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Pathogenesis and Treatment of Hepatitis E Virus Infection

  • Heiner Wedemeyer
    Correspondence
    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. fax: +49 511 532 8662
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology and IFB-Tx Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
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  • Sven Pischke
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology and IFB-Tx Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
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  • Michael P. Manns
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology and IFB-Tx Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
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      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

      Abbreviations used in this paper:

      HEV (hepatitis E virus), HIV (human immunodeficiency virus), ORF (open reading frame)
      Hepatitis E is an inflammatory liver disease caused by infection with the hepatitis E virus (HEV).
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      Oral administration of pooled stool extracts from cases with non-A/non-B hepatitis led to acute hepatitis in a human volunteer.
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      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.
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      Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis.
      HEV is endemic in several Asian and African countries, where the prevalence of HEV IgG antibody could be as high as 50%.
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      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.
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      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.
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      It is not clear whether HEV incidence rates are really changing or if more cases are detected through increased surveillance.
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      Hepatitis E: an emerging infectious disease in Germany?.
      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.
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      Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury.

      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.
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      Hepatitis E: an emerging awareness of an old disease.
      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.
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      Hepatitis E virus: molecular virology, clinical features, diagnosis, transmission, epidemiology, and prevention.
      ORF-1 contains a hypervariable region that does not have a major role for virus infectivity.
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      • Opriessnig T.
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      Deletions of the hypervariable region (HVR) in open reading frame 1 of hepatitis E virus do not abolish virus infectivity: evidence for attenuation of HVR deletion mutants in vivo.
      The capsid protein is encoded by ORF-2 and recombinant ORF-2 protein has been tested as a vaccine candidate.
      • Shrestha M.P.
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      • Joshi D.M.
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      Safety and efficacy of a recombinant hepatitis E vaccine.
      The icosahedral HEV capsid is 27–34 nm in diameter; a crystal structure of HEV-like particles has recently been characterized.
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      • Miyazaki N.
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      Biological and immunological characteristics of hepatitis E virus-like particles based on the crystal structure.
      Distinct amino acid mutations in the capsid could attenuate the virus and have implications for vaccine development.
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      • Huang Y.W.
      • Opriessnig T.
      • et al.
      Three amino acid mutations (F51L, T59A, and S390L) in the capsid protein of the hepatitis E virus collectively contribute to virus attenuation.
      The small, 114 amino acid protein encoded by ORF-3 has multiple functions that regulate the cellular environment.
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      • Holla R.P.
      • Jameel S.
      Molecular virology of hepatitis E virus.
      Figure thumbnail gr1
      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.
      • Suneetha P.V.
      • Pischke S.
      • Schlaphoff V.
      • et al.
      HEV-specific T-cell responses are associated with control of HEV infection.
      HEV cell culture systems are rather inefficient—the virus was only recently cultured in human cells.
      • Shukla P.
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      • Torian U.
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      Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant.
      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.
      • Kalia M.
      • Chandra V.
      • Rahman S.A.
      • et al.
      Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection.
      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 (Figure 1B). HEV genotype 1 is responsible for most endemic and epidemic cases of hepatitis E in Asia,
      • Purcell R.H.
      • Emerson S.U.
      Hepatitis E: an emerging awareness of an old disease.
      and genotype 2 is prevalent in Central America and Africa
      • Purcell R.H.
      • Emerson S.U.
      Hepatitis E: an emerging awareness of an old disease.
      (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,
      • Goens S.D.
      • Perdue M.L.
      Hepatitis E viruses in humans and animals.
      deer,
      • Meng X.J.
      Recent advances in hepatitis E virus.
      wild boars,
      • Kaci S.
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      • Johne R.
      Detection of hepatitis E virus in archived German wild boar serum samples.
      mongeese,
      • Meng X.J.
      Recent advances in hepatitis E virus.
      shellfish,
      • Said B.
      • Ijaz S.
      • Kafatos G.
      • et al.
      Hepatitis E outbreak on cruise ship.
      and rodents.
      • Goens S.D.
      • Perdue M.L.
      Hepatitis E viruses in humans and animals.
      In the United States, farmed swine more frequently tested positive for anti-HEV than samples from bison, cattle, dogs, feral swine, or Norway rats.
      • Dong C.
      • Meng J.
      • Dai X.
      • et al.
      Restricted enzooticity of hepatitis E virus genotypes 1 to 4 in the United States.
      Several studies detected HEV RNA in commercial food products such as porcine livers or pig sausages.
      • Wenzel J.J.
      • Preiss J.
      • Schemmerer M.
      • et al.
      Detection of hepatitis E virus (HEV) from porcine livers in Southeastern Germany and high sequence homology to human HEV isolates.
      • Colson P.
      • Borentain P.
      • Queyriaux B.
      • et al.
      Pig liver sausage as a source of hepatitis E virus transmission to humans.
      Persons with close contact to animals that are potential carriers of HEV frequently test positive for anti-HEV, based on a study of Danish farmers.
      • Christensen P.B.
      • Engle R.E.
      • Hjort C.
      • et al.
      Time trend of the prevalence of hepatitis E antibodies among farmers and blood donors: a potential zoonosis in Denmark.
      Figure thumbnail gr2
      Figure 2(A) Worldwide prevalence of HEV and (B) the geographic distribution of the different HEV genotypes.
      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.
      • Tei S.
      • Kitajima N.
      • Takahashi K.
      • et al.
      Zoonotic transmission of hepatitis E virus from deer to human beings.
      • Tomiyama D.
      • Inoue E.
      • Osawa Y.
      • et al.
      Serological evidence of infection with hepatitis E virus among wild Yezo-deer, Cervus nippon yesoensis, in Hokkaido, Japan.
      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.
      • Colson P.
      • Borentain P.
      • Queyriaux B.
      • et al.
      Pig liver sausage as a source of hepatitis E virus transmission to humans.
      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.
      • Pischke S.
      • Suneetha P.V.
      • Baechlein C.
      • et al.
      Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients.
      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 Asia
      • Zhang W.
      • Shen Q.
      • Mou J.
      • et al.
      Hepatitis E virus infection among domestic animals in Eastern China.
      • Chang Y.
      • Wang L.
      • Geng J.
      • et al.
      Zoonotic risk of hepatitis E virus (HEV): a study of HEV infection in animals and humans in suburbs of Beijing.
      (Figure 2). HEV genotype 4 was identified in a single study of European swine.
      • Hakze-van der Honing R.W.
      • van Coillie E.
      • Antonis A.F.
      • et al.
      First isolation of hepatitis E virus genotype 4 in Europe through swine surveillance in the Netherlands and Belgium.
      The risk for food-borne HEV transmission can be reduced by cooking meat, because HEV can be inactivated by temperatures >70°C.
      • Emerson S.U.
      • Arankalle V.A.
      • Purcell R.H.
      Thermal stability of hepatitis E virus.
      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.
      • Schielke A.
      • Filter M.
      • Appel B.
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      Thermal stability of hepatitis E virus assessed by a molecular biological approach.
      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,
      • Arankalle V.A.
      • Chobe L.P.
      Retrospective analysis of blood transfusion recipients: evidence for post-transfusion hepatitis E.
      Hong Kong,
      • Lee C.K.
      • Chau T.N.
      • Lim W.
      • et al.
      Prevention of transfusion-transmitted hepatitis E by donor-initiated self exclusion.
      and Japan.
      • Matsubayashi K.
      • Nagaoka Y.
      • Sakata H.
      • et al.
      Transfusion-transmitted hepatitis E caused by apparently indigenous hepatitis E virus strain in Hokkaido, Japan.
      Interestingly, transfusion-associated HEV infections were also reported in nonhyperendemic European countries, such as Great Britain
      • Boxall E.
      • Herborn A.
      • Kochethu G.
      • et al.
      Transfusion-transmitted hepatitis E in a 'nonhyperendemic' country.
      and France.
      • Colson P.
      • Coze C.
      • Gallian P.
      • et al.
      Transfusion-associated hepatitis E, France.
      A recent study showed that 1 of 7986 and 1 of 4525 plasma donations tested positive for HEV RNA in Sweden and Germany, respectively.
      • Baylis S.A.
      • Gartner T.
      • Nick S.
      • et al.
      Occurrence of hepatitis E virus RNA in plasma donations from Sweden, Germany and the United States.
      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.
      • Baylis S.A.
      • Koc O.
      • Nick S.
      • et al.
      Widespread distribution of hepatitis E virus in plasma fractionation pools.
      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.
      • Schlosser B.
      • Stein A.
      • Neuhaus R.
      • et al.
      Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient.
      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.
      • le Coutre P.
      • Meisel H.
      • Hofmann J.
      • et al.
      Reactivation of hepatitis E infection in a patient with acute lymphoblastic leukaemia after allogeneic stem cell transplantation.
      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.
      • Koenecke C.
      • Pischke S.
      • Heim A.
      • et al.
      Chronic hepatitis E in hematopoietic stem cell transplant patients in a low-endemic country?.
      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.
      • Legrand-Abravanel F.
      • Kamar N.
      • Sandres-Saune K.
      • et al.
      Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France.
      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 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.
      • Drobeniuc J.
      • Meng J.
      • Reuter G.
      • et al.
      Serologic assays specific to immunoglobulin M antibodies against hepatitis E virus: pangenotypic evaluation of performances.
      • Herremans M.
      • Bakker J.
      • Duizer E.
      • et al.
      Use of serological assays for diagnosis of hepatitis E virus genotype 1 and 3 infections in a setting of low endemicity.
      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.
      • Legrand-Abravanel F.
      • Thevenet I.
      • Mansuy J.M.
      • et al.
      Good performance of immunoglobulin M assays in diagnosing genotype 3 hepatitis E virus infections.
      These variations could account for some of the discrepancy in rates of HEV seroprevalence reported in different studies.
      Figure thumbnail gr3
      Figure 3Diagnosis 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.
      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.
      • Pischke S.
      • Suneetha P.V.
      • Baechlein C.
      • et al.
      Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients.
      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.
      • Baylis S.A.
      • Hanschmann K.M.
      • Blumel J.
      • et al.
      Standardization of hepatitis E virus (HEV) nucleic acid amplification technique-based assays: an initial study to evaluate a panel of HEV strains and investigate laboratory performance.
      HEV RNA might be quantified to determine response to antiviral treatment, but there is also considerable variation among the quantification assays.
      • Baylis S.A.
      • Hanschmann K.M.
      • Blumel J.
      • et al.
      Standardization of hepatitis E virus (HEV) nucleic acid amplification technique-based assays: an initial study to evaluate a panel of HEV strains and investigate laboratory performance.
      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.
      • Zhu F.C.
      • Zhang J.
      • Zhang X.F.
      • et al.
      Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial.
      HEV infections are rarely associated with clinical symptoms during childhood.
      • Buti M.
      • Plans P.
      • Dominguez A.
      • et al.
      Prevalence of hepatitis E virus infection in children in the northeast of Spain.
      In symptomatic cases, the incubation period ranges from 2 to 8 weeks, with a mean of 40 days.
      • Purcell R.H.
      • Emerson S.U.
      Hepatitis E: an emerging awareness of an old disease.
      Initial symptoms of acute hepatitis E are typically unspecific and include flu-like 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 γ-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.
      • Bhatia V.
      • Singhal A.
      • Panda S.K.
      • et al.
      A 20-year single-center experience with acute liver failure during pregnancy: is the prognosis really worse?.
      The severe course in pregnant women might result from hormonal and immunologic features of pregnancy.
      • Navaneethan U.
      • Al Mohajer M.
      • Shata M.T.
      Hepatitis E and pregnancy: understanding the pathogenesis.
      Reduced expression of the progesterone receptor was associated with fatal outcomes from hepatitis E in pregnant women.
      • Bose P.D.
      • Das B.C.
      • Kumar A.
      • et al.
      High viral load and deregulation of the progesterone receptor signaling pathway: association with hepatitis E-related poor pregnancy outcome.
      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).
      • Srivastava R.
      • Aggarwal R.
      • Sachdeva S.
      • et al.
      Adaptive immune responses during acute uncomplicated and fulminant hepatitis E.
      Prolonged courses of HEV viremia have been described in some immunocompetent individuals.
      • Mallet V.
      • Louvet A.
      • Chakvetadze C.
      • et al.
      Ribavirin treatment for chronic hepatitis E: a case-series.
      • Gonzalez Tallon A.I.
      • Moreira Vicente V.
      • Mateos Lindemann M.L.
      • et al.
      [Chronic hepatitis E in an immunocompetent patient.].
      • Liu L.
      • Liu Y.
      Analysis of acute to chronic hepatitis E: 6–10 year follow-up.
      However, HEV-associated liver cirrhosis or hepatocellular carcinoma has not been reported to develop in immunocompetent individuals.

      Infections in Organ Transplant Recipients

      Chronic HEV infection has been described in liver and kidney transplant recipients in Europe since 2008.
      • Pischke S.
      • Suneetha P.V.
      • Baechlein C.
      • et al.
      Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients.
      • Kamar N.
      • Selves J.
      • Mansuy J.M.
      • et al.
      Hepatitis E virus and chronic hepatitis in organ-transplant recipients.
      • Gerolami R.
      • Moal V.
      • Colson P.
      Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.
      • Haagsma E.B.
      • Niesters H.G.
      • van den Berg A.P.
      • et al.
      Prevalence of hepatitis E virus infection in liver transplant recipients.
      Kamar et al initially reported 14 cases of acute hepatitis E in Southwest France among patients who received kidney or liver transplants.
      • Kamar N.
      • Selves J.
      • Mansuy J.M.
      • et al.
      Hepatitis E virus and chronic hepatitis in organ-transplant recipients.
      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.
      • Pischke S.
      • Suneetha P.V.
      • Baechlein C.
      • et al.
      Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients.
      • Schlosser B.
      • Stein A.
      • Neuhaus R.
      • et al.
      Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient.
      • Gerolami R.
      • Moal V.
      • Colson P.
      Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.
      • Haagsma E.B.
      • Niesters H.G.
      • van den Berg A.P.
      • et al.
      Prevalence of hepatitis E virus infection in liver transplant recipients.
      • Halac U.
      • Beland K.
      • Lapierre P.
      • et al.
      Chronic hepatitis E infection in children with liver transplantation.
      • Kamar N.
      • Garrouste C.
      • Haagsma E.B.
      • et al.
      Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants.
      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.
      • Kamar N.
      • Garrouste C.
      • Haagsma E.B.
      • et al.
      Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants.
      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).
      • Pischke S.
      • Voigtlaender T.
      • Koenecke C.
      • et al.
      Chronic hepatitis E in immunosuppressed patients beyond liver- and kidney transpantation.
      • de Man R.A.
      • Pas S.D.
      • Osterhaus A.D.
      • et al.
      Diagnosis and clinical consequences of hepatitis E virus infection in orthotopic heart transplant recipients.
      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 HEV-specific T-cell responses in organ transplant recipients. In a prospective study, T-cell responses became detectable after spontaneous or treatment-induced clearance of HEV.
      • Suneetha P.V.
      • Pischke S.
      • Schlaphoff V.
      • et al.
      HEV-specific T-cell responses are associated with control of HEV infection.
      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,
      • Fainboim H.
      • Gonzalez J.
      • Fassio E.
      • et al.
      Prevalence of hepatitis viruses in an anti-human immunodeficiency virus-positive population from Argentina A multicentre study.
      • Balayan M.S.
      • Fedorova O.E.
      • Mikhailov M.I.
      • et al.
      Antibody to hepatitis E virus in HIV-infected individuals and AIDS patients.
      but chronic hepatitis E was not described in an HIV-infected patient before 2009.
      • Dalton H.R.
      • Bendall R.P.
      • Keane F.E.
      • et al.
      Persistent carriage of hepatitis E virus in patients with HIV infection.
      This patient had acquired immunodeficiency syndrome with a CD4+ T-cell count <200 and high levels of HIV RNA (>100,000 copies/mL). However, subsequent studies from Spain (93 patients),
      • Madejón A.
      • Vispo E.
      • Bottecchia M.
      • et al.
      Lack of hepatitis E virus infection in HIV patients with advanced immunodeficiency or idiopathic liver enzyme elevations.
      Germany (123 patients),
      • Pischke S.
      • Ho H.
      • Urbanek F.
      • et al.
      Hepatitis E in HIV-positive patients in a low-endemic country.
      and England (138 patients)
      • Keane F.
      • Gompels M.
      • Bendall R.
      • et al.
      Hepatitis E virus coinfection in patients with HIV infection.
      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.
      • Kaba M.
      • Richet H.
      • Ravaux I.
      • et al.
      Hepatitis E virus infection in patients infected with the human immunodeficiency virus.
      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.
      • Kamar N.
      • Izopet J.
      • Cintas P.
      • et al.
      Hepatitis E virus-induced neurological symptoms in a kidney-transplant patient with chronic hepatitis.
      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.
      • Kamar N.
      • Bendall R.P.
      • Peron J.M.
      • et al.
      Hepatitis E virus and neurologic disorders.
      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 al
      • Kamar N.
      • Bendall R.P.
      • Peron J.M.
      • et al.
      Hepatitis E virus and neurologic disorders.
      ). Chronic HEV infection was recently associated with renal manifestations, including a decrease in glomerular filtration rate or appearance of glomerulonephritis or cryoglobulinemia.
      • Kamar N.
      • Weclawiak H.
      • Guilbeau-Frugier C.
      • et al.
      Hepatitis E virus and the kidney in solid-organ transplant patients.

      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.
      • Gerolami R.
      • Borentain P.
      • Raissouni F.
      • et al.
      Treatment of severe acute hepatitis E by ribavirin.
      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%).
      • Kamar N.
      • Abravanel F.
      • Selves J.
      • et al.
      Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation.
      Pegylated interferon alfa is another treatment option.
      • Kamar N.
      • Rostaing L.
      • Abravanel F.
      • et al.
      Pegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation.
      • Haagsma E.
      • Riezebos-Brilman A.
      • Van den Berg A.P.
      • et al.
      Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b.
      Treatment durations range from 3 to 12 months; 4 of 5 patients were successfully treated with pegylated interferon alfa, which led to sustained clearance of HEV RNA. However, interferon therapy can cause significant side effects and organ rejection in transplant recipients. Interferon-alfa 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.
      • Mallet V.
      • Nicand E.
      • Sultanik P.
      • et al.
      Brief communication: case reports of ribavirin treatment for chronic hepatitis E.
      • Kamar N.
      • Rostaing L.
      • Abravanel F.
      • et al.
      Ribavirin therapy inhibits viral replication on patients with chronic hepatitis E virus infection.
      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).
      • Mallet V.
      • Louvet A.
      • Chakvetadze C.
      • et al.
      Ribavirin treatment for chronic hepatitis E: a case-series.
      • Pischke S.
      • Voigtlaender T.
      • Koenecke C.
      • et al.
      Chronic hepatitis E in immunosuppressed patients beyond liver- and kidney transpantation.
      Table 1Treatment of Patients With Chronic HEV Infection
      Group of patientsTreatmentOutcomesFirst author, year
      16 Liver and kidney transplantation patients with chronic HEV infectionReduction of immunosuppression4 of 16 patients HEV RNA–negativeKamar, 2011
      • Kamar N.
      • Abravanel F.
      • Selves J.
      • et al.
      Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation.
      56 Liver and kidney transplant recipients with chronic HEV infectionReduction of immunosuppression18 of 56 patients HEV RNA–negativeKamar, 2011
      • Kamar N.
      • Garrouste C.
      • Haagsma E.B.
      • et al.
      Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants.
      3 Liver transplant recipients with chronic HEV infection3-month course with pegylated interferon-alfa-2a2 of 3 patients cleared HEV RNA, 1 relapsed after treatmentKamar, 2010
      • Kamar N.
      • Rostaing L.
      • Abravanel F.
      • et al.
      Pegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation.
      2 Liver transplant recipients with chronic HEV infection16 weeks or 1 year of treatment with pegylated interferon-alfa-2b2 of 2 patients cleared HEV RNAHaagsma, 2010
      • Haagsma E.
      • Riezebos-Brilman A.
      • Van den Berg A.P.
      • et al.
      Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b.
      1 HIV-infected patient with chronic HEV infection6 months pegylated interferon monotherapy, followed by 12 weeks of therapy with the combination of interferon and ribavirinPatient tested negative for HEV RNADalton, 2011, Ann Intern Med
      • Dalton H.R.
      • Keane F.E.
      • Bendall R.
      • et al.
      Treatment of chronic hepatitis E in a patient with HIV infection.
      7 Recipients of solid organ transplantsTreatment with ribavirin monotherapy for 5 months6 of 7 patients cleared the virus, and 1 is still a carrier of HEVUnpublished data from our group
      6 Recipients of solid organ transplantsTreatment with ribavirin monotherapy for 3 months4 of 6 patients achieved sustained virologic response, 2 relapsedKamar, 2010
      • Kamar N.
      • Rostaing L.
      • Abravanel F.
      • et al.
      Ribavirin therapy inhibits viral replication on patients with chronic hepatitis E virus infection.
      9 Patients with various conditions of immunosuppressionTreatment with ribavirin monotherapy for 3 months9 of 9 patients cleared the virus, no relapseMallet, 2010, AASLD Annual Meeting
      • Mallet V.
      • Louvet A.
      • Chakvetadze C.
      • et al.
      Ribavirin treatment for chronic hepatitis E: a case-series.
      AASLD, American Association for the Study of Liver Disease.
      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.
      • Zhou Y.H.
      • Purcell R.H.
      • Emerson S.U.
      A truncated ORF2 protein contains the most immunogenic site on ORF2: antibody responses to non-vaccine sequences following challenge of vaccinated and non-vaccinated macaques with hepatitis E virus.
      HEV-specific CD4+ and CD8+ T-cell responses are detectable in patients with acute hepatitis E
      • Husain M.M.
      • Aggarwal R.
      • Kumar D.
      • et al.
      Effector T cells immune reactivity among patients with acute hepatitis E.
      and long-term in individuals who have recovered from infection.
      • Suneetha P.V.
      • Pischke S.
      • Schlaphoff V.
      • et al.
      HEV-specific T-cell responses are associated with control of HEV infection.
      Immunodominant regions within ORFs 2 and 3 induce T-cell responses.
      • Husain M.M.
      • Aggarwal R.
      • Kumar D.
      • et al.
      Effector T cells immune reactivity among patients with acute hepatitis E.
      • Aggarwal R.
      • Shukla R.
      • Jameel S.
      • et al.
      T-cell epitope mapping of ORF2 and ORF3 proteins of human hepatitis E virus.
      Immunity against HEV seems to persist for life—seropositive patients who become reinfected do not develop symptomatic hepatitis.
      • Zhu F.C.
      • Zhang J.
      • Zhang X.F.
      • et al.
      Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial.
      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.
      • Shrestha M.P.
      • Scott R.M.
      • Joshi D.M.
      • et al.
      Safety and efficacy of a recombinant hepatitis E vaccine.
      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.
      • Zhu F.C.
      • Zhang J.
      • Zhang X.F.
      • et al.
      Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial.
      This vaccine is based on HEV genotype 1, produced in bacterial cells, and contains 30 μg 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.
      • Wu T.
      • Zhu F.C.
      • Huang S.J.
      • et al.
      Safety of the hepatitis E vaccine for pregnant women: a preliminary analysis.
      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.
      • Wedemeyer H.
      • Pischke S.
      Hepatitis: hepatitis E vaccination—is HEV 239 the breakthrough?.
      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).

      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.

      Supplementary material

      Figure thumbnail gre1
      Supplementary Figure 1H&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×).

      Acknowledgments

      The authors thank Dr Svenja Hardtke (Hannover Medical School), Sarah Williamson, and Brook Ashley Simpson (Gastroenterology editorial office) for editorial assistance.

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