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1 Division of Gastroenterology and Hepatology Centre Hospitalier Universitaire Vaudois University of Lausanne Darius Moradpour [email protected] www.gastro-hepato.ch Swiss Hepatitis Strategy Symposium Berne, November 15, 2017 Most common cause of acute hepatitis and jaundice in the world HEV gt 1 and 2 infect 20 mio people and claim 70,000 lives every year 1 HEV gt 3 and 4 increasingly recognized as zoonotic infection in the developed world (seroprevalence rates up to 86%) 2 HEV gt 3 can persist in immunocompro- mised pts and cause neurologic complic. 1 Rein DB et al. Hepatology 2012;55:988-997. 2 Mansuy JM, Gallian P et al. Hepatology 2016;63:1145-1154. Reviewed in Hoofnagle JH et al. NEJM 2012;367:1237-1244, Kamar N et al. Lancet 2012;379:2477-2488 and Dalton HR et al. Nat Rev Neurol 2016;12:77-85. The Challenge of Hepatitis E Suspected in the late 1970ies 1 , discovered in 1983 2 and cloned in 1990 3 Family Hepeviridae, genus Orthohepevirus 4 Non-enveloped virus, resistant capsid, 7.2-kb (+)-strand RNA genome One serotype, four major genotypes 1 Khuroo MS. Am J Med 1980;68:818-824 | 2 Balayan MS et al. Intervirology 1983;20:23-31 | 3 Reyes GR et al. Science 1990;247:1335-1339 | 4 Smith DB et al. JGV 2017, in press. Reviewed in Emerson SU and Purcell RH. In: Fields Virology, 6 th ed, 2013, pp. 2242-2258 and Debing Y et al. J Hepatol 2016;65:200-212. Hepatitis E Virus Capsid RNA 32-34 nm The Expanding Hepeviridae Family Debing Y et al. J Hepatol 2016;65:200-212. Green A. Lancet 2017;390:443-444. Hepatitis E in Europe ECDC Surveillance Report 2005-2015 https://ecdc.europa.eu/en/hepatitis-e.

The Challenge of Hepatitis E Berne, November 15, 2017 · Hepatitis E Diagnosis Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514 ! Broad spectrum of liver disease severity:

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Page 1: The Challenge of Hepatitis E Berne, November 15, 2017 · Hepatitis E Diagnosis Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514 ! Broad spectrum of liver disease severity:

1

Division of Gastroenterology and Hepatology Centre Hospitalier Universitaire Vaudois

University of Lausanne

Darius Moradpour

[email protected] www.gastro-hepato.ch

Swiss Hepatitis Strategy Symposium Berne, November 15, 2017

l  Most common cause of acute hepatitis and jaundice in the world

l  HEV gt 1 and 2 infect 20 mio people and claim 70,000 lives every year1

l  HEV gt 3 and 4 increasingly recognized as zoonotic infection in the developed world (seroprevalence rates up to 86%)2

l  HEV gt 3 can persist in immunocompro-mised pts and cause neurologic complic.

1Rein DB et al. Hepatology 2012;55:988-997. 2Mansuy JM, Gallian P et al. Hepatology 2016;63:1145-1154.

Reviewed in Hoofnagle JH et al. NEJM 2012;367:1237-1244, Kamar N et al. Lancet 2012;379:2477-2488 and Dalton HR et al. Nat Rev Neurol 2016;12:77-85.

The Challenge of Hepatitis E

l  Suspected in the late 1970ies1, discovered in 19832 and cloned in 19903

l  Family Hepeviridae, genus Orthohepevirus4

l  Non-enveloped virus, resistant capsid, 7.2-kb (+)-strand RNA genome

l  One serotype, four major genotypes 1Khuroo MS. Am J Med 1980;68:818-824 | 2Balayan MS et al. Intervirology 1983;20:23-31 |

3Reyes GR et al. Science 1990;247:1335-1339 | 4Smith DB et al. JGV 2017, in press. Reviewed in Emerson SU and Purcell RH. In: Fields Virology, 6th ed, 2013,

pp. 2242-2258 and Debing Y et al. J Hepatol 2016;65:200-212.

Hepatitis E Virus Capsid

RNA

32-34 nm

The Expanding Hepeviridae Family

Debing Y et al. J Hepatol 2016;65:200-212.

Green A. Lancet 2017;390:443-444.

Hepatitis E in Europe ECDC Surveillance Report 2005-2015

https://ecdc.europa.eu/en/hepatitis-e.

Page 2: The Challenge of Hepatitis E Berne, November 15, 2017 · Hepatitis E Diagnosis Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514 ! Broad spectrum of liver disease severity:

2

Kupferschmidt K. Science 2016;353:862-863 | See also Lancet 2017;390:334. Müller A et al. Int J Food Microbiol 2017;242:107-115 | Schnegg A et al. PLoS One.

2013;8:e62980 | Niederhauser C et al. Vox Sang 2016;111 (Suppl 1):305. Moradpour D and Frossard J-L. Rev Med Suisse 2017;13:1451-1452 and refs. therein.

l  300,000 new cases per year estimated in Germany ...

l  ... and 100,000 in the UK

l  1500 to 10,000 or more new cases per year in CH

l  Mean seroprevalence in Swiss domestic pigs 58.1%

l  1.3% of Swiss pig livers HEV RNA-positive

l  Mean seroprevalence in Swiss blood donors ~20% (4.2-21.8% in VD, 33.6% in TI)

Switzerland

??

SheepBatCowChickenRabbitRat

PigWild boarDeerCamel

Blood orBlood products

Dire

ct tr

ansm

issio

n

Mussels

Sewage

Food consumption

Run-off fromfarms and land

Irrigation

Crops

Adapated from Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514.

Symptoms

0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks

Anti-HEV IgM

Anti-HEV IgG

ALT

HEV in stool

Viremia

Acute Hepatitis E

Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514.

Hepatitis E Diagnosis

Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514.

l  Broad spectrum of liver disease severity: asymptomatic - mild hepatitis - liver failure1

l  Extrahepatic manifestations2,3 l  High fatality rate in pregnant women (gt 1)4

and patients with underlying liver disease l  Autochthonous acute hepatitis E "hides"

in drug-induced5 and other liver injuries l  Chronic hepatitis and cirrhosis in immuno-

compromised patients6,7

1Manka P et al. CGH 2015;13:1836-1842 | 2Dalton HR et al. NRN 2016;12:77-85 | 3Pischke S et al. J Hepatol 2017;66:1082 | 4Krain LJ et al. AJTMH 2014;90:365 |

5Davern TJ et al. Gastroenterology 2011;141:1665-1672 | 6Kamar N et al. NEJM 2008;358:811-817 | 7Kamar N et al. NEJM 2014;370:1111-1120.

Clinical Manifestations of Hepatitis E

0

100

200

300

400

500

600

700

800

900

1 2 3 4 5 62011 2013 2012 2015 2014 2016

Positive samples Negative samples

Num

ber o

f sam

ples

test

ed

Year

PCR Analyses for HEV RNA Performed at the CHUV

Fraga M et al. Liver Int, in press (epub Aug 23, 2017).

Page 3: The Challenge of Hepatitis E Berne, November 15, 2017 · Hepatitis E Diagnosis Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514 ! Broad spectrum of liver disease severity:

3

l  110 HEV RNA-positive cases of hepatitis E

102 autochthonous (gt 3 or 4)

8 travel-related (gt 1 or 4)

93 acute 9 chronic

Hepatitis E in Switzerland The CHUV Experience

Fraga M et al. Liver Int, in press (epub Aug 23, 2017).

l  Median HEV RNA 7.5 x 104 IU/ml (5.3 to 4.7 x 107 IU/ml)

l  HEV gt 3 in 75 and gt 4 in 3 patients (undeterm. in 15)

l  Fourty-nine patients (53%) presented with jaundice; median peak ALT 1378 U/l (range, 80-5001 U/l)

l  Symptomatic cases were predominantly middle-aged or elderly men (71/93 [76%] men | 49/71 [69%] ≥ 50 yrs)

l  Particularly severe courses in patients with pre-existing chronic liver disease (two †)

l  Six patients (7%) with neuralgic amyotrophy and several with severe myalgia

Acute Hepatitis E Acquired in Switzerland The CHUV Experience

Fraga M et al. Liver Int, in press (epub Aug 23, 2017).

*

* Temporal and geographical clusters

*

gt 4

*

*

Acute Hepatitis E Acquired in Switzerland The CHUV Experience

Fraga M et al. Liver Int, in press (epub Aug 23, 2017).

Hepatitis E Neurologic Complications

l  Develop in ~5% of autochthon. cases l  Neuralgic amyotrophy (brachial neuritis,

Parsonage-Turner syndrome)1,2

l  Guillain-Barré syndrome, meningo-encephalitis and likely others

l  Hepatitis usually mild l  Include hepatitis E early in diagnostic

algorithm! 1van Eijk JJ et al. Neurology 2014;82:498-503.

2van Eijk JJ, Dalton HR, Ripellino P et al. Neurology 2017;89:909-917. Reviewed in Dalton HR et al. Nat Rev Neurol 2016;12:77-85.

Courtesy of Paolo Ripellino and Claudio Gobbi

•  57 HEV + compared to 61 HEV cases •  Bilat. involvement 80.0 vs. 8.6% (p < 0.001) •  Damage outside brachial plexus

58.5 vs. 10.5% (p < 0.01)

Hepatitis E Neurologic Complications

l  Develop in ~5% of autochthon. cases l  Neuralgic amyotrophy (brachial neuritis,

Parsonage-Turner syndrome)1,2

l  Guillain-Barré syndrome, meningo-encephalitis and likely others

l  Hepatitis usually mild l  Include hepatitis E early in diagnostic

algorithm! 1van Eijk JJ et al. Neurology 2014;82:498-503.

2van Eijk JJ, Dalton HR, Ripellino P et al. Neurology 2017;89:909-917. Reviewed in Dalton HR et al. Nat Rev Neurol 2016;12:77-85. Kamar N et al. N Engl J Med 2008;358:811-817.

Page 4: The Challenge of Hepatitis E Berne, November 15, 2017 · Hepatitis E Diagnosis Béguelin C, Fraga M et al. Swiss Med Forum 2016;16:510-514 ! Broad spectrum of liver disease severity:

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Chronic Hepatitis E l  Immunosuppressed patients (transplant

recipients, hematologic cancer, HIV, ...) l  HEV genotype 3 (as well as 4 and 7) l  May rapidly progress to liver cirrhosis l  Serology often negative ! HEV RNA l  Reduction of immunosuppr. ! RBV l  RBV resistance emerges as a challenge

! need for new therapeutic options Kamar N et al. NEJM 2008;358:811-817 and 2014;370:1111-1120; Debing Y et al. J Hepatol.

2016;65:499; Todt D, Gisa A et al. Gut 2016;65:1733 | Reviewed in Kamar N et al. Lancet. 2012;379:2477; Behrendt P et al. J Hepatol 2014;61:1418-1429; Gouttenoire J et al.

Gut 2016;65:1583 and Todt D et al. Viruses 2016;8:283.

1Hogema BM et al. Transfusion 2016;56:722-8 | 2Sauleda S et al. Transfusion. 2015;55:972-9 | 3Baylis SA et al. Vox Sang 2012;102:182-3 | 4Hauser L et al. Blood 2014;123:796-7 |

5Mallet V et al. Ann Intern Med 2016;164:851-2 | 6Gallian P et al. EID 2014;20:1914-7 | 7Hewitt PE et al. Lancet 2014;384:1766-73.

Domanovic D et al. Euro Surveill 2017;22:30514.

HEV in the Blood Supply l  Prevalence of HEV RNA-positive blood

donations ~1:2000 (1:7261 - 1:3,3332) l  10% of plasma fractionation pools + 3 l  Current inactiv. procedures inefficient4,5

l  Most viremic donors neg. for anti-HEV6,7

l  Level and duration of viremia variable l  UK: 79 of 225'000 (1:2848) donations +

! 18/43 recipients (42%) infected7

l  Hepatitis E represents a major global health challenge

l  Two patterns of hepatitis E l  Broad and evolving spectrum of clinical

manifestations l  Varying sensitivity and specificity of

serologic assays l  Chronic hepatitis in immunosuppressed

patients (gt 3)

Conclusions l  Improved understanding of the molecular

virology and pathogenesis l  Optimization and standardization of

diagnostic assays l  Deeper insight into the epidemiology of

autochthonous hepatitis E l  Further delineation of clinical phenotype l  Implementation of preventive measures l  Implications for blood supply

Challenges

The CHUV Hepatitis E Aficionados l  Basic research

Viet Loan Dao Thi and Jérôme Gouttenoire l  Seroprevalence studies

Katharine E.A. Darling and Matthias Cavassini l  Serologic diagnostics

Vincent Aubert and Giuseppe Pantaleo l  Molecular diagnostics

Roland Sahli, Amalio Telenti and Gilbert Greub l  Clinical epidemiology and management

Montserrat Fraga and Christopher Doerig l  Neurology

David Benninger and Thierry Kuntzer

Alessio Aghemo Hepatitis C

Cristina Marcu and Andreas Cerny Tough hepatitis cases

Charles M. Rice Hepatitis B

Heiner Wedemeyer Hepatitis E

10th Challenges in Viral Hepatitis CHUV, January 18, 2018

www.gastro-hepato.ch