management of hepatitis e virus infection...

Management of Hepatitis E Virus

Infection

Masterclass 2019

Prof.Dr.R.A. de Man

Department of Gastroenterology and

Hepatology

Erasmus MC, Rotterdam, Netherlands

r.deman@erasmusmc.nl

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

r.deman@erasmusmc.nl