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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 1389 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 1390 WEDEMEYER ET AL GASTROENTEROLOGY Vol. 142, No. 6 HEPATITIS E VIRUS 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 1391 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. HEPATITIS E VIRUS May 2012 1392 WEDEMEYER ET AL GASTROENTEROLOGY Vol. 142, No. 6 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 HEPATITIS E VIRUS May 2012 1394 WEDEMEYER ET AL GASTROENTEROLOGY Vol. 142, No. 6 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. 17. 18. 19. 20. 21. 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. References 1. Purcell RH, Emerson SU. Hepatitis E: an emerging awareness of an old disease. J Hepatol 2008;48:494 –503. 2. Aggarwal R, Jameel S. Hepatitis E. Hepatology 2011;54:2218 – 2226. 3. Balayan MS, Andjaparidze AG, Savinskaya SS, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 1983;20:23–31. 4. 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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). HEPATITIS E VIRUS May 2012 1397.e1 WEDEMEYER ET AL GASTROENTEROLOGY Vol. 142, No. 6 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⫻).