Hepatitis E virus (HEV) infection can lead to acute and chronic hepatitis as well as to extrahepatic manifestations such as neurological and renal disease; it is the most common cause of acute viral hepatitis worldwide. Four genotypes are responsible for most infection in humans, of which HEV genotypes 1 and 2 are obligate human pathogens and HEV genotypes 3 and 4 are mostly zoonotic. Until quite recently, HEV was considered to be mainly responsible for epidemics of acute hepatitis in developing regions owing to contamination of drinking water supplies with human faeces. However, HEV is increasingly being recognized as endemic in some developed regions. In this setting, infections occur through zoonotic transmission or contaminated blood products and can cause chronic hepatitis in immunocompromised individuals. HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool. Although an effective HEV vaccine exists, it is only licensed for use in China. Acute hepatitis E is usually self-limiting and does not require specific treatment. Management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin.
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Balayan, M. S. et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 20, 23–31 (1983).
Kamar, N., Dalton, H. R., Abravanel, F. & Izopet, J. Hepatitis E virus infection. Clin. Microbiol. Rev. 27, 116–138 (2014).
Maila, H. T., Bowyer, S. M. & Swanepoel, R. Identification of a new strain of hepatitis E virus from an outbreak in Namibia in 1995. J. Gen. Virol. 85, 89–95 (2004).
Kamar, N. et al. Hepatitis E. Lancet 379, 2477–2488 (2012).
Hartl, J. et al. Hepatitis E seroprevalence in Europe: a meta-analysis Viruses 8, 211 (2016).
Mansuy, J. M. et al. Hepatitis E virus antibody in blood donors, France. Emerg. Infect. Dis. 17, 2309–2312 (2011).
Aggarwal, R. Hepatitis E: historical, contemporary and future perspectives. J. Gastroenterol. Hepatol. 26 (Suppl. 1), 72–82 (2011).
Okamoto, H. Genetic variability and evolution of hepatitis E virus. Virus Res. 127, 216–228 (2007).
Rein, D. B., Stevens, G. A., Theaker, J., Wittenborn, J. S. & Wiersma, S. T. The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology 55, 988–997 (2012).
Viswanathan, R. Epidemiology. Indian J. Med. Res. 45 (Suppl.), 1–29 (1957). This paper describes the first and largest outbreak of HEV infection, which led to many deaths.
Naik, S. R., Aggarwal, R., Salunke, P. N. & Mehrotra, N. N. A large waterborne viral hepatitis E epidemic in Kanpur, India. Bull. World Health Organ. 70, 597–604 (1992).
Khuroo, M. S. Chronic liver disease after non-A, non-B hepatitis. Lancet 2, 860–861 (1980).
Teshale, E. H. et al. Evidence of person-to-person transmission of hepatitis E virus during a large outbreak in Northern Uganda. Clin. Infect. Dis. 50, 1006–1010 (2010).
Thompson, K. et al. Investigation of hepatitis E outbreak among refugees — Upper Nile, South Sudan, 2012–2013. MMWR Morb. Mortal. Wkly Rep. 62, 581–586.
Aggarwal, R. & Naik, S. R. Hepatitis E: intrafamilial transmission versus waterborne spread. J. Hepatol. 21, 718–723 (1994).
Somani, S. K., Aggarwal, R., Naik, S. R., Srivastava, S. & Naik, S. A serological study of intrafamilial spread from patients with sporadic hepatitis E virus infection. J. Viral Hepat. 10, 446–449 (2003).
Aggarwal, R. Hepatitis E virus and person-to-person transmission. Clin. Infect. Dis. 51, 477–478 (2010).
Nishiura, H. Household data from the Ugandan hepatitis E virus outbreak indicate the dominance of community infection. Clin. Infect. Dis. 51, 117–118 (2010).
Khuroo, M. S., Kamili, S. & Jameel, S. Vertical transmission of hepatitis E virus. Lancet 345, 1025–1026 (1995).
Khuroo, M. S., Kamili, S. & Khuroo, M. S. Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV-infected mothers. J. Viral Hepat. 16, 519–523 (2009).
Khuroo, M. S., Kamili, S. & Yattoo, G. N. Hepatitis E virus infection may be transmitted through blood transfusions in an endemic area. J. Gastroenterol. Hepatol. 19, 778–784 (2004).
Arankalle, V. A. & Chobe, L. P. Retrospective analysis of blood transfusion recipients: evidence for post-transfusion hepatitis E. Vox Sang. 79, 72–74 (2000).
Viswanathan, R. Infectious hepatitis in Delhi (1955–1956): a critical study — epidemiology. Indian J. Med. Res. 45 (Suppl. 12), 1–29 (1957).
World Health Organization. Waterborne outbreaks of hepatitis E: recognition, investigation and control. Technical report (WHO, 2014)
Fix, A. D. et al. Prevalence of antibodies to hepatitis E in two rural Egyptian communities. Am. J. Trop. Med. Hyg. 62, 519–523 (2000).
Stoszek, S. K. et al. High prevalence of hepatitis E antibodies in pregnant Egyptian women. Trans. R. Soc. Trop. Med. Hyg. 100, 95–101 (2006).
Dai, X. et al. Hepatitis E virus genotype 4, Nanjing, China, 2001–2011. Emerg. Infect. Dis. 19, 1528–1530 (2013).
Inagaki, Y. et al. A nationwide survey of hepatitis E virus infection and chronic hepatitis E in liver transplant recipients in Japan. EBioMedicine 2, 1607–1612 (2015).
Minagi, T. et al. Hepatitis E virus in donor plasma collected in Japan. Vox Sang. 111, 242–246 (2016).
Pischke, S. et al. High clinical manifestation rate in an imported outbreak of hepatitis E genotype 1 infection in a German group of travellers returning from India. Ann. Hepatol. 16, 57–62 (2017).
Van Cauteren, D. et al. Estimated annual numbers of foodborne pathogen-associated illnesses, hospitalizations, and deaths, France, 2008–2013. Emerg. Infect. Dis. 23, 1486–1492 (2017). This recent and well-documented study shows that hepatitis E has become the leading cause of viral hepatitis in France and is responsible for a large number of hospitalizations and death.
Hewitt, P. E. et al. Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet 384, 1766–1773 (2014). This paper is one of the first studies that clearly assessed the prevalence of HEV RNA among blood donors; it described blood component-induced HEV transmission that leads to chronic hepatitis in immunosuppressed patients.
Faber, M. S. et al. Hepatitis E virus seroprevalence among adults Germany. Emerg. Infect. Dis. 18, 1654–1657 (2012).
Aspinall, E. J. et al. Hepatitis E virus infection in Europe: surveillance and descriptive epidemiology of confirmed cases 2005 to 2015. Eurosurveillance 22 29 (2017).
Doting, M. H. E., Weel, J., Niesters, H. G. M., Riezebos-Brilman, A. & Brandenburg, A. The added value of hepatitis E diagnostics in determining causes of hepatitis in routine diagnostic settings in the Netherlands. Clin. Microbiol. Infect. 23, 667–671 (2017).
Wenzel, J. J. et al. Decline in hepatitis E virus antibody prevalence in southeastern Germany, 1996–2011. Hepatology 60, 1180–1186 (2014).
Kuniholm, M. H. et al. Epidemiology of hepatitis E virus in the United States: results from the Third National Health and Nutrition Examination Survey, 1988–1994. J. Infect. Dis. 200, 48–56 (2009).
Ditah, I. et al. Current epidemiology of hepatitis E virus infection in the United States: low seroprevalence in the National Health and Nutrition Evaluation Survey. Hepatology 60, 815–822 (2014).
Roth, N. J. et al. Low hepatitis E virus RNA prevalence in a large-scale survey of United States source plasma donors. Transfusionhttp://dx.doi.org/10.1111/trf.14285 (2017).
Nelson, K. E., Kmush, B. & Labrique, A. B. The epidemiology of hepatitis E virus infections in developed countries and among immunocompromised patients. Expert Rev. Anti Infect. Ther. 9, 1133–1148 (2011).
Kuniholm, M. H. et al. Acute and chronic hepatitis E virus infection in human immunodeficiency virus-infected U.S. women. Hepatology 63, 712–720 (2016).
Chapuy-Regaud, S. et al. Characterization of the lipid envelope of exosome encapsulated HEV particles protected from the immune response. Biochimie 141, 70–79 (2017).
Koonin, E. V. et al. Computer-assisted assignment of functional domains in the nonstructural polyprotein of hepatitis E virus: delineation of an additional group of positive-strand RNA plant and animal viruses. Proc. Natl Acad. Sci. USA 89, 8259–8263 (1992).
Lhomme, S. et al. Influence of polyproline region and macro domain genetic heterogeneity on HEV persistence in immunocompromised patients. J. Infect. Dis. 209, 300–303 (2014).
Shukla, P. et al. Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant. Proc. Natl Acad. Sci. USA 108, 2438–2443 (2011).
Johne, R. et al. An ORF1-rearranged hepatitis E virus derived from a chronically infected patient efficiently replicates in cell culture. J. Viral Hepat. 21, 447–456 (2014).
Nair, V. P. et al. Endoplasmic reticulum stress induced synthesis of a novel viral factor mediates efficient replication of genotype-1 hepatitis E virus. PLoS Pathog. 12, e1005521 (2016).
Zafrullah, M., Ozdener, M. H., Kumar, R., Panda, S. K. & Jameel, S. Mutational analysis of glycosylation, membrane translocation, and cell surface expression of the hepatitis E virus ORF2 protein. J. Virol. 73, 4074–4082 (1999).
Guu, T. S. et al. Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding. Proc. Natl Acad. Sci. USA 106, 12992–12997 (2009).
Yamashita, T. et al. Biological and immunological characteristics of hepatitis E virus-like particles based on the crystal structure. Proc. Natl Acad. Sci. USA 106, 12986–12991 (2009).
Xing, L. et al. Structure of hepatitis E virion-sized particle reveals an RNA-dependent viral assembly pathway. J. Biol. Chem. 285, 33175–33183 (2010).
Tang, X. et al. Structural basis for the neutralization and genotype specificity of hepatitis E virus. Proc. Natl Acad. Sci. USA 108, 10266–10271 (2011).
Xing, L. et al. Spatial configuration of hepatitis E virus antigenic domain. J. Virol. 85, 1117–1124 (2011).
Lhomme, S. et al. HEV quasispecies and the outcome of acute hepatitis E in solid-organ transplant patients. J. Virol. 86, 100006–100014 (2012).
Tyagi, S., Korkaya, H., Zafrullah, M., Jameel, S. & Lal, S. K. The phosphorylated form of the ORF3 protein of hepatitis E virus interacts with its non-glycosylated form of the major capsid protein, ORF2. J. Biol. Chem. 277, 22759–22767 (2002).
Emerson, S. U. et al. Release of genotype 1 hepatitis E virus from cultured hepatoma and polarized intestinal cells depends on open reading frame 3 protein and requires an intact PXXP motif. J. Virol. 84, 9059–9069 (2010).
Nagashima, S. et al. A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells. J. Gen. Virol. 92, 269–278 (2011).
Purdy, M. A. & Khudyakov, Y. E. Evolutionary history and population dynamics of hepatitis E virus. PLoS ONE 5, e14376 (2010).
Brayne, A. B., Dearlove, B. L., Lester, J. S., Kosakovsky Pond, S. L. & Frost, S. D. Genotype-specific evolution of Hepatitis E Virus. J. Virol. 91, e02241-16 (2017).
Purcell, R. H. & Emerson, S. U. Hepatitis E: an emerging awareness of an old disease. J. Hepatol. 48, 494–503 (2008).
Purcell, R. H. et al. Pathobiology of hepatitis E: lessons learned from primate models. Emerg. Microbes Infect. 2, e9 (2013).
Meng, X. J. et al. Experimental infection of pigs with the newly identified swine hepatitis E virus (swine HEV), but not with human strains of HEV. Arch. Virol. 143, 1405–1415 (1998).
La Rosa, G., Pourshaban, M., Iaconelli, M., Vennarucci, V. S. & Muscillo, M. Molecular detection of hepatitis E virus in sewage samples. Appl. Environ. Microbiol. 76, 5870–5873 (2010).
Mansuy, J. M. et al. A nationwide survey of hepatitis E viral infection in French blood donors. Hepatology 63, 1145–1154 (2016). This paper shows that HEV is endemic among blood donors in France and describes risk factors for anti-HEV IgG and anti-HEV IgM prevalence.
Doceul, V., Bagdassarian, E., Demange, A. & Pavio, N. Zoonotic hepatitis E virus: classification, animal reservoirs and transmission routes. Viruses 8, 270 (2016).
Schlosser, J. et al. Natural and experimental hepatitis E virus genotype 3-infection in European wild boar is transmissible to domestic pigs. Vet. Res. 45, 121 (2014).
Izopet, J. et al. Hepatitis E virus strains in rabbits and evidence of a closely related strain in humans, france. Emerg. Infect. Dis. 18, 1274–1281 (2012).
Yan, B. et al. Hepatitis E Virus in yellow cattle, Shandong, Eastern China. Emerg. Infect. Dis. 22, 2211–2212 (2016).
Casas, M. et al. Longitudinal study of hepatitis E virus infection in Spanish farrow-to-finish swine herds. Vet. Microbiol. 148, 27–34 (2011).
Salines, M., Andraud, M. & Rose, N. From the epidemiology of hepatitis E virus (HEV) within the swine reservoir to public health risk mitigation strategies: a comprehensive review. Vet. Res. 48, 31 (2017).
Colson, P. et al. Pig liver sausage as a source of hepatitis E virus transmission to humans. J. Infect. Dis. 202, 825–834 (2010).
Renou, C., Roque-Afonso, A. M. & Pavio, N. Foodborne transmission of hepatitis E virus from raw pork liver sausage, France. Emerg. Infect. Dis. 20, 1945–1947 (2014).
Riveiro-Barciela, M. et al. Phylogenetic demonstration of hepatitis E infection transmitted by pork meat ingestion. J. Clin. Gastroenterol. 49, 165–168 (2015).
Huang, F. et al. Excretion of infectious hepatitis E virus into milk in cows imposes high risks of zoonosis. Hepatology 64, 350–359 (2016).
Lange, H. et al. Hepatitis E in Norway: seroprevalence in humans and swine. Epidemiol. Infect. 145, 181–186 (2017).
Colson, P., Kaba, M., Bernit, E., Motte, A. & Tamalet, C. Hepatitis E associated with surgical training on pigs. Lancet 370, 935 (2007).
Perez-Gracia, M. T. et al. Autochthonous hepatitis E infection in a slaughterhouse worker. Am. J. Trop. Med. Hyg. 77, 893–896 (2007).
Renou, C. et al. Possible zoonotic transmission of hepatitis E from pet pig to its owner. Emerg. Infect. Dis. 13, 1094–1096 (2007).
Chaussade, H. et al. Hepatitis E virus seroprevalence and risk factors for individuals in working contact with animals. J. Clin. Virol. 58, 504–508 (2013).
Di Bartolo, I. et al. Hepatitis E virus in pork production chain in Czech Republic, Italy, and Spain, 2010. Emerg. Infect. Dis. 18, 1282–1289 (2012).
Nantel-Fortier, N. et al. Detection and phylogenetic analysis of the hepatitis E virus in a Canadian swine production network. Food Environ. Virol. 8, 296–304 (2016).
van Gageldonk-Lafeber, A. B. et al. Hepatitis E virus seroprevalence among the general population in a livestock-dense area in the Netherlands: a cross-sectional population-based serological survey. BMC Infect. Dis. 17, 21 (2017).
Cossaboom, C. M., Cordoba, L., Cao, D., Ni, Y. Y. & Meng, X. J. Complete genome sequence of hepatitis E virus from rabbits in the United States. J. Virol. 86, 13124–13125 (2012).
Lhomme, S. et al. Wildlife reservoir for hepatitis E virus, Southwestern France. Emerg. Infect. Dis. 21, 1224–1226 (2015).
Abravanel, F. et al. Rabbit hepatitis E virus infections in humans, France. Emerg. Infect. Dis. 23, 1191–1193 (2017).
Liu, P. et al. Transmission of hepatitis E virus from rabbits to cynomolgus macaques. Emerg. Infect. Dis. 19, 559–565 (2013).
Cossaboom, C. M. et al. Cross-species infection of pigs with a novel rabbit, but not rat, strain of hepatitis E virus isolated in the United States. J. Gen. Virol. 93, 1687–1695 (2012).
Lee, G. H. et al. Chronic infection with camelid hepatitis E virus in a liver transplant recipient who regularly consumes camel meat and milk. Gastroenterology 150, 355–357.e3 (2016).
Li, T. C. et al. Generation of hepatitis E virus-like particles of two new genotypes G5 and G6 and comparison of antigenic properties with those of known genotypes. Vet. Microbiol. 178, 150–157 (2015).
Grodzki, M. et al. Bioaccumulation efficiency, tissue distribution, and environmental occurrence of hepatitis E virus in bivalve shellfish from France. Appl. Environ. Microbiol. 80, 4269–4276 (2014).
Crossan, C. et al. Hepatitis E virus genotype 3 in shellfish, United Kingdom. Emerg. Infect. Dis. 18, 2085–2087 (2012).
Said, B. et al. Hepatitis E outbreak on cruise ship. Emerg. Infect. Dis. 15, 1738–1744 (2009).
Tedder, R. S. et al. Hepatitis E risks: pigs or blood-that is the question. Transfusion 57, 267–272 (2017).
Zhang, L. et al. Prevalence of hepatitis E virus infection among blood donors in mainland China: a meta-analysis. Transfusion 57, 248–257 (2017).
Satake, M. et al. Unique clinical courses of transfusion-transmitted hepatitis E in patients with immunosuppression. Transfusion 57, 280–288 (2017).
Baylis, S. A. et al. Unusual serological response to hepatitis E virus in plasma donors consistent with re-infection. Vox Sang. 109, 406–409 (2015).
Suneetha, P. V. et al. Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection. Hepatology 55, 695–708 (2012).
Abravanel, F. et al. Conventional and innate lymphocytes response at the acute phase of HEV infection in transplanted patients. J. Infect. 72, 723–730 (2016).
Cao, D. et al. Pig model mimicking chronic hepatitis E virus infection in immunocompromised patients to assess immune correlates during chronicity. Proc. Natl Acad. Sci. USA 114, 6914–6923 (2017).
Bouwknegt, M. et al. The course of hepatitis E virus infection in pigs after contact-infection and intravenous inoculation. BMC Vet. Res. 5, 7 (2009).
Aggarwal, R., Kini, D., Sofat, S., Naik, S. R. & Krawczynski, K. Duration of viraemia and faecal viral excretion in acute hepatitis E. Lancet 356, 1081–1082 (2000).
Williams, T. P. et al. Evidence of extrahepatic sites of replication of the hepatitis E virus in a swine model. J. Clin. Microbiol. 39, 3040–3046 (2001).
Geng, Y. et al. Detection and assessment of infectivity of hepatitis E virus in urine. J. Hepatol. 64, 37–43 (2016).
Drave, S. A. et al. Extra-hepatic replication and infection of hepatitis E virus in neuronal-derived cells. J. Viral Hepat. 23, 512–521 (2016).
Bose, P. D. et al. Evidence of extrahepatic replication of hepatitis E virus in human placenta. J. Gen. Virol. 95, 1266–1271 (2014).
Pischke, S. et al. Blood-borne Hepatitis E Virus Transmission: A Relevant Risk for Immunosuppressed Patients. Clin. Infect. Dis. 63, 569–570 (2016).
Zhang, J. et al. Protection against hepatitis E virus infection by naturally acquired and vaccine-induced immunity. Clin. Microbiol. Infect. 20, O397–O405 (2014).
Aggarwal, R. Diagnosis of hepatitis E. Nat. Rev. Gastroenterol. Hepatol. 10, 24–33 (2013).
Wen, G. P. et al. A valuable antigen detection method for diagnosis of acute hepatitis E. J. Clin. Microbiol. 53, 782–788 (2015).
Huang, S. et al. Profile of acute infectious markers in sporadic hepatitis E. PLoS ONE 5, e13560 (2010).
Norder, H. et al. Diagnostic performance of five assays for anti-hepatitis E virus IgG and IgM in a large cohort study. J. Clin. Microbiol. 54, 549–555 (2016).
Abravanel, F. et al. Performance of anti-HEV assays for diagnosis acute hepatitis E in immunocompromised patients. J. Clin. Virol. 58, 624–628 (2013).
Legrand-Abravanel, F. et al. Good performance of immunoglobulin M assays in diagnosing genotype 3 hepatitis E virus infections. Clin. Vaccine Immunol. 16, 772–774 (2009).
Bendall, R., Ellis, V., Ijaz, S., Ali, R. & Dalton, H. A comparison of two commercially available anti-HEV IgG kits and a re-evaluation of anti-HEV IgG seroprevalence data in developed countries. J. Med. Virol. 82, 799–805 (2010). This study is the first to show discrepancies between HEV serological assays.
Abravanel, F. et al. Hepatitis E virus reinfections in solid-organ-transplant recipients can evolve into chronic infections. J. Infect. Dis. 209, 1900–1906 (2014).
Abravanel, F. et al. Performance of two commercial assays for detecting hepatitis E virus RNA in acute or chronic infections. J. Clin. Microbiol. 51, 1913–1916 (2013).
Abravanel, F. et al. Genotype 3 diversity and quantification of hepatitis E virus RNA. J. Clin. Microbiol. 50, 897–902 (2012).
Sauleda, S. et al. Seroprevalence of hepatitis E virus (HEV) and detection of HEV RNA with a transcription-mediated amplification assay in blood donors from Catalonia (Spain). Transfusion 55, 972–979 (2015).
Gou, H. et al. Rapid and sensitive detection of type II porcine reproductive and respiratory syndrome virus by reverse transcription loop-mediated isothermal amplification combined with a vertical flow visualization strip. J. Virol. Methods 209, 86–94 (2014).
Debing, Y. et al. Hepatitis E virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity. J. Hepatol. 65, 499–508 (2016).
Lhomme, S. et al. Mutation in the hepatitis E virus polymerase and outcome of ribavirin therapy. Antimicrob. Agents Chemother. 60, 1608–1614 (2015).
Tremeaux, P. et al. Performance of an antigen assay for diagnosing acute hepatitis E virus genotype 3 infection. J. Clin. Virol. 79, 1–5 (2016).
Abravanel, F., Lhomme, S., Rostaing, L., Kamar, N. & Izopet, J. Protracted fecal shedding of HEV during ribavirin therapy predicts treatment relapse. Clin. Infect. Dis. 60, 96–99 (2015).
Dalton, H. R., Bendall, R., Ijaz, S. & Banks, M. Hepatitis E: an emerging infection in developed countries. Lancet Infect. Dis. 8, 698–709 (2008).
Blasco-Perrin, H. et al. Hepatitis E virus in patients with decompensated chronic liver disease: a prospective UK/French study. Aliment. Pharmacol. Ther. 42, 574–581 (2015).
Kumar, A. & Saraswat, V. A. Hepatitis E and acute-on-chronic liver failure. J. Clin. Exp. Hepatol. 3, 225–230 (2013).
Shalimar, S. K. et al. Severity and outcome of acute-on-chronic liver failure is dependent on the etiology of acute hepatic insults: analysis of 368 patients. J. Clin. Gastroenterol. 51, 734–741 (2017).
Naik, A. et al. Lack of evidence of hepatitis E virus infection among renal transplant recipients in a disease-endemic area. J. Viral Hepat. 20, e138–e140 (2013).
Naidu, S. S. & Viswanathan, R. Infectious hepatitis in pregnancy during Delhi epidemic. Indian J. Med. Res. 45, 71–76 (1957).
Jilani, N. et al. Hepatitis E virus infection and fulminant hepatic failure during pregnancy. J. Gastroenterol. Hepatol. 22, 676–682 (2007).
Zhu, F. C. 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. Lancet 376, 895–902 (2010). This paper reports the results of a prospective randomized trial that assessed the efficacy and safety of the available vaccine against HEV.
Guillois, Y. et al. High proportion of asymptomatic infections in an outbreak of hepatitis E associated with a spit-roasted piglet, France, 2013. Clin. Infect. Dis. 62, 351–357 (2016).
Peron, J. M. et al. Fulminant liver failure from acute autochthonous hepatitis E in France: description of seven patients with acute hepatitis E and encephalopathy. J. Viral Hepat. 14, 298–303 (2007).
Manka, P. et al. Hepatitis E virus infection as a possible cause of acute liver failure in Europe. Clin. Gastroenterol. Hepatol. 13, 1836–1842 (2015).
Aherfi, S. et al. Liver transplantation for acute liver failure related to autochthonous genotype 3 hepatitis E virus infection. Clin. Res. Hepatol. Gastroenterol. 38, 24–31 (2014).
Haim-Boukobza, S. et al. Hepatitis E infection in patients with severe acute alcoholic hepatitis. Liver Int. 35, 870–875 (2015).
Anty, R. et al. First case report of an acute genotype 3 hepatitis E infected pregnant woman living in South-Eastern France. J. Clin. Virol. 54, 76–78 (2012).
Renou, C. et al. Prospective study of Hepatitis E Virus infection among pregnant women in France. Virol. J. 11, 68 (2014).
Kamar, N. et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N. Engl. J. Med. 358, 811–817 (2008). This is the first series of chronic HEV infections reported in immunosuppressed patients, that is, in patients who received SOT.
Gerolami, R., Moal, V. & Colson, P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. N. Engl. J. Med. 358, 859–860 (2008).
Kamar, N. et al. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology 140, 1481–1489 (2011).
Hoerning, A. et al. Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients — a single-center experience. Pediatr. Transplant. 16, 742–747 (2012).
Koenecke, C. et al. Hepatitis E virus infection in a hematopoietic stem cell donor. Bone Marrow Transplant. 49, 159–160 (2014).
Tavitian, S. et al. Hepatitis E virus excretion can be prolonged in patients with hematological malignancies. J. Clin. Virol. 49, 141–144 (2010).
Ollier, L. et al. Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab. Ann. Intern. Med. 150, 430–431 (2009).
Bauer, H. et al. Outcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: a French retrospective multicenter study. Medicine 94, e675 (2015).
Dalton, H. R., Bendall, R., Keane, F., Tedder, R. & Ijaz, S. Persistent carriage of hepatitis E virus in patients with HIV infection. N. Engl. J. Med. 361, 1025–1027 (2009).
Kamar, N., Rostaing, L., Legrand-Abravanel, F. & Izopet, J. How should hepatitis E virus infection be defined in organ-transplant recipients? Am. J. Transplant. 13, 1935–1936 (2013).
Geng, Y. et al. Persistent hepatitis e virus genotype 4 infection in a child with acute lymphoblastic leukemia. Hepat. Mon. 14, e15618 (2014).
Kamar, N. et al. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation. Transplantation 89, 353–360 (2010).
Kamar, N. et al. Hepatitis E virus-related cirrhosis in kidney- and kidney-pancreas-transplant recipients. Am. J. Transplant. 8, 1744–1748 (2008).
Kamar, N., Izopet, J. & Rostaing, L. No reactivation of hepatitis E virus after kidney retransplantation. Am. J. Transplant. 12, 507–508 (2012).
Dalton, H. R. et al. Hepatitis E virus and neurological injury. Nat. Rev. Neurol. 12, 77–85 (2016). In this Review, the authors summarize all available data regarding HEV-associated neurological manifestations.
Kamar, N. et al. Hepatitis E virus and neurologic disorders. Emerg. Infect. Dis. 17, 173–179 (2011).
Woolson, K. L. et al. Extra-hepatic manifestations of autochthonous hepatitis E infection. Aliment. Pharmacol. Ther. 40, 1282–1291 (2014).
van den Berg, B. et al. Guillain-Barre syndrome associated with preceding hepatitis E virus infection. Neurology 82, 491–497 (2014).
Geurtsvankessel, C. H. et al. Hepatitis E and Guillain-Barre syndrome. Clin. Infect. Dis. 57, 1369–1370 (2013).
Fukae, J. et al. Guillain-Barre and Miller Fisher syndromes in patients with anti-hepatitis E virus antibody: a hospital-based survey in Japan. Neurol. Sci. 37, 1849–1851 (2016).
Stevens, O., Claeys, K. G., Poesen, K., Saegeman, V. & Van Damme, P. Diagnostic challenges and clinical characteristics of hepatitis E virus-associated Guillain-Barre syndrome. JAMA Neurol. 74, 26–33 (2017).
van Eijk, J. J. et al. Neuralgic amyotrophy and hepatitis E virus infection. Neurology 82, 498–503 (2014).
Dalton, H. R. et al. Hepatitis E infection and acute non-traumatic neurological injury: a prospective pilot multicenter study. J. Hepatol. http://dx.doi.org/10.1016/j.jhep.2017.07.010 (2017).
Kamar, N. et al. Hepatitis E virus-induced neurological symptoms in a kidney-transplant patient with chronic hepatitis. Am. J. Transplant. 10, 1321–1324 (2010).
Silva, M. et al. Hepatitis E virus infection as a direct cause of neuralgic amyotrophy. Muscle Nerve 54, 325–327 (2016).
Dalton, H., Keane, F., Bendall, R., Mathew, J. & Ijaz, S. Treatment of chronic hepatitis E in a HIV positive patient. Ann. Intern. Med. 155, 479–480 (2011).
Shi, R. et al. Evidence of Hepatitis E virus breaking through the blood-brain barrier and replicating in the central nervous system. J. Viral Hepat. 23, 930–939 (2016).
Zhou, X. et al. Hepatitis E virus infects neurons and brains. J. Infect. Dis. 215, 1197–1206 (2017).
Kamar, N. et al. Acute hepatitis and renal function impairment related to infection by hepatitis E virus in a renal allograft recipient. Am. J. Kidney Dis. 45, 193–196 (2005).
Kamar, N. et al. Hepatitis E virus and the kidney in solid-organ-transplant patients. Transplantation 93, 617–623 (2012).
Ali, G., Kumar, M., Bali, S. & Wadhwa, W. Heptitis E associated immune thrombocytopenia and membranous glomerulonephritis. Indian J. Nephrol. 11, 70–72 (2001).
Taton, B. et al. Hepatitis E virus infection as a new probable cause of de novo membranous nephropathy after kidney transplantation. Transpl. Infect. Dis. 15, E211–E215 (2013).
Guinault, D. et al. Hepatitis E virus-induced cryglobulinemic glomerulonephritis in a non-immunocompromised person. Am. J. Kidney Dis. 67, 660–663 (2016).
Del Bello, A. et al. Successful treatment of hepatitis E virus-associated cryoglobulinemic membranoproliferative glomerulonephritis with ribavirin. Transpl. Infect. Dis. 17, 279–283 (2015).
de Vos, A. S., Janssen, M. P., Zaaijer, H. L. & Hogema, B. M. Cost-effectiveness of the screening of blood donations for hepatitis E virus in the Netherlands. Transfusion 57, 258–266 (2017).
Haque, F. et al. An outbreak of hepatitis E in an urban area of Bangladesh. J. Viral Hepat. 22, 948–956 (2015).
Feagins, A. R., Opriessnig, T., Guenette, D. K., Halbur, P. G. & Meng, X. J. Inactivation of infectious hepatitis E virus present in commercial pig livers sold in local grocery stores in the United States. Int. J. Food Microbiol. 123, 32–37 (2008).
Barnaud, E., Rogee, S., Garry, P., Rose, N. & Pavio, N. Thermal inactivation of infectious hepatitis E virus in experimentally contaminated food. Appl. Environ. Microbiol. 78, 5153–5159 (2012).
Johne, R., Trojnar, E., Filter, M. & Hofmann, J. Thermal stability of hepatitis E virus as estimated by a cell culture method. Appl. Environ. Microbiol. 82, 4225–4231 (2016).
Emerson, S. U., Arankalle, V. A. & Purcell, R. H. Thermal stability of hepatitis E virus. J. Infect. Dis. 192, 930–933 (2005).
Schielke, A. et al. Hepatitis E virus antibody prevalence in hunters from a district in Central Germany, 2013: a cross-sectional study providing evidence for the benefit of protective gloves during disembowelling of wild boars. BMC Infect. Dis. 15, 440 (2015).
Zhang, J. et al. Long-term efficacy of a hepatitis E vaccine. N. Engl. J. Med. 372, 914–922 (2015). This is the first paper to show the long-term efficacy of the anti-HEV vaccine.
Su, Y. Y. et al. Persistence of antibodies acquired by natural hepatitis E virus infection and effects of vaccination. Clin. Microbiol. Infect. 23, 336.e1–336.e4 (2017).
World Health Organization. Global Advisory Committee on Vaccine Safety, 11–12 June 2014. Wkly Epidemiol. Rec. 89, 325–336 (2014).
Tillmann, H., Patel, K. & McHutchison, J. Hepatitis B virus viral load and treatment decision. Hepatology 49, 699 (2009).
Wiegand, J. et al. Treatment of severe, nonfulminant acute hepatitis B with lamivudine versus placebo: a prospective randomized double-blinded multicentre trial. J. Viral Hepat. 21, 744–750 (2014).
Deterding, K. et al. Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study. Lancet Infect. Dis. 17, 215–222 (2017).
Peron, J. M. et al. Treatment of autochthonous acute hepatitis E with short-term ribavirin: a multicenter retrospective study. Liver Int. 36, 328–333 (2016).
Gerolami, R. et al. Treatment of severe acute hepatitis E by ribavirin. J. Clin. Virol. 52, 60–62 (2011).
Pischke, S. et al. Ribavirin treatment of acute and chronic hepatitis E: a single-centre experience. Liver Int. 33, 722–726 (2013).
Goyal, R., Kumar, A., Panda, S. K., Paul, S. B. & Acharya, S. K. Ribavirin therapy for hepatitis E virus-induced acute on chronic liver failure: a preliminary report. Antivir. Ther. 17, 1091–1096 (2012).
Kamar, N. et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. N. Engl. J. Med. 370, 1111–1120 (2014). This paper describes the largest series of patients who received SOT with chronic hepatitis who were given ribavirin therapy. A sustained virological response was observed in the majority of patients.
Kamar, N. et al. An early viral response predicts the virological response to ribavirin in hepatitis E virus organ transplant patients. Transplantation 99, 2124–2131 (2015).
Wang, Y. et al. Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology 146, 1775–1783 (2014).
Debing, Y. et al. A mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with ribavirin treatment failure in organ transplant recipients. Gastroenterology 147, 1008–1011.e7 (2014).
Todt, D. et al. Antiviral activities of different interferon types and subtypes against hepatitis E virus replication. Antimicrob. Agents Chemother. 60, 2132–2139 (2016).
Ikram, A. et al. Genotype-specific acquisition, evolution and adaptation of characteristic mutations in hepatitis E virus. Virulencehttp://dx.doi.org/10.1080/21505594.2017.1358349 (2017).
Kamar, N. et al. Pegylated interferon-α for treating chronic hepatitis E virus infection after liver transplantation. Clin. Infect. Dis. 50, e30–e33 (2010).
Haagsma, E. B., Riezebos-Brilman, A., van den Berg, A. P., Porte, R. J. & Niesters, H. G. Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b. Liver Transpl. 16, 474–477 (2010).
Kamar, N. et al. Three-month pegylated interferon-alpha-2a therapy for chronic hepatitis E virus infection in a haemodialysis patient. Nephrol. Dial Transplant. 25, 2792–2795 (2010).
Rostaing, L. et al. Treatment of chronic hepatitis C with recombinant interferon alpha in kidney transplant recipients. Transplantation 59, 1426–1431 (1995).
Mallet, V. et al. Brief communication: case reports of ribavirin treatment for chronic hepatitis E. Ann. Intern. Med. 153, 85–89 (2010).
Kamar, N. et al. Ribavirin therapy inhibits viral replication in patients with chronic hepatitis E virus infection. Gastroenterology 139, 1612–1618 (2010).
Alric, L., Bonnet, D., Laurent, G., Kamar, N. & Izopet, J. Chronic hepatitis E virus infection: successful virologic response to pegylated interferon-α therapy. Ann. Intern. Med. 153, 135–136 (2010).
Alric, L., Bonnet, D., Beynes-Rauzy, O., Izopet, J. & Kamar, N. Definitive clearance of a chronic hepatitis E virus infection with ribavirin treatment. Am. J. Gastroenterol. 106, 1562–1563 (2011).
Tavitian, S. et al. Ribavirin for chronic hepatitis prevention among patients with hematologic malignancies. Emerg. Infect. Dis. 21, 1466–1469 (2015).
Neukam, K. et al. Chronic hepatitis E in HIV patients: rapid progression to cirrhosis and response to oral ribavirin. Clin. Infect. Dis. 57, 465–468 (2013).
Hajji, H., Gerolami, R., Solas, C., Moreau, J. & Colson, P. Chronic hepatitis E resolution in a human immunodeficiency virus (HIV)-infected patient treated with ribavirin. Int. J. Antimicrob. Agents 46, 595–597 (2013).
Labrique, A. B. et al. Epidemiology and risk factors of incident hepatitis E virus infections in rural Bangladesh. Am. J. Epidemiol. 172, 952–961 (2010).
Krain, L. J., Nelson, K. E. & Labrique, A. B. Host immune status and response to hepatitis E virus infection. Clin. Microbiol. Rev. 27, 139–165 (2014).
Zhou, X. et al. Rapamycin and everolimus facilitate hepatitis E virus replication: revealing a basal defense mechanism of PI3K-PKB-mTOR pathway. J. Hepatol. 61, 746–754 (2014).
Pischke, S. et al. Chronic hepatitis E in heart transplant recipients. Am. J. Transplant. 12, 3128–3133 (2012).
Dao Thi, V. L. et al. Sofosbuvir inhibits hepatitis E virus replication in vitro and results in an additive effect when combined with ribavirin. Gastroenterology 150, 82–85.e4 (2016).
Wang, W. et al. Distinct antiviral potency of sofosbuvir against hepatitis C and E viruses. Gastroenterology 151, 1251–1253 (2016).
van der Valk, M., Zaaijer, H. L., Kater, A. P. & Schinkel, J. Sofosbuvir shows antiviral activity in a patient with chronic hepatitis E virus infection. J. Hepatol. 66, 242–243 (2017).
Kamar, N., Wang, W., Dalton, H. R. & Pan, Q. Direct-acting antiviral therapy for hepatitis E virus? Lancet Gastroenterol. Hepatol. 2, 154–155 (2017).
Donnelly, M. C. et al. Review article: hepatitis E—a concise review of virology, epidemiology, clinical presentation and therapy. Aliment. Pharmacol. Ther. 46, 126–141 (2017).
Shrestha, A. C. et al. Hepatitis E virus RNA in Australian blood donations. Transfusion 56, 3086–3093 (2016).
Shrestha, A. C. et al. Hepatitis E virus and implications for blood supply safety, Australia. Emerg. Infect. Dis. 20, 1940–1942 (2014).
Guo, Q. S. et al. Prevalence of hepatitis E virus in Chinese blood donors. J. Clin. Microbiol. 48, 317–318 (2010).
Harritshoj, L. H. et al. Low transfusion transmission of hepatitis E among 25,637 single-donation, nucleic acid-tested blood donors. Transfusion 56, 2225–2232 (2016).
Beale, M. A., Tettmar, K., Szypulska, R., Tedder, R. S. & Ijaz, S. Is there evidence of recent hepatitis E virus infection in English and North Welsh blood donors? Vox Sang. 100, 340–342 (2011).
Gallian, P. et al. Hepatitis E virus infections in blood donors, France. Emerg. Infect. Dis. 20, 1914–1917 (2014).
Vollmer, T. et al. Novel approach for detection of hepatitis E virus infection in German blood donors. J. Clin. Microbiol. 50, 2708–2713 (2012).
Baylis, S. A., Gartner, T., Nick, S., Ovemyr, J. & Blumel, J. Occurrence of hepatitis E virus RNA in plasma donations from Sweden, Germany and the United States. Vox Sang. 103, 89–90 (2012).
Wenzel, J. J., Preiss, J., Schemmerer, M., Huber, B. & Jilg, W. Test performance characteristics of anti-HEV IgG assays strongly influence hepatitis E seroprevalence estimates. J. Infect. Dis. 207, 497–500 (2013).
O’Riordan, J. et al. Hepatitis E virus infection in the Irish blood donor population. Transfusion 56, 2868–2876 (2016).
Fukuda, S. et al. Prevalence of antibodies to hepatitis E virus among Japanese blood donors: identification of three blood donors infected with a genotype 3 hepatitis E virus. J. Med. Virol. 73, 554–561 (2004).
Cleland, A. et al. Hepatitis E virus in Scottish blood donors. Vox Sang. 105, 283–289 (2013).
Zaaijer, H. L. No artifact, hepatitis E is emerging. Hepatology 62, 654 (2015).
Slot, E. et al. Silent hepatitis E virus infection in Dutch blood donors 2011 to 2012. Eurosurveillance 18, 20550 (2013).
Xu, C. et al. An assessment of hepatitis E virus (HEV) in US blood donors and recipients: no detectable HEV RNA in 1939 donors tested and no evidence for HEV transmission to 362 prospectively followed recipients. Transfusion 53, 2505–2511 (2013).
Stramer, S. L. et al. Hepatitis E virus: seroprevalence and frequency of viral RNA detection among US blood donors. Transfusion 56, 481–488 (2015).
H.R.D. has received travel and accommodation costs and consultancy fees from GlaxoSmithKline, Roche and Wantai; he has received travel, accommodation and lecture fees from GFE Blut GmBh, Gilead and Merck; and he has received travel and accommodation fees from the Gates Foundation and Médecins sans Frontières and a grant from the British Medical Association. All other authors declare no competing interests related to this Primer.
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Kamar, N., Izopet, J., Pavio, N. et al. Hepatitis E virus infection. Nat Rev Dis Primers 3, 17086 (2017). https://doi.org/10.1038/nrdp.2017.86
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