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

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.

The Hepatitis E VirusFamily: 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

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

Geographic Distribution of HEV

www.cdc.gov/hepatitis/HEV/HEVfaq.htm

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

Hepatitis E Virus Genome

Kamar N et al. Clin. Microbiol. Rev. 2014;27:116-138

Capsid (660aa):assemblyimmunogenicitytarget cells

P113: virion morphogenesis & release

ORF1

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

Dendrogram Based on Full-Length Sequences of HEV Strains

Kamar N et al. Clin. Microbiol. Rev. 2014;27:116-138

Piscihepevirus

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

HEV Markers

Incubation 2-6 wks

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.

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

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

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.

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

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.

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

Extrahepatic Manifestations of HEV

• Neurological disorders• Kidney injury

• Pancreatitis (HEV1)• Haematological disorders:

– Aplastic anaemia– Thrombocytopaenia

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.

Kidney Injury

• Detected in acute and chronic hepatitis• Immunocompetent and immunocompromised• HEV1 & 3• Two patterns of glomerulonephritis:

– Membrano-proliferative– Membranous

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

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

Rapid Progression of Hepatitis E to Cirrhosis after Solid Organ Transplantation

KAMAR et al, Am J Transplant 2008;8:1744-8

Factors Associated with Chronic HEV Infection in Solid Organ Transplantation

• Amount of immunosuppression

• Type of immunosuppression:– Tacrolimus > Cyclosporine

Management of Chronic Hepatitis E in Immunocompromised Patients

• Reduce or switch immunosuppression• Introduce HAART• Pegylated interferon alpha• Ribavirin

HEV Clearance Following HAART

KENFAK-FOQUENA et al, Emerg Infect Dis 2011

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

Hepatitis E Virus (HEV) Concentration during Ribavirin Therapy.

Kamar N et al. N Engl J Med 2014;370:1111-1120.

Hepatitis E Virus (HEV) Concentration during Ribavirin Therapy

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.

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.

Effects of RBV on Innate and Adaptive Immunity

Mondelli MU. Hepatology 2014, in press.

Phase II Vaccination Trial

90% received all three doses

3 (0.3%) in vaccinees66 (7.4%) in placebo

developed HE

Vaccine efficacy95.5% (95% CI 85.6-98.6)

SHRESTHA et al, N Eng J Med 2007;356:895-903

Cumulative hazard of afirst hepatitis E episodein all study participantswho received at leastone dose of placebo or vaccine

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

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

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