow transplantation
• HIV infection only with decreased CD4
• Specific anti T-cell therapy eg. Rheumatoid
Arthritis
• Cancer Chemotherapy in leucopenic phase
Chronic HEV in solid organ recipients
• Chronic HEV infection reported in the transplant setting
• Persistent viraemia
• Persistently raised transaminase activity
• Histological features associated with chronic hepatitis
• Evidence of rapid development of cirrhosis within years
• Association with a more profound immunosuppression
Kamar, N Engl J Med 2008;358(8):811-7.
Haagsma, Liver Transplantation 2009;15(10):1225-8
Schlosser, J Hepatol 2012;56:500-502.
Halac U, Gut 2012;:61:597-603.
Extrahepatic manifestations
HEV can enter and replicate in neural
tissue.
•Guillain Barré syndrome
•Neuralgic Amyotrophy
•Encephalitis/ myelitis
Nat Reviews Neurol 2016;12:77-85; J Vir Hepatis 2016;23:512-521
Extrahepatic manifestations
HEV RNA is detected in kidney and urine
•Cryoglobulinaemia
•Membranoproliferative and
membranous glomerulonephritis
•Acute Tubular Necrosis
J Hepatol 2016 ;65:200. Liv Int April 2016. Lancet Infect Dis
2014;14:678-679
Acute HEV in elderly male using Methotrexate
Acute renal dysfunction after HEV infection
0
50
100
150
200
250
300
05-02-2016 12-02-2016 19-02-2016 26-02-2016 04-03-2016 11-03-2016
kre
ati
nin
um
ol/l
Kreatinin after HEV infection
Treatment of acute HEV infection
• Wait and see policy
• Reduction or change of immunosuppression
• Early Drug treatment ? Unclear (n = 21)
• Severe disease protrombine time below 50%
• Age > 70 years
• Chemotherapy solid cancers
Peron JM, Liver Intern 2016;36:328-33.
Treatment of chronic HEV infection
• Wait and see policy: 3 months
• Reduction or change of immunosuppression
• Off-label Drug treatment:
• Peg-interferon alpha
• Ribavirin
• Others…
Drug Treatment for chronic HEV
Gastro 2011;140:1481 . J Hepatol 2016 ;65:200–12
• N= 59 cases Solid Organ Transplantation
• Ribavarin 600 mg/day (29-1200 mg/day)
• 66% 3-months or less treated
• SVR 6 months post-treatment 46/59 (78%)
• Relapse n=10; re-treatment: SVR in 4/6
• Side effect: anemia
Kamar N; N Engl J Med 2014;370:111-20
.
Ribavarin treatment: outcome
Ribavarin in chronic HEV infection
Kamar N; N Engl J Med 2014;370:111-20
Changes in virus host interaction
•Acute Liver failure needing
transplantation is related to certain viral
mutations
•During ribavirin treatment evolution of
HEV quasispecies; G1634R mutation
•Selection of drug resistant mutants has
been documented in non-responders to
ribavirinTodt D,Gut 2016;65:1734-44 Debbing ,J Hepatol 2016;65:499-508
2014;14:678-679
• Sporadic endemic HEV hepatitis, genotype 3
• HEV is a zoonotic infection with a pig, boar
and deer reservoir
• Highly prevalent in Europe
• Serology in immune competent patients
• HEV PCR in immune compromised patients
Take home message: HEV infection
• Silent seroconversion: the majority
• Acute symptomatic HEV infection, risk profile
• HEV mimicking DILI, liver transplant rejection
and Graft versus Host Disease
• Chronic HEV infection in immune suppressed
patients: mainly solid organ or bone marrow
transplant patients
Take home message:
Outcome after infection
Take home message: chronic HEV infection
• Persistent viraemia
• Persistently raised transaminase activity
• Misleading: transaminases respond favourably
to an increase in immunosuppression
• Histological features associated with chronic
hepatitis with rapid development of cirrhosis
Take home message: treatment
• Chronic HEV infection
• Reduce immunosuppressive drugs
• ? Change in immunosuppressive regimen
positive role of mycephenolate mofetil
• 3-months Ribavarin estimated SVR 78%
• Severe acute (on chronic) HEV and extrahepatic
manifestations:
• treatment depends on expert opinion.
Management of Hepatitis E Virus
Infection
Masterclass 2019
Prof.Dr.R.A. de Man
Department of Gastroenterology and
Hepatology
Erasmus MC, Rotterdam, Netherlands