Download Pathogenesis and Treatment of Hepatitis E Virus Infection

GASTROENTEROLOGY 2012;142:1388 –1397
Pathogenesis and Treatment of Hepatitis E Virus Infection
Heiner Wedemeyer
Sven Pischke
Michael P. Manns
Department of Gastroenterology, Hepatology and Endocrinology and IFB-Tx Integrated Research and Treatment Center Transplantation, Hannover Medical School,
Hannover, Germany
HEPATITIS E VIRUS
Hepatitis E has been considered to be a travel-associated, acute, self-limiting liver disease that causes fulminant hepatic failure in specific high-risk groups
only. However, hepatitis E virus (HEV) infection can
also be acquired in industrialized countries—HEV genotype 3 infection is a zoonosis, with pigs and rodents
serving as animal reservoirs. In recent years, cases of
chronic HEV infection that were associated with progressive liver disease have been described in several
cohorts of immunocompromised individuals, including recipients of organ transplants. The topic of hepatitis E is therefore re-emerging and has raised the
following important questions: what is the risk for
HEV infection in Western countries (eg, from eating
uncooked meat)? How frequently does chronic hepatitis E develop among human immunodeficiency virus–infected patients and recipients of organ transplants? What are the treatment options? What is the
current status of vaccine development? What do we
know about the pathogenesis of HEV infection, and
why does it have a more severe course in pregnant
women? This review summarizes the current knowledge on the pathogenesis and treatment of HEV infection.
Keywords: Hepatitis E; HEV; Acute Hepatitis; Chronic Hepatitis E.
H
epatitis E is an inflammatory liver disease caused by
infection with the hepatitis E virus (HEV).1,2 An
enteric infectious agent that differed from hepatitis A and
hepatitis B viruses and was suspected to cause acute liver
disease was reported in India in the 1970s.2 Oral administration of pooled stool extracts from cases with non-A/
non-B hepatitis led to acute hepatitis in a human volunteer.3 Virus-like particles were then identified in stool
samples of this volunteer shortly before and during the
clinical phase of hepatitis; this was the first description of
HEV virions. The enteric pathogen could be transmitted
to cynomolgus macaques, which led to hepatitis. An RNA
species was identified from livers of infected animals and
named hepatitis E virus.4
HEV is endemic in several Asian and African countries,
where the prevalence of HEV IgG antibody could be as
high as 50%.5 It has recently been estimated that HEV
infection causes ⬎3 million symptomatic cases of acute
hepatitis E each year, resulting in approximately 70,000
deaths worldwide.6 Pregnant women and patients with
pre-existing chronic liver diseases are at a particular risk of
fulminant hepatic failure upon HEV infection. Industrialized countries were considered nonendemic, but an increasing number of non–travel-associated cases of HEV
infections has been reported in recent years, particularly
in Europe.7–9 It is not clear whether HEV incidence rates
are really changing or if more cases are detected through
increased surveillance.7 Hepatitis E should also be considered in the differential diagnosis of drug-induced liver
injury, as 3% of patients in the US Drug-Induced Liver
Injury Network tested positive for IgM against HEV.10
The Virus and Its Epidemiology
HEV is a single-stranded, nonenveloped RNA virus
and is the only virus within the genus Hepevirus and the
family Hepeviridae.1 The HEV genome includes 2 short,
noncoding regions that surround 3 open reading frames
(ORFs 1–3) (Figure 1A). ORF-1 encodes the nonstructural
proteins required for replication and protein processing,
including an RNA helicase, an RNA-dependent RNA polymerase, a methyltransferase, and a cysteine protease.11
ORF-1 contains a hypervariable region that does not have
a major role for virus infectivity.12 The capsid protein is
encoded by ORF-2 and recombinant ORF-2 protein has
Abbreviations used in this paper: HEV, hepatitis E virus; HIV, human
immunodeficiency virus; ORF, open reading frame.
© 2012 by the AGA Institute
0016-5085/$36.00
doi:10.1053/j.gastro.2012.02.014
PATHOGENESIS AND TREATMENT OF HEV INFECTION
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HEPATITIS E VIRUS
May 2012
Figure 1. (A) Genomic organization of HEV including the 3 ORFs. The scale shows nucleotides in thousands. (B) Phylogenetic tree depicting different
genotypes and subtypes of HEV. The sequences from patients with chronic HEV genotype 3 infection are shown as a separate phylogenetic tree
(right). Red squares show chronic HEV patients from Hannover after either heart (HTx) or lung (LTx) transplantation.66
been tested as a vaccine candidate.13 The icosahedral HEV
capsid is 27–34 nm in diameter; a crystal structure of
HEV-like particles has recently been characterized.14 Distinct amino acid mutations in the capsid could attenuate
the virus and have implications for vaccine development.15 The small, 114 amino acid protein encoded by
ORF-3 has multiple functions that regulate the cellular
environment.16
HEV cell culture systems are rather inefficient—the virus was
only recently cultured in human cells.17 The HEV receptor has
not been identified and the detailed mode of entry into hepatocytes is unknown. Similar to other viruses, binding of the
HEV capsid involves heparin sulfate proteoglycans.18
Five different HEV genotypes have been described. HEV
genotypes 1– 4 infect humans, and HEV genotype 5 has only
been detected in birds and is therefore called avian HEV
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Figure 2. (A) Worldwide prevalence of HEV and (B) the geographic distribution of the different HEV genotypes.
(Figure 1B). HEV genotype 1 is responsible for most endemic
and epidemic cases of hepatitis E in Asia,1 and genotype 2 is
prevalent in Central America and Africa1 (Figure 2). There is
no known animal reservoir for HEV genotypes 1 and 2.
Transmission occurs mainly via the oral–fecal route. In contrast, HEV genotype 3 can infect humans and other animal
species, including pigs,19 deer,20 wild boars,21 mongeese,20
shellfish,22 and rodents.19 In the United States, farmed swine
more frequently tested positive for anti-HEV than samples
from bison, cattle, dogs, feral swine, or Norway rats.23 Several
studies detected HEV RNA in commercial food products
such as porcine livers or pig sausages.24,25 Persons with close
contact to animals that are potential carriers of HEV fre-
quently test positive for anti-HEV, based on a study of
Danish farmers.26
The ability of HEV genotype 3 to cross species barriers has
been reported. Several case series were described in Japan,
where individuals became infected with HEV after eating
infected raw meat from deer.27,28 Identical strains of HEV
genotype 3 were detected in Southern France in pig liver
sausages and patients with acute hepatitis E, indicating that
HEV-positive meat might have been the source of infection.25 The reverse, anthropozoonotic potential of HEV genotype 3 was proven by infecting pigs with HEV derived
from a liver transplant recipient with persistent HEV infection.29 Thus, zoonotic transmission represents an important
mode of transmission for HEV genotype 3 and should be
considered as the main source for autochthonous HEV infection in North America and Europe.
HEV genotype 4 has been detected in humans and pigs
and is mainly present in Eastern Asia30,31 (Figure 2). HEV
genotype 4 was identified in a single study of European
swine.32 The risk for food-borne HEV transmission can be
reduced by cooking meat, because HEV can be inactivated
by temperatures ⬎70°C.33 Cooking meat for 1 minute at
70°C led to a 0.48 log reduction in concentration of
infectious HEV particles, and heating it at 95°C reduced
the concentration another 3.67 log.34 Obviously, the best
way to prevent foodborne-transmitted hepatitis E is to
avoid eating uncooked meat.
HEV can also be transmitted by blood transfusion. IgM
and IgG against HEV were detected in recipients of blood
transfusions in India,35 Hong Kong,36 and Japan.37 Interestingly, transfusion-associated HEV infections were also reported in nonhyperendemic European countries, such as
Great Britain38 and France.39 A recent study showed that 1 of
7986 and 1 of 4525 plasma donations tested positive for
HEV RNA in Sweden and Germany, respectively.40 Considering that about 3500 donations are used per plasma pool, it
is not surprising that 10% of plasma pools tested positive for
HEV RNA in Germany.41 This high number of HEV-contaminated blood donations indicates that most HEV infections take a subclinical course.
Recently, a German patient was reported to have become infected with HEV from a liver transplant.42 The
patient tested positive for HEV RNA 150 days after transplantation and phylogenetic analysis indicated that a similar strain of HEV was isolated from the donor, who was
negative for anti-HEV. Therefore, occult HEV infection
(asymptomatic presence of HEV RNA) is a potential concern. Reactivation of hepatitis E was described in a patient
that received allogeneic stem cell transplantation.43 However, a study of patients who received hematopoietic stem
cell transplants and had increased levels of liver transaminases did not find evidence for HEV transmission or
reactivation.44 In addition, a study from France of 700
recipients of solid organs did not find any cases of HEV
reactivation after transplantation, even though 99 patients tested positive for HEV antibodies before transplantation.45 Occult hepatitis E seems to be rare, and not a
major clinical problem. Testing for HEV might not be
necessary for organ transplant donors or donors of blood
products in countries with a low prevalence of HEV.
However, testing for HEV RNA should be performed in
areas where HEV is endemic or if it is suspected that a
donor was exposed to the virus.
Diagnosis
Testing for hepatitis E should be part of the diagnostic analysis of all patients with acute or chronic hepatitis that cannot be explained by other causes. Acute HEV
infection is diagnosed in immunocompetent individuals
based on detection of anti-HEV IgM. Increased titers of
PATHOGENESIS AND TREATMENT OF HEV INFECTION
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anti-HEV IgG can indicate recent HEV infection (Figure
3). However, there are variations in sensitivity, specificity,
and agreement of results among assays that detect these
antibodies.46,47 Several assays are based on antigens expressed by a single HEV genotype; these might be limited
in detecting all HEV genotypes. Although most commercial assays detect HEV genotype 3 infection with high
levels of specificity, sensitivity values can be lower.48 These
variations could account for some of the discrepancy in
rates of HEV seroprevalence reported in different studies.
Immunocompromised individuals should always be
tested for HEV RNA if there is suspicion that they are
infected because seroconversion could be delayed in these
patients.29 HEV RNA can be detected in blood and stool for
several weeks during acute HEV infection. However, tests for
HEV nucleic acid have not been well standardized; a study of
20 laboratories from 10 different countries showed a 100- to
1000-fold difference in sensitivities of assays.49 HEV RNA
might be quantified to determine response to antiviral treatment, but there is also considerable variation among the
quantification assays.49 HEV RNA assays are therefore in
need of standardization and genotype-specific polymerase
chain reaction assays might be necessary.
Clinical Course of Infection
Most HEV infections have a clinically silent course.
In an HEV vaccine trial in China of ⬎110,000 individuals,
⬍5% of individuals who seroconverted (began producing
anti-HEV) during the observation time developed symptoms of acute hepatitis.50 HEV infections are rarely associated with clinical symptoms during childhood.51 In
symptomatic cases, the incubation period ranges from 2
to 8 weeks, with a mean of 40 days.1 Initial symptoms of
acute hepatitis E are typically unspecific and include flulike myalgia, arthralgia, weakness, and vomiting. Some
patients have jaundice, itching, uncolored stools, and
darkened urine, accompanied by increased levels of liver
transaminases, bilirubin, alkaline phosphatase, and ␥-glutamyltransferase.
HEV infection can lead to more severe, acute liver disease
in pregnant women or patients with underlying chronic liver
diseases and sometimes progress to fulminant hepatic failure.52 The severe course in pregnant women might result
from hormonal and immunologic features of pregnancy.53
Reduced expression of the progesterone receptor was associated with fatal outcomes from hepatitis E in pregnant
women.54 Variants in the gene that encodes the progesterone
receptor variants can alter its expression level. Mortality was
also associated with a high load of HEV. HEV-specific T-cell
responses could be weaker in patients with fulminant hepatitis E (Figure 4).55
Prolonged courses of HEV viremia have been described
in some immunocompetent individuals.56 –58 However,
HEV-associated liver cirrhosis or hepatocellular carcinoma has not been reported to develop in immunocompetent individuals.
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HEPATITIS E VIRUS
Figure 3. Diagnosis of hepatitis
E. Typical evolution of the serologic titer of HEV-specific antibodies and levels of alanine aminotransferase (ALT) levels during (A)
acute self-limited or (B) chronic
HEV infection.
Infections in Organ Transplant
Recipients
Chronic HEV infection has been described in liver
and kidney transplant recipients in Europe since
2008.29,59 – 61 Kamar et al initially reported 14 cases of acute
hepatitis E in Southwest France among patients who
received kidney or liver transplants.59 Eight developed a
chronic course that led to persistent increases in levels of
alanine aminotransferase, significant histological activity,
and fibrosis after a median follow-up period of ⬎12
months (range, 10 –18 months). Additional cases of
chronic HEV infection among transplant recipients were
reported by several groups.29,42,60 – 63 A recent study summarized retrospective data collected from 17 centers on
hepatitis E in transplant recipients. Overall, 85 cases of
HEV infection were described and 56 patients (66%) developed chronic hepatitis E. Interestingly, chronic infection was associated with the use of tacrolimus and low
platelet counts.63 However, most patients had been recruited by 1 center (Toulouse), so data from other regions
and transplantation centers need to be collected and analyzed.
Chronic courses of HEV infection have also been reported in recipients of heart transplants (See also Supplementary Figure 1).64,65 Overall, recipients of solid organ
transplant with increased levels of liver enzymes should be
tested for HEV RNA, unless there are other obvious causes
of hepatitis. Immunosuppressed individuals should be
tested for HEV RNA because antibody tests might not be
sensitive enough for these patients.
Chronic hepatitis E is associated with impaired HEVspecific T-cell responses in organ transplant recipients.
In a prospective study, T-cell responses became detectable after spontaneous or treatment-induced clearance
of HEV.66 Blocking T-cell co-inhibitory receptors restored T-cell reactivity to the virus in vitro, indicating
exhaustion of T-cell responses in chronically infected
patients. Tests for HEV-specific T-cell responses might
be developed to identify individuals who can spontaneously clear HEV and those who will progress to chronic
infection.
Patients With HIV Infection
Human immunodeficiency virus (HIV)–infected individuals more frequently have positive results from tests
for anti-HEV than individuals without HIV infection,67,68
but chronic hepatitis E was not described in an HIVinfected patient before 2009.69 This patient had acquired
immunodeficiency syndrome with a CD4⫹ T-cell count
⬍200 and high levels of HIV RNA (⬎100,000 copies/mL).
PATHOGENESIS AND TREATMENT OF HEV INFECTION
However, subsequent studies from Spain (93 patients),70
Germany (123 patients),71 and England (138 patients)72
could not identify persistent HEV infections in HIV-infected cohorts. HEV RNA was detected for ⬎10 months in
only 1 of 184 HIV-positive individuals in France.73 This
patient also had a low CD4⫹ T-cell count (⬍50 cells/mm);
2 patients with greater numbers of CD4⫹ T cells were able
to clear HEV clearance spontaneously. Persistent HEV
infection is therefore rarely observed in HIV-infected patients; only subjects with strong immune impairments
seem to be at risk for chronic hepatitis E.
Extrahepatic Manifestations
There is some evidence that HEV infections are
associated with extrahepatic manifestations. One case
report described muscular weakness and a pyramidal
syndrome in a kidney transplant recipient with persistent HEV infection.74 In addition, neurological disorders, including polyradiculopathy, Guillain–Barré syndrome, bilateral brachial neuritis, encephalitis, or
proximal myopathy have been reported in patients with
acute and chronic HEV infections.75 The mechanisms
and clinical relevance of these associations require further investigation. However, manifestation of neurological symptoms in patients with acute or chronic hepatitis E are not common, and occur in only 2%–5% of
cases (unpublished data by our own group and Kamar
et al75). Chronic HEV infection was recently associated
with renal manifestations, including a decrease in glo-
Figure 4. Course
infection.
of
HEV
1393
merular filtration rate or appearance of glomerulonephritis or cryoglobulinemia.76
Treatment
In immunocompetent individuals, acute hepatitis
E does not usually require antiviral therapy. Some patients might require treatment of symptoms, but almost
all are able to clear the HEV infection spontaneously. A
patient infected with HEV genotype 3 who developed
severe acute hepatitis E and impaired liver function was
treated with ribavirin monotherapy. This patient responded with a rapid decrease in liver transaminases and
had improved international normalized ratio and level of
bilirubin.77 Prospective studies are needed to evaluate if
ribavirin treatment can prevent progression to liver failure
in patients with severe acute hepatitis E. Liver transplantation is the only treatment option for patients with
fulminate hepatic failure.
Treatment options for patients with chronic hepatitis E
include reduction of immunosuppression and administration of pegylated interferon alfa or ribavirin (Table 1).
The first step in the treatment of chronic HEV infection
should be to evaluate if it is possible to reduce immunosuppression. Reduction of immunosuppression in 16 recipients of solid organ transplants with chronic hepatitis
E led to clearance of HEV in 4 cases (25%).78 Pegylated
interferon alfa is another treatment option.79,80 Treatment durations range from 3 to 12 months; 4 of 5 patients were successfully treated with pegylated interferon
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Table 1. Treatment of Patients With Chronic HEV Infection
Group of patients
Treatment
Outcomes
First author, year
HEPATITIS E VIRUS
16 Liver and kidney transplantation
Reduction of immunosuppression
patients with chronic HEV infection
4 of 16 patients HEV
RNA–negative
Kamar, 201178
56 Liver and kidney transplant
recipients with chronic HEV
infection
Reduction of immunosuppression
18 of 56 patients HEV
RNA–negative
Kamar, 201163
3 Liver transplant recipients with
chronic HEV infection
3-month course with pegylated interferonalfa-2a
2 of 3 patients cleared HEV RNA, Kamar, 201079
1 relapsed after treatment
2 Liver transplant recipients with
chronic HEV infection
16 weeks or 1 year of treatment with
pegylated interferon-alfa-2b
2 of 2 patients cleared HEV RNA
Haagsma, 201080
1 HIV-infected patient with chronic
HEV infection
6 months pegylated interferon
monotherapy, followed by 12 weeks of
therapy with the combination of
interferon and ribavirin
Patient tested negative for HEV
RNA
Dalton, 2011, Ann
Intern Med88
7 Recipients of solid organ
transplants
Treatment with ribavirin monotherapy for 5
months
6 of 7 patients cleared the virus,
and 1 is still a carrier of HEV
Unpublished data
from our group
6 Recipients of solid organ
transplants
Treatment with ribavirin monotherapy for 3
months
4 of 6 patients achieved
Kamar, 201082
sustained virologic response, 2
relapsed
9 Patients with various conditions of
immunosuppression
Treatment with ribavirin monotherapy for 3
months
9 of 9 patients cleared the virus,
no relapse
Mallet, 2010, AASLD
Annual Meeting56
AASLD, American Association for the Study of Liver Disease.
alfa, which led to sustained clearance of HEV RNA. However, interferon therapy can cause significant side effects
and organ rejection in transplant recipients. Interferonalfa therapy is therefore not recommended for recipients
of heart or kidney transplants. The antiviral efficacy of
ribavirin monotherapy has been evaluated by 2 French
groups.81,82 A 3-month virologic response was observed in
2 of 2 and 4 of 6 treated patients, respectively. Preliminary
reports of ribavirin treatment of additional patients confirmed these findings (Figure 4).56,64
Although data are limited, ribavirin monotherapy
(600 –1000 mg per day) for at least 3 months seems to be
the first treatment option for patients with chronic hepatitis E who are not able to clear HEV after immunosuppression is reduced. The mechanism by which ribavirin
suppresses HEV replication is not known and requires
further investigation. Only limited data have been published on the treatment of chronic hepatitis E, so patients
require individualized therapeutic strategies based on the
severity of liver disease and options to reduce immunosuppression, comorbidities, and the potential side effects
of antiviral drugs.
Vaccination
Recovery from HEV infection results in protective
immunity—neutralizing antibodies can be detected in sera
of individuals exposed to HEV genotypes 1– 4.83 HEVspecific CD4⫹ and CD8⫹ T-cell responses are detectable in
patients with acute hepatitis E84 and long-term in indi-
viduals who have recovered from infection.66 Immunodominant regions within ORFs 2 and 3 induce T-cell
responses.84,85 Immunity against HEV seems to persist for
life—seropositive patients who become reinfected do not
develop symptomatic hepatitis.50
Protective immunity can also be induced by vaccination. A
recombinant vaccine developed by GlaxoSmithKline and the
Walter Reed Army Institute proved successful in a Phase II
study of 2000 Nepalese soldiers, with a 96% efficacy after
administration of 3 doses.13 However, this vaccine has not
been further developed. A Phase III study of ⬎100,000
Chinese adults reported that a recombinant HEV vaccine
(HEV 239) prevented acute hepatitis E with 94%–100%
efficacy.50 This vaccine is based on HEV genotype 1, produced in bacterial cells, and contains 30 ␮g purified HEV
antigen adsorbed to 0.8 mg aluminum hydroxide. Vaccination was not associated with any obvious, unexpected
side effects and was also safe in pregnant women.86 It
protected against infection with HEV genotypes 1 and 4,
but its efficacy against HEV genotype 3 is not known. The
vaccine requires further evaluation in special risk groups,
such as patients with end-stage liver disease or immunosuppressed individuals. Additional studies are also required to determine what anti-HEV titers can be considered protective and how fast these decrease after
vaccination.87 The vaccine has been approved in China in
December 2011. No other HEV vaccine candidate is currently in advanced stages of development (according to
Clinicaltrials.gov database on January 15, 2012).
PATHOGENESIS AND TREATMENT OF HEV INFECTION
Future Directions
HEV infection is a major global health burden that
causes significant morbidity and mortality worldwide.
Pregnant women have increased risks for fulminant hepatic failure upon HEV infection. Hepatitis E also occurs
in industrialized countries; zoonotic transmission seems
to be a major cause of HEV infections in the United
States, Europe, and Japan. Tests for hepatitis E should
therefore be included in evaluations of all patients with
increased levels of liver transaminases. It is particularly
important to test immunocompromised individuals with
elevated liver enzymes for HEV RNA because chronic
hepatitis E has been observed in HIV-positive patients and
organ transplant recipients. Patients with chronic hepatitis E should be considered for treatment with ribavirin
because prolonged viremia has been associated with the
development of liver cirrhosis and hepatic failure.
15.
16.
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Supplementary Material
Note: To access the supplementary material
accompanying this article, visit the online version of
Gastroenterology at www.gastrojournal.org, and at doi:
10.1053/j.gastro.2012.02.014.
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PATHOGENESIS AND TREATMENT OF HEV INFECTION
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Received January 17, 2012. Accepted February 14, 2012.
Reprint requests
Address requests for reprints to: Heiner Wedemeyer, MD,
Department of Gastroenterology, Hepatology and Endocrinology,
Medizinische Hochschule Hannover Carl-Neuberg Str. 1, 30625
Hannover, Germany. e-mail: [email protected];
fax: ⴙ49 511 532 8662.
Acknowledgments
The authors thank Dr Svenja Hardtke (Hannover Medical School),
Sarah Williamson, and Brook Ashley Simpson (Gastroenterology
editorial office) for editorial assistance.
Conflicts of interest
The authors disclose no conflicts.
Funding
This work was supported by a grant from the German Federal
Ministry of Education and Research (reference number: 01EO0802)
and a grant by the Robert Koch Institute (Berlin) (reference number
1362-1097).
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Supplementary Figure 1. H&E staining of a biopsy sample from a patient with chronic hepatitis E shows portal inflammation with predominant
lymphocyte infiltration and interface hepatitis (A, 100⫻; B, 400⫻).