Journal of Clinical Virology 59 (2014) 81–88

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Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv

Review

Hepatitis E: An emerging infection in high income countries J.E. Arends a,g,∗ , V. Ghisetti b,g , W. Irving c,g , H.R. Dalton d , J. Izopet e , A.I.M. Hoepelman a,g , D. Salmon f,g a

Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands Microbiology & Virology Laboratory, Department of Infectious Diseases, Amedeo di Savoia Hospital, Turin, Italy Faculty of Medicine & Health Sciences, NIHR Nottingham Digestive Diseases Biomedical Research Unit, Queen’s Medical Centre, Nottingham, United Kingdom d Peninsula College of Medicine and Dentistry, Royal Cornwall Hospital Trust, Truro, United Kingdom e Centre de Physiopathologie de Toulouse-Purpan, Université Paul Sabatier, Toulouse, France f Department of Infectious Diseases, Hôpital Cochin, Paris, France g Members of the European Study Group on Viral Hepatitis (ESGVH) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Switzerland b c

a r t i c l e

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Article history: Received 21 December 2012 Received in revised form 11 November 2013 Accepted 25 November 2013 Keywords: Hepatitis E Genotype 3 Ribavirin, Autochthonous transmission

a b s t r a c t Hepatitis E virus (HEV) genotype 3 is the most recently characterized hepatotropic virus and is increasingly being recognized as the cause of unexplained liver disease in many western countries. Although asymptomatic in most cases, HEV GT3 may be responsible for a wide range of illnesses, from mild to fulminant acute hepatitis, and also chronic hepatitis in immunocompromised patients. Extrahepatic manifestations have been occasionally described. Anti-HEV antibody detection by immunoassays is hampered by moderate test accuracy particularly in immunocompromised hosts while a WHO international standard for molecular detection of HEV RNA by RT-PCR has recently been introduced. This review describes the basic virology, epidemiology, clinical virology and treatment of HEV GT3 infections in high income countries. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

4. 5.

6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basic virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Morphology, genome organization and genetic variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Replication cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Serological tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Molecular tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of hepatitis E genotypes 3 and 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Routes of transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical manifestations of hepatitis E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Acute hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Hepatitis E in patients with chronic liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Hepatitis E in immunocompromised patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Extra hepatic HEV manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic approaches to chronic hepatitis E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis E vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: University Medical Center Utrecht, Heidelberglaan 100, P.O. Box 85000, F.02.126, 3508 AB Utrecht, The Netherlands. Tel.: +31 88 7556228; fax: +31 30 2523741. E-mail address: [email protected] (J.E. Arends). 1386-6532/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2013.11.013

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Hepatitis E virus (HEV) is the most recently discovered of the hepatotropic viruses, its genome having been identified in 1991 [1]. To date, 4 different HEV genotypes are able to infect humans of which GT 3 and 4 are increasingly being recognized in high income countries [2]. In the developed world, autochthonous transmission of the virus causes both asymptomatic infections in healthy individuals as well as fulminant hepatitis in mostly immunocompromised patients. This review summarizes the current available data of HEV GT 3 and 4 in high income countries. 2. Basic virology 2.1. Morphology, genome organization and genetic variability HEV is a small (27–34 nm) non-enveloped virus belonging to the Hepeviridae family [3]. The viral genome consists of a singlestranded, positive-sense RNA molecule of 7.2 kb in length, with a capped 5 terminus that is essential for infectivity. The genome contains three open reading frames (ORF1, 2 and 3) with some overlap, flanked at the 5 and 3 ends by highly conserved non-coding regions [4] (Fig. 1). ORF1, the largest coding unit, is involved in viral replication and protein processing through an RNA-dependent RNA-polymerase (RdRp) responsible for genome replication [5]. The RdRp activity lacks a proof-reading correction mechanism resulting in a high error rate (mutation rate: 1.40–1.72 × 10E3 base substitutions per site per year) responsible for a significant genetic variability of the virus. ORF2 is a relatively highly conserved unit encoding the viral capsid protein, which is involved in attachment to host cells and induction of neutralizing antibodies. Finally, ORF3 is a small unit overlapping ORF2 and encoding for a small immunogenic phosphorylated protein (pORF3) involved in virion morphogenesis and release (Fig. 1). pORF3 is thought to interact with various cellular proteins such as a MAP kinase phosphatase and other extracellular regulated kinases thus promoting cell survival through activation of intra-cellular signaling pathways [6]. The full genome sequence of HEV was first determined in a strain from Myanmar showing a greater than 88.2% nucleotide similarity to isolates obtained from other developing countries [7]. Further studies showed a significant degree of nucleic acid variability among different isolates from different regions of the world (12% within and more than 19% between genotypes) [8], leading to the recognition of four distinct genotypes so far [9]. HEV genotypes are further classified into subtypes: genotype 1 – five (1a–1e); genotype 2 – two (2a and 2b); genotype 3 – ten (3a–3j); and genotype 4 – seven (4a–4g) [9]. Although significant genetic heterogeneity has been identified among HEV strains, evidence of serologic heterogeneity is limited and all human HEV isolates so far studied appear to belong to a single serotype. Though humans are traditionally regarded the only reservoir for genotype 1 (Asia and North Africa) and 2, there are reports of genotype 1 circulating in pigs as well which either point to possible zoonotic origin of infection or to co-existence of two distinct circulating genotypes [10,11]. This zoonotic potential is well-demonstrated for genotype 3 (North and South America, Europe and Asia) and 4 (Asia) viruses since these are also found in pigs or wild animals [12–15]. Viruses of avian origin (avian

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HEV), distantly related to HEV genotype 1–4 viruses but probably belonging to a new genus, are thought to be non-infectious for humans [16–18]. Unclassified HEV sequences with