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 ~  Abstract
 ~ Introduction
 ~ Virus Biology
 ~ Epidemiology
 ~  Other Routes of ...
 ~ Clinical Features
 ~ Laboratory Diagnosis
 ~ Antiviral Treatment
 ~  Hepatitis E Viru...
 ~  References
 ~  Article Figures
 ~  Article Tables

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  Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 36  |  Issue : 3  |  Page : 317-323
 

Hepatitis E virus infection: An old virus with a new story!


Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India

Date of Web Publication14-Nov-2018

Correspondence Address:
Dr. Ekta Gupta
Department of Clinical Virology, Institute of Liver and Biliary Sciences, Sector D1, Vasant Kunj, New Delhi - 110 070
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_18_149

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 ~ Abstract 

Hepatitis E virus (HEV) infection is an important public health problem. HEV infection has been identified as a major cause of enterically transmitted acute sporadic hepatitis in India especially in adult age group. India is hyperendemic for HEV, with the disease presenting both as outbreaks and as cases of acute sporadic viral hepatitis. Most of these outbreaks can be traced to contamination of drinking water supplies with human fecal matter. The last decade has witnessed tremendous change in our understanding of the virus in its epidemiology, clinical features, diagnostic approaches, treatment options and the need for vaccination. With the identification of culture systems for HEV and development of animal models for its replication, knowledge regarding its replication and pathogenesis has evolved. This review attempts to discuss the nuances in our understanding of this virus, its pathogenesis and diagnosis, especially with reference to the Indian scenario.


Keywords: Diagnosis, epidemiology, hepatitis E virus, infection


How to cite this article:
Gupta E, Agarwala P. Hepatitis E virus infection: An old virus with a new story!. Indian J Med Microbiol 2018;36:317-23

How to cite this URL:
Gupta E, Agarwala P. Hepatitis E virus infection: An old virus with a new story!. Indian J Med Microbiol [serial online] 2018 [cited 2018 Dec 10];36:317-23. Available from: http://www.ijmm.org/text.asp?2018/36/3/317/245380



 ~ Introduction Top


Hepatitis E virus (HEV) infection is an important public health problem. The virus causes an estimated 20 million infections annually across the globe, leading to over 3 million symptomatic cases. As per the World Health Organization (WHO) estimates, there were approximately 44,000 hepatitis E-related deaths reported in 2015.[1]

Ever since the epidemic in the Kashmir valley, HEV infection was believed to be an acute infection limited to the developing world.[2] India is hyperendemic to HEV and it has been identified as a major cause of enterically transmitted sporadic and epidemic hepatitis in India. This is also the most important acute aetiology on an underlying chronic liver disease (CLD) leading to acute-on-chronic liver failure (ACLF).[3] The last decade has witnessed tremendous change in our understanding of the virus in epidemiology, clinical features, diagnostic modalities, treatment options and the need for vaccination. With the identification of culture systems for HEV and development of animal models for its replication, knowledge regarding its replication and pathogenesis has evolved. It has been proved beyond doubt that HEV can also cause chronic hepatitis in the immunocompromised hosts and this has caught the Western world off guard.[4] As the virus continues to perplex clinicians and virologists alike, this review attempts to discuss the nuances in our understanding of this virus, its pathogenesis and diagnosis, especially with reference to the Indian scenario.


 ~ Virus Biology Top


Classified in the genus Hepevirus under the family Hepeviridae, HEV is a small non-enveloped virus with a size of 27–34 nm. The virus has a positive sense, 7.2-kb, single-stranded RNA genome which contains three partially overlapping open reading frames (ORFs) flanked by non-coding regions. ORF1 encodes a non-structural 1693-amino acid long polypeptide that is involved in viral replication and protein processing. ORF2 encodes the viral capsid protein of 660 amino acids which serves as the most conserved region and provides a binding site for both neutralising antibody and cellular receptors, thus justifying its role as a vaccine target. ORF3 encodes a 123-amino acid long protein required for virion morphogenesis and egress from infected cells. Following a faecal–oral transmission, HEV reaches liver through small intestine and replicates in the cytoplasm of the hepatocytes. The virus is released into both blood and bile. HEV virions that circulate in the blood are usually surrounded by lipids and membrane-associated quasi-enveloped forms. These forms are recently discovered and their exact relevance is largely unknown, while the one that is shed into the faeces is in the non-enveloped form.[5] The virus is not cytopathic and the damage to liver is mainly immune mediated, induced by cytotoxic T-cells and natural killer cells.[6]

Hepeviridae is broadly divided into two genera Orthohepevirus and Piscihepevirus; Orthohepevirus is further divided into four species, namely A to D. Orthohepevirus A is the species infecting human, swine and other animals with possible human spread/transmission and Orthohepevirus B includes all three avian HEV strains. HEV has eight identified genotypes. Genotypes 1–4 and 7 display human tropism. Genotype 1 of the virus (HEV-1), predominant in Asia and Africa, and HEV-2, present in Mexico and parts of Africa, are restricted to human only.[2] HEV-3, which circulates amongst human, swine, rabbit and deer, has a worldwide distribution. HEV-4, mostly present in Southeast Asia, circulates between human and swine. HEV-5 and HEV-6, phylogenetically close to HEV-4, were identified in Japanese wild boars.[7] HEV-7 and HEV-8 were identified as camel genotypes in the Middle East,[8] but the recent report of chronic HEV-7 infection in a liver transplant recipient consuming camel milk and meat[7] highlights the potential of these novel genotypes to impact human health.


 ~ Epidemiology Top


HEV infection exhibits two characteristic epidemiologic patterns, distinct in endemic and non-endemic countries. In the tropical and subtropical areas of Asia, Africa, the Middle East and Central America, the disease is highly endemic and transmitted mostly through faecal–oral route. Maternofoetal and parenteral routes are less common modes of infection and are discussed in later sections. HEV infection in these areas causes acute sporadic hepatitis as well as outbreaks, with clinical presentations varying from self-limiting hepatitis to subacute and acute liver failure. The virus most commonly infects young adults and can cause severe disease in pregnant women and individuals with pre-existing CLD. Infection in endemic regions is caused largely by HEV genotypes 1 and 2. On the contrary, in the developed non-endemic regions such as the United States, Europe and Japan, HEV infection causes infrequent sporadic cases mostly in the elderly. While hepatitis E in the industrialised world was earlier believed to be associated with travel to the developing world, autochthonous infection is now a well-recognised entity.

India is hyperendemic for hepatitis E, with the disease presenting both as outbreaks and as cases of acute sporadic viral hepatitis. India has witnessed numerous outbreaks, most of which have been traced to contamination of drinking water supplies with human faecal matter. Discovery of hepatitis E came to limelight when the 1978 Kashmir epidemic of hepatitis was investigated. Kashmir recorded four major epidemics of hepatitis E from 1978 to 1982, which involved about 52,000 cases of icteric hepatitis and 1700 deaths.[9] [Table 1][10],[11],[12] enlists some outbreaks that have affected various parts of our country.
Table 1: Major outbreaks of hepatitis E virus infection in India

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HEV infection has been reported to account for up to 70% of adult cases with sporadic hepatitis in adults from our country.[3] Some epidemiological traits exhibited by the virus in both sporadic and epidemic cases include predominant involvement of adolescents and young adults, presentation as acute hepatitis with occasional fulminancy and severe disease in pregnancy. Person-to-person transmission and secondary attack rates amongst household contacts of infected patients are low, both in the sporadic and epidemic settings.


 ~ Other Routes of Transmission Top


Zoonotic transmission

It has been shown that autochthonous hepatitis E cases in areas of low endemicity are caused by zoonotic spread of infection from wild or domestic animals. Such cases are caused by HEV genotypes 3 or 4, in which inter-species transmission is well demonstrated. Pigs, boars and deer have been identified as reservoirs, and foodborne transmission by consumption of meat has been proven beyond doubt.[13] Direct contact with the infected animals and environmental contamination with animal excreta are other possible routes.[14]

On the contrary, zoonotic origin has not been shown for HEV-1 and HEV-2, prevalent in developing countries. In India, HEV infection is ubiquitous in several animal species, including domestic pigs, sheep, goats and buffalo. However, HEV-1 is responsible for human infections, while HEV-4 isolated from swine has failed to show transmissibility to human.[15] Interestingly, China, another highly endemic country, has witnessed a changing epidemiology of hepatitis E infection. Initially hyperendemic for HEV-1, HEV-4 is presently the dominant genotype infecting the Chinese population as well as animals.[16]

Parenteral transmission

Ability of the virus to cause subclinical infections and asymptomatic viraemia makes HEV potentially transfusion transmissible. Studies from many parts of the world have reported on-going subclinical infections in blood donors and transmission to blood or blood product recipients. The earliest report dates back to 2000 when Arankalle and Chobe from Pune, India, showed viraemia in 3 out of 200 blood donors suggesting the possibility of transfusion-associated infection, though post-transfusion hepatitis could not be demonstrated by molecular tools.[17] Thereafter, Khuroo et al. in their case–control study demonstrated significantly higher HEV infections in multiple transfused participants (13 out of 145) as compared to controls (2 out of 250). In another part of the same study, they prospectively found three cases of post-transfusion infection in 22 susceptible (IgG anti-HEV negative) patients, all of which were traced to viraemic but asymptomatic blood donors (4 out of 107).[18]

Thereafter, a number of studies across the globe have shown viraemia in healthy blood donors, HEV RNA positivity being 1 in 2848 in England, 1 in 744 in Japan, 1 in 672 in Germany and 1 in 3179 in China.[19],[20],[21],[22] Contrastingly, in a study in the US, HEV viraemia was absent in 1939 unselected blood donors, and no evidence of transmission was seen in 362 prospectively followed recipients.[23] Transmission of HEV through blood or blood products may have severe implications in immunocompromised hosts such as recipients of organ transplants and patients with haematological malignancies and possibly to pregnant women. Since blood transfusion appears to be only a minor route of HEV transmission, routine screening of blood donors may not be warranted. However, it may be worthwhile to screen each immunosuppressed patient with unexplained elevated liver enzymes for the presence of HEV RNA, especially in regions of high endemicity.

Vertical transmission

There has been increasing concern regarding vertical transmission of HEV during pregnancy, leading to poor foetal and neonatal outcomes. Bose et al. demonstrated replication of the virus in the placenta of infected pregnant patients.[24] Few studies demonstrating vertical transmission of the virus and its effect are enlisted in [Table 2]. High rates of vertical transmission of HEV and considerable neonatal mortality have been shown in these studies. The clinical profile of HEV-infected babies varies from elevated liver enzymes alone, elevated bilirubin alone or combination of the two. However, surviving neonates have had a self-limiting disease,[25] consistent with the natural history of HEV infection. There are no reports of chronic viraemia in neonates, although this is theoretically possible in an immunocompromised baby. Noteworthy is the fact that only genotype 1 HEV is associated with an adverse faetomaternal outcome. In a HEV genotype 1 hyperendemic country like ours, the virus continues to be a threat to mother and children alike.
Table 2: Vertical transmission of hepatitis E virus from mother to foetus

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 ~ Clinical Features Top


Hepatitis E is the most common cause of acute sporadic viral hepatitis in adults in India. Most infections by the virus are asymptomatic, and the disease is usually self-limiting. After an incubation period of 2–6 weeks, symptoms of hepatitis, including fever, nausea, vomiting, abdominal pain, anorexia, malaise and hepatomegaly, are seen. The course of the infection and the sequence of appearance of laboratory markers are depicted in [Figure 1]. About 60% of patients may become jaundiced. The virus affects mainly young adult males (15–30 years), but pregnant females are particularly vulnerable. The mortality rate may be as high as 30% during the 3rd trimester of pregnancy. It is also the most common cause of acute insult in an underlying CLD referred as ACLF as reported by us earlier.[3] Extrahepatic manifestations including neurological disorders and impaired kidney functioning can also rarely occur in hepatitis E. A few special clinical conditions associated with hepatitis E deserve a mention and are elaborated below.
Figure 1: Schematic representation of hepatitis E virus infection, including appearance of various laboratory markers

Click here to view


Hepatitis E virus in pregnancy

A unique feature of hepatitis E outbreaks is the occurrence of a higher disease attack rate and excess mortality rate amongst pregnant women. Pregnant women die of obstetric problems, including haemorrhage or eclampsia, or develop fulminant hepatic failure. The mortality rate can be as high as 30% and usually occurs in the 3rd trimester.[30] Premature delivery, low-birth-weight neonates and stillbirths are common. High vertical transmission rates and neonatal morbidity and mortality have been discussed in a previous section. A number of studies have tried to elucidate the reason underlying the association of hepatitis E and pregnancy. The immunological and hormonal changes that ensue in pregnancy are implicated for the same. Decreased T-cell activity, increased levels of oestrogen, progesterone and β-human chorionic gonadotropin, increased tumour necrosis factor-α, decreased cytokine production and an overall shift to Th2 immunological profile are some of the postulates studied.[30] The excess mortality in pregnancy is a characteristic feature of HEV genotypes 1 and 2, although there are a few documented cases by genotypes 3 and 4.[31]

Hepatitis E virus in acute-on-chronic liver failure

ACLF is an increasingly recognised entity which refers to acute deterioration of liver function in individuals with pre-existing CLD, secondary to a precipitating event. By far, HEV infection is thought to be the most common aetiology of acute event deteriorating the underlying liver condition, especially in India.[3],[32] The mortality associated with HEV-related ACLF is variable with average around 34%; in few studies, a very high mortality up to 67% is also reported.[33] The first report of HEV superinfection causing severe decompensation in CLD patients was published from Pakistan in 2002.[34] In 2004, three groups from different parts of India reported considerable morbidity and mortality by HEV in participants with CLD. Ramachandran et al. from Vellore found nine patients of CLD to be superinfected with HEV, of whom six died of advanced liver failure.[35] Kumar et al. from Lucknow studied 32 ACLF cases, of whom 14 (44%) were attributable to hepatitis E, in contrast with 3 out of 48 (6%) controls with stable cirrhosis.[36] Two of the 14 patients succumbed to the infection. Similarly, Monga et al. from Delhi diagnosed HEV superinfection in 10 CLD cases, with a mortality rate of 30% (3/10).[37] Hyperendemicity of the virus in India was thought to be one of the reasons behind this; however, a few recent studies have shown results not completely coherent. A recent study from New Delhi[38] involving 368 ACLF cases found alcohol consumption to be the major culprit (150 [40.8%] patients), followed by hepatitis B virus (HBV) infection (71 [19.3%] patients) and then HEV superinfection (45 [12.2%] patients). Moreover, the mortality in HEV-ACLF group (17.8%) was lower than alcohol-ACLF (64.0%), cryptogenic-ACLF (62.7%) and HBV-ACLF (45.1%). A case–control study conducted in Gambia, West Africa, where HEV infection is also endemic, did not find any case of hepatitis E in 40 cases of ACLF or 71 controls.[39]

Hepatitis E virus infection in solid-organ transplant recipients

Recent studies from developed countries have identified chronic infections in immunocompromised individuals, especially solid-organ transplant (SOT) recipients including kidney, liver, heart and pancreas.[4] More than half of acute HEV infections in the transplanted individuals progress to chronicity.[40] It is noteworthy that almost all cases of chronic HEV infection are attributable to genotype 3, other than rare reports of persistent HEV genotype 4 infection.[41]

It is still under debate whether HEV-1 or HEV-2 can also induce chronic hepatitis E. Screening of renal transplant recipients receiving immunosuppressive therapy with elevated alanine transaminase from India showed no HEV involvement.[42] However, a recent case report showed chronic infection with HEV-1 leading to CLD in a child cured of acute leukaemia from India.[43] In a recent study published by us where we screened 30 liver transplant recipients for HEV infection before and till 6 months after transplant, the evidence of HEV exposure was seen in 6 (20%) cases post-transplant, but none of the recipients demonstrated active viraemia or antigenemia.[44] This suggests that the circulating genotype of HEV in our population might have limited potential to cause chronic infections. More evidence needs to be generated to associate the genotype of the virus with causation of chronic infection.


 ~ Laboratory Diagnosis Top


Since hepatitis E is difficult to differentiate from other aetiologies of acute viral hepatitis clinically, laboratory confirmation is essential. Serology is the mainstay of the diagnosis of the infection. Infection with the virus elicits IgM and IgG, in addition to IgA antibody response. IgM anti-HEV rises rapidly within a month of the infection, the peak coinciding with the symptoms and liver enzyme derangement. The IgM response weans by 32 weeks and is followed by an IgG response which lasts long, the exact duration of positivity being variable. Immunoassays detecting anti-HEV IgM are the most commonly employed methods for diagnosing a recent HEV infection. These assays target immunodominant parts of the ORF2 and ORF3 proteins and exhibit wide variations in sensitivity and specificity,[45] with performance being better in endemic areas. Very often, high titres of IgG coexist with IgM in acute infections in endemic areas, interfering with assay performance. IgM capture assays overcome this phenomenon and exhibit better performance. Immunochromatographic tests for IgM detection have also been devised, with reasonable sensitivity and specificity.[46] Isolated anti-HEV IgG positivity denotes past exposure and has been used in seroprevalence studies. Again, wide variations in assay characteristics make it difficult to compare seroprevalence rates both within and beyond geographic locations.[47] Serum anti-HEV IgG levels may be a useful marker of protection post-vaccination or natural infection. A vaccine study found an antibody concentration of 2.5U/ml to be protective.[48]

It was until a decade ago that HEV RNA detection was considered an epidemiologic tool rather than a diagnostic one. Viraemia appears very early in the disease and would test positive only if the patient is sampled in the early symptomatic phase, disappearing from blood in 3 weeks and from faeces in another 2 weeks. However, in the immunocompromised host, HEV RNA in blood becomes the first-line diagnostic test due to impaired antibody production. HEV RNA detection in blood or stool for 3 months is also necessary to establish chronicity of the infection. HEV RNA measurement is also needed to monitor response to antiviral treatment. Another potential application of nucleic acid testing is in blood donor screening, considering the fact that transfusion-transmitted HEV is becoming an increasingly recognised entity, especially in endemic areas.[49] A number of in-house and commercially available real-time polymerase chain reaction (PCR)-based assays are available, most of them targeting ORF3. The recently established the WHO international standard (genotype 3a) would go a long way in standardisation and comparison of molecular techniques. The newly developed loop-mediated isothermal amplification assay is a cost-effective and suitable tool for resource-limited settings.

Genotyping is needed to determine the distribution of viral strain and epidemiological studies.

Detection of HEV antigen (HEV Ag) is an effective alternative to nucleic acid detection and will help establish an early acute infection. Studies have found a good correlation between HEV Ag and HEV RNA.[50],[51] Antigen detection can be a good cost-effective alternative to real-time PCR. [Table 3] enlists the utilities of the various markers of hepatitis E infection.
Table 3: Diagnosis of hepatitis E virus infection

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Till, a few years ago, cell culture system for HEV was inefficient and limited, which hampered in vitro study of the basic biology of the virus. First robust cell culture systems were developed by researchers from Japan using PLC/PRF/5 (human hepatocarcinoma) and A549 cells (human lung adenocarcinoma).[52],[53] HEV stains from both serum and stool samples could replicate efficiently on these cell lines. Thereafter, HepG2/C3A cells, also derived from human hepatocarcinoma, permitted replication of the HEV-3 Kernow strain purified from the faeces of a chronically infected patient.[54] Replication is dependent on the HEV RNA concentration in the inoculum but is not hampered by the presence of anti-HEV antibodies in serum.[53] Recently, complete replication cycle of HEV could be recapitulated in hepatocytes derived from pluripotent stem cells, which could serve as an attractive tool to study the virus biology.[55] Hopefully, these new in vitro culture systems would play a significant role in our understanding of the viral pathogenesis.


 ~ Antiviral Treatment Top


Acute hepatitis E in immunocompetent persons usually requires only symptomatic management, as most of them are able to clear the virus spontaneously. Ribavirin has been used to treat cases of fulminant HEV infection and ACLF.[56],[57] In SOT patients with chronic HEV infection, the reduction of immunosuppressive therapy, especially of agents that target T-cell function, is the first-line therapy. In patients who do not respond in 3 months and in those with a high immunological risk, ribavirin monotherapy for 3 months is advisable.[58] Viral persistence in stool or serum after 3 months of therapy warrants ribavirin administration for additional 3 months. If HEV viraemia increases after ceasing ribavirin therapy, a 6-month long course of ribavirin can be proposed. Pegylated interferon therapy for 3 months may be considered for refractory cases of liver transplantation but not for other SOTs.[58] Recently, sofosbuvir (SOF), a direct-acting antiviral with activity of hepatitis C virus RNA-dependent RNA polymerase inhibitor, has been shown to be inhibiting HEV RNA replication in the replicon systems.[59] The combination of SOF and ribavirin might result in an additive antiviral effect. However, there is very little evidence available to support its role as of now.


 ~ Hepatitis E Virus Vaccine Top


HEV is the leading cause of acute sporadic hepatitis worldwide. Although the disease is benign and self-limiting in the vast majority of cases, it can cause significant morbidity in individuals living in suboptimal living conditions, like those in refugee camps and military recruits. Moreover, hepatitis E can run a severe course in pregnant women and patients with CLD. Immunocompromised hosts are at risk of developing chronic infection. Considering all of this, an efficacious and safe HEV vaccine is desirable.

Since the virus has a single serotype, a univalent vaccine would provide protection against all the HEV genotypes. This fact has made the development of a HEV vaccine reasonable. Two recombinant candidate HEV genotype 1 vaccines i.e. recombinant HEV, developed by GlaxoSmithKline, and HEV 239 (trade name Hecolin), developed by Innovax (Xiamen, China), have been evaluated in clinical trials. Of the two, Hecolin has been licensed for use in China since 2012. It is a recombinant vaccine consisting of 239 (368-606) amino acid region of ORF2 from HEV-1 expressed in Escherichia coli. Three doses of the vaccine administered at 0, 1 and 6 months are recommended for use in individuals more than 16 years of age. The vaccine has been shown to provide sustained protection against hepatitis E for up to 4.5 years, efficacy being 86.8%.[60] However, there is a lack of data regarding safety of the vaccine in high-risk groups like transplant recipients, patients with underlying CLD, paediatric patients and the elderly. There is limited evidence about the safety of the vaccine in pregnant women.[61] Whether the vaccine should show similar efficacy in a hyperendemic country like ours with a much greater background HEV attack rate than China is still questionable. More evidence needs to be generated in above mentioned groups before any decision is taken regarding its routine use in national programmes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

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2004 - Indian Journal of Medical Microbiology
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