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Hepatitis E: An emerging global disease - From discovery towards control and cure
Abstract
SUMMARY. Hepatitis E is a systemic disease affecting the liver predominantly and caused by infection with the hepatitis E virus (HEV). HEV has marked genetic heterogeneity and is known to infect several animal species including pigs, boar, deer, mongoose, rabbit, camel, chicken, rats, ferret, bats and cutthroat trout. HEV is the sole member of the family Hepeviridae and has been divided into 2 genera: Orthohepevirus (mammalian and avian HEV) and Piscihepevirus (trout HEV). Human HEVs included within the genus Orthohepevirus are designated Orthohepevirus A (isolates from human, pig, wild boar, deer, mongoose, rabbit and camel). Hepatitis E is an important public health concern, and an estimated onethird of the world population has been infected with HEV. In recent years, autochthonous hepatitis E is recognized as a clinical problem in industrialized countries. Several animal species especially domestic swine, wild boar and wild deer are reservoirs of genotype HEV-3 and HEV-4 in these countries. Human infections occur through intake of uncooked or undercooked meat of the infected animals and pig livers or sausages made from these livers and sold in supermarkets. HEV can be transmitted through blood and blood component transfusions, and donor screening for HEV is under serious consideration. Chronic hepatitis E resulting in rapidly progressive liver cirrhosis and end-stage liver disease has been described in organ transplant patients. Ribavirin monotherapy attains sustained virological response in most patients. HEV 239 vaccine has been marketed in China and its long-term efficacy over four and a half years reported.
... Ранее известный как гепатит, передающийся водным путем и протекавший в виде водных вспышек в развивающихся странах, в настоящее время приобрел широкое распространение. Одна треть населения в мире инфицирована данным вирусом, включая и экономические развитые страны [1]. Ежегодно регистрируется до 20 миллионов случаев ВГЕ в мире и 70 000 летальных исходов в исходе данного заболевания [2,3]. ...
... Только в Соединенных Штатах Америки ежегодно болеют более 2 миллионов человек [4]. Накопленные данные позволили выделить эпидемиологические и клинические особенности течения заболевания в развивающихся и промышленно развитых странах [1]. Вирус гепатита Е (HEV) оказался способен вызвать не только классический острый гепатит, но и хроническую инфекцию. ...
... Характеризуются эндемичностью и вызывают эпидемии. Более 25% всех случаев острого спорадического и молниеносного гепатита в этих странах принадлежит вирусному гепатиту Е (ВГЕ) [1]. ...
The article presents an analysis of the literature data on the prevalence of viral hepatitis E, the peculiarities of the course of the disease, including in children, and describes own cases of viral hepatitis E in children.Viral hepatitis E is a common infection worldwide. Sporadic and group cases of the disease are also registered on the territory of the Russian Federation. Epidemio-logical and clinical features of the course of the disease depending on the genotype were revealed. Children rarely get sick with manifest forms all over the world.Infection of the fetus and newborns with the development of fulminant hepatitis is typical for developing countries. The development of chronic infection is described in children who have undergone liver transplantation. In the Udmurt Republic, during the period of rising incidence of viral hepatitis A, 4 cases of viral hepatitis E were registered in 2017 in different age groups and different clinical manifestations. Registered cases of viral hepatitis E in children in the Russian Federation determine the need for mandatory examination of patients with cytolysis syndrome for this infection.
Enteric hepatitis, represented by the hepatitis A virus (HAV) and hepatitis E virus (HEV), remains a significant global public health concern. While much progress has been made, many aspects of the biology and pathophysiology of HAV and HEV are still not fully understood. One of the major challenges is the absence of a reliable system for virus replication. Additionally, the lack of standardized and widely accessible diagnostic tests contributes to the underestimation of the true prevalence of these viruses. Factors such as climate change, environmental shifts, globalization and increased population mobility further complicate the spread of these infections by affecting pathogen transmission, water quality and the distribution of vectors. This review approaches the emergent research challenges and trends of enteric hepatitis and focuses on developing more efficient diagnostic tools, exploring the role of zoonotic transmission and addressing the impact of environmental and climate changes on disease dynamics, underscoring the need for collaborative, interdisciplinary efforts to effectively combat enteric hepatitis in a rapidly changing world.
The hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. HEV is classified into eight genotypes, labeled HEV-1 through HEV-8. Genotypes 1 and 2 exclusively infect humans, while genotypes 3, 4, and 7 can infect both humans and animals. In contrast, genotypes 5, 6, and 8 are restricted to infecting animals. While most individuals with a strong immune system experience a self-limiting infection, those who are immunosuppressed may develop chronic hepatitis. Pregnant women are particularly vulnerable to severe illness and mortality due to HEV infection. In addition to liver-related complications, HEV can also cause extrahepatic manifestations, including neurological disorders. The immune response is vital in determining the outcome of HEV infection. Deficiencies in T cells, NK cells, and antibody responses are linked to poor prognosis. Interestingly, HEV itself contains microRNAs that regulate its replication and modify the host’s antiviral response. Diagnosis of HEV infection involves the detection of HEV RNA and anti-HEV IgM/IgG antibodies. Supportive care is the mainstay of treatment for acute infection, while chronic HEV infection may be cleared with the use of ribavirin and pegylated interferon. Prevention remains the best approach against HEV, focusing on sanitation infrastructure improvements and vaccination, with one vaccine already licensed in China. This comprehensive review provides insights into the spread, genotypes, prevalence, and clinical effects of HEV. Furthermore, it emphasizes the need for further research and attention to HEV, particularly in cases of acute hepatitis, especially among solid-organ transplant recipients.
Hepatitis E (Hepatitis E, HE) is an acute and chronic infectious hepatitis caused by hepatitis E virus (Hepatitis E Virus, HEV) infection, which is responsible for most acute hepatitis in the world and is a significant public health problem. The pathogen, HEV, has three Open Reading Frames (ORFs) ORF1, ORF2, and ORF3, each of which has a different function. Most of the current research is focused on ORF1 and ORF2, while the research on ORF3 is still relatively small. To provide more ideas for the study of HEV pathogenesis and the prevention and treatment of HE, this paper reviews the effects of ORF3 on the ERK pathway, growth factors, immune response, and virus release.
Hepatitis E virus (HEV) is an emerging zoonotic pathogen that is transmitted primarily through the fecal‐oral route and can cause acute hepatitis in humans. Since HEV was identified as a zoonotic pathogen, different species of HEV strains have been globally identified from various hosts, leading to an expanding range of hosts. The HEV genome consists of a 5' noncoding region, three open reading frames (ORFs), and a 3' noncoding region. The ORF3 protein is the smallest but has many functions in HEV release and pathogenesis. In this review, we systematically summarize recent progress in understanding the functions of the HEV ORF3 protein in virion release, biogenesis of quasi‐enveloped viruses, antigenicity, and host environmental regulation. This review will help us to understand HEV replication and pathogenesis mechanisms better.
Background
Hepatitis E virus (HEV) is a major public health disease causing large outbreaks and sporadic cases of acute hepatitis. We investigated an outbreak of HEV infection that occurred in September 2018 in the health district (HD) of Bocaranga-Koui, located in the northwestern part of Central African Republic (CAR).
Methods
Blood samples were collected from 352 patients aged 0–85 years suspected to be infected with yellow fever (YF), according to the World Health Organization YF case definition. The notification forms from recorded cases were used. Water consumed in the HD were also collected. Human samples found negative for anti-YF IgM were then tested by ELISA for anti-HEV IgM and IgG antibodies. Positive anti-HEV (IgM and/or IgG) samples and collected water were then subjected to molecular biology tests using a real time RT-PCR assay, followed by a nested RT-PCR assay for sequencing and phylogenetic analysis.
Results
Of the 352 icterus patients included, anti-HEV IgM was found in 142 people (40.3%) and anti-HEV IgG in 175 (49.7%). Although HEV infection was detected in all age groups, there was a significant difference between the 0–10 age groups and others age groups (P = 0.001). Elevated levels of serum aminotransferase were observed in anti-HEV IgM-positive subjects. Phylogenetic analysis showed HEV genotype 1e in infected patients as well as in the contaminated water.
Conclusion
This epidemic showed that CAR remains an HEV-endemic area. The genotype 1e strain was responsible for the HEV outbreak in Bocaranga-Koui HD. It is necessary to implement basic conditions of hygiene and sanitation to prevent further outbreaks of a HEV epidemics, to facilitate access to clean drinking water for the population, to launch intensive health education for basic hygiene measures, to sett up targeted hygiene promotion activities and, finally, to ensure that formal health care is available.
Hepatitis E virus (HEV), an emerging zoonotic pathogen, poses a significant public health concern worldwide. Recently, rat HEV ( Rocahepevirus ratti genotype C1; HEV‐C1) has been reported to cause zoonotic infections and hepatitis in humans. Human infections with HEV‐C1 are considered to be underestimated worldwide due to limited knowledge of transmission routes, genome epidemiology, and the risk assessment of zoonosis associated with these viruses. A total of 186 wild Norway rats ( Rattus norvegicus ) were collected from the Republic of Korea (ROK) between 2011 and 2021. The prevalence of HEV‐C1 RNA was 8 of 180 (4.4%) by reverse‐transcription polymerase chain reaction. We first reported three nearly whole‐genome sequences of HEV‐C1 newly acquired from urban rats in the ROK. Phylogenetic analysis demonstrated that Korea‐indigenous HEV‐C1 formed an independent genetic group with those derived from R. norvegicus rats in other countries, indicating geographical and genetic diversity. Our findings provide critical insights into the molecular prevalence, genome epidemiology, and zoonotic potential of Rocahepevirus . This report raises awareness of the presence of Rocahepevirus ‐related hepatitis E among physicians in the ROK.
Introduction
Several studies have reported on hepatitis E virus (HEV) prevalence in various regions of China, but the results vary widely. Herein, we conducted a systematic review and meta-analysis to assess the seroprevalence, RNA-positive rate, genotype distribution of HEV in China, and its risk factors.
Methods
We included 208 related studies involving 1,785,569 participants published between 1997 and 2022. Random-effects models were used to pool prevalence, and subgroup analyses were conducted by population, gender, age, study period, regions, and rural–urban distribution. The meta regression models and pooled odds ratios (OR) were performed to identify risk factors for HEV infections.
Results
The pooled anti-HEV IgG, IgM, and Ag seroprevalence, and RNA detection rates in China from 1997 to 2022 were 23.17% [95% confidence interval (CI): 20.23–26.25], 0.73% (95% CI: 0.55–0.93), 0.12% (95% CI: 0.01–0.32), and 6.55% (95% CI: 3.46–12.05), respectively. The anti-HEV IgG seropositivity was higher in the occupational population (48.41%; 95% CI: 40.02–56.85) and older adult aged 50–59 years (40.87%; 95% CI: 31.95–50.11). The dominant genotype (GT) of hepatitis E in China was GT4. Notably, drinking non-tap water (OR = 1.82; 95% CI: 1.50–2.20), consumption of raw or undercooked meat (OR = 1.47; 95% CI: 1.17–1.84), and ethnic minorities (OR = 1.50; 95% CI: 1.29–1.73) were risk factors of anti-HEV IgG seroprevalence.
Discussions
Overall, the prevalence of hepatitis E was relatively high in China, especially among older adults, ethnic minorities, and humans with occupational exposure to pigs. Thus, there is a need for preventive measures, including HEV infection screening and surveillance, health education, and hepatitis E vaccine intervention in high-risk areas and populations.
Systematic review registration
https://www.crd.york.ac.uk/prospero/, identifier CRD42023397036.
The story of the discovery of hepatitis E originated in the late 1970s with my extreme belief that there was a hidden saga in the relationship between jaundice and pregnancy in developing countries and the opportunity for a massive epidemic of viral hepatitis, which hit the Gulmarg Kashmir region in November 1978. Based on data collected from a door-to-door survey, the existence of a new disease, epidemic non-A, non-B hepatitis, caused by a hitherto unknown hepatitis virus, was announced. This news was received by the world community with hype and skepticism. In the early 1980s, the world watched in awe as an extreme example of human self-experimentation led to the identification of VLP. In 1990, a cDNA clone from the virus responsible for epidemic non-A, non-B hepatitis was isolated. Over the years, we traversed three eras of ambiguity, hope, and hype of hepatitis E research and conducted several seminal studies to understand the biology of HEV and manifestations of hepatitis E. Many milestones have been reached on the long and winding road of hepatitis E research to understand the structure, biology, and diversity of the agent, changing the behavior of the pathogen in developed countries, and the discovery of a highly effective vaccine.
Emerging infectious disease threats are becoming more frequent due to various social, political, and geographical pressures, including increased human-animal contact, global trade, transportation, and changing climate conditions. Since blood products for transfusion are derived from donated blood from the general population, emerging agents spread by blood contact or the transfusion of blood products are also a potential risk. Blood transfusions are essential in treating patients with anemia, blood loss, and other medical conditions. However, these lifesaving procedures can contribute to infectious disease transmission, particularly to vulnerable populations. New methods have been implemented on a global basis for the prevention of transfusion transmissions via plasma, platelets, and whole blood products. Implementing proactive pathogen reduction methods may reduce the likelihood of disease transmission via blood transfusions, even for newly emerging agents whose transmissibility and susceptibility are still being evaluated as they emerge. In this review, we consider the Mirasol PRT system for blood safety, which is based on a photochemical method involving riboflavin and UV light. We provide examples of how emerging threats, such as Ebola, SARS-CoV-2, hepatitis E, mpox and other agents, have been evaluated in real time regarding effectiveness of this method in reducing the likelihood of disease transmission via transfusions.
Viral gastroenteritis is the most common viral illness that affects the gastrointestinal (GI) tract, causing inflammation and irritation of the lining of the stomach and intestines. Common signs and symptoms associated with this condition include abdominal pain, diarrhea, and dehydration. The infections commonly involved in viral gastroenteritis are rotavirus, norovirus, and adenovirus, which spread through the fecal-oral and contact routes and cause non-bloody diarrhea. These infections can affect both immunocompetent and immunocompromised individuals. Since the pandemic in 2019, coronavirus gastroenteritis has increased in incidence and prevalence. Morbidity and mortality rates from viral gastroenteritis have declined significantly over the years due to early recognition, treatment with oral rehydration salts, and prompt vaccination. Improved sanitation measures have also played a key role in reducing the transmission of infection. In addition to viral hepatitis causing liver disease, herpes virus, and cytomegalovirus are responsible for ulcerative GI disease. They are associated with bloody diarrhea and commonly occur in im-munocompromised individuals. Hepatitis viruses, Epstein-Barr virus, herpesvirus 8, and human papillomavirus have been involved in benign and malignant diseases. This mini review aims to list different viruses affecting the GI tract. It will cover common symptoms aiding in diagnosis and various important aspects of each viral infection that can aid diagnosis and management. This will help primary care physicians and hospitalists diagnose and treat patients more easily.
The hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals, two of them were tested in human and evidenced to be well-tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin® (HEV 239 vaccine), was licensed in China and launched in 2012.
Hepatitis E virus (HEV) is an increasingly recognized etiological agent of acute, chronic and extrahepatic human infections with primarily zoonotic origin in Europe. Limited numbers of comprehensive population-based studies are available related to HEV seroepidemiology, especially from Central Europe.
The aim of this study was to investigate the seroprevalence and trends of total and IgM antibodies against HEV in different age groups in the population of South Transdanubia, Hungary, within a thirteen years long period between the years 2010 and 2022.
We retrospectively analysed the serological test results of HEV total and HEV IgM antibodies carried out by ELISA technique using Dia.Pro (Diagnostic Bioprobes, Italy) kit from serum samples collected from patients with or without hepatitis between January 1, 2010 and December 31, 2022.
The number of tested samples (∑6,996 for total antibody and ∑6,582 for IgM) increased during the study period. The average HEV total and the IgM antibody seropositivities were 33% (2,307/6,996 samples) and 9.6% (642/6,582 samples), respectively, in the study population. The HEV total antibody seropositivity varied in different age groups between 3.9% (age group 1–5 years) and 58.6% (86–90 years) and showed an increasing positivity by age. At the age groups >50 years, nearly half (43%) of the population had antibodies against HEV. The HEV IgM positivity had an increasing trend of up to 13.9% in the age group 81–85 years.
High HEV total and IgM antibody seroprevalence were detected in South Transdanubia, Hungary, confirming that this region is highly endemic for HEV infections in Europe.
Background:
Medical treatment of inflammatory bowel disease (IBD) has evolved significantly, and treatment with immunomodulators is recommended. These medications may alter the patient's immune response and increase the risk of opportunistic infections. Our aim was to evaluate the prevalence and the incidence of acute or chronic HEV infection in IBD patients under immunomodulatory treatment.
Patients and methods:
We conducted a retrospective, multicenter, observational study between 2017 and 2018. IBD outpatients hospitalized for the infusion of immunomodulators were included in 16 French centers. During their daily hospitalization, blood samples were drawn for HEV serology (IgM and IgG) and HEV RNA detection.
Results:
A total of 488 patients were included, of which 327 (67%) patients had Crohn's disease and 161 (33%) ulcerative colitis. HEV IgM was detected in 3 patients, but HEV RNA was undetectable in all patients. The HEV IgG seroprevalence rate was 14.2%. IgG-positive patients were older at sampling (p = 0.01) and IBD diagnosis (p = 0.03), had higher seafood consumption (p = 0.01) and higher doses of azathioprine (p = 0.03). Ileal and upper digestive tract involvement was more frequent in IgG-positive patients (p = 0.009), and ileocolic involvement was more frequent in IgG-negative patients (p = 0.01). Under multivariate analysis, age > 50 years [OR: 2.21 (1.26, to 3.85), p = 0.004] was associated with previous HEV infection.
Conclusion:
Systematic screening for HEV infection is not needed among IBD patients on immunomodulatory medications. However, in the event of abnormal liver test findings, HEV should be part of the classic diagnostic assessment.
Hepatitis E virus (HEV) is the causative agent of Hepatitis E infections across the world. Intrinsically disordered protein regions (IDPRs) or Intrinsically Disordered Protein (IDPs) are regions or proteins that are characterized by a lack of definite structure. These regions or proteins play significant roles in a wide range of biological processes, such as cell cycle regulation, control of signaling pathways, etc. IDPRs or IDPs in proteins are associated with the virus’s pathogenicity and infectivity. The occurrence of intrinsic disorder in the proteome of rat HEV remains to be elucidated, which prompted us to explore its dark proteome. In this study, the unstructured/disordered regions of ORF proteins of rat HEV have been examined. We have analyzed the prevalence of intrinsic disorder by using a set of computational predictors. The intrinsic disorder propensity analysis showed that the ORF proteins consisted of a varying fraction of intrinsic disorder. The ORF3 protein was identified with a maximum propensity for intrinsic disorder while the protein ORF6 showed the least propensity for the intrinsic disorder. Further, the analysis revealed ORF6 as highly structured protein (ORDP); ORF1 and ORF4 as moderately disordered proteins (IDPRs); and ORF3 and ORF5 as highly disordered proteins, categorizing them as ordered protein (ORDP), a protein having Intrinsically Disordered Region (IDPR) and Intrinsically Disordered Proteins (IDP) respectively. Such disordered regions may play several important roles in the pathogenesis and replication of viruses. Collectively, this comprehensive study data from our investigation suggested ORF protein’s role in the regulation and pathogenesis of rat herpesvirus.
The present chapter presents information pertinent to foodborne pathogens (bacteria and bacterial toxins, viruses, and parasites) and other biological issues (prions and biogenic amines) with importance to the safety of meat and meat products. Aspects covered refer mainly to the characteristics of the most important pathogenic organisms, their distribution in the environment, their transmission routes to humans, as well as their epidemiology and association with sporadic or epidemic foodborne illness. Current and emerging challenges to meat safety assessment and management also are discussed.
Hepatitis E Virus (HEV) is a causative agent of viral hepatitis E. In Japan, HEV genotype 3 (G3) and G4 are detected predominantly, while G1, mainly imported from countries in continental Asia, is rare. In the present study, we detected a G1 HEV strain from a patient who came to Japan from India. When cells of the PLC/PRF/5 line (subclone 4-21) were inoculated with a stool suspension from this patient, an accumulation of HEV RNA was observed in the spent culture medium, indicating that HEV had been isolated successfully from this specimen. A nearly complete HEV genome was obtained by amplification via RT-PCR. Phylogenetic analyses revealed that the newly isolated HEV strain, designated 9HE36c, belongs to subtype 1g of HEV G1.
Hepatitis E virus (HEV) is an emerging zoonotic pathogen with multiple species and genotypes, which may be classified into human, animal, and zoonotic HEV. Codon usage bias of HEV remained unclear. This study aims to characterize the codon usage of HEV and elucidate the main drivers influencing the codon usage bias. A total of seven HEV genotypes, HEV-1 (human HEV), HEV-3 and HEV-4 (zoonotic HEV), HEV-8, HEV-B, HEV-C1, and HEV-C2 (emerging animal HEV), were included in the study. Complete coding sequences, ORF1, ORF2, and ORF3, were accordingly obtained in the GenBank. Except for HEV-8, the other six genotypes tended to use codons ending in G/C. Based on the analysis of relatively synonymous codon usage (RSCU) and principal component analysis (PCA), codon usage bias was determined for HEV genotypes. Codon usage bias differed widely across human, zoonotic, and animal HEV genotypes; furthermore, it varied within certain genotypes such as HEV-4, HEV-8, and HEV-C1. In addition, dinucleotide abundance revealed that HEV was affected by translation selection to form a unique dinucleotide usage pattern. Moreover, parity rule 2 analysis (PR2), effective codon number (ENC)-plot, and neutrality analysis were jointly performed. Natural selection played a leading role in forming HEV codon usage bias, which was predominant in HEV-1, HEV-3, HEV-B and HEV-C1, while affected HEV-4, HEV-8, and HEV-C2 in combination with mutation pressure. Our findings may provide insights into HEV evolution and codon usage bias.
Hepatitis E virus (HEV) is the main cause of acute hepatitis worldwide. HEV accounts for up to 30% mortality rate in pregnant women, with highest incidences reported for genotype 1 (G1) HEV. The contributing factors in adverse cases during pregnancy in women due to HEV infection is still debated. The mechanism underlying the pathogenesis of viral infection is attributed to different genomic component of HEV, i.e., open reading frames (ORFs): ORF1, ORF2, ORF3 and ORF4. Recently, ORF4 has been discovered in enhancing the replication of GI isolates of HEV through regulation of an IRES-like RNA element. However, its characterization through computational methodologies remains unexplored. In this novel study, we provide comprehensive overview of ORF4 protein's genetic and molecular characteristics through analyzing its sequence and different structural levels. A total of three different datasets (Human, Rat and Ferret) of ORF4 genomes were built and comparatively analyzed. Several non-synonymous mutations in conjunction with higher entropy values were observed in rat and ferret datasets, however, limited variation was observed in human ORF4 genomes. Higher transition to tranversion ratio was observed in the ORF4 genomes. Studies have reported the association of intrinsic disordered proteins (IDP) with drug discovery due to its role in several signaling and regulatory processes through protein-protein interactions (PPIs). As PPIs are potent drug target sources, thus the ORF4 protein was explored by analyzing its polypeptide structure in order to shed light on its intrinsic disorder. Pressures that lead towards preponderance of disordered-promoting amino acid residues shaped the evolution of ORF4. The intrinsic disorder propensity analysis revealed ORF4 protein (Human) as a highly disordered protein (IDP). Predominance of coils and lack of secondary structure further substantiated our findings suggesting its involvement in binding to ligand molecules. Thus, ORF4 contributes to cellular signaling processes through protein-protein interactions, as IDPs are targets for regulation to accelerate the process of drug designing strategies against HEV infections.
There has been an increase in the reported number of animals worldwide that carry the hepatitis E virus (HEV). This study aimed to explore potential animal hosts for HEV through codon usage analysis. Full-length HEV sequences of six genotypes as well as codon usage of potential animal hosts were collected. Moreover, nucleotide composition and codon usage bias were compared across HEV genotypes and animal hosts. Based on the analysis for human HEV-1 and humans, the results were basically consistent with epidemiology evidence. Among 17 potential animal hosts, all HEV genotypes exhibited a preference for guanine/cytosine in the third position of synonymous codons. Furthermore, non-human primates and humans have large high-frequency codons identical to HEV in addition to a high correlation of codon fraction with HEV. Some animals in close contact with humans showed high preference for HEV, including cattle, dogs, and rats with HEV-A, cats, dogs, and swine with HEVC1. Codon usage bias has limited efficiency in determining the hosts for HEV, but it may provide indicative clues for potential animal hosts when combined with experimental and epidemiological evidence.
Hepatitis E virus (HEV) is the causative agent of Hepatitis E infections across the world. Intrinsically disordered protein regions (IDPRs) or intrinsically disordered proteins (IDPs) are regions or proteins that are characterized by lack of definite structure. These IDPRs or IDPs play significant roles in a wide range of biological processes, such as cell cycle regulation, control of signaling pathways, etc. IDPR/IDP in proteins is associated with the virus’s pathogenicity and infectivity. The prevalence of IDPR/IDP in rat HEV proteome remains undetermined. Hence, we examined the unstructured/disordered regions of the open reading frame (ORF) encoded proteins of rat HEV by analyzing the prevalence of intrinsic disorder. The intrinsic disorder propensity analysis showed that the different ORF proteins consisted of varying fraction of intrinsic disorder. The protein ORF3 was identified with maximum propensity for intrinsic disorder while the ORF6 protein had the least fraction of intrinsic disorder. The analysis revealed ORF6 as a structured protein (ORDP); ORF1 and ORF4 as moderately disordered proteins (IDPRs); and ORF3 and ORF5 as highly disordered proteins (IDPs). The protein ORF2 was found to be moderately as well as highly disordered using different predictors, thus, was categorized into both IDPR and IDP. Such disordered regions have important roles in pathogenesis and replication of viruses.
Viral hepatitis remains a significant global health problem. All forms of viral hepatitis A through E (A-E) can lead to acute symptomatic infection, while hepatitis B and C can lead to chronic infection associated with significant morbidity and mortality related to progression to cirrhosis, end-stage-liver disease, and liver cancer. Viral hepatitis occurs worldwide, though certain regions are disproportionately affected. We now, remarkably, have highly effective curative regimens for hepatitis C, and safe and tolerable medications to suppress hepatitis B activity, and to prevent liver damage and slow disease progression. We have effective vaccines for hepatitis A and B which provide long-lasting immunity, while improved sanitation and awareness can curb outbreaks of hepatitis A and E. However, more effective and available preventive and curative strategies are needed to achieve global eradication of viral hepatitis. This review provides an overview of the epidemiology, transmission, diagnosis, and clinical features of each viral hepatitis with a primary focus on current and future therapeutic and curative options.
Hepatitis E virus (HEV) is a major causative agent of acute hepatitis in developing countries. The Norway rat HEV genome consists of six open reading frames (ORFs), i.e., ORF1, ORF2, ORF3, ORF4, ORF5 and ORF6. The additional reading frame encoded protein ORF5 is attributed to life cycle of rat HEV. The ORFF5 protein’s function remains undetermined. Therefore, it is of interest to analyze the ORF5 protein for its physiochemical properties, primary structure, secondary structure, tertiary structure and functional characteristics using bioinformatics tools. Analysis of the ORF5 protein revealed it as highly unstable, hydrophilic with basic pI. The ORF5 protein consisted mostly of Arg, Pro, Ser, Leu and Gly. The 3D structural homology model of the ORF5 protein generated showed mixed α/β structural fold with predominance of coils. Structural analysis revealed the presence of clefts, pores and a tunnel. This data will help in the sequence, structure and functional annotation of ORF5.
The Hepatitis E Virus (HEV) is the causative agent of Hepatitis E and thereby the leading cause for acute viral hepatitis involving approximately 20 million individuals, with 3.3 million symptomatic infections and 44 000–70 000 deaths per year. Although HEV is usually a self-limiting disease, immunocompromised individuals are at risk to develop a chronic course of infection with rapid progression to fibrosis, cirrhosis, or even the development of liver failure. The current therapy options are limited to the unspecific antivirals ribavirin (RBV) and pegylated Interferon- α (pegIFN- α ). RBV leads to viral clearance in only 80% of chronically infected patients; however, it has not been evaluated in acutely infected patients and is contraindicated in the major risk group of pregnant women, emphasizing the urgency of new therapy options. In this chapter, we first recapitulate the knowledge in HEV molecular virology, clinical course of infection and current therapeutic options, and then provide an overview of the ongoing developments in antiviral strategies against HEV.
Background
Hepatitis E virus (HEV) of the family Hepeviridae is a major causative agent of acute hepatitis in developing countries. The Y-domain is derived from multi-domain non-structural polyprotein encoded by open reading frame 1 (ORF1). Previous studies have demonstrated the essentiality of Y-domain sequences in HEV life cycle; however, its function remains completely unexplored. The following study was thus conceptualized to examine the detailed computational investigation for the putative Y-domain to estimate its phylogenetic assessment, physiochemical properties, structural and functional characteristics using in silico analyses.
Results
The phylogenetic assessment of Y-domain with a vast range of hosts indicated that the protein was very well conserved throughout the course of evolution. The Y-domain was found to be unstable, hydrophilic and basic in nature with high thermostability value. Structural analysis of Y-domain revealed mixed α/β structural fold of the protein having higher percentage of alpha-helices. The three-dimensional (3D) protein model generated through homology modelling revealed the presence of clefts, tunnels and pore. Gene ontology analysis predicted Y-domain protein’s involvement in several binding and catalytic activities as well as significant biological processes. Mutations in the conserved amino acids of the Y-domain suggested that it may stabilize or de-stabilize the protein structure that might affect its structure–function relationship.
Conclusions
This theoretical study will facilitate towards deciphering the role of unexplored Y-domain, thereby providing better understanding towards the pathogenesis of HEV infection.
Background
Currently, there is a paucity of data on the knowledge and practice of preventive measures for Hepatitis E infection in Nigerian populations. This study provided data on the prevalence, knowledge and practices of prevention in an adolescent population from Nigeria.
Methods
This cross-sectional study was conducted over 3 months among rural Nigerian secondary school adolescents. An interviewer-based questionnaire was used to collect data on sociodemographic profile, knowledge, and practice of preventive measures for Hepatitis E infection. Blood samples collected from participants were analysed for Hepatitis E IgG using Elisa Kits (Sigma Diagnostics, USA). Data were analysed using SPSS software version 20.0. Tests of association were done with a level of significance set at 5%.
Results
A total of 9 out of the 414 participants tested positive for Hepatitis E IgG antibodies giving a prevalence of 2.2%. Significant factors for Hepatitis E infection were male gender { P = 0.004} and school { P < 0.001, however logistic regression gave infinite value. Most participants (98.6%) had poor knowledge of Hepatitis E infection, 239(57.7%) had good preventive practices, while 175(42.3%) had average preventive practices.
Conclusion
A low prevalence of HEV infection was recorded among study participants. There was poor knowledge of Hepatitis E, and association could not be established between HEV infection and individual preventive practices.
Aim: Hepatitis E virus (HEV) has different genotypes 1–4, which is generally associated with mild to severe complications among immunocompromised patients and pregnant women. Materials & methods: Immunoglobulin M (IgM) HEV-positive samples were collected from the diagnostic center. HEV infection was further confirmed by RT-based PCR and genotyping was done to affirm the prevailing genotype. Results: This study identified 28 patients from Islamabad who were confirmed to have immunoglobulins type M against HEV showing acute infection, of which 17 were pregnant and 11 were non-pregnant women. All pregnant women were in their third trimester of pregnancy. Conclusion: Genotype-1 is commonly associated with pregnant females presenting with HEV infections in Islamabad. There is a need to further identify both the sources & route of infections.
Hepatitis E virus (HEV) is considered an emergent source of viral hepatitis worldwide, with an increasing burden of jaundice, liver failure, extrahepatic illnesses, and deaths in developed countries. With the scarcity of data from efficient animal models, there are still open-ended questions about designing new models to study pathogenesis, types, virology, and evolution of these viruses. With an emphasis on available data and updates, there is still enough information to understand the HEV life cycle, pathogen interaction with the host, and the valuation of the role of vaccine and new anti-HEV therapies. However, the World Health Organization (WHO) and the European Association for the Study of the Liver (EASL) preferred to stress prevention and control measures of HEV infections in animals, zoonotic transmission, and foodborne transmission. It is being reviewed that with current knowledge on HEV and existing prevention tools, there is an excellent room for in-depth information about the virus strains, their replication, pathogenicity, and virulence. The current knowledge set also has gaps regarding standardized and validated diagnostic tools, efficacy and safety of the vaccine, and extrahepatic manifestations specifically in pregnant females, immunocompromised patients, and others. This review highlights the areas for more research exploration, focusing on enlisted research questions based on HEV infection to endorse the need for significant improvement in the current set of knowledge for this public health problem.
Hepatitis E virus (HEV) is a major causative agent of hepatitis E infections across the globe. Although the essentiality of HEV nonstructural polyprotein (pORF1) putative Y-domain (Yd) has been established in viral pathogenesis, its structural-functional role remains elusive. The current research discusses the novel exploration on Yd protein expression, purification, biophysical characterization and structure-based docking analysis. The codon optimized synthetic gene and optimized expression parameters i.e., 5 h induction with 0.25 mM IPTG at 37 °C, resulted in efficient production of Yd protein (∼40 kDa) in E. coli BL21(DE3) cells. Majority of the recombinant Yd (rYd) protein expressed as inclusion bodies was solubilized in 0.5% N-lauroylsarcosine and purified using Ni-NTA chromatography. Circular dichroism (CD) and UV visible absorption spectroscopic studies on Yd revealed both secondary and tertiary structure stability in alkaline range (pH 8.0–10.0), suggesting correlation with its physiological activity. Thus, loss in structure at low pH perhaps play crucial role in cytoplasmic-membrane interaction. The biophysical data were in good agreement with in-silico structural analyses, which suggested mixed α/β fold, non-random and basic nature of Yd protein. Furthermore, due to Yd protein essentiality in HEV replication and pathogenesis, it was considered as a template for docking and drug-likeness analyses. The 3D modeling of Yd protein and structure-based screening and drug-likeness of inhibitory compounds, including established antiviral drugs led to the identification of top nine promising candidates. Nonetheless, in vitro studies on the predicted interaction of Yd with intracellular-membrane towards establishing replication-complexes as well as validations of the proposed therapeutic agents are warranted.
Background:
Hepatitis E, an acute zoonotic disease caused by the hepatitis E virus (HEV), has a relatively high burden in developing countries. The current research model on hepatitis E mainly uses experimental animal models (such as pigs, chickens, and rabbits) to explain the transmission of HEV. Few studies have developed a multi-host and multi-route transmission dynamic model (MHMRTDM) to explore the transmission feature of HEV. Hence, this study aimed to explore its transmission and evaluate the effectiveness of intervention using the dataset of Jiangsu Province.
Methods:
We developed a dataset comprising all reported HEV cases in Jiangsu Province from 2005 to 2018. The MHMRTDM was developed according to the natural history of HEV cases among humans and pigs and the multi-transmission routes such as person-to-person, pig-to-person, and environment-to-person. We estimated the key parameter of the transmission using the principle of least root mean square to fit the curve of the MHMRTDM to the reported data. We developed models with single or combined countermeasures to assess the effectiveness of interventions, which include vaccination, shortening the infectious period, and cutting transmission routes. The indicator, total attack rate (TAR), was adopted to assess the effectiveness.
Results:
From 2005 to 2018, 44 923 hepatitis E cases were reported in Jiangsu Province. The model fits the data well (R2 = 0.655, P < 0.001). The incidence of the disease in Jiangsu Province and its cities peaks are around March; however, transmissibility of the disease peaks in December and January. The model showed that the most effective intervention was interrupting the pig-to-person route during the incidence trough of September, thereby reducing the TAR by 98.11%, followed by vaccination (reducing the TAR by 76.25% when the vaccination coefficient is 100%) and shortening the infectious period (reducing the TAR by 50.05% when the infectious period is shortened to 15 days).
Conclusions:
HEV could be controlled by interrupting the pig-to-person route, shortening the infectious period, and vaccination. Among these interventions, the most effective was interrupting the pig-to-person route.
In the last decade, the number of reported hepatitis E virus (HEV) infections in Germany, including Bavaria, has continued to rise. In order to identify risk factors associated with HEV infection, we investigated notified hepatitis E cases from Bavaria during 2017. The project “Intensified Hepatitis E Surveillance in Bavaria” included interviews with questionnaires, collection and genotyping of stool, serum and food samples. In addition, certain risk factors were examined in a sample comparison with healthy population using univariable analysis and logistic regression. In total, 135 hepatitis E cases from Bavaria were included in the analysis. Mean age for women was 46 (range 20–74) years and 47.5 (range 20–85) for men. 56 of the cases (41.5%) were asymptomatic. Among the symptomatic cases, both men and women were equally affected with symptoms like fever (16.3%), jaundice (18.8%) and upper abdominal pain (28.2%). 145 human samples (serum, stool) and 6 food samples were collected. 15.9% of the human samples (n = 23) were positive for HEV RNA by reverse-transcription quantitative real-time PCR (RT-qPCR). Identified risk factors significantly associated with hepatitis E were sausage consumption with odds ratio 9.6 (CI 1.3–70.1), fish with OR 2.2 (CI 1.1–4.4) and cat ownership with OR 1.9 (CI 1.3–3.0) in multivariable analyses. Further investigation is needed to confirm the role of fish in HEV transmission. Autochthonous HEV genotype 3 is prevalent in Bavaria and there could be more transmission routes contributing to the spread of HEV than previously known. Undercooked meat, offal, sausages, fish, shellfish and contact with animals and pets are possible sources for infection.
Background and aim:
Hepatitis E virus (HEV) may cause chronic liver disease in solid organ transplant recipients. We determined HEV seroprevalence and associated factors in liver transplant recipients.
Materials and methods:
Patients followed at the outpatient clinic of liver transplantation between January 2019 and January 2020 were screened retrospectively for HEV serology (HEV immunoglobulin M [IgM] and HEV immunoglobulin G [IgG]).
Results:
Of the 150 patients (male/female, 104/46; age, 55.4±13.2 years), anti-HEV IgG was positive in 31 (20.7%), and anti-HEV IgM was negative in all. The mean time after liver transplantation (72 [48%] deceased and 78 [52%] living donors) was 81±78.5 months. Drinking water consisted of carboy and tap water in 88 (58.7%) and 62 patients (41.3%), respectively. Of the patients, 120 (80%) and 30 (20%) lived in urban and rural areas, respectively. On comparison, the difference between positive and negative anti-HEV IgG groups in terms of age, place of birth, water supply, and donor type was statistically significant (p=0.007, p=0.000, p=0.034, and p=0.049, respectively).
Conclusion:
HEV seroprevalence was more frequent in liver transplant recipients compared with the normal population. Older age, water supply, and place of birth were risk factors for HEV seroprevalence.
Genotype 3 (GT3) is responsible for most European autochthonous hepatitis E virus (HEV) infections. This study analyzed circulating genotypes and GT3 subtypes in the Lazio region, Italy, between 2011 and 2019, as well as their pathogenic characteristics. Of the 64 evaluable HEV GT3 patient-derived sequences, identified subtypes included GT3f (n = 36), GT3e (n = 15), GT3c (n = 9), GT3a (n = 1) and three unsubtyped GT3 sequences. GT3c strains were similar to Dutch sequences (96.8-98.1% identity), GT3e strains showed high similarity (96.8%) with a United Kingdom sequence, while the most related sequences to GT3f Italian strains were isolated in France, Belgium and Japan. One sequence was closely related to another Italian strain isolated in raw sewage in 2016. The liver functioning test median values for 56 evaluable GT3 patients were: alanine aminotransferase (ALT), 461 (range 52-4835 U/L); aspartate aminotransferase (AST), 659 (range 64-6588 U/L); and total bilirubin, 3.49 (range 0.4-33 mg/dL). The median HEV RNA viral load for 26 evaluable GT3 patients was 42,240 IU/mL (range 5680-895,490 IU/mL). Of the 37 GT3 patients with available clinical information, no correlation was observed between HEV clinical manifestations and GT3 subtype. HEV symptoms were comparable among GT3c/e/f patients across most analyzed categories except for epigastric pain, which occurred more frequently in patients with HEV GT3e (75%) than in patients with GT3c (50%) or GT3f (19%) (p = 0.01). Additionally, patients with HEV GT3c exhibited significantly higher median international normalized ratio (INR) than patients with GT3e and GT3f (p = 0.033). The severity of GT3 acute hepatitis E was not linked to HEV RNA viral load or to the GT3 subtype.
Background
Identifying pig farms infected with hepatitis E virus (HEV) is a key aspect to implement surveillance programmes for this emerging zoonotic agent. Detection of HEV in blood has several drawbacks, including animal handling, economic costs and animal stress. The objective of this study was to evaluate the effectiveness of a non-invasive screening approach for determining the HEV status of pig farms under different management systems.
Methods
Forty stool samples randomly collected from the pen floor of 17 intensive pig farms and the yard of nine extensive ones were tested for HEV RNA. The invasive method used to confirm the HEV status of the farm was HEV RNA analysis of serum samples randomly collected from 40 animals on each farm.
Results
Twenty-one HEV-positive farms were detected by invasive and non-invasive methods. No positive serum or stool samples were detected on five intensive farms. A high intertest agreement ( K =1; P<0.00001) was observed between both methodologies, showing the stool screening approach a 100 per cent of sensitivity and specificity with respect to the invasive method. Likewise, a significant negative relationship was observed between the HEV within-farm prevalence and the number of the first HEV-positive stool sample found (Spearman’s rho=−0.64; P=0.0004). This negative relationship was higher in intensively managed farms.
Conclusion
This non-invasive screening approach could be reliably applied in a large-scale surveillance programme for determining the HEV status of pig farms under different management systems.
Discovery of five hepatitis viruses A to E has followed distinctive definable phases. Human experiments at Willowbrook identified two forms of hepatitis namely infectious hepatitis and serum hepatitis. The discovery of Australia antigen in 1965 led to rapid scientific developments in viral hepatitis. SH antigen was detected in sera of patients with serum hepatitis and soon SH antigen & Australia antigen were found to be identical and selectively associated with serum hepatitis. In 1970, 42 nm Dane particles were detected in Australia antigen positive sera and linked to the virus of serum hepatitis. Subsequently, a new antigen-antibody system (e-antigen/antibody) was detected in such patients and associated with infectivity. Next DNA polymerase was found in concentrated pellets containing Australia antigen. HBV DNA cloning and sequencing of HBV followed these developments. In 1973, 27 nm hepatitis A virus like particles were visualized in stool samples obtained during acute phase of illness following inoculation of MS-1 strain in volunteers. Cloning and sequencing of HAV followed. In 1977, a new antigen-antibody system (δ antigen-antibody system) was identified by chance associated with HBV. Based on animal transmission studies, δ agent was found to be another virus (HDV) that is defective, requires the helper functions of HBV and interferes with HBV replication. The search for hepatitis C virus started when non-A, non-B hepatitis was recognised in multiply transfused patients with subsequent successful animal transmission. HCV was identified by a novel immunoscreening approach involving screening of cDNA libraries from infectious sera. The story of hepatitis E is historically linked to discovery of water-borne Epidemic Non-A, Non-B Hepatitis from Kashmir, India. virus-like-particles of the agent were identified in stool samples of a human volunteer following a self-experimentation. HEV cDNA was detected in bile-enriched infectious samples and full-length HEV RNA genome was subsequently cloned and sequenced.
Viral hepatitis can cause significant maternal and neonatal morbidity and mortality. Hepatitis A and E mainly present as acute hepatitis during pregnancy, while hepatitis C and D are usually found as chronic infection in pregnant women. Hepatitis A remains self-limiting during pregnancy while hepatitis E has a higher prevalence and manifests with a rigorous course in pregnant women. The role of screening of hepatitis C during pregnancy and its subsequent management during pregnancy is still a debatable topic. New treatments of hepatitis C and E require further evaluation for the use in pregnancy. This review summarizes the prevalence, clinical manifestations, maternal, fetal and neonatal effects, the management of hepatitis A, C, D and E virus infection during pregnancy.
The hepatitis E virus (HEV) causes acute and chronic hepatitis in humans. Investigation of HEV replication is hampered by the lack of broadly applicable, efficient cell culture systems and tools for site-directed mutagenesis of HEV. The cell culture-adapted genotype 3c strain 47832c, which represents a typical genotype predominantly detected in Europe, has previously been used for several basic and applied research studies. Here, a plasmid-based reverse genetics system was developed for this strain, which efficiently rescued the infectious virus without the need for in vitro RNA transcription. The cotransfection of T7 RNA polymerase-expressing BSR/T7 cells with one plasmid encoding the full-length viral genome and two helper plasmids encoding vaccinia virus capping enzymes resulted in the production of infectious HEV, which could be serially passaged on A549/D3 cells. The parental and recombinant virus exhibited similar replication kinetics. A single point mutation creating an additional restriction enzyme site could be successfully introduced into the virus genome of progeny virus, indicating that the system is suitable for site-directed mutagenesis. This system is the first plasmid-based HEV reverse genetics system, as well as the first reverse genetics system for HEV genotype 3c, and should therefore be of broad use for basic and applied HEV research.
Hepatitis E virus (HEV) infection contributes to a considerable proportion of acute-on-chronic liver failure (ACLF) in patients with chronic hepatitis B virus (HBV) infection. This study aimed to predict the prognosis of chronic HBV infection patients precipitating acute HEV infection. A total of 193 patients were enrolled in this study. The performances of three chronic liver disease prognostic models (CTP score, MELD score, and CLIF-C ADs) were analyzed for predicting the development of ACLF following HEV superimposing chronic HBV infection. Subsequently, the performances of five ACLF prognostic assessment models (CTP score, MELD score, CLIF-C ACLFs, CLIF-C OFs, and COSSH-ACLFs) were analyzed for predicting the outcome of those ACLF patients. Of 193 chronic HBV infection patients precipitating acute HEV infection, 13 patients were diagnosed ACLF on admission, 54 patients developed to ACLF after admission, and 126 patients had non-ACLF during the stay in hospital. For predicting the development of ACLF, CTP score yielded a significantly higher AUROC compared with MELD score and CLIF-C ADs (0.92, 0.88, and 0.86, respectively; all p < 0.05). For predicting the poor prognosis of ACLF patients, the COSSH-ACLFs yielded a significantly higher AUROC compared with CLIF-C ACLFs, CLIF-C OFs, MELD score, and CTP score (0.89, 0.83, 0.81, 0.67, and 0.58, respectively; all p < 0.05). In conclusion, the stepwise application of CTP score and COSSH-ACLFs can predict the prognosis of chronic HBV infection patients precipitating acute HEV infection.
Hepatitis E is an enteric disease highly prevalent in the developing countries. The basis for high mortality among pregnant hepatitis E patients remains unclear. Importantly, a large proportion of infected pregnant women present with subclinical infection as well. In order to understand the possible mechanisms influencing clinical presentation of hepatitis E in pregnant women, we explored a system biology approach. For this, PBMCs from various categories were subjected to RNAseq analysis. These included non-pregnant (NPR, acute and convalescent phases) and pregnant (PR, 2nd and 3rd trimesters, acute phase and subclinical HEV infections) patients and corresponding healthy controls. The current study deals with immune response genes.
In contrast to exclusive up-regulation of nonspecific, early immune response transcripts in the NPR patients, the PR patients exhibited broader and heightened expression of genes associated with innate as well as adaptive T and B cell responses. The study identified for the first time (1) inverse relationship of immunoglobulin (Ig) genes overexpression and (2) association of differential expression of S100 series genes with disease presentation. The data suggests possible involvement of TLR4 and NOD1 in pregnant patients and alpha defensins in all patient categories suggesting a role in protection. Induction of IFNγ gene was not detected during the acute phase irrespective of pregnancy. Association of response to vitamin D, transcripts related to NK/NKT and regulatory T cells during subclinical infection are noteworthy.
The data obtained here could be correlated with several studies reported earlier in hepatitis E patients suggesting utility of PBMCs as an alternate specimen. The extensive, informative data provided here for the first time should form basis for future studies that will help in understanding pathogenesis of fulminant hepatitis E.
The five human hepatitis viruses, A to E, belong to five different virus families with distinct genomic structures and replication strategies. Hepatitis A virus is an enteric picornavirus that is readily transmitted under conditions of crowding and poor sanitation. Hepatitis B virus (HBV) is transmitted primarily from blood or blood‐derived products. After the discovery of HAV and HBV and the development of early diagnostic tools in 1974, Hepatitis C virus was realized that a substantial number of cases of transfusion‐associated acute and chronic hepatitis could not be accounted for by these two viruses. Hepatitis D virus was first detected as a novel antigen, termed hepatitis delta antigen, present in the nuclei of hepatocytes of some HBV carriers in Italy experiencing episodes of acute hepatitis. Hepatitis E virus is responsible for major outbreaks of acute food‐borne hepatitis in tropical resource‐poor countries, particularly in Asia, Africa, and Central America.
Hepatitis E, a liver disease caused by infection with the hepatitis E virus (HEV) is a worldwide emerging disease. The diagnosis is based on the detection of viral RNA and of HEV-specific immunoglobulins (Ig). For the latter, various assays are commercially available but still lack harmonization.
In this study, a Luminex®-based multiplex serological assay was established, that measures the presence of total IgG, IgA and IgM antibodies, targeting a short peptide derived from the viral E2 protein. For the validation, 160 serum samples with a known HEV serostatus were used to determine the assay cut-off and accuracy. Thereby, HEV-IgG and -RNA positive sera were identified with a sensitivity of 100% and a specificity of 98% [CI 95% 94-100%].
Application of the assay by re-testing 514 sera previously characterised with different HEV-IgG or total antibody tests, revealed a high level of agreement between the assays (Cohens Kappa 0.58-0.99).
The established method is highly sensitive, specific and can be easily implemented in a multiplex format to facilitate rapid differential diagnostics with a few microliters of sample input.
Hepatitis E virus (HEV) is a zoonotic agent, which is mainly transmitted by consumption of undercooked meat products originating from infected animals. Domestic pigs and wild boars are the major animal reservoirs, but HEV infections have been also repeatedly described in wild deer species. However, farmed deer has been only sparsely investigated so far. Here, 108 blood and 106 liver samples from fallow deer, red deer, and sika deer strictly hold in game enclosures from 11 farms in Germany were analyzed for markers of HEV infection. Using a commercial double antigen sandwich ELISA, 3/108 (2.7%) serum samples were scored borderline for HEV-specific antibodies, whereas the remaining samples were negative. No HEV-RNA (0%) was detected in the 106 liver samples. The results suggest a low risk of HEV infection in farmed deer in Germany.
Background:
Hepatitis E virus (HEV) infection is a cause of chronic hepatitis in immunosuppressed patients. Sustained virologic response rates to a 12-wk course of ribavirin therapy were reported to be > 70% in the West. This study describes the outcome of HEV treatment in a transplant center in Singapore.
Aim:
To study the outcome of ribavirin treatment in a series of chronic HEV patients, and the cause of treatment failure.
Methods:
We studied all of the transplant recipients who were diagnosed with HEV infection between 2012 to 2015. The outcome of therapy and virologic relapse are monitored for three years after the end of therapy.
Results:
Ten transplant recipients (4 liver, 5 kidney, and 1 bone marrow transplantation) with positive HEV RNA were studied. Nine patients received at least 12 wk of ribavirin therapy, and the remaining patient resolved after reducing immunosuppression therapy. Two subjects had prolonged viremia that lasted more than one year, despite continuous ribavirin therapy. Four ribavirin-treated patients (44.4%) had HEV RNA relapse after achieving a virologic response by the end of treatment. The overall failure rate is 66.7%. Being a kidney transplant recipient is the strongest risk factor for not achieving an initial sustained virologic response (0/5 treated, Chi-Square test, P < 0.05). The most common side effect of ribavirin is anemia (100%) (haemoglobin reduction of 3-6.2 g/dL). Seven patients required either a blood transfusion or erythropoietin therapy.
Conclusion:
The sustained virologic response rate of 12-wk ribavirin therapy for HEV infection in this Asian series was lower than expected. Kidney transplant recipients had a higher rate of treatment failure due to higher immunosuppression requirements and adverse effects.
Hepatitis E virus (HEV) is the most common cause of acute hepatitis worldwide including large water-borne outbreaks, zoonotic infections and transfusion transmissions. Several countries have initiated or are considering blood donor screening in response to high HEV-RNA donation prevalence leading to transfusion-transmission risk. Because HEV transmission is more common through food sources, the efficacy of blood donor screening alone may be limited. HEV-nucleic acids in 101 489 blood donations in the United States and Canada were studied. A risk-based decision-making framework was used to evaluate the quantitative risks and cost-benefit of HEV-blood donation screening in Canada comparing three scenarios: no screening, screening blood for all transfused patients or screening blood for only those at greatest risk. HEV-RNA prevalence in the United States was one per 16 908 (95% confidence interval [CI], 1:5786-1:81987), whereas Canadian HEV-RNA prevalence was one per 4615 (95% CI, 1:2579-1:9244). Although 4-fold greater, Canadian HEV-RNA prevalence was not significantly higher than in the United States. Viral loads ranged from 20 to 3080 international units per mL; all successfully typed infections were genotype 3. No HEV-RNA false-positive donations were identified for 100 percent specificity. Without donation screening, heart and lung transplant recipients had the greatest HEV-infection risk (1:366962) versus kidney transplant recipients with the lowest (1:2.8 million) at costs of 561 810 per quality-adjusted life-year (QALY) gained for partial or universal screening, respectively. Higher cost per QALY would be expected in the United States. Thus, HEV prevalence in North America is lower than in countries performing blood donation screening, and if implemented, is projected to be costly under any scenario.
Dromedary, or one-humped, camels Camelus dromedarius are an almost exclusively domesticated species that are common in arid areas as both beasts of burden and production animals for meat and milk. Currently, there are approximately 30 million dromedary camels, with highest numbers in Africa and the Middle East. The hardiness of camels in arid regions has made humans more dependent on them, especially as a stable protein source. Camels also carry and may transmit disease-causing agents to humans and other animals. The ability for camels to act as a point source or vector for disease is a concern due to increasing human demands for meat, lack of biosafety and biosecurity protocols in many regions, and a growth in the interface with wildlife as camel herds become sympatric with non-domestic species. We conducted a literature review of camel-borne zoonotic diseases and found that the majority of publications (65%) focused on Middle East respiratory syndrome (MERS), brucellosis, Echinococcus granulosus, and Rift Valley fever. The high fatality from MERS outbreaks during 2012–2016 elicited an immediate response from the research community as demonstrated by a surge of MERS-related publications. However, we contend that other camel-borne diseases such as Yersinia pestis, Coxiella burnetii, and Crimean–Congo hemorrhagic fever are just as important to include in surveillance efforts. Camel populations, particularly in sub-Saharan Africa, are increasing exponentially in response to prolonged droughts, and thus, the risk of zoonoses increases as well. In this review, we provide an overview of the major zoonotic diseases present in dromedary camels, their risk to humans, and recommendations to minimize spillover events.
In recent years various studies showed, that hepatitis E virus (HEV) is a growing public health problem in many developed countries. Therefore, HEV infections might bear a transmission risk by blood transfusions. The clinical relevance still requires further investigations. The aim of this study was to provide an overview of acute HEV infections in Upper Austrian blood donors as well as a risk estimation of this transfusion-related infection.
A total of 58,915 blood donors were tested for HEV RNA using a commercial HEV RT-PCR Kit. 7 of these donors (0.01%) were PCR-positive with normal laboratory parameters in absence of clinical signs of hepatitis. Viral load determined by quantitative real-time PCR showed a HEV nucleic acid concentration of 2,217 293,635 IU/ml. At follow-up testing (2-11 weeks after donation) all blood donors had negative HEV RNA results. Additionally, genotyping was performed by amplification and sequencing of the ORF1 or ORF2 region of the HEV genome. All HEV RNA positive donor samples revealed a genotype 3 isolate. For the antibody screening, anti-HEV IgM and IgG were detected by ELISA. Follow up serological testing revealed that no donor was seropositive for HEV IgM or IgG antibodies at time of donation. Moreover, we verified the prevalence of anti-HEV IgG in 1,203 of the HEV RNA negative tested blood donors. Overall 13.55% showed positive results for anti-HEV IgG.
In the presented study, we investigated HEV infections in blood donations of Upper Austria over 1 year. We concluded that 1 out of 8,416 blood donations is HEV RNA positive. Seroprevalence of anti HEV IgG results in an age-related increase of 13.55%. Therefore, based on this data, we recommend HEV-PCR screening to prevent transmission of hepatitis E virus by transfusion.
Background:
At least 17% of the population in Germany has been infected with the hepatitis E virus (HEV); thus, HEV infections are more frequent than was previously assumed. However, fewer than 500 HEV infections were reported to the Robert Koch Institute in 2013.
Method:
Review of pertinent literature retrieved by a selective search in PubMed.
Results:
Persons living in Germany generally acquire hepatitis E infection within the country by consuming infected and undercooked pork; in rare cases, hepatitis E infections are imported from the tropics. HEV can be transmitted via blood products, blood transfusions, and organ transplantation. More than 99% of HEV infections are asymptomatic and self-limiting, but there are also severe cases with acute liver failure. Immunosuppressed persons can develop chronic HEV infection, potentially leading, within a few years, to liver cirrhosis with life-threatening sequelae. Moreover, HEV infection may be associated with extrahepatic manifestations such as Guillain-Barré syndrome. In two retrospectively evaluated case series, ribavirin was found to be active against HEV and can be used to treat either acute or chronic HEV infection.
Conclusion:
Hepatitis E must be considered in the differential diagnosis of elevated hepatic enzyme levels and of systemic and neurological conditions of uncertain origin. The infection is usually self-limiting but can take a severe course in immunosuppressed persons. In such cases, ribavirin can be used as an antiviral treatment.
The family Hepeviridae consists of positive-stranded RNA viruses that infect a wide range of mammalian species, as well as chickens and trout. A subset of these viruses infects humans and can cause a self-limiting acute hepatitis that may become chronic in immunosuppressed individuals. Current published descriptions of the taxonomical divisions within the family Hepeviridae are contradictory in relation to the assignment of species and genotypes. Through analysis of existing sequence information, we propose a taxonomic scheme in which the family is divided into the genera Orthohepevirus (all mammalian and avian hepatitis E virus (HEV) isolates) and Piscihepevirus (cutthroat trout virus). Species within the genus Orthohepevirus are designated Orthohepevirus A (isolates from human, pig, wild boar, deer, mongoose, rabbit and camel), Orthohepevirus B (isolates from chicken), Orthohepevirus C (isolates from rat, greater bandicoot, Asian musk shrew, ferret and mink) and Orthohepevirus D (isolates from bat). Proposals are also made for the designation of genotypes within the human and rat HEVs. This hierarchical system is congruent with hepevirus phylogeny, and the three classification levels (genus, species and genotype) are consistent with, and reflect discontinuities in the ranges of pairwise distances between amino acid sequences. Adoption of this system would include the avoidance of host names in taxonomic identifiers and provide a logical framework for the assignment of novel variants.
Background:
The prevalence of hepatitis E virus (HEV) genotype 3 infections in the English population (including blood donors) is unknown, but is probably widespread, and the virus has been detected in pooled plasma products. HEV-infected donors have been retrospectively identified through investigation of reported cases of possible transfusion-transmitted hepatitis E. The frequency of HEV transmission by transfusion and its outcome remains unknown. We report the prevalence of HEV RNA in blood donations, the transmission of the virus through a range of blood components, and describe the resulting morbidity in the recipients.
Methods:
From Oct 8, 2012, to Sept 30, 2013, 225,000 blood donations that were collected in southeast England were screened retrospectively for HEV RNA. Donations containing HEV were characterised by use of serology and genomic phylogeny. Recipients, who received any blood components from these donations, were identified and the outcome of exposure was ascertained.
Findings:
79 donors were viraemic with genotype 3 HEV, giving an RNA prevalence of one in 2848. Most viraemic donors were seronegative at the time of donation. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused before identification of the infected donation. Follow-up of 43 recipients showed 18 (42%) had evidence of infection. Absence of detectable antibody and high viral load in the donation rendered infection more likely. Recipient immunosuppression delayed or prevented seroconversion and extended the duration of viraemia. Three recipients cleared longstanding infection after intervention with ribavirin or alteration in immunosuppressive therapy. Ten recipients developed prolonged or persistent infection. Transaminitis was common, but short-term morbidity was rare; only one recipient developed apparent but clinically mild post-transfusion hepatitis.
Interpretation:
Our findings suggest that HEV genotype 3 infections are widespread in the English population and in blood donors. Transfusion-transmitted infections rarely caused acute morbidity, but in some immunosuppressed patients became persistent. Although at present blood donations are not screened, an agreed policy is needed for the identification of patients with persistent HEV infection, irrespective of origin, so that they can be offered antiviral therapy.
Funding:
Public Health England and National Health Service Blood and Transplant.
Hepatitis E virus (HEV) infection is an important public health concern in many developing countries, causing waterborne outbreaks as well as sporadic autochthonous hepatitis. HEV is mainly transmitted by the fecal-oral route in endemic areas through drinking of contaminated water. However, zoonotic transmission from animal reservoirs to humans has also been suggested. Three additional routes of HEV transmission have been proposed to occur: blood borne, human to human, and vertical transmission from mother to child. Acute HEV infection is usually diagnosed by detecting specific anti-HEV antibodies. However, the performance of the available assays in different settings is not optimal. Analysis of HEV ribonucleic acid in biologic specimens such as stools, serum, and liver biopsy by using nucleic acid amplification techniques is also employed. Nonetheless, additional consensus regarding the best technologies suitable for serosurveys and diagnosis of acute HEV infection is also needed. This review article summarizes the current status of HEV infection end epidemiology with particular emphasis in transmission, diagnosis, and clinical management.
Background
Recent studies show that endemic hepatitis E virus (HEV) infection occurs frequently in some developed countries. In the Netherlands in 2013, the routine screening of 35,220 plasma donations for HEV RNA showed 20 donors to be viremic (1:1761), which seems to contradict reports of declining HEV seroprevalence in the recent past.Study Design and Methods
To asses HEV infection pressure changes over time, archived samples from Dutch blood donations collected in 1988 and 2000 were tested for anti-HEV immunoglobulin (Ig)G. The findings were compared to the HEV seroprevalence among donors in 2011.ResultsThe age-adjusted prevalence of anti-HEV IgG for Dutch donors aged 18 to 64 declined from 46.6% in 1988 to 27.3% in 2000 and to 20.9% in 2011. The reduction of seroprevalence was apparent for all age groups between 1988 and 2000, and for donors older than 40 between 2000 and 2011, but the seroprevalence among donors aged 18 to 29 increased between 2000 and 2011. Recent changes in HEV infection pressure are more apparent in the youngest donors, who to a lesser extent reflect cumulative exposure to HEV in the past. Donors aged 18 to 21 showed decreasing HEV seroprevalence from 19.8% in 1988 to 7.0% in 1995 and to 4.3% in 2000, followed by an increase to 12.7% in 2011.ConclusionHEV antibody patterns in young and old Dutch donors, in 1988 to 2011, suggest that decades ago, HEV was ubiquitous and most persons acquired infection. Subsequently HEV incidence was low during a prolonged period, to increase again in recent years.
SUMMARY Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries.
Hepatitis E virus (HEV), a single-stranded, positive-sense RNA virus, is responsible for acute hepatitis E epidemics in many developing countries, and the virus is also endemic in some industrialized countries. Hepatitis E is a recognized zoonotic disease, and several animal species, including pigs, are potential reservoirs for HEV. The genome of HEV contains three open reading frames (ORFs). ORF1 encodes the nonstructural proteins, ORF2 encodes the capsid protein, and ORF3 encodes a small multifunctional protein. The ORF2 and ORF3 proteins are translated from a single, bicistronic mRNA. The coding sequences for these two ORFs overlap each other, but neither overlaps with ORF1. Whereas the mechanisms underlying HEV replication are poorly understood, the construction of infectious viral clones, the identification of cell lines that support HEV replication, and the development of small animal models have allowed for more detailed study of the virus. As result of these advances, recently, our understanding of viral entry, genomic replication and viral egress has improved. Furthermore, the determination of the T=1 and T=3 structure of HEV virus-like particles has furthered our understanding of the replication of HEV. This article reviews the latest developments in the molecular biology of HEV with an emphasis on the genomic organization, the expression and function of genes, and the structure and replication of HEV.
Hepatitis E virus (HEV) is responsible for epidemics and endemics of acute hepatitis in humans, mainly through waterborne, foodborne, and zoonotic transmission routes. HEV is a single-stranded, positive-sense RNA virus classified in the family Hepeviridae and encompasses four known Genotypes (1-4), at least two new putative genotypes of mammalian HEV, and one floating genus of avian HEV. Genotypes 1 and 2 HEVs only affect humans, while Genotypes 3 and 4 are zoonotic and responsible for sporadic and autochthonous infections in both humans and several other animal species worldwide. HEV has an ever-expanding host range and has been identified in numerous animal species. Swine serve as a reservoir species for HEV transmission to humans; however, it is likely that other animal species may also act as reservoirs. HEV poses an important public health concern with cases of the disease definitively linked to handling of infected pigs, consumption of raw and undercooked animal meats, and animal manure contamination of drinking or irrigation water. Infectious HEV has been identified in numerous sources of concern including animal feces, sewage water, inadequately-treated water, contaminated shellfish and produce, as well as animal meats. Many aspects of HEV pathogenesis, replication, and immunological responses remain unknown, as HEV is an extremely understudied but important human pathogen. This article reviews the current understanding of HEV transmission routes with emphasis on food and environmental sources and the prevalence of HEV in animal species with zoonotic potential in humans.
The risk of transfusion-transmitted hepatitis E virus (HEV) infections by contaminated blood products remains unknown. In the present study, we evaluated and compared different nucleic acid amplification technique (NAT) methods for the detection of HEV in blood components. Minipools of a total of 16,125 individual blood donors were screened for the presence of HEV RNA using the highly sensitive RealStar HEV RT-PCR kit, revealing a minimum detection limit of 4.66 IU/ml. Thirteen donors were HEV RNA positive (0.08%), and of these donors, only three already showed reactive IgM antibody titers. The detected HEV strains all belonged to genotype 3 and were most closely related to German HEV strains from wild boars and pigs as well as from human hepatitis E cases. Furthermore, HEV RNA and HEV-specific IgM and IgG titers were determined in 136 blood donors with elevated alanine aminotransferase (ALT) levels and in 200 donors without pathological findings. HEV RNA was not detectable, but 8.08% (elevated ALT) and 0.5% (nonelevated ALT) of donors showed reactive HEV IgM titers. The overall seroprevalence rate of HEV IgG amounted to 5.94% (elevated ALT, 5.88%; nonelevated ALT, 6.0%). The clinical relevance of transfusion-associated hepatitis E infection still requires further investigation. However, in connection with raising concerns regarding blood safety, our NAT method provides a sensitive possibility for HEV testing.
Unlabelled:
We estimated the global burden of hepatitis E virus (HEV) genotypes 1 and 2 in 2005. HEV is an emergent waterborne infection that causes source-originated epidemics of acute disease with a case fatality rate thought to vary by age and pregnancy status. To create our estimates, we modeled the annual disease burden of HEV genotypes 1 and 2 for 9 of 21 regions defined for the Global Burden of Diseases, Injuries, and Risk Factors Study (the GBD 2010 Study), which represent 71% of the world's population. We estimated the seroprevalence of anti-HEV antibody and annual incidence of infection for each region using data from 37 published national studies and the DISMOD 3, a generic disease model designed for the GBD Study. We converted incident infections into three mutually exclusive results of infection: (1) asymptomatic episodes, (2) symptomatic disease, and (3) death from HEV. We also estimated incremental cases of stillbirths among infected pregnant women. For 2005, we estimated 20.1 (95% credible interval [Cr.I.]: 2.8-37.0) million incident HEV infections across the nine GBD Regions, resulting in 3.4 (95% Cr.I.: 0.5-6.5) million symptomatic cases, 70,000 (95% Cr.I.: 12,400-132,732) deaths, and 3,000 (95% Cr.I.: 1,892-4,424) stillbirths. We estimated a probability of symptomatic illness given infection of 0.198 (95% Cr.I.: 0.167-0.229) and a probability of death given symptomatic illness of 0.019 (95% Cr.I.: 0.017-0.021) for nonpregnant cases and 0.198 (95% Cr.I.: 0.169-0.227) for pregnant cases.
Conclusion:
The model was most sensitive to estimates of age-specific incidence of HEV disease.
This review details the molecular virology of the hepatitis E virus (HEV). While replicons and in vitro infection systems have recently become available, a lot of information on HEV has been generated through comparisons with better-studied positive-strand RNA viruses and through subgenomic expression of viral open reading frames. These models are now being verified with replicon and infection systems. We provide here the current knowledge on the HEV genome and its constituent proteins--ORF1, ORF2 and ORF3. Based on the available information, we also modify the existing model of the HEV life cycle.
Hepatitis E virus (HEV) is an enterically transmitted hepatropic virus. It segregates as four genotypes. All genotypes infect humans while only genotypes 3 and 4 also infect several animal species. It has been suggested that hepatitis E is zoonotic, but no study has analyzed the evolutionary history of HEV. We present here an analysis of the evolutionary history of HEV.
The times to the most recent common ancestors for all four genotypes of HEV were calculated using BEAST to conduct a Bayesian analysis of HEV. The population dynamics for genotypes 1, 3 and 4 were analyzed using skyline plots. Bayesian analysis showed that the most recent common ancestor for modern HEV existed between 536 and 1344 years ago. The progenitor of HEV appears to have given rise to anthropotropic and enzootic forms of HEV, which evolved into genotypes 1 and 2 and genotypes 3 and 4, respectively. Population dynamics suggest that genotypes 1, 3 and 4 experienced a population expansion during the 20(th) century. Genotype 1 has increased in infected population size ∼30-35 years ago. Genotype 3 and 4 have experienced an increase in population size starting late in the 19(th) century until ca.1940-45, with genotype 3 having undergone additional rapid expansion until ca.1960. The effective population size for both genotype 3 and 4 rapidly declined to pre-expansion levels starting in ca.1990. Genotype 4 was further examined as Chinese and Japanese sequences, which exhibited different population dynamics, suggesting that this genotype experienced different evolutionary history in these two countries.
HEV appears to have evolved through a series of steps, in which the ancestors of HEV may have adapted to a succession of animal hosts leading to humans. Analysis of the population dynamics of HEV suggests a substantial temporal variation in the rate of transmission among HEV genotypes in different geographic regions late in the 20(th) Century.
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in the world. Most of South Asia is HEV endemic, with frequent seasonal epidemics of hepatitis E and continuous sporadic cases. This author group's epidemiologic work and clinical reports suggest that Bangladesh is HEV endemic, but there have been few population-based studies of this country's HEV burden. The authors calculated HEV infection rates, over an 18-month interval between 2003 and 2005, by following a randomly selected cohort of 1,134 subjects between the ages of 1 and 88 years, representative of rural communities in southern Bangladesh. Baseline prevalence of antibody to hepatitis E virus (anti-HEV) was 22.5%. Seroincidence was 60.3 per 1,000 person-years during the first 12 months and 72.4 per 1,000 person-years from >12 to 18 months (during the monsoon season), peaking by age 50 years and with low rates during childhood. Few of the seroconverting subjects reported hepatitis-like illness. Overall incidence was calculated to be 64 per 1,000 person-years, with 1,172 person-years followed. No significant associations were found between anti-HEV incidence and demographic or socioeconomic factors for which data were available. This is the first study to document annual HEV infection rates among "healthy" and very young to elderly subjects in a rural Bangladeshi population.
Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale epidemics of acute viral hepatitis, particularly in developing countries. In men and non-pregnant women, the disease is usually self-limited and has a case-fatality rate of less than <0.1%. However, in pregnant women, particularly from certain geographical areas in India, HEV infection is more severe, often leading to fulminant hepatic failure and death in a significant proportion of patients. In contrast, reports from Egypt, Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in non-pregnant women. The reasons for this geographical difference are not clear. The high mortality rate in pregnancy has been thought to be secondary to the associated hormonal (oestrogen and progesterone) changes during pregnancy and consequent immunological changes. These immunological changes include downregulation of the p65 component of nuclear factor (NF-kappaB) with a predominant T-helper type 2 (Th2) bias in the T-cell response along with host susceptibility factors, mediated by human leucocyte antigen expression. Thus far, researchers were unable to explain the high HEV morbidity in pregnancy, why it is different from other hepatitis viruses such as hepatitis A with similar epidemiological features and the reason behind the difference in HEV morbidity in pregnant women in different geographical regions. The recent developments in understanding the immune response to HEV have encouraged us to review the possible mechanisms for these differences. Further research in the immunology of HEV and pregnancy is required to conquer this disease in the near future.
FAILURE TO DETECT CHRONIC LIVER DISEASE AFTER EPIDEMIC NON-A, NON-B HEPATITIS
Sir, - A waterborne epidemic of non-A, non-B hepatitis occurred in the Kashmir valley between November, 1978, and April, 1979.1 From January to March, 1980, the cases recorded during this epidemic were assessed for evidence of chronic liver disease. Four villages in which 102 cases of viral hepatitis had been recorded were surveyed. 4 patients died in the first two weeks of their illness with fulminant hepatic failure. None of the others had since died. One patient was positive for HBsAg, and liver biopsy in this patient 7 months after the infection showed features of chronic active hepatitis and cirrhosis. This patient was excluded from the study. 15 patients were not available for assessment at the time of survey.
The remaining 82 patients were interviewed and given a detailed physical examination. Blood was drawn for estimation of serum bilirubin, serum glutamic pyruvic transaminase (SGPT), and HBsAg. The illness in these patients had lasted from 5 days to 3 months (mean 29 days). The present assessment was done 8 to 17 months after the original illness (mean 14.8 months). None of the patients had persistent jaundice, ascites, or hepatic encephalopathy. 16 (19.5%) had recurrent mild abdominal pain, 11 (13.5%) had lost weight; 8 (9.8%) had anorexia, and 6 occasionally had dark urine. 3 patients had had a second distinct episode of jaundice after recovery from the original illness. 6 patients (7%) had soft palpable hepatomegaly, and in 5 (6 %) the spleen was palpable below the costal margin. Serum bilirubin was below 1 mg/dl in all cases. SGPT levels were within normal limits in 78 cases, in 4 cases SGOT levels were above the upper limit of normal (35, 42, 45, and 50 IU/l). Liver biopsy was not done in any of the cases.
In addition, 30 patients who had had acute viral hepatitis from this epidemic were followed up 2 to 6 months from the onset of their disease by serial liver function tests. In all cases serum bilirubin and serum enzymes returned to normal after a variable interval.
Evidence of chronic liver disease was lacking in most of our patients. Various abdominal complaints and palpable liver and spleen can occur after acute viral hepatitis in the presence of normal liver histology and were seen nearly the same percentage in healthy contacts.2 None of the patients in the present study had chronic or recurrent jaundice or raised serum bilirubin in one year follow-up. 4 had raised SGPT levels and could have developed chronic liver disease. However, none had symptoms or abnormal physical findings, and in none was SGPT raised to twice the upper limit of normal. We decided not to do liver biopsies in these cases. Liver functions, especially serum hepatic enzymes, can fluctuate in chronic liver disease,3 and a single estimation of liver-function tests could have overlooked chronic liver disease in some of our cases. This possibility was excluded, because 30 patients with acute non-A, non-B hepatitis followed prospectively had no residual abnormality of liver function on repeated testing.
Non-A, non-B hepatitis was first described after blood transfusion,4 and chronic liver disease followed in a high percentage of cases.3,5,6 We, however, failed to detect chronic liver disease after acute non-parentally transmitted non-A, non-B hepatitis. The reason for this is not clear, but possible explanation are the large amount of viral protein administered during transfusion or, perhaps more importantly, the existence of at least two non-A, non-B viral agents, one of which is more commonly associated with post-transfusion hepatitis as well as an unusual tendency to be associated with the development of chronic liver disease.
MOHAMMAD SULTAN KHUROO MOHAMMAD SALEEM MOHAMMAD RAMZAN TELI MOHAMMAD AMIN SOFI
Department of Medicine,
Medical College, Srinagar,
Kashmir
1. Khuroo MS. Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type. Am J Med (in press).
2. Chuttani HK, Sidhu AS, Wig KL, Gupta DN, Ramalingaswami V. Follow up study of cases from the Delhi epidemic of infectious hepatitis of 1955-56. Br Med J 1966;ii:676-79.
3. Berman M, Alter HJ, Ishak KG, Purcell RH, Jones EA. The chronic sequel of non-A, non-B hepatitis. Ann Intern Med 1979;91:1-6.
4. Feinstone SM, Kapikian AZ, Purcell RH, et al. Transfusion associated hepatitis not due to viral hepatitis type A or B. N Engl J Med 1975;292:767-70.
5. Knodell RG, Conrad ME, Ishaq KG. Development of chronic liver disease after acute non-A, non-B post-transfusion hepatitis. Role of globulin prophylaxis in its prevention. Gastroenterology 1977;72:902-07.
6. Rekela J, Redeker AG. Chronic liver disease after acute non-A, non-B viral hepatitis. Gastroenterology 1979;77:1200-02.
Background: Hepatitis E virus infection is vertically transmitted from mother to the fetus, often leading to severe fetal and neonatal disease. The relationship between severity of disease in the mother and fetus is not known. We studied clinical and biochemical characteristics of 36 consecutive pregnant women with acute HEV infection. Babies borne to these women were assessed for vertically transmitted HEV infection and the severity of liver disease in the newborn. The severity of disease in the newborn was correlated with the maternal disease. Of the 36 pregnant women with HEV infection, 20 (55.6%) had nonfulminant disease and 16 (44.4%) had fulminant hepatic failure (FHF). Nine (56.3%) of the 16 mothers with FHF had disseminated intravascular coagulation. Six (37.5%) women with FHF survived and 10 (62.5%) died. Twenty-five (69.4%) infants had HEV infection at birth. Fourteen (56%) of such infants died with a clinical syndrome resembling FHF. Babies borne to mothers with FHF were more often HEV infected and viremic ((15/16; 93.8%% for both) than those with nonfulminant disease (10/20; 50% and 5/20; 25%) (p=0.004 and <0.001 respectively). Twelve (75%) of the 16 babies borne to mothers with FHF had clinical syndrome of FHF because of massive hepatic necrosis. In contrast only two (10%) of the 20 mothers with nonfulminant disease delivered babies who developed FHF (p=0.008) All the six mothers who survived had delivered babies within 4 days (2.3±1.0 days) of onset of encephalopathy. In contrast, all the 10 mothers who died had delivered babies 4 days (9.6±3.0 days) after onset of encephalopathy (p=0.02). The severity of hepatitis E virus infection in the mother and the fetus is related to each other and needs further studies to define cause and affect relationship.
Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined.
In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years.
During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person-years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups.
Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.).
Hepatitis E 2010 Hepatitis E discovery has completed 30 years since the first description of "Epi-demic Non-A, Non-B hepatitis" in January 1980 (Khuroo, M. S. Study of an epi-demic of Non-A, Non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion Non-A, Non-B type. American Journal of Medi-cine, 1980; 68:818-825). This occasion was celebrated by International medi-cal fraternity by hosting an important scientific meeting entitled "International Symposium on Hepatitis E" at International Vaccine Institute, Seoul, South Ko-rea on September 15-16, 2010. The event was sponsored by Bill & Melinda Gates Foundation; Center for Disease Control (CDC), Atlanta, Georgia, USA and World Health Organization (WHO). The focus of the symposium was to establish an "International consortium for Control and Prevention of viral Hepa-titis E". Faculty of the symposium included (among others) Dr.. In view of the disturbed conditions in Kashmir in September 2010 and my inability to travel to Seoul, I addressed this meeting from my office in Srinagar through Telemedi-cine. The deliberations of this meeting along with power-point presentations of the speakers are now available at: http://www.ivi.int/popup/hepE_sympo-sium/default_2010.asp. I have drafted an article entitled "Discovery of hepatitis E: The epidemic Non-A, Non-B hepatitis 30 years down the memory lane". This article is based on my personal experience of how I have seen the story of hepatitis E uncovering over these 3 decades. It has major inputs from the presentations of the distinguished international faculty of the "International symposium of hepatitis E". I have taken liberty of including 2 articles published in American Journal of Medicine [Amer-ican Journal of Medicine, 1980; 68:818-82 & 1981;70:252-255]. These articles are based on studies done on Kashmir epidemic 1978. These articles established the existence of hepatitis E as a clinical disease and subsequently led to transmis-sion studies, identification of VLP and cloning of hepatitis E virus (HEV).
Award winning Plenary session presentation. This work was published in "American Journal of Medicine 1980;68:818-24" and has been included as one of the "Classic Papers in Viral hepatitis" in the book "Classic Papers in Viral Hepatitis" edited by Lee CA, Thomas HC, Science Press Ltd. 1988. London P184-190.
Hepatitis E virus (HEV) is a non-enveloped RNA virus transmitted by the fecal-oral route. Autochthonous hepatitis E occurring in developed countries is caused by genotypes 3 and 4 and is a zoonotic infection. Humans are infected mostly after ingestion of undercooked meat from infected animals. Most HEV 3 and 4 infections are clinically inapparent. However, genotype 3 (HEV 3) can lead to chronic hepatitis in immuno-compromised patients such as organ-transplant recipients and patients with haematological malignancies. In Europe, HEV 3 is implicated in transfusion-transmitted HEV infection. In France, as observed in several European countries, prevalence of HEV RNA and specific IgG antibodies are high indicating that viral circulation is important. The systematic HEV NAT screening of blood donations used for preparation of solvent detergent plasma indicate that 1 to 2218 donation is infected by HEV RNA. The need or implementation's impacts of safety measures to prevent HEV transmission by blood transfusion are under reflexion by French's health authorities. The HEV NAT screening is the only available tool of prevention. Alternative strategies are under investigation including individual or mini pool NAT testing all or part of blood donations.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Hepatitis E virus (HEV) is a non-enveloped RNA virus transmitted by the fecal-oral route. Autochthonous hepatitis E occurring in developed countries is caused by genotypes 3 and 4 and is a zoonotic infection. Humans are infected mostly after ingestion of undercooked meat from infected animals. Most HEV 3 and 4 infections are clinically inapparent. However, genotype 3 (HEV 3) can lead to chronic hepatitis in immuno-compromised patients such as organ-transplant recipients and patients with haematological malignancies. In Europe, HEV 3 is implicated in transfusion-transmitted HEV infection. In France, as observed in several European countries, prevalence of HEV RNA and specific IgG antibodies are high indicating that viral circulation is important. The systematic HEV NAT screening of blood donations used for preparation of solvent detergent plasma indicate that 1 to 2218 donation is infected by HEV RNA. The need or implementation's impacts of safety measures to prevent HEV transmission by blood transfusion are under reflexion by French's health authorities. The HEV NAT screening is the only available tool of prevention. Alternative strategies are under investigation including individual or mini pool NAT testing all or part of blood donations.
The risk of hepatitis E virus (HEV) infection from blood transfusion has aroused increasing concern in many countries. The aim of this study was to analyze the potential risk of HEV infection through blood transfusion in China.
Qualified blood donations and donations with isolated alanine aminotransferase (ALT) elevations from five geographically diverse Chinese regions were tested for anti-HEV immunoglobulin (Ig)M and IgG and HEV antigen. The positive samples for anti-HEV IgM and HEV antigen were tested for HEV RNA. HEV open reading frame (ORF)2 partial sequences were analyzed from HEV RNA-positive samples.
The seroprevalence rates of HEV antigen and anti-HEV IgM and IgG among qualified donations were 0.06% (6/10,741), 1.02% (109/10,741), and 27.42% (2945/10,741), respectively. Samples with isolated ALT elevations had higher prevalence of HEV markers, namely, HEV antigen of 0.25% (2/797), anti-HEV IgM of 2.76% (22/797), and anti-HEV IgG of 40.02% (319/797). The HEV antibody prevalence varied significantly by age, sex, and geographic region. All 131 samples that were anti-HEV IgM positive were negative for HEV RNA, whereas four of eight (50%) samples positive for HEV antigen were HEV RNA positive. HEV ORF2 sequences from three of four HEV RNA-positive samples were determined and grouped with Genotype 4.
Qualified donations after routine blood donor screening still carry potential risk for transmitting HEV. HEV antigen screening could be one measure to reduce the risk of HEV transmission by blood transfusion.
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis (AVH) globally. It causes large scale epidemics of AVH across the low- and middle income countries in Asia and Africa, and also causes sporadic cases of AVH in the same geographical region. AVH due to HEV is usually an acute, self-limiting illness, similar in clinical presentation to AVH caused by hepatitis A virus (HAV). When HEV causes AVH in patients of chronic liver disease it may worsen rapidly to a syndrome called acute-on-chronic liver failure (ACLF) leading to very high mortality. Acute deterioration of liver function in a patient with compensated chronic liver disease is the characteristic feature of ACLF. The typical disease course of patients with ACLF is the appearance of organ failure, which progresses to multi-organ failure and death. Many publications have reported HEV as one of the leading causes for ACLF from Asia and Africa, where HEV is endemic. The mortality rate of HEV-related ACLF (HEV-ACLF) ranges from 0% to 67% with a median being 34%. These patients require admission in the intensive care unit and they benefit from a team approach of clinicians with expertise in both hepatology and critical care. The goals of treatment are to prevent further deterioration in liver function, reverse precipitating factors, and support failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. One preliminary report suggests that ribavirin may be an effective and safe drug for treatment of HEV-ACLF however this requires validation in large trials.
It is now well accepted that hepatitis E virus (HEV) infection can induce chronic hepatitis and cirrhosis in immunosuppressed patients. Chronic genotype-3 HEV infections were first reported in patients with a solid-organ transplant. Thereafter, cases of chronic HEV infection have been reported in patients with hematological disease and in those who are human immunodeficiency virus (HIV)-positive. HEV-associated extra-hepatic manifestations, including neurological symptoms, kidney injuries, and hematological disorders, have been also reported. In transplant patients, reducing the dosage of immunosuppressive drugs allows the virus to be cleared in some patients. In the remaining patients, as well as hematological patients and patients who are HIV-positive, anti-viral therapies, such as pegylated interferon and ribavirin, have been found to be efficient in eradicating HEV infection. This review summarizes our current knowledge of chronic HEV infection, its treatment, and the extra-hepatic manifestations induced by HEV.
Background
Hepatitis E virus (HEV) is transmissible by transfusion. More data are needed about seroprevalence, incidence, and viremia in blood donors for the assessment of risk of transfusion-transmitted (TT)-HEV infections. Study Design and Methods
Samples from 1019 whole blood donors were tested for anti-HEV immunoglobulin (Ig)G by enzyme-linked immunosorbent assay and Western blot. The incidence of HEV and presence of HEV RNA in donors who seroconverted were determined by testing archive samples and recipients of viremic donations were traced. Anti-HEV IgM and alanine transaminase (ALT) testing were also performed to assess the value of such measures in the prevention of TT-HEV infections. ResultsA total of 69 of 1019 donors tested positive for anti-HEV IgG (6.8% seroprevalence), and seroconversion for anti-HEV IgG occurred in seven of 69 donors within 2 years (incidence, 0.35%/year). Three of seven (42.8%) seroconverting donors provided an archive sample in which HEV RNA was detectable. One recipient of these donations was traceable; anti-HEV IgG, IgM, and HEV RNA testing were negative 41 days after transfusion. Neither ALT levels nor anti-HEV IgM detection correlated with the presence of HEV RNA. Conclusions
The seroprevalence of HEV was 6.8%, and the annual incidence 0.35%. HEV RNA was detectable in several seroconverting donors, without evidence for HEV transmission in the only traceable recipient. Since neither ALT nor anti-HEV IgM testing correlate with the presence of HEV RNA, HEV nucleic acid testing currently provides the only method for the prevention of TT-HEV infection. However, before implementation, more data about clinical relevance of TT-HEV infections and infectious dose of HEV are required.
A prospective field study was carried out during an epidemic of non-A non-B hepatitis for determining the incidence and severity of hepatitis in pregnant women, nonpregnant women of child bearing age and men (15 to 45 years old). In 36 (17.3 percent) of 208 pregnant women viral hepatitis developed, as compared to 71 (2.1 percent) of 3,350 nonpregnant women and 107 (2.8 percent) of 3,822 men. The incidence of disease in pregnant women was higher than in the two control groups. The incidence of viral hepatitis in the first, second and third trimesters was 8.8 percent, 19.4 percent, and 18.6 percent, respectively. The incidence in all three trimesters was higher, when compared to that in nonpregnant women. In eight pregnant women (22.2 percent) with viral hepatitis, fulminant hepatic failure developed, as compared to its occurrence in three men (2.8 percent) and in no nonpregnant women. This significantly increased incidence of fulminant hepatitis in pregnancy was indicative of a greater severity of hepatitis during pregnancy. Increased susceptibility to fulminant hepatitis was observed exclusively in the last trimester. Nonfulminant viral hepatitis did not influence the course of pregnancy or fetal well-being. Fetal loss in fatal fulminant hepatitis was a consequence of maternal death and could not be ascribed to direct effect on the fetus or pregnancy.
Hepatitis E virus (HEV) is an emerging infectious threat to blood safety. In recent years, there have been a number of publications delineating this threat by providing evidence of the transmissibility of this virus through transfusions. The extent of transmission and its clinical relevance are issues under debate at present. HEV usually causes a self-limiting illness which subsides in a few weeks barring a few cases where fulminant hepatic failure occurs. The virus poses a risk of higher morbidity and mortality in pregnant females, patients with pre-existing liver disease and solid organ transplant recipients. As these categories of patient often require repeated transfusions or massive transfusions, they are exposed to a greater risk of transmission of HEV. At present, there is little evidence to advocate universal screening for this virus but considering that there is no definitive treatment for HEV induced hepatitis, selective screening should be advocated in blood products for high risk recipients in endemic areas.
Development of accurate diagnostic assays for the detection of serological markers of hepatitis E virus (HEV) infection remains challenging. In the course of nearly 20 years after the discovery of HEV, significant progress has been made in characterizing the antigenic structure of HEV proteins, engineering highly immunoreactive diagnostic antigens, and devising efficient serological assays. However, many outstanding issues related to sensitivity and specificity of these assays in clinical and epidemiological settings remain to be resolved. Complexity of antigenic composition, viral genetic heterogeneity and varying epidemiological patterns of hepatitis E in different parts of the world present challenges to the refinement of HEV serological diagnostic assays. Development of antigens specially designed for the identification of serological markers specific to acute infection and of IgG anti-HEV specific to the convalescent phase of infection would greatly facilitate accurate identification of active, recent and past HEV infections.
Hepatitis E virus (HEV) causes large epidemics of enterically transmitted acute hepatitis and accounts for a majority of sporadic acute hepatitis in endemic countries. Due to a very high mortality rate among infected pregnant women and substantial morbidity, disability and costs associated with hepatitis E, concerted efforts are being made to develop an efficacious vaccine. Experimental vaccines, based on recombinant proteins derived from the capsid gene of HEV, have been shown efficacious in pre-clinical trials in macaques conferring cross-protection against various genotypes. Two vaccine candidates, the rHEV vaccine expressed in baculovirus and the HEV 239 vaccine, expressed in Escherichia coli, were successfully evaluated in Phase II/III trials. However, at this time no approved vaccine against hepatitis E is commercially available.
The risk of hepatitis E virus (HEV) to blood safety remains unknown in England. Reports of persistent HEV infection with serious disease sequelae indicate that transfusion transmitted HEV is not a trivial disease in immunosuppressed patients. Materials and
Samples from unselected blood donors and donors with a history of jaundice were tested for HEV antibody and RNA.
Overall, 10% of the donor sera were anti-HEV IgG reactive. Four of the donor samples were anti-HEV IgM reactive but HEV RNA negative.
There is evidence of probable recent HEV infections in donors with a predicted attack rate of 2.8%.
Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs.
We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months.
Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance.
HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients.
Large-scale waterborne epidemics of hepatitis E occur in developing countries. It is not known why these epidemics occur repeatedly and selectively in adult population?
We studied seroepidemiology of an outbreak of hepatitis E in one of 15 villages that had recorded first epidemic of hepatitis E 30 years back. Another village not affected by the second epidemic was taken as a control. Overall, 1,216 sera were collected (638 from the epidemic village and 578 from the control village) for serological markers of both hepatitis A virus (HAV) and hepatitis E virus (HEV).
The seroprevalence of anti-HEV in this population following the first epidemic in 1978 was 29.4%. Antibodies were detected in only 47% of the 45 patients affected by icteric HEV infection 14 years after the first epidemic. At 30-year follow-up, the seroprevalence of anti-HEV was only 4.5% (26/578). In the village affected by second epidemic, 138 (21.6%) subjects had serological evidence of recent HEV infection. The attack rate was 23.6% (78/330) in children (≤14 years) and 19.4% (60/308) in adults (P = 0.21). The attack rate of anicteric HEV infection was 21.8% (72/330) in children and 14.6% (45/308) in adults (P = 0.02).
Following hepatitis E epidemics, there is a gradual loss of antibodies in the community over the decades and poor exposure to HEV infection in the cohort of population born during the interepidemic period. The next epidemic occurs when antibody levels fall to critically low levels and there is associated gross fecal contamination of water resources. During epidemic, persons of all age groups are exposed to infection, with predominant anicteric disease in children.
Seroprevalence data suggest that a third of the world's population has been infected with the hepatitis E virus. Our aim was to assess efficacy and safety of a recombinant hepatitis E vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China) in a randomised, double-blind, placebo-controlled, phase 3 trial.
Healthy adults aged 16-65 years in, Jiangsu Province, China were randomly assigned in a 1:1 ratio to receive three doses of HEV 239 (30 microg of purified recombinant hepatitis E antigen adsorbed to 0.8 mg aluminium hydroxide suspended in 0.5 mL buffered saline) or placebo (hepatitis B vaccine) given intramuscularly at 0, 1, and 6 months. Randomisation was done by computer-generated permuted blocks and stratified by age and sex. Participants were followed up for 19 months. The primary endpoint was prevention of hepatitis E during 12 months from the 31st day after the third dose. Analysis was based on participants who received all three doses per protocol. Study participants, care givers, and investigators were all masked to group and vaccine assignments. This trial is registered with ClinicalTrials.gov, number NCT01014845.
11,165 of the trial participants were tested for hepatitis E virus IgG, of which 5285 (47%) were seropositive for hepatitis E virus. Participants were randomly assigned to vaccine (n=56,302) or placebo (n=56,302). 48,693 (86%) participants in the vaccine group and 48,663 participants (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis. During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group. Vaccine efficacy after three doses was 100.0% (95% CI 72.1-100.0). Adverse effects attributable to the vaccine were few and mild. No vaccination-related serious adverse event was noted.
HEV 239 is well tolerated and effective in the prevention of hepatitis E in the general population in China, including both men and women age 16-65 years.
Chinese National High-tech R&D Programme (863 programme), Chinese National Key Technologies R&D Programme, Chinese National Science Fund for Distinguished Young Scholars, Fujian Provincial Department of Sciences and Technology, Xiamen Science and Technology Bureau, and Fujian Provincial Science Fund for Distinguished Young Scholars.
Hepatitis E virus (HEV) infection is known to run a self-limited course. Recently, chronic hepatitis E has been described in several immunosuppressed patients after solid organ transplantation. The prevalence of HEV infection after transplantation, however, is unknown. We studied HEV parameters [HEV RNA, HEV immunoglobulin M (IgM), and HEV immunoglobulin G (IgG) by enzyme-linked immunosorbent assay and confirmatory immunoblotting] in a cohort of 285 adult liver transplant recipients. The most recent freeze-stored sera were investigated, and if they were positive, a retrospective analysis was performed. Samples from 274 patients (96.1%) tested negative for all HEV parameters. This included a patient described earlier as having experienced an episode of chronic HEV hepatitis in the past. One patient was found positive for HEV RNA without HEV antibodies. She presently suffers from chronic HEV hepatitis and has also been described before. Sera from 9 patients tested positive for HEV IgG without HEV IgM or HEV RNA. Six of these 9 patients (2.1% of the total) were found to have HEV IgG antibodies in retrospect related to an HEV infection at some time pre-transplant as they also tested positive in a pretransplant serum sample. One of these 9 patients suffered in retrospect from a chronic HEV infection with mild hepatitis between 2 and 5 years after liver transplantation on the basis of the course of HEV RNA, IgM, and IgG, aminotransferases, and liver histology. Overall, the prevalence of acquired HEV hepatitis after liver transplantation was 1% in this cohort. We conclude that liver transplant recipients have a risk for chronic HEV infection, but the prevalence is low.
Infection with the hepatitis E virus (HEV) causes a self-limiting acute hepatitis. However, prolonged viremia and chronic hepatitis has been reported in organ transplant recipients. Vertically transmitted HEV infection is known to cause acute hepatitis in newborn babies. The clinical course and duration of viremia in vertically transmitted HEV infection in neonates in not known. We studied 19 babies born to HEV infected mothers. Babies were studied at birth and on a monthly basis to evaluate clinical profile, pattern of antibody response and duration of viremia in those infected with HEV. Fifteen (78.9%) babies had evidence of vertically transmitted HEV infection at birth (IgM anti-HEV positive in 12 and HEV RNA reactive in 10) and three had short-lasting IgG anti-HEV positivity because of trans-placental antibody transmission. Seven HEV-infected babies had icteric hepatitis, five had anicteric hepatitis and three had high serum bilirubin with normal liver enzymes. Seven babies died in first week of birth (prematurity 1, icteric HEV 3, anicteric HEV 2 and hyperbilirubinemia 1). Nine babies survived and were followed up for clinical, biochemical, serological course and duration of viremia. Five of 9 babies who survived were HEV RNA positive. HEV RNA was not detectable by 4 weeks of birth in three babies, by 8 weeks in one and by 32 weeks in one. All surviving babies had self-limiting disease and none had prolonged viremia. Thus HEV infection is commonly transmitted from mother-to-foetus and causes high neonatal mortality. HEV infection in survivors is self-limiting with short lasting viremia.
Hepatitis E is an emerging infectious disease. This review will focus on recent advances in the zoonotic transmission, global distribution and control of hepatitis E.
Hepatitis E virus infection is known to cause waterborne epidemics and sporadic infections in developing countries. Recently, there have been several reports on zoonotic foodborne autochthonous infections of hepatitis E in developed countries. Hepatitis E typically causes self-limited acute infection. Recent reports have documented hepatitis E virus causing chronic hepatitis and cirrhosis in patients after solid organ transplantation. High incidence and severity of hepatitis E in pregnant women have been re-confirmed. The reason for high mortality in pregnant women remains ill understood. A recombinant hepatitis E vaccine has been evaluated in a phase 2, randomized, placebo-controlled trial in Nepal and was found to be well tolerated and efficacious.
There has been considerable advance in understanding the epidemiology of hepatitis E virus infections in western countries. The occurrence of chronic hepatitis in organ transplant recipients opens a new chapter in hepatitis E epidemiology. The report on an efficacious and well tolerated recombinant vaccine gives hope for control of the disease in the near future.
This study was undertaken to assess the role of person-to-person transmission in hepatitis E and the ability of immune serum globulin (ISG) from an Indian source to prevent such transmission. Seventy six subjects (62 household contacts of patients with sporadic hepatitis E and 14 controls with no household contacts) were studied clinically, biochemically and serologically at entry and fortnightly thereafter for the next 8 weeks. Thirty two household contacts received 2 mL of 16.5% ISG 16.5% while the other 30 household contacts and 14 controls received 2 mL of normal saline intramuscularly at entry. Eighteen (29%) household contacts and none of the control subjects developed biochemical evidence of acute hepatitis E (p less than 0.01). The enzyme elevation occurred after a mean interval of 31.0 +/- 4.5 days from the onset of disease in the index case. This suggested that the disease in the case contacts had been contracted by household contact with the index case and not by simultaneous infection of the index case and the household contact. The incidence of disease was similar in the household contacts receiving ISG and normal saline (25% and 33.3% respectively, p = ns). ISG had no effect on the time interval to SGPT rise or on the severity of disease in household contacts.