Hepatitis E:

Epidemiology, transmission and

treatment

Antonio Rivero-Juarez

Unidad de Enfermedades Infecciosas

Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)

Hospital Universitario Reina Sofía

Universidad de Córdoba

Disclosure

• I declare no competing interests for this presentation

• Outside the current presentation, I have received consulting

fees, conference travel support, and lectures fees from:

– Bristol-Myers Squibb

– Abbott

– Roche

– Merck Sharp & Dohme

– Janssen-Cilag

– ViiV Health Care

• I´m not vegetarian

The case of David

• Male, 32 years old

• HIV infected on HAART with undetectable viral

load (CD4+ 357 cells/mL)

• Digestive symptoms: diarrhea and vomit

• Flu-like symptoms

• AST 650 IU/dL and ALT 750 IU/dL

• CMV, Epstein-Barr, HAV, HCV and HVB viral

load: undetectable

• RT-PCR VHE: 100.000 IU/mL

Today´s agenda

• Key virological bullets

• HEV in Europe:

– Epidemiology: an emergence disease?

– Transmission: public health risk?

– Clinical and Treatment: just an acute hepatic disease?

• Conclusions

HEV key virological points

• Orthohepeviridae family1

• RNA+ non-enveloped: 7,2 kba2

• Four know genotypes that can infect humans3

1. Hepeviridae Study Group. J Gen Virol 2014

2. Hoofnagle. NEJM 2012

3. Kamar. Clin Microb Infect 2014

EPIDEMIOLOGY

¿HOW FREQUENT IS HEV?

HEV global distributtion

CDC Public Health Service 2016

HEV in Low income countries:

Country Affected Transsmision Reference

India 29,300 Waterborne Viswanathan et al. J Med Res 1957

Kashmir 270 Waterborne Khuroo et al. Am J Med 1980

Mexico 200 Waterborne Velazquez et al. JAMA 1990

Ethiopia 750 Monsoon rains Tsega et al. J Med Virol 1991

India 79,000 Waterborne Naik et al. WHO 1992

China 119,000 Waterborne Zhang et al. Gastroenterol 1991

Vietnan 300 Waterborne Corwin et al. A J Trop Med Hyg 1996

Sudan 2,600 Waterborne Guthmann et al. Clin Infec Dis 2006

Uganda 10.000 Person-person Teshale et al. Emerg Infec Dis 2010

Bangladesh 62 Waterborne Haque et al. J Viral Hep 2015

Nepal 10.000 Waterborne/ person-person Shrestha et al. Emerg Infect Dis 2015

Adpatated and updated from Teshale EH. Clin Infect Dis 2010

The case of David

• No travel history to high endemic/ epidemic

countries

HEV in high income countries

Ijaz. J Clin Microbiol 2005

Two different diseases

Hoofnagle NEJM 2012

Prevalence of Endemic HEV in Europe

9.3%

20%

4.7%

20%

11%25%

5%

52%

5%

21%

4%4%

4%

5%

15%

HEV prevalence in Córdoba

(HIV patients)

Rivero-Juarez. J Infection 2015

Prevalence: 21.2% (9.8% confirmated by Western-blot)

HEV incidence in Córdoba

(HIV patients)

Incidence rate:

7.2 seroconversion /100 patients-year

Incidence rate:

Rural: 17.4 seroconversion /100 patients-year

Urban: 5.8 seroconversion / 100 patients-years

Rivero-Juarez. CROI 2015

The case of David

• Inhabitant of a rural town of Córdoba

TRANSMISSION

¿HOW COULD BE INFECTED?

Routes of transmission

Direct

Transmission

Blood

HEV viremia in blood donors

Country Tested Positive Reference

Austria 58,915 7 (0.01%) Fischer et al. PLoS One 2015

England 225,000 79 (0.03%) Hewit et al. Lancet 2014

USA 18,829 9 (0.04%) Stramer et al. Transfusion 2015

France 89 (HSC) 0 (0%) Frange et al. J Infection 2015

The case of David

• No blood transfusion

Routes of transmission

Direct

Transmission

Blood

HEV in animals

Siridhar S. J Formo Med Ass 2015

HEV seroprevalence in pigs

12.5%

39%

63%

61%

65%

30%

27%

75%

92.8%

50%

HepEpork Study: Pigs

• Córdoba: 2nd province of Spain in Pork production

• Home-town of Black Iberian pig

Intensive

farming

Extensive farming

HepEpork Study (partial data)

Global

0

20

40

60

80

100

% o

f p

igs

HE

V-R

NA

po

sitiv

e

N = 499

22.2%

• 13 farms tested (26 farms proyected)

• 499 pigs tested (1040 pigs proyected)

Intensive farming Extensive farming

0

20

40

60

80

100

Farm

% o

f p

igs

HE

V-R

NA

po

sit

ive

N = 419 N = 80

15.5%

57.5%

p < 0.001

Rivero-Juarez. [Unpublished data]

• 40 animals per farm tested

• Prevalence: 8/13 (61.5%)

The case of David

• Not veterinarian

• No relation with pigs farming

HEV viremia in wild life

3.3%

16%4%

20%

19%

11%

HepEpork Study: Wild boar

• Wild boars: in contact with extensive farming

Rivero-Juarez. [Unpublished data]

HepEpork Study: Wild boar

• 45 wild boars tested

Global

0

20

40

60

80

100

% o

f w

ild

s b

oa

r H

EV

-RN

A p

os

itiv

e

N = 45

55.5%

Rivero-Juarez. [Unpublished data]

The case of David

• Father and brother: wild boar hunters

Routes of transmission

Direct

Transmission

Blood

Presence of HEV in food (pork)Pork related food Tested HEV-RNA Country Reference

Raw liver sausages 45 10

(22%)

Italy Di Bartolo et al. Inter J Food Microb 2015

Meat 40 1

(2.5%)

Czech Republic Di Bartolo et al. Inter Emerg Infec Dis

2012

Sausages 93 6

(6.4%)

Spain Di Bartolo et al. Inter Emerg Infec Dis

2012

Meat 33 2

(6%)

Italy Di Bartolo et al. Inter Emerg Infec Dis

2012

Foie related 394 68

(17.2%)

France Pavio et al. N Emerg Infect Dis 2015

Chops 878 31

(3.5%)

Canada Wilhekm et al. Inter J Food Microbiol

2014

Sausages 63 6

(9.5%)

UK Berto et al. Emerg Infect Dis 2012

Presence of HEV in other foodMollusk Tested HEV-RNA Country Reference

Mussel 37 3

(8.1%)

Italy Donia et al. J Viro Meth 2012

Mussel 51 0

(2.5%)

Finland Diez-Valcarce et al. Food Environ Virol

2012

Mussel 51 3

(6%)

Spain Diez-Valcarce et al. Food Environ Virol

2012

Clams 65 5

(7.6%)

France Grodzki et al. AEM 2014

Cockles 49 6

(12.5%)

France Grodzki et al. AEM 2014

Mussels 94 7

(7.4%)

France Grodzki et al. AEM 2014

Oyster 66 3

(4.5%)

France Grodzki et al. AEM 2014

The case of David

• Consumption of undercooked wild boar

The case of David

Father Mother

Brother Sister Sister DavidBrother

in law

Rivero-Juarez. [Unpublished data]

The case of David

Brother

(40.000 UI/mL)

Sister

(30.000 UI/mL)

Sister

(30.000 UI/mL)

David

(20.000 UI/mL)

Father

(50.000 IU/mL)Mother

(20.000 IU/mL)

Brother in law

(30.000 UI/mL)

Rivero-Juarez. [Unpublished data]

The case of David

200.000 UI/mL 150.00 UI/mL

Phylogenetic analysis in process

Rivero-Juarez. [Unpublished data]

Routes of transmission

Direct

Transmission

Blood

Veggies? Breast feeding?

Others

The case of David

Brother

(40.000 UI/mL)

Sister

(30.000 UI/mL)

Sister

(30.000 UI/mL)

David

(20.000 UI/mL)

Father

(50.000 IU/mL)Mother

(20.000 IU/mL)

Brother in law

(30.000 UI/mL)

4 months8 years

Breast feeding?Rivero-Juarez. [Unpublished data]

The case of David

1.000 IU/mL

Children currently under studyRivero-Juarez. [Unpublished data]

CLINICAL AND TREATMENT

¿Is just an hepatic disease?

Clinical manifestation:

Woolson Aliment Pharmacol Ther 2014

Extra-hepatic manifestations

Aggarwal. Virus reserach 2011 Woolson Aliment Pharmacol Ther 2014

Special population:

Cirrhotic patientsHigher mortality Higher decompensation rate

Rivero-Juarez. CROI 2015Acharya. J Hepatol 2007

Special population:

HIV infected patients

Rivero-Juarez. CROI 2015

Special population:

HIV infected patients

Rivero-Juarez. J Infection 2015Dalton. NEJM 2009

The case of David

0

20000

40000

60000

80000

100000

120000

0 7 14 28 35 42

HEV-RNA (IU/mL)

HEV-RNA (IU/mL)

HE

V v

ira

l lo

ad

(IU

/mL)

Days since diagnosticRivero-Juarez. [Unpublished data]

Treatment

Peters van Ton J Viral Hep 2015

Conslusions

• HEV is frequent in EU

• The prevalence found in pigs and wild animals is

high

• The presence of the virus in food is frequent,

supposing an important route of transmission

• The course: mainly acute self-resolved

• Treatment not well established: RBV 6 months?

• Preventive measures in high risk population:

Farm testing?

Acknowledgement

InstitutionsHospital Universitario Reina Sofía:

• UGC Enfermedades Infecciosas

• UGC Análisis Clínico Hospital

Enfermedades Infecciosas Hospital Valme

HepEpork Study Team:• Mario Frias

• Isamel Zafra

• Diego Rodriguez Cano

• Laura Ruiz

• Angela Camacho

• Francisca Cuenca

• Ana Gordon

• Antonio Martinez

• Angeles Risalde

• Jose Carlos Villamandos

• Vicente Fernandez