An updated slideset on HEV

1. Hepatitis E Virus (HEV)
Mario U. Mondelli
Research Laboratories, Department of Infectious Diseases,
Fondazione IRCCS Policlinico San Matteo and Department of Internal
Medicine, University of Pavia, Italy.
Infectious Diseases in the Mediterranean and the Middle East: Current Challenges.
Izmir, September 22-24, 2014

2. Hepatitis E: A True Story
• In 1983, Dr. Balayan was investigating an outbreak of non-A, non-B
hepatitis among Soviet soldiers in Afghanistan. Though he wanted to
bring samples back to his Moscow laboratory, he lacked refrigeration.
So he made a shake of yogurt and an infected patient’s stool, drank it,
went back to Moscow, and waited until a few weeks later when he
developed symptoms of hepatitis.
• He then started collecting and analyzing his own samples. In these he
found a new virus, similar to HAV by EM, that produced liver injury in
laboratory animals. Dr. Balayan already had antibodies against the HAV
which did not protect him from the infection.
Balayan MS, et al. Intervirology 1983;20:23–31.

3. The Hepatitis E Virus
Family: Hepeviridae, Genus: Hepevirus
• 1/3 of world population exposed to HEV
• Mostly transmitted via fecal-oral route, rarely by blood
products. HEV RNA per blood donation: 1:1,430-1:7,040
• Usually acute self-limiting
disease
• Case fatality ratio: 1-3%
(pregnant women up to 25%)
• Genotype 1: Asia, Africa
• Genotype 2: Mexico, Africa
• Genotype 3: Western countries
• Genotype 4: Asia, Europe

4. How Is HEV Inactivated?
• Virus remains viable after heating for 1h at 56°C
• Cooking temperatures of 71°C for 20 min are
required to fully inactivate the virus

5. Geographic Distribution of HEV
www.cdc.gov/hepatitis/HEV/HEVfaq.htm

6. Hepatitis E: Incidence
• Developing countries: variable
– Bangladesh 64/1,000 patient-years
• Developed countries: variable
– US 7/1,000 patient-years
– Southern France 30/1,000 patient-years

7. Hepatitis E Virus Genome
Kamar N et al. Clin. Microbiol. Rev. 2014;27:116-138
Capsid (660aa):assembly
immunogenicity
target cells
P113: virion morphogenesis
& release
ORF1

8. Consensus Proposals for Classification of the Family
HEPEVIRIDAE
• Orthohepevirus: all mammalian and avian HEV isolates
 Orthohepevirus A isolates from human, pig, wild boar, deer,
mongoose, rabbit and camel)
 Orthohepevirus B (isolates from chicken)
 Orthohepevirus C (isolates from rat, greater bandicoot, Asian
musk shrew, ferret and mink)
 Orthohepevirus D (isolates from bat)
• Piscihepevirus: cutthroat trout virus
Smith DB, et al. J Gen Virol 2014, in press

9. Dendrogram Based on Full-Length Sequences of HEV Strains
Kamar N et al. Clin. Microbiol. Rev. 2014;27:116-138
Piscihepevirus

10. Two Distinct Clinico-Epidemiological Patterns
• In areas of poor sanitation, HEV1 and HEV2 are transmitted
between humans by the fecal-oral route, usually via
contaminated water. This results in frequent sporadic cases and
occasional large outbreaks.
– Excess mortality in pregnant women
• In developed countries, HEV3 and HEV4 are sporadically
transmitted zoonotically from animal reservoirs through
consumption of undercooked pork or game meat and shellfish.
– Elderly males are at higher risk for unexplained reasons.
– HEV3 may cause chronic infection

11. HEV Markers
Incubation 2-6 wks

12. HEV Infection and Pregnancy
• Excess mortality in pregnant women (20-25%):
– Haemorrhage, eclampsia, FHF
– No excess mortality in Egypt
• Increased neonatal morbidity and mortality1
• Apparently restricted to HEV1 & 2
• Pathogenesis unknown
1. . Khuroo MS, et al. Lancet 345:1025–6. 3.

13. HEV Infection in Pre-Existing Liver Disease
• Poor prognosis:
– 12-month mortality rate 70%1
• Pork meat consumption linked to decompensation2
1. Kumar Acharya S, et al. J Hepatol 46:387–94. 2. Dalton HR, et al. Epidemiol Infect 2010;138:174–182

14. Mini-Cluster, Pavia Spring 2014
• 3 male patients (61- 65 yr-old):
 Pt.1: acute on chronic liver failure. Refused for OLT
because of preexisting malignancy→ died.
 Pt. 2: typical acute hepatitis
 Pt. 3: mild increase in ALT
• 2 reported eating pork meat (same grocery store)
• 2 presented with increased creatinine
• 2 treated with ribavirine (including the fatal case)
• All IgM and IgG positive, HEV RNA range 6x103 –
8x107 cp/mL

15. Seroprevalence of anti-HEV IgG in the General Population
• Most children under age 10 have not been exposed to
HEV1, except Egypt2
• In endemic areas, dramatical increase between the
ages of 15 and 30 years, which plateaus at around 30%
• Low sensitivity of old assays may have underestimated
prevalence data
1. Arankalle VA, et al. J Infect Dis171:447–450. 2. Fix AD, et al. Am J Trop Med Hyg 62:519–523.

16. National Health and Nutrition Evaluation
Survey (NHANES) USA, 2009-10
• 8,814 individuals, 37 years (IQR 17-58 years), M:F= 1
• Weighted HEV seroprevalence 6% (0.5% IgM+ve)
• Factors associated with HEV positivity:
– Univariate analysis:
• Increasing age
• Birth outside US
• Hispanic ethnicity
• Meat consumption >10 times/month
– Multivariate analysis:
• Older age
Ditah I, et al. Hepatology 2014, in press

17. Seroprevalence of anti-HEV IgG among Blood Donors
(0.25 WHO U/mL)
• High sensitivity assays show prevalences of:
– 52% in SW France1
– 29% in Germany2
– 27% in the Netherlands3
– 16% in SW England4
1. Mansuy JM, et al. Emerg Infect Dis 2013;17:2309–2312. 2. Wenzel JJ, et al. J Infect Dis 2013;207:497–500.
3. Slot e, et al. Euro Surveill 2013;18:20550. 4. Dalton HR, et al. Eur J Gastroenterol Hepatol 2008;20:784–790.

18. Prevalence of Anti-HEV IgG in the Midi-Pyrenées
Region (France), According to Age
Kamar N et al. Clin. Microbiol. Rev. 2014;27:116-138

19. Extrahepatic Manifestations of HEV
• Neurological disorders
• Kidney injury
• Pancreatitis (HEV1)
• Haematological disorders:
– Aplastic anaemia
– Thrombocytopaenia

20. Neurological Disorders
• Retrospectively found in 7/126 (5.5%) of patients with HEV
infection: 3 immunocompetent, 4 immunosuppressed (3 SOT, 1
HIV)1
• HEV RNA in CSF from all patients: QS compartmentalization
(neurotropic variants?)2
• Described in HEV1 and acute and chronic HEV3
– Guillain-Barré syndrome
– Bell’s palsy
– Neuralgic amyotrophy
– Acute transverse myelitis
– Meningoencephalitis
Reviewed in Kamar N, et al. Clin Microbiol Rev 2014:27:116-38
1. Kamar N, et al. Emerg Infect Dis 2011;17:173–9. 2. Kamar N, et al. Am J Transplant 2010;10:1321–4.

21. Kidney Injury
• Detected in acute and chronic hepatitis
• Immunocompetent and immunocompromised
• HEV1 & 3
• Two patterns of glomerulonephritis:
– Membrano-proliferative
– Membranous

22. Chronic Hepatitis E
• No standard definition
• It may be defined by analogy with other forms of viral
hepatitis, i.e.: Elevated liver enzymes and detectable HEV
RNA in serum and/or stools for 3-6 months from diagnosis
• Caused by HEV3 only
• Reported in immunocompetent and immunocompromised
patients:
• Transplant recipients
• HIV-positive persons
• Patients with haematological malignancies

23. Chronic Hepatitis E in Transplant Recipients:
A Retrospective Study
• 56 pts. (66%) developed chronic hepatitis E:
• 18 achieved sustained HEV clearance following a reduction in the dose
of immunosuppression 19.5 (10–106) months after diagnosis of HEV
infection
• 20 received antivirals (peginterferon-a in 5, ribavirin in 14 and the
combination in 1) (at last follow-up, 14 had achieved SVR and 6 were
still viremic and still receiving therapy)
• 9 (9%) developed cirrhosis
• 5 died (2 of decompensated cirrhosis)
• 2 required a second liver transplant
• No reactivation was observed after HEV clearance
KAMAR et al, Gastroenterology 2011;140:1481-9

24. Rapid Progression of Hepatitis E to Cirrhosis
after Solid Organ Transplantation
KAMAR et al, Am J Transplant 2008;8:1744-8

25. Factors Associated with Chronic HEV
Infection in Solid Organ Transplantation
• Amount of immunosuppression
• Type of immunosuppression:
– Tacrolimus > Cyclosporine

26. Management of Chronic Hepatitis E in
Immunocompromised Patients
• Reduce or switch immunosuppression
• Introduce HAART
• Pegylated interferon alpha
• Ribavirin

27. HEV Clearance Following HAART
KENFAK-FOQUENA et al, Emerg Infect Dis 2011

28. PEG-IFNa for Chronic Hepatitis E
KAMAR N et al, Clin Infect Dis 2010
Three LT recipients with
chronic HEV infection
• PEG-IFN-a2a
• 135 mg/week
• Three months
• SVR: 2/3

29. Hepatitis E Virus Hepatitis (HEV) E Virus Concentration (HEV) Concentration during during Ribavirin Therapy.
Ribavirin Therapy
Kamar N et al. N Engl J Med 2014;370:1111-1120.

30. Outcomes of Ribavirin Therapy in Solid-Organ
Transplant Recipients with HEV Infection
• 59 patients (37 kidney, 10 liver, 5 heart, 5 kidney/pancreas, 2
lung).
• All 54 genotyped patients had HEV3
• Treatment started: median 9 months (range 1-82) after diagnosis
• RBV dose: median 8.1 mg/kg bw (range 0.6-16.3)
• Treatment duration: median 3 months (range 1-18). 66% received
RBV for less than 3 months
• 46/59 (78%) had SVR
• Of the relapsing 10, 2 died and 6 were retreated 5 SVR
• Higher baseline lymphocyte count associated with SVR
Kamar N, et al. N Engl J Med 2014;370:1111-20.

31. Treatment of Immunosuppressed
Patients with Chronic HEV Infection
• Both IFN and RBV are effective against HEV in SOT recipients
but IFN may unleash an acute rejection
• Reduction of immunosuppressive therapy, especially of
agents that target T-cell function, is first-line therapy,
followed by ribavirin monotherapy in patients who fail to
clear HEV
Kamar N, et al. Am J Transplant 2012;12:2281–7.

32. Effects of RBV on Innate and Adaptive Immunity
Mondelli MU. Hepatology 2014, in press.

33. Phase II Vaccination Trial
90% received
all three doses
3 (0.3%) in vaccinees
66 (7.4%) in placebo
developed HE
Vaccine efficacy
95.5% (95% CI 85.6-98.6)
Cumulative hazard of a
first hepatitis E episode
in all study participants
who received at least
one dose of placebo
or vaccine
SHRESTHA et al, N Eng J Med 2007;356:895-903

34. Phase III Vaccination Trial
(HEV239, Hecolin, Xiamen Innovax Biotech, Xiamen, China)
(NIH clinicaltrial.gov NCT01014845)
Placebo Vaccinees
n 56,302 56,302
Per-protocol analysis (3 doses) 48,663 (86%) 48,693 (86%)
Developed HE (12-month FU) 15 0
Efficacy 100% (95% CI 72.1 – 100.0)
AE: mild, no SAE
ZHU et al, Lancet 2010;376:895-902

35. HEV. Conclusions (I)
• HEV infection is more prevalent worldwide than hitherto
recognised and is associated with significant morbidity and
mortality
• Excess mortality in pregnant women
• Seroprevalence of IgG anti-HEV in blood donors may reach 50% in
some geographical areas
• Hepatitis E in developed countries is a zoonosis transmitted by
raw or undercooked pork or game meat and shellfish
• Pre-existing liver disease may cause hepatic decompensation

36. HEV. Conclusions (II)
• Extrahepatic manifestations may occur
• HEV3 infection may cause CLD in immunocompetent and,
particularly, immunosuppressed patients
• Chronic hepatitis E in the immunosuppressed may rapidly
progress to cirrhosis
• Reduction of immunosuppression followed by ribavirin
treatment are currently accepted therapies of chronic hepatitis E
but guidelines are lacking
• Excellent vaccines have been developed in the East and the
West, but marketed only in China, which could be used in
populations at risk