Joost PH Drenth

Department of Gastroenterology and Hepatology, RadboudumcNijmegen, The Netherlands28 november 2018

Epidemie in NL

Hepatitis E

Disclosure of Conflicts of Interest

• I herewith declare the following paid or unpaid consultancies, businessinterests or sources of honoraria payments since October 1, 2016, andanything else which could potentially be viewed as a conflict of interest:

• Joost PH Drenth has served on advisory boards of AbbVie, Gilead, andIntercept, His Department receives research funding from Gilead, Abbvie,and Ipsen. All reimbursements go to the Radboudumc

Case

• 70-year old male

• No relevant medical history• Presentation with jaundice & pruritis• Laboratory

• At presentation bilirubine total 309 umol/l, AP 170U/l, gGT 47U/l, ASAT 93U/l, en ALAT 97 U/L

Liver biopsy

Disturbed architecture of the liver parenchyma apoptic hepatocytes, extensive

cholestasis and infiltration of the portal fields with a mixed cell infiltrate consisting of

eosinophils, lymphocytes and neutrophils

Diagnosis of (viral) hepatitis

• Clinical presentation

• Biochemical markers• Serology: auto-antibodies • Detection of viral material

• Indirect: Serology• Direct : Detection of virus particles

• In this case• HEV serology positive (IgM as well as IgG)

• Diagnosis hepatitis E

Hepatitis E identified in various hosts

Debing Y, et al. J Hepatol 2016;65:200–12

Hepatitis E virus, genotype 3• Cause:

• Food‐borne zoonosis• Genotype 3 host species: pigs, deer, rabbits, mongoose, sheep and

horses

• Transmission• Contaminated food products (eg, pork)• Blood products

• Solid organ transplantation• Presentation

• Immunocompetent: Acute hepatitis

• Immunosuppressed: Chronic hepatitis

Aliment Pharmacol Ther. 2017;46:126 141.

Hepatitis E source• Consumption of undercooked meat from pigs, wild boar, and deer

• 3 min @ 70 C for decontamination • Risk of patient-to-patient transmission is poorly defined

• Sexual transmission has been described in MSM

• Stool contains high amounts of infectious HEV particles• A vaccine has been developed but is only licensed in China

• Hepatitis E-virus in the Netherlands• 69/70 varkensbedrijven serologisch HEV positief • Onderzoek Sanquin

• Varkensvleesproducten HEV PCR positief • 43 / 55 (78%) leverworsten • 12 / 15 (80%), Varkens paté monsters

• Onderzoek NVWA • 48 / 58 (83%) leverworsten

https://www.veearts.nl/2017/hev-vrij-varkensvlees-is-voorlopig-een-utopie/http://rivm-lci.m13.mailplus.nl/genericservice/code/servlet/React?encId=9vRn24CiVmfDuRp&actId=507413&command=openhtml

Acute hepatitis E

• Acute HEV GT 3 infection is clinically silent in most patients

• <5% may develop symptoms of acute hepatitis• Elevated liver enzymes, jaundice and non-specific symptoms

• Immunocompetent patients clear the infection spontaneously

• Progression to ALF is rare with HEV GT 3• ACLF occurs occasionally

• Non-sterilizing immunity develops after infection has cleared

• Re-infection possible, but with lower risk of symptomatic hepatitis

• Extrahepatic manifestations

• Neurological • Neuralgic amyotrophy; Guillain–Barré syndrome; Meningoencephalitis;

Mononeuritis multiplex; Myositis• Renal

• Membranoproliferative and membranous glomerulonephritis; IgA

nephropathy

EASL CPG HEV. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.005 [

Neuralgic Amyotrophy

Neuralgic amyotrophy painful peripheral neuropathy that causes episodes of multifocal paresis and sensory loss in a brachial plexus distribution

https://www.nature.com/articles/nrneurol.2011.62

Chronic Hepatitis E

• Immunosuppressed patients can fail to clear HEV infection

• Progression to chronic hepatitis• Immunosuppressed groups include:

• Solid organ transplant recipients

• ~50–66% of HEV-infected organ transplant recipients develop chronic hepatitis

• Patients with haematological disorders

• HIV positives • Rheumatic disorders with intense immunosuppression

• Most patients are asymptomatic and present with mild and persistent LFT

abnormalities

EASL CPG HEV. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.005 [

Hepatitis E after transplantation

40−50%

Solid organ transplanted individual

Clearance

50−60%*

HEV is cleared in ~30% of patientsby reducing immunosuppression

Cirrhosis~10% rapidprogression

DeathNeed for LTx

Chronic infection

HEV epidemiology

• European Map

Netherlands • Infections seen in Dutch Laboratories• Infections in University hospitals

• Infections in Blood donors• Screening of Plasma Donors

HEV ‘hot spots’ in Europe

J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.005

Scotland, 2016: 1:2,481 donors viraemic1

SW France, 2016: incidence 3−4%2

The Netherlands, 2014: 1:600 donors viraemic3

Western Germany, 2015: 1:616 donors viraemic4

Czech Republic, 2015: 400 lab-confirmed cases5

Abruzzo, Italy, 2016:seroprevalence 49%6

Western/Central Poland, 2017:seroprevalence 50%7

HEV infections in Germany

http://dx.doi.org/10.1016/j.jcv.2016.06.010 1386-6532/© 2016 Published by Elsevier B.V.

HEV epidemiology in the Netherlands

HEV cumulative

Hepatitis E in Nederland

• UMCG 2012-2017

• 75 patientsImmunocompetent : n=40Immunosuppressed: n=35

• Radboudumc 2013-2017• 42 patients

• Chronic HEV n=22 • Acute HEV n=20

• AMC 2011-2016• 32 patients• Chronic HEV n=14

• Acute HEV n=14• Unclear n=4

Incident HEV cases

2012 2014 2016 20180

5

10

15

20

25

Year

nu

mb

er

of

cases

Dr. Erik Verschuuren UMCG, H.L.Zaaijer, AMC 2018

• HEV PCR op pools van 24 donaties. Pool = pos: dan deconstructie naar donor(s).

• Sinds 3-7-17: 565.207 donaties (tm wk44 2018), gemid. 8074 donaties per week.

• 231/565.207 donaties HEV bevestigd PCR positief, oftewel 1 : 2447 donaties.

• Significante dalende trend.

Dutch HEV PCR donorscreening

Viral Load

Ditribution of HEV virale load

• in 231 PCR positieve bloed donors

Risk factors for HEV positivity among donors• 2100 plasma samples of blood donors from all over the Netherlands aged

18-70 years were tested for anti-HEV IgG antibodies

• IgG-seroprevalence was 31% (648/2100) and increased with age

• 1562 participants completed the questionnaire

• Risk factors : Frequent consumption of • Raw sausages “cervelaat”, “fijnkost”, “salami” (OR 1.5; 95%CI 1.2-1.9)• Bovine steak (OR 1.3; 95%CI 1.0-1.7)

• Smoked beef (OR 1.3 95%CI 1.0-1.7)• Contact with contaminated water (OR 2.5; 95%CI 1.5-4.4).

https://doi.org/10.1186/s12879-018-3078-9

Screening of Plasma donations

- HEV PCR screening van 2000 a 3000 plasmadonaties / maand, in pools van 96.- Piek medio 2014 - op willekeurige dag was 1:600 Nederlanders HEV viremisch incidentie van ~ 1% / jaar.

HEV by numbers • Estimation of HEV in the Netherlands:

• 61,000 HEV infections per year; • 85 via blood transfusion (= 1:700)• 60915 via other routes

• HEV donor screening (in pools of 24) of blood • 79 HEV transmissions prevented, 6 HEV infections slipped through

• 1722 Organ- and bone marrow transplant patients per year• HEV infections

• via food: 5.5 chronic cases of hepatitis E / year• via bloodtransfusion: 2.2 chronic cases of hepatitis E / year.

HEV donor screening prevents 79 of 85 transfusion transmissions, and• 2.0 of the 2.2 transfusion associated chronic hep E cases annually.

• 1.4 M€ testing costs/year; ~ € 700,000 per prevented chronic case.

Gezondheidsraad advies

• De commissie adviseert het testen van alle bloeddonaties op hepatitis E-

virus voorlopig voort te zetten• Bloeddonoren zijn regelmatig met HEV geïnfecteerd, zonder dat zij

ziekteverschijnselen vertonen die bloeddonatie zouden beletten.

• Bloedproducten kunnen een HEV-infectie overgedragen• Voor immuungecompromitteerde mensen, die veel bloedproducten

ontvangen, kan een HEV-infectie ernstige of zelfs fatale gevolgen hebben

• HEV-NAT-screening is effectief: het vermindert het aantal besmettingen door bloedproducten van 187 tot 13 besmettingen per jaar

• Er zijn geen alternatieve maatregelen die kunnen voorkomen dat

bloedproducten besmet zijn met HEV.

Treatment of acute HEV infection

EASL CPG HEV. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.005 [Epub ahead of print]

• Acute HEV infection does not usually require antiviral therapy

• Most cases of HEV infection are spontaneously cleared• Some patients may progress to liver failure

• Ribavirin

• Early therapy of acute HEV may shorten course of disease and reduce

overall morbidity

Hepatitis E treatment

• Chronic Hepatitis E• Wait for 3 months (to establish chronicity) • Two strategies

Ribavirin 600-900 mg/d

Reduceimmunesuppression

Immune system

Management of chronic HEV

EASL CPG HEV. J Hepatol 2018;doi: 10.1016/j.jhep.2018.03.005

HEV clearance

Relapse after

ceasing ribavirin

No HEV clearance

3-month course of

ribavirin monotherapy

Chronic HEV infection

Serum and stool

HEV RNA negative

No response to

ribavirin or intolerant

6-month course of

ribavirin monotherapy

Persistent HEV replication

in serum or HEV relapse

Pegylated interferon for 3 months in LTx patients

No alternative available therapy in other transplant patients

Reduction of immunosuppression

Resultsn = 27

n = 1 died of complicated colon surgery before HEV

infection could be evaluated

n = 26

n = 18 ribavirin treatment

GROUP B

n = 8Stop/lower

immunosuppressantsGROUP A

Comparing treatment strategies

• Cohort Study

• 25 patients• Renal transplantation 11/25

• Strategy

• Reduction Immunosuppression • cure 9/9

• Ribavirin

• cure 14/16

Cohort of 25 chronic HEV patients

Tjwa EASL 2017

Ribavirin therapy

• What is the correct ribavirin dosage ?

• 600 mg/ day some favor higher dosages (SVR~80%) • How long should I treat HEV infection with ribavirin for?

• For chronic HEV infection, the initial course of ribavirin therapy should

be for 3 months• If the patient is immunosuppressed, eg, is a solid organ transplant

recipient, consider a trial of a reduction in immunosuppression in the

first instance• What should I do in the case of ribavirin nonresponse?

• Extend course of ribavirin therapy for a further 3 months

• If still no response, continue ribavirin for further 6 months• Consider trial of pegylated interferon for 3 months (not in renal

transplant recipients

Aliment Pharmacol Ther. 2017;46:126–141

Case

• 1981 diffuse membranoproliferatieve glomerulonefritis

2004 renal transplantation 2013 diabetes mellitus type 2

• Medication • Tacrolimus 2dd 1 mg (prograft) prednison 1dd 7.5mg

• Biochemistry • ALAT 258 IU/L, ASAT 156 IU/L, Gamma GT 681 IU/L, AF 142 IU/L, Bili 14

umol/L

Case

• September 2015 & May 2016 positive PCR HEV

• Juni-december 2016. • 24 weeks Ribavine

• 27 june 2016: 600 mg ribavirine • 18 july 2016 : 400 mg ribavirine

• Maart 2017 HEV PCR negative: SVR