A clinical textbook

Hepatology 2018

4. Hepatitis E: a relevant disease with many aspects

Sven Pischke and Heiner Wedemeyer

Introduction

Hepatitis E is an inflammatory liver disease caused by the hepatitis E virus (HEV): This infection has been described to be endemic in many tropical countries with reduced sanitary conditions in the 1980ies. For more than two decades it has been considered to be a travel-associated, acute, self-limiting liver disease that only causes fulminant hepatic failure in specific, high-risk groups (Pischke 2013b). It has recently been estimated that HEV infection causes approximately 56,000 deaths each year worldwide (WHO 2014). Within the last decade sporadic cases of HEV infections have emerged also in industrialised countries, mostly caused by HEV genotype 3, for which zoonotic transmission has been described (Wedemeyer 2012, Pischke 2013).

In immunocompetent individuals infection with HEV usually leads to a clinically silent seroconversion or to an acute self-limited inflammation of the liver. In pregnant women and patients with pre-existing chronic liver diseases cases of fulminant liver failure by HEV infection are reported (Wedemeyer 2012).

Moreover, cases of chronic HEV infection associated with progressive liver disease have been described in several cohorts of immunocompromised individuals. In this context, diagnosis of HEV infection should rely on detection of HEV RNA, as testing for HEV-specific antibodies may lack sensitivity (Pischke 2010b).

To study the in vitro replication of HEV and possible inhibitors a stem cell derived cell culture system has been established and the in vitro antiviral effect of ribavirin and interferon has been demonstrated (Helsen 2015). Furthermore human liver chimeric mice have been established as a new model of chronic hepatitis E virus infection for preclinical drug evaluation (Allweis 2016, Sayed 2016). Furthermore, there is increasing evidence that HEV-specific T cell responses contribute to the control of HEV infection (Suneetha Hepatology 2012). Very recently, HEV-specific T cell responses have been characterised targeting the entire HEV genome without distinct immunodominant regions (Brown 2016).

Therapeutic options for chronic hepatitis E include reduction of immunosuppressive medication (Kamar 2011a), treatment with interferon α (Haagsma 2010, Kamar 2010a) or therapy with ribavirin (Kamar 2010b, Mallet 2010, Pischke 2013a, Kamar 2014). Recently the direct acting antiviral (DAA) sofosbuvir, which has been developed for the treatement of hepatitis C has been shown to be effective against HEV in vitro as well as in some single patients, while other patients did not respond to sofosbuvir treatment (Dao 2016, van der Valk 2017, Donelly 2017, de Martin 2016).

In 2012 a recombinant HEV vaccine was approved for use in China. This vaccine showed an efficacy of >90% in preventing acute symptomatic hepatitis E (Zhu 2010). It is unknown yet if and when this vaccine might become available in other countries.

In 2018 the European Association for the Study of the Liver (EASL) released their clinical practice guidelines on hepatitis E (EASL 2018).

Genetic characteristics of HEV

The hepatitis E virus is a non-enveloped, single-stranded RNA virus (Wedemeyer 2012). HEV has been classified into the species Orthohepevirus A in the virus family Hepeviridae. Other species within this familye (Orthohepevirus B-D) infect a wide range of mammalian species including rodents and bats. The relevance of these species for humans is still under debate.

Previously 4 different classical HEV-genotypes (HEV GT 1-4) and 24 subtypes (1a–1e, 2a, 2b, 3a–3j, 4a–4g) have been separated (Meng 1999). However, basing on the identification of HEV-strains from rabbits, wild boars and camels a novel classification separated 8 HEV-genotypes and various subtypes have been identified (Smith 2016). The HEV genome includes two short non-coding regions surrounding three open reading frames (ORF 1 to 3). These ORFs contain the genetic information for various proteins that are necessary for capsid formation, virus replication and infectivity of HEV. Recently a novel viral protein named ORF 4 was identified which is specific to HEV GT 1 (Nair 2016).

HEV genotype 1 is responsible for endemic and epidemic infections by HEV in Asia and Africa, while genotype 2 is endemic in Western Africa and Mexico (Figure 1). These genotypes are usually transmitted fecal-orally by contaminated drinking water under conditions of poor sanitation. Only one study has described the possibility of HEV genotype 1 of infecting swine (Caron 2006). There is no known further report on zoonotic transmission for this genotype.
In contrast, HEV genotype 3 can be found in humans and animals in Europe, the US and Asia (Wedemeyer 2012). For this genotype, zoonotic transmission, foodborne transmission or via contact with infected animals has been well described.

Figure 1. Worldwide distribution of the four classical humanoathogenic HEV genotypes (GT 1–4)

Hepatitis E diagnosis

In immunocompetent patients the diagnosis of hepatitis E usually relies on the detection of HEV-specific antibodies. While IgG antibodies indicate acute and past HEV infections, IgM antibodies can only be found in patients with recent infections (Wedemeyer 2012), while HEV-specific IgG antibodies can be detected in patients with previous contact with HEV and ongoing HEV. There are different commercial assays available for detection of HEV-specific IgM and IgG antibodies. Comparison of six anti HEV IgM assays reveals a wide variation of diagnostic sensitivities and specificities as well as interassay disagreements (Drobeniuc 2010). A large European meta-analysis studying 73 studies demonstrated the large inter-assay variability and showed large differences in IgG seroprevalence rates between different European countries (Hartl 2016). The country with the highest seroprevalence rate was France, while the lowest anti-HEV frequency was described for Great Britain (Hartl 2016). Recently a further meta-analysis compared the anti HEV IgG seroprevalence in North and South America (Horvatits 2018). Hepatitis E virus is common in the USA, while the risk of HEV exposure was lower in many poorer South American countries. Thus a higher socioeconomic status does not protect populations from hepatitis E virus exposure. In addition the study demonstrated that anti HEV IgG seroprevalence did not differ significantly between Europe and the USA. Hence, hepatitis E virus is not limited to countries with low sanitary standards, and a higher socioeconomic status does not protect populations from hepatitis E virus exposure.

In addition to serological tests detection of HEV RNA by PCR has been established, to prove ongoing infection. Numerous assays using different primers have been developed (Meng 1999, Zhao 2007). Furthermore, quantitative PCR assays have been described (Ahn 2006, Enouf 2006). Recently a novel WHO-approved RNA standard assay has been developed (Baylis 2011).

In immunocompromised individuals, diagnosis of HEV infection may only be based on the detection of HEV RNA as seroassays lack sensitivity especially in the early phase of infection (Pischke 2010b). HEV RNA can not only be detected in serum samples but also in stool (Wedemeyer 2012), and thus infectivity of HEV infected persons can be determined by investigating stool for HEV RNA. Furthermore HEV RNA and HEV antigen could be detected in urine of patients with acute and chronic hepatitis E as well as in experimentally infected monkeys (Geng 2016), but the clinical relevance of this observation still needs to be determined. An HEV antigen assay for detection of HEV has been recently described (Gupta 2013). HEV antigen and HEV RNA show significant correlations but the sensitivity of HEV antigen testing might be lower (Zhao 2015). Analysis of a small outbreak of hepatitis E affecting 5/24 travelers to India showed that none of them tested positive for the antigen assay, while all of them were HEV RNA positive (Pischke 2017). This indicates the poor sensitivity for this assay for the detection of genotype 1 infections.

Worldwide distribution of HEV infections

Hepatitis E causes more than 70,000 deaths each year worldwide (Rein 2011). Most of these cases occur in the tropics, in areas with reduced hygienic standards, due to poor sanitation. Outbreaks in refugee camps are of major relevance, as reported in 2013 from the Sudan (CDC 2013).

However, the disease is not limited to developing countries. In the last few years an increasing frequency of diagnosed cases of HEV infections has been reported from various industrialised countries (Wedemeyer 2012, Adlhoch 2016). The presence of HEV RNA in urban sewage samples from Spain, the US and France has been shown, suggesting that HEV may be more prevalent in industrialised countries than previously assumed (Clemente-Casares 2003). In each of these three countries it was possible to discover HEV contamination in sewage samples in a notably high frequency. These findings may partially explain the huge gap between seroprevalence rates and the rather low numbers of diagnosed and reported cases of acute hepatitis E in western countries. The mismatch between high seroprevalence rates and the low number of symptomatic cases has also been investigated in a recent study from Egypt. 919 anti-HEV seronegative individuals from rural Egypt were followed and, interestingly, 3.7% (n=34) of these individuals seroconverted to anti-HEV within 11 months of follow up (Stoszek 2006). However, none of these 34 individuals suffered from symptomatic hepatitis E. This finding corresponds with data from a recently published large vaccine study performed in China where very few of the patients in the placebo group who seroconverted during a follow-up period developed symptomatic acute hepatitis E (Zhu 2010). Overall, these data suggest that far less than 5% of all contacts with HEV lead to symptomatic hepatitis E (Wedemeyer 2011). In contrast to these findings small or large outbreaks may occur. E.g. an outbreak including five symptomatic, viraemic patients could be observed within a group of 24 German travelers to India (Pischke 2017).This demonstrates that some strains of HEV might lead to a higher clinical manifestation rate under special circumstances.

A rapid increase in reported HEV infections has been recognised in several industrialised countries over the last decade (Adlhoch 2016). To investigate the potential underlying reasons for this phenomenon, we analysed the time trend of the anti-HEV seroprevalence in healthy German individuals versus the number of reported cases of acute hepatitis E. Even though the number of reported cases has increased more than 5-fold in the last ten years (Figure 2), the anti-HEV IgG seroprevalence rate remained rather stable over the last 15 years (Pischke 2011a). In contrast, the number of scientific articles on HEV infections published in PubMed increased sharply during the same period (Figure 2). These findings may indicate that the increase of reported HEV cases in Germany and other industrialised countries is based on an increased awareness associated with more frequent diagnosis of hepatitis E but not a true increase in incidence rates (Pischke 2011a). In contrast to this observation, in the Netherlands the number of HEV positive blood products significantly increased between January 2013 and December 2014 indicating that new HEV transmission routes resulting an higher exposure of the general population of the Netherland might exist (Hogea 2015). However, this observation needs to be verified in further studies.

Figure 2. Number of reported HEV infections in Germany over the last decade and number of publications on HEV over the same time period.

Transmission of HEV

The vast majority of HEV infections worldwide is transmitted by the fecal-oral route. Patient-to-patient transmission is very rare but has been described from a large outbreak in Northern Uganda (Teshale 2011) and from hematology wards in Europe (Wedemeyer 2012). Blood borne transmission of HEV was suggested already in the late nineties (Fainboim 1999). Subsequent studies from Hong Kong, Japan, Great Britain and France confirmed blood transfusions as a possible source of HEV transmission (Wedemeyer 2012). A study from Germany investigating 1019 blood donors determined, that 0.35% seroconverted within 1 year (Juhl 2013). Another large study in 18737 German blood donors demonstrated a rate of 0.1% to be HEV RNA positive (Westhölter 2018). Consumption of uncooked pig meat could be identified as source of infection in the majority of the viremic donors. A study from the Netherlands revealed that 13 out of 40,176 blood donors were HEV-viremic (Slot 2013). These data correspond to one HEV positive blood donation per day in the Netherlands. A large study from England investigating 225,000 blood products confirmed blood transfusions as a possible source for HEV transmission with 0.035% of blood products being viremic for HEV (Hewitt 2014). Post-transfusion infections were associated with viral load in the blood product and absence of HEV antibodies. In the United States, a study identified two HEV RNA positive samples among 18,829 tested donations (Stramer 2015).

A study from the Netherlands estimated a viraemia duration of 68 days in apparently healthy blood donors with subclinical HEV infections (Hogema 2015). In line with these findings a study from Germany on 27 HEV viremic blood donors recently reported a median time span for confirmed HEV RNA viral clearance of 55 days (Kraef 2018). Three of these donors experienced prolonged viraemia of more than 100 days. At donation,serological testing failed to identify viremic donors as 70.4% of viremic donors had no detectable antibody response. The median time until first detection of anti-HEV IgM or IgG in antibody-naïve donors was 53 and 57 days respectively.

In contrast to blood-borne HEV infection, only three cases of HEV transmission by transplantation of a graft (liver or kidneys) from a patient with occult hepatitis E have been reported (Schlosser 2011, Pourbaix 2016).

Zoonotic transmission of HEV has been assumed to be the main source of HEV infections in industrialised countries (Figure 3). Both direct contact with HEV-infected domestic animals and foodborne transmission are possible (Wedemeyer 2012). Commercial food products such as pig meat may be contaminated with HEV as shown in studies from the Netherlands, France and Germany (Colson 2010, Melenhorst 2007, Wenzel 2011). Meat should be cooked higher than70°C to prevent foodborne HEV infections (Emerson 2005, Johne 2016). Interestingly an HEV infection transmitted by camel meat leading to chronic hepatitis E in a liver transplant recipient has been demonstrated (Lee 2015). Although this is surely of limited relevance in European countries and the USA it highlights a novel mode of transmission in Arabian countries.

Figure 3. Possible sources of HEV infection

Acute hepatitis E in immunocompetent individuals

In the vast majority of cases, contact with HEV takes an asymptomatic course (Stoszek 2006, Wedemeyer 2012, Wedemeyer 2013), especially if the contact happens during childhood (Buti 2008). Immunocompetent individuals should be able to clear the virus spontaneously. In symptomatic cases the incubation period of HEV infections ranges from three to eight weeks with a mean of 40 days (Wedemeyer 2012). Recently a study focusing on 85 travel-related HEV genotype 1 infetions found a median incubation period of 30m days (Azman 2018). The peak of HEV viraemia can be detected in the early phase of infection while the peak of ALT elevation usually occurs around 6 weeks after infection (Wedemeyer 2012).

Initial symptoms in acute hepatitis E are typically unspecific and can include flu-like myalgia, arthralgia, weakness and vomiting. In some patients jaundice, itching, uncoloured stool and darkened urine occur accompanied by elevation of liver transaminases, bilirubin, alkaline phosphatase and gamma-glutamyl transferase.

HEV infection can lead to more severe acute liver disease in pregnant women or patients with underlying chronic liver diseases progressing to fulminant hepatic failure in individual cases (Wedemeyer 2012). Possible explanations for the more severe course in pregnant women are hormonal and immunological changes during pregnancy (Navaneethan 2008). Recently an association between reduced expression of the progesterone receptor and fatal outcome of hepatitis E in pregnant women has been reported (Bose 2011).

Single cases of prolonged courses of HEV infection in immunocompetent individuals with up to two years of viraemia have been described from France (Mallet 2010), Spain (Gonzalez Tallon 2011) and China (Liu 2011). However, no case of HEV-associated liver cirrhosis or development of hepatocellular carcinoma has been reported in immunocompetent individuals. Prolonged HEV viraemia may indicate a previously undiagnosed disturbance of the immune system in otherwise healthy individuals (Höner zu Siederdissen 2014).

Acute and chronic HEV infections in organ transplant recipients

Chronic courses of HEV infection have been described in European liver or kidney transplant recipients since 2008 (Gerolami 2008, Haagsma 2009, Kamar 2008, Pischke 2010b, Behrendt 2014). 14 cases of acute hepatitis E were initially reported in kidney- and liver-transplanted patients from southwest France (Kamar 2008). Eight of them developed a chronic course leading to persistently elevated ALT levels, significant histological activity and fibrosis after a follow-up of more than 12 months (range 10 to 18). Subsequently, additional cases of chronic HEV infections have been reported in transplant patients by several groups (Wedemeyer 2012), clearly demonstrating that chronic hepatitis E can be associated with progressive liver disease in patients after organ transplantation (Kamar 2011c).

A study from Germany examined 226 liver-transplant patients and 129 patients with chronic liver disease to evaluate the frequency of chronic HEV infections in liver transplant recipients in a low endemic country (Pischke 2010b). All patients were tested for HEV RNA and anti-HEV IgG. Two cases of chronic HEV infections in liver transplant patients were identified. One of them developed significant liver fibrosis (ISHAK F3) within less than 2 years. Both patients were infected with HEV genotype 3. The possibility of reverse zoonotic transmission was experimentally confirmed by infecting pigs with a patient’s blood. HEV RNA was detectable in various organs of the pigs including muscle. Thus, these findings further support the recommendations that eating uncooked meat should be avoided by organ transplant recipients as this may represent a source for acquiring HEV infection.

Retrospective data on hepatitis E in transplant recipients were summarised from 17 centres. Overall, 85 cases of HEV infection were described, 56 (66%) of whom developed chronic hepatitis E. Of note, chronicity was associated with the use of tacrolimus and with low platelet count (Kamar 2011c). However it has to be considered that the vast majority of patients had been recruited by one centre and experiences from other regions and transplant centres need to be reported.

Chronic courses of HEV infection have also been reported in heart transplant recipients (de Man 2011, Pischke 2012b). A study from Germany investigating heart transplant recipients and non-transplant cardiac patients revealed that the seroprevalence of HEV-specific antibodies is increased 5-fold in these patient groups in comparison to healthy controls (Pischke 2012b). It has been assumed that medical procedures, especially blood products, could explain this difference in seroprevalence rates.

Chronic HEV infections have also been described in lung transplant recipients from the Netherlands (Rizebos-Brilman 2013) and Germany (Pischke 2014).

Overall, all recipients of solid organ transplant with elevated liver enzymes should be tested for HEV RNA unless other obvious reasons already explain the hepatitis. In immunosuppressed patients, testing for HEV RNA should be applied as antibody testing may lack sensitivity. Distinct immunosuppressive drugs may indirectly or directly affect HEV replication, which needs to be considered in the management of organ transplant recipients (Behrendt 2014).

In contrast to solid organ transplant recipients, studies from Germany (Koenecke 2012) and France (Abravanel 2012) did not observe any case of chronicity in stem cell transplant recipients, leading to the assumption that this phenomenon is rare in this patient population. However, a large study from the Netherlands, investigating 328 stem cell transplant recipients, identified 8 cases (2.4%) of chronic HEV viraemia. Four of these patients died after development of hepatitis, while the other four patients cleared HEV infection after a median period of 6.3 months. These data demonstrate that chronic HEV infections in stem cell transplant recipients are indeed relevant (Versluis 2013).

Hepatitis E in patients with HIV infection or other immunological deficiencies

Chronic hepatitis E was described for the first time in a patient with underlying HIV infection in 2009 (Dalton 2009). This patient had a CD4 T cell count of less than 200 cells and high HIV RNA levels (>100,000 copies/mL). However, subsequent studies from Spain (n=93) (Madejon 2009), Germany (n=123) (Pischke 2010a) and England (n=138) (Keane 2012) could not identify cases of chronic hepatitis in HIV-infected individuals. HEV RNA was detected for more than 10 months in only one out of 184 HIV positive individuals in France (Kaba 2010). This patient had particularly low CD4 counts (<50 cells/mm) while two additional patients with higher CD4 levels were able to clear HEV spontaneously. Thus, persistent HEV infection is rarely observed in HIV-infected patients. However, it has been demonstrated that HEV may still persist in single HIV infected patients despite improvement of their immune system (Kuniholm 2015, Ingiliz 2016).

In addition to HIV positive patients, chronic HEV infections in patients with different underlying conditions of immunosuppression including lupus erythematodes, granulomatosis, retroperitoneal fibrosis or CD4 deficiency have been reported (Grewal 2013, Höner zu Siederdissen 2014). In contrast to these diseases there was no case of chronic HEV infection within a German cohort of 73 patients with common variable immunodeficiency (CVID). It has been hypothesised that eventually regular immunoglobulin infusions in these patients may have protected them from infection (Pischke 2012a).

Extrahepatic manifestations of hepatitis E

Several symptoms have been assumed to be extrahepatic manifestations of acute or chronic or previous HEV infections (Pischke 2016). Neurological symptoms associated with acute or chronic HEV infection have been described in single cases in the past few years (Kamar 2011b). More recently, HEV infections were linked with neuralgic amyotrophy (van Eijk 2014) and Guillain-Barré syndrome (Van den Berg 2014). Especially the association of HEV and neuralgic amyotrophy seems to be proven. Within a large multicentric study 57 patients with neuralgic amyotrohy and simultaneous HEV infection have been compared with 61 neuralgic amyotrophy cases without HEV infection (van Eijk 2017). Those patients with HEV infection showed significantly more frequently bilateral involvement, damage outside the brachial plexus and involvement of phrenic nerve and lumbosacral plexus injury (van Eijk 2017). Furthermore a study on patients presenting with various non-traumatic neurological symptoms (n=464) identified that 2% had current/recent HEV infection, including patients with neuralgic amyotrophy, cerebral ischaemia or encephalitis (Dalton 2017). In addition to this observation a Chinese study found 5% of Myasthenia gravis patients (n=188) to be anti HEV IgM positive and 2% were viremic (Wang 2018). Thus there is an association of HEV infections with various neurological diseases.

Various additional case reports describing associations of HEV infection with cases of pancreatitis, thyroiditis and haematological disorders were published (Kamar 2015). The underlying mechanisms and the clinical relevance of these associations require further investigation. Possible explanations may be distinct features of heterologous immunity of HEV and HEV replication in non-liver tissues (Wedemeyer 2016).

In addition, an increased anti-HEV seroprevalence rate in patients with autoimmune hepatitis has beenreported, indicating a possible role of previous HEV infections in later development of autoimmune hepatitis (Pischke 2014).

It still needs to be determined if extrahepatic manifestations are caused by direct effects of the virus or if, indirectly, immunological mechanisms are responsible (Pischke 2016). A possible link between HEV and cryoglobulinaemia has been suggested (Pischke 2014, Kamar 2012).

Treatment of chronic hepatitis E

Treatment options for chronic hepatitis E include reduction of immunosuppression, administration of pegylated interferon α or use of ribavirin. The first step in the treatment of chronic HEV infection should be to evaluate if it is possible to reduce the immunosuppressive medication (Wedemeyer 2012). Reduction of immunosuppression in 16 solid organ transplant recipients with chronic hepatitis E led to clearance of HEV in 4 cases (25%) (Kamar 2011a). A second possible treatment option is the use of PEG-IFN α (Haagsma 2010, Kamar 2010a). Treatment durations varied between 3 and 12 months. Overall, 4 out 5 patients were successfully treated with sustained clearance of HEV RNA. However, the use of interferon can be associated with significant side effects and may cause rejection in organ transplant recipients. Interferon α is therefore not recommended in heart or kidney transplant recipients. The antiviral efficacy of ribavirin monotherapy has been evaluated by two French groups (Kamar 2010b, Mallet 2010). A sustained virologic response was observed in 2/2 and 4/6 treated patients, respectively. Ribavirin has also been used in a non-transplanted patient with severe acute hepatitis E who showed rapid improvement of symptoms and liver function tests during treatment (Gerolami 2011).

A study from France demonstrated the safe use of ribavirin in non-transplant individuals with acute HEV genotype 3 infections (Peron 2015). Furthermore the use of ribavirin has been demonstrated in one single case with severe HEV genotype 1 infection (Pischke 2013a). Starting and stopping rules for ribavirin treatment of acute hepatitis E still need to be defined. In contrast to immunocompetent individuals, in solid organ transplant recipients with chronic HEV infection ribavirin remains a frequently used therapeutic option. A multicentre French study confirmed that treatment of chronic HEV infections in transplant recipients with ribavirin is safe and efficient (Kamar 2014). However, ribavirin treatment failures have been described (Pischke 2012b, Pischke 2013a) that may be linked to selection of a distinct HEV polymerase variant (G1634R) with increased replication fitness (Debing 2014). Still, the role of the G1634 variant for treatment response requires further investigation if it increases the risk of ribavirin treatment failure (Lhomme 2015). The G1634R variant has been detected as a minor viral population already before therapy in patients with subsequent treatment failure (Todt 2016). Of note, ribavirin induces HEV mutagenesis in vivo and additional HEV variants may emerge during treatment (Todt 2016).

Sofosbuvir displays activity against HEV in vitro (Dao 2016). It has been debated that the dose required to induce antiviral effects might be much higher than steady state concentrations achieved in patients with the standard sofosbuvir dose of 400 mg qd (Wang 2016). Nevertheless, a decline in HEV RNA was observed in a patient who failed to clear HEV with ribavirin therapy who received sofosbuvir but viral relapse occurred after the end of therapy (Van der Walk 2017). Another patient who has been co-infected with HCV and HEV and who was treated with sofosbuvir and daclatasvir did not show a virological response concerning HEV. Thus, further research is required to answer the question if sofosbuvir, could have a role in the therapy of chronic hepatitis E. Currently there is a registered ongoing study (Sof-E) evaluating the effect of sofosbuvir in chronically HEV infected patients who failed to achieve HEV clearance under ribavirin treatment.

An in vitro study demonstrated that silvestrol, a natural compound isolated from the plant Aglaia foveolata is a potent inhibitor of the release of HEV infectious viral particles (Biedenkopf 2017). The clinical relevance of this finding still needs to be studied.

Vaccination

A vaccine developed by GSK and the Walter Reed Army Institute that was successfully tested in a phase 2 study (Shrestha 2007) has not been further developed. A group from China reported data from a very large successful phase 3 vaccine trial (Zhu 2010). This trial included almost 110,000 individuals who received either a recombinant HEV vaccine (“Hecolin”) or placebo. The vaccine efficacy after three doses was 100% concerning prevention of symptomatic acute hepatitis. This vaccine was approved in China in early 2012. It is currently not known if and when this vaccine will become available outside China. Moreover, the efficacy of this vaccine needs to be evaluated in special risks groups such as patients with end-stage liver disease or immunosuppressed individuals. It is also unknown if HEV 239 also protects from HEV genotype 3 infection (Wedemeyer 2011). However, it was demonstrated that either the vaccine or naturally acquired, post-infectious antibodies are able to prevent symptomatic hepatitis E, but not asymptomatic infection (Zhang 2013). Furthermore it was shown that this vaccine could be safely used in pregnant women (Wu 2012). However, it is important to note that the vaccine does not induce sterilising immunity and that asymptomatic infection occurred in vaccinated individuals.

The use of this vaccine in developing countries needs to be discussed and investigated. Eventually this vaccine may help to prevent the morbidity and mortality caused by hepatitis E.

Conclusions and recommendations

In general, HEV infection has a self-limiting course associated with the clinical picture of acute hepatitis in immunocompetent populations. Special populations like pregnant women may be more likely to develop hepatic failure. In patients with immunosuppression of different etiologies, chronic cases have been reported.

In organ transplant recipients the diagnosis of HEV infection should not be based on serological assays alone as these assays may lack sensitivity. Detection of HEV RNA by PCR in serum or stool represents the gold standard for diagnosis of HEV infection.

The prevalence of chronic HEV infection in solid organ transplant recipients depends on the general prevalence in the population and is low in most industrialised countries. However, chronic hepatitis E occurs and needs to be considered in the differential diagnosis of graft hepatitis, as persistent HEV infection can be associated with progressive graft hepatitis and the development of liver cirrhosis. Currently, all reported cases of chronic HEV infections in transplant recipients have been due to HEV genotype 3 or 4. It is not known if chronic hepatitis E can also be caused by the genotypes 1 or 2.

Organ transplant recipients and other immunocompromised individuals should avoid eating uncooked meats to avoid infection with HEV.

First results indicate that ribavirin treatment of chronic hepatitis E (3 to 5 months duration) is effective to achieve sustained virologic response in immunocompromised persons. In contrast, in immunocompetent individuals with acute HEV infection this treatment is only required in few cases to avoid liver failure.

The relevance of extrahepatic manifestations associated with acute or chronic HEV infection needs further exploration, especially the association between positive anti-HEV serostatus and autoimmune hepatitis, cryoglobulinaemia or neurological symptoms.

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