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Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
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MINI REVIEW
Hepatitis E virus: Chronic infection, extra-hepatic manifestations, and treatment Nassim Kamar a,∗,b,c, Florence Abravanel b,c,d, Sebastien Lhomme b,c,d, Lionel Rostaing a,b,c, Jacques Izopet b,c,d a
Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France b Inserm U1043, IFR—BMT, CHU Purpan, Toulouse, France c Université Paul-Sabatier, Toulouse, France d Laboratory of Virology, CHU Purpan, Toulouse, France
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. It is an underdiagnosed disease because of the use of low-sensitivity serological assays; however, diagnostics tools, including nucleic-acid tests, have improved. HEV infection is usually an acute self-limiting disease, but causes chronic infection with rapidly progressive cirrhosis in adult and pediatric organ-transplant-patients. HEV infection evolves to chronic hepatitis in nearly 60% of HEV-infection solid-organ-transplant patients. HEV can also cause extra-hepatic manifestations, such as neurological symptoms and kidney injury. Reducing immunosuppression in transplant patients can lead to HEV clearance in one-third of patients with chronic hepatitis. The use of anti-viral therapies, such as pegylated-interferon and ribavirin, has been found to efficaciously treat HEV infection. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction
∗
Corresponding author. Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France. Tel.: +33 5 61 32 23 35; fax: +33 5 61 32 39 89. E-mail address: [email protected] (N. Kamar).
Hepatitis E virus (HEV) infection is a worldwide disease [1]. An improved understanding of the natural history of HEV infection has been achieved within the last decade. In this mini-review, we shall briefly describe the transmission modes, the virological tools for HEV diagnosis, and its
http://dx.doi.org/10.1016/j.clinre.2014.07.005 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
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clinical course. We shall focus on chronic HEV infection, extra-hepatic manifestations, and HEV treatment.
Hepatitis E virus and its epidemiology HEV is a small non-enveloped virus with a size of 27—34 nanometers, and has a positive-sense, single-stranded RNA 7.2-kilobase-long genome, which is capped and polyadenylated at the 5 and 3 -termini, respectively [2,3]. It is now classified within the Hepaviridae family. The HEV genome contains three open reading frames (ORF). ORF1 encodes a protein of 1693 amino acids containing functional motifs and domains present in the non-structural proteins of other positive-stranded RNA viruses. ORF2 encodes the capsid protein, and ORF3 encodes a protein essential for virus egress. Comparative analyses of the nucleotide sequences of HEV strains have led to the identification of four major genotypes and several subtypes within each genotype known to affect humans [4]. Genotypes 1 and 2 are isolated only from humans and are mainly responsible for large waterborne epidemics and sporadic cases of acute hepatitis associated with high mortality rates among pregnant women in developing countries [5]. Genotype 1 includes strains from Asia and Africa, genotype 2 includes the Mexican strain and a few variants from Africa. Large HEV outbreaks reported from these areas have been associated with fecally contaminated drinking water [6]. Genotypes 3 and 4 are zoonotic, present in different animals, particularly feral and domestic pigs [7,8]. They are distributed in most parts of the world, including most developed countries. However, the animal reservoir of Hepeviridae is still the object of research. HEVrelated viruses have also been isolated from several other animal species including chickens [9], rats [10], rabbits [11], ferret [12], camels [13], and the cutthroat trout [14], All these strains appear to belong to previously unrecognized genotypes.
The detection of anti-HEV IgG is considered a sign of past exposure to HEV. However, several studies have highlighted the great differences in sensitivity of this serological test, which can affect estimates of seroprevalence [20—22].
Clinical course In developing countries, HEV causes a self-limiting illness, which lasts days to several weeks. Patients are generally young adults (15—30 years). Symptoms of hepatitis develop after an incubation period of two to six weeks: these include fever and nausea, followed by abdominal pain, vomiting, anorexia, malaise, and hepatomegaly. Jaundice occurs in about 40% of patients [23]. Greater mortality is seen in patients with chronic liver disease and pregnant women [24,25]: mortality rate is 25%, with most deaths occurring in the third trimester [24]. Pregnant women die of obstetric complications, including hemorrhage, eclampsia, or they develop fulminant hepatic failure. Stillbirths are common, as is vertical transmission to infants, which leads to increased neonatal morbidity and mortality [26,27]. The excess mortality in pregnancy caused by HEV genotypes 1 and 2 is not seen with genotypes 3 and 4. The pathophysiological mechanisms of HEV genotypes 1 and 2 are unknown. In developed countries, the clinical features of acute autochthonous hepatitis E caused by genotypes 3 and 4 are indistinguishable from those in developing countries, except that patients in developed countries are usually middleaged/elderly males [28]. Jaundice and asthenia are the most common symptoms [29]. HEV infection can be mistaken for drug-induced liver injury in 3—13% of patients with ‘‘criterion referenced’’ drug-induced liver injury [30,31]. Extra hepatic manifestations can also occur (see below). Immunosuppressed patients, mainly with a solid-organtransplant (SOT), are usually asymptomatic [32].
Chronic HEV infection HEV diagnosis Cases of acute hepatitis E are primarily diagnosed by detecting anti-HEV antibodies, mainly anti-HEV IgM, or by detecting viral RNA in the serum and/or feces during the acute phase of the disease [15]. A recent evaluation of two anti-HEV IgM tests, available in Europe, has shown that both anti-HEV IgM assays were highly specific and their sensitivity in immunocompetent patients was 97.5%, but was 85% in immunocompromised patients [16]. Several in-house conventional or real-time RT-PCRs were recently evaluated [17]: this study found that the sensitivities of the majority of assays differed greatly. Moreover, virus diversity influenced the performance of HEV RNA assays, indicating that an RT-PCR protocol based on ORF3 provides the most suitable tool for assaying HEV RNA [18]. Commercial assays for detecting HEV RNA have only recently become available. The Ceeram and Altona assays are both valid assays for detecting genotype 3 HEV RNA. They provide good analytical sensitivity with high reproducibility [19]. HEV RNA assays are a useful complement to serological methods for detecting and monitoring HEV infections, particularly in immunocompromised patients.
Within the last few years, it has been shown that genotype-3 HEV infection can lead to chronic hepatitis in immunosuppressed patients, i.e., SOT patients, stem-cell-transplant patients, patients infected by the human immunodeficiency virus (HIV), hematology patients receiving chemotherapy, and rheumatology patients receiving immunotherapy [33—35]. No chronic HEV infection has been reported in patients infected by genotypes 1, 2, or 4 HEV [36].
Chronic HEV infection in organ- and stem-cell-transplant patients In SOT patients, the prevalence and incidence of positive HEV RNA ranges from 0.9—3.2% [37—44]. In this population, the mode of HEV transmission is similar to the general population [45,46]. Only one case of HEV transmission via a liver-allograft has been reported [47]. Because of the high prevalence of HEV RNA among blood donors and the high proportion of organ-transplant patients who receive blood products in the peri-operative period, blood transfusion may be a mode of HEV transmission in this setting [48]. However, this hypothesis has yet to be proven.
Please cite this article in press as: Kamar N, et al. Hepatitis E virus: Chronic infection, extra-hepatic manifestations, and treatment. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.005
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Hepatic and extra-hepatic manifestations of HEV In the published literature, chronic HEV infection has been defined as the persistence of detectable HEV RNA in the serum and/or the stools for at least six months. However, it has been shown that no spontaneous clearance of HEV infection is observed between three and six months after infection, suggesting that chronic HEV infection can be defined as persisting HEV replication beyond three months after infection [49]. Among adult SOT patients, HEV infection evolves to chronic HEV infection in nearly 60% of patients [32]. Strikingly, nearly 10% of SOT patients with HEV develop cirrhosis within a short period (3—5 years) after primary infection [32,50]. Chronic cases of HEV infection have been also observed in pediatric organ-transplant patients [51—53]. Chronic HEV infection seems to occur mainly in heavily immunosuppressed patients. Indeed, having a lower CD4-positive T-cell count, having a lower HEV-specific Tcell response, and receiving a potent immunosuppressive therapy have all been associated with chronic HEV infection [32,33,54]. The use of tacrolimus rather cyclosporine A has been also identified as an independent predictive factor for chronic HEV infection [32]. It has been suggested that the use of mycophenolic acid may have a protective effect against the evolution of chronic HEV infection [41]. Increased quasispecies heterogeneity in the capsid protein and the polyproline region is seen in patients with chronic infection compared to those with resolving hepatitis [55,56]. By means of univariate analysis, patients who have high liver-enzyme levels during HEV infection were more likely to have resolving hepatitis [32]. HEV reinfection and evolution to chronic hepatitis was observed in HEV seropositive SOT patients who had an anti-HEV IgG concentration < 7 WHO IU/mL [44]. Patients who received a transplant with ongoing HEV replication can develop chronic hepatitis [57]. Conversely, after HEV clearance, no HEV reactivation has been observed [58]. In stem-cell-transplant patients, the incidence of positive HEV RNA in the serum ranges between 0 and 2.4% [59—61]. The mode of transmission has not been fully studied. Recently, HEV RNA has been detected in a hematopoietic stem-cell donor [62]. Chronic HEV infections, leading in some patients to cirrhosis, have been reported in both adults and pediatric patients with a bone-marrow transplant [61—64]. Finally, two cases of HEV reactivation have been reported [61,65].
Chronic HEV infection in HIV patients Cases of chronic HEV infection have been described in HIVpositive patients, especially those with a low CD4-positive cell count (< 250/mm3 ) [66—69]. All strains of HEV belong to genotype 3. The seroprevalence of anti-HEV IgG amongst HIV-positive patients varies from 1.5—11.2%. The incidence of HEV infection, defined by detection of HEV RNA in the plasma, ranges from 0—1.3% [46]. The clinical and biological presentation is quite similar to that observed in SOT patients. HEV infection can also lead to cirrhosis in patients infected by HIV [70,71]. The modes of HEV acquisition are probably similar to those in SOT patients and the general population. The possibility of sexual transmission is controversial. A recent study suggests that men having sex with men could be at risk for HEV contamination [72]. It is likely
3 that anti-retroviral therapy-induced immune reconstitution may induce HEV clearance in HIV patients [73].
Chronic HEV infection in hematological patients Chronic HEV infection has been reported in hematological patients receiving chemotherapy [63,74—76]. The clinical and biological presentation is quite similar to that observed in SOT patients. Recently, an acute infection with HEV-3 was diagnosed in a patient with chronic lymphatic B-cell leukemia at six weeks after infusion of donor lymphocytes. The patient died at 39 days later from acute liver failure [77]. This case report prompted clinicians to screen such patients with elevated liver-enzyme levels for HEV RNA before stem-cell transplantation.
Extra-hepatic manifestations of HEV Several extra-hepatic manifestations of HEV have been reported.
Neurological symptoms Neurological manifestations are the most frequent extrahepatic manifestation associated with genotype 1 or 3 HEV [78]. The main neurological manifestations associated with HEV are: Guillain-Barré syndrome, neuralgic amyotrophy, acute transverse myelitis, and acute meningoencephalitis. These manifestations have been observed at acute or chronic phases. In a retrospective study that included organ-transplant-patients and immunocompetent patients, the incidence of neurological symptoms was 5.5% [79]. These symptoms were observed in SOT patients, HIVpatients, and immunocompetent patients [79]. In patients with chronic hepatitis E and neurological symptoms, HEV RNA has been found in the cerebrospinal fluid (CSF) [79]. Analysis of HEV RNA from the CSF shows that the variants differed from those observed at the same time point in the serum: this suggests the presence of neurotropic variants [80]. Other groups have also found HEV RNA in the CSF [81]. Very recently, a Dutch case-controlled study assessed the incidence of HEV infection among of 201 patients with Guillain—Barré syndrome and 201 control patients [82]. The prevalence of anti-HEV IgM was 5% in the Guillain—Barré group and 0.5% in the healthy control group [82]. HEV RNA was detected in the serum of 1.5% of patients with Guillain—Barré syndrome. However, HEV RNA was not detected in the CSF of any of these patients. Another UK—Dutch study assessed the incidence of HEV infection among 47 patients who had neuralgic amyotrophy. The incidence of HEV infection was 10% [83]. Interestingly, in both studies, liver-enzyme levels were only slightly increased [82,83]. Finally, one case of Guillain—Barré syndrome associated with severe myositis has been reported [84].
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Kidney injury In the first case report of acute HEV infection in a kidneytransplant patient, an increase in kidney function was observed [85]. One case of membranous glomerulonephritis has been also reported in an immunocompetent patient infected by genotype-1 HEV [86]. Recently, in a retrospective study, it has been shown that a decrease in glomerular filtration rate is observed during the acute phase of genotype-3 HEV infection in SOT patients [87]. In addition, at acute and chronic phases of HEV infection, some patients develop renal injury, such as membranoproliferative and membranous glomerulonephritis [87]. More recently, another case of membranous glomerulonephritis associated with HEV infection has been reported [88]. Interestingly, in this latter case, proteinuria regressed after ribavirin therapy induced HEV clearance. Finally, cryoglobulinemia was observed in 80% of patients with HEV replication, but then disappeared after HEV clearance [87].
Acute pancreatitis Several cases of acute pancreatitis have been described in patients infected by HEV-1 in its acute phase [89—91]. However, no cases of acute pancreatitis have been reported in patients infected by HEV genotypes 3 or 4 [92].
Hematological manifestations Some hematological manifestations, such as aplastic anemia [93] and severe thrombocytopenia, have been reported in patients infected by HEV [94,95]. Interestingly, a lower platelet count at HEV infection has been identified as a predictive factor for chronic hepatitis among SOT patients [32]. However, the relationship between HEV infection and platelet count is still unknown.
Treatment of HEV infection In SOT patients with chronic HEV infection, the reduction of immunosuppressants, especially those targeting T-cells, has achieved HEV clearance in one-third of patients [32,50]. Indeed, those who were cleared of the virus had a significantly lower tacrolimus trough level and needed a lower daily steroid dose compared to those who remained viremic [50]. In vitro, both calcineurin inhibitors and mTOR inhibitors have been found to promote HEV replication [96,97]. It has been shown that cyclophilins A and B inhibit replication of HEV [96]. By inhibiting cyclophilins A and B, cyclosporin A has promoted replication of HEV in subgenomic and infectious models [96]. High doses of tacrolimus have promoted infection of liver cells by HEV [96]. In vitro, it has been also shown that mTOR inhibitors facilitate HEV replication by inhibiting the PI3K—PKB—mTOR pathway, which limits HEV infection through the phosphorylated eIF4E-binding protein 1 (4E-BP1) [97]. Hence, reducing the dose of immunosuppressants that target T-cells can be considered as a first-line therapeutic option. In liver-transplant patients who remained viremic despite immunosuppressive therapy dose reduction and in a hemodialysis patient,
pegylated interferon was successfully used [98—100]. However, interferon therapy is contraindicated in heart-, lung-, and kidney-transplant patients because it increases the risk of acute rejection [101]. Hence, clinicians have assessed the efficacy of ribavirin alone. In several case reports and small series, ribavirin has been found to be efficient at treating SOT patients with chronic HEV infection [41,43,53,84,102—107]. More recently, this was confirmed in a large multicenter retrospective study [108]. Fifty-nine HEV-positive solid-organ-transplant patients were given ribavirin for 3 (1—18) months. Two-third of patients was given ribavirin for 3 months. The large majority of these patients had chronic hepatitis. The time between diagnosis and initiation of ribavirin was 9 (range: 1—82) months. The median initial dose of ribavirin was 600 (range: 29—1200) mg/d. A sustained virological response (SVR) was observed in 78% of patients: i.e., 74% among patients treated for ≤ 3 months and 85% among those who received ribavirin for > 3 months. Six of the 10 relapsers who were initially treated for three months, were re-treated for six months. Four of them were completely cleared of the virus, which raised the sustained virological rate to 85% [108]. Having a high lymphocyte count at the initiation of ribavirin therapy was the sole independent predictive factor for a SVR [108]. Anemia was the sole adverse event observed in this population. The mechanism of action of ribavirin against HEV is unknown. It has been suggested that ribavirin inhibits HEV replication through depletion of guanosine 5-triphosphate (GTP) [109]. Mycophenolic acid also depletes GTP pools via inhibition of inosine monophosphate dehydrogenase. In vitro, Wang et al. have shown that the combination of mycophenolic acid and ribavirin had a greater ability to inhibit HEV replication than mycophenolic acid or ribavirin alone [96]. However, this finding has not been confirmed in a clinical setting. In HIV-positive patients and patients with hematological disease and receiving chemotherapy, case reports show that interferon alone, ribavirin alone, or a combination of both have been efficient at treating HEV infection [110—113]. In patients presenting with severe acute HEV infection and acute-on-chronic cases, anti-viral therapy has been also used [114—116]. Nevertheless, no comparison between anti-viral therapy and no-therapy has been performed. Thus, the role of antiviral therapy in acute infection remains to be established. Finally, anti-viral therapy can be considered in patients developing severe extra-hepatic manifestations.
HEV vaccine Although effective vaccines have been developed, only one vaccine is validated by the Chinese health authorities, named HEV239. It is a recombinant vaccine based on the genotype-1 capsid protein expressed in Escherichia coli. In a phase-III trial conducted in China, more than 100,000 healthy people were randomized to receive either three doses of HEV 239 at 0, one and six months, or hepatitis B vaccine as a placebo. The vaccine was well tolerated and protected against hepatitis E, with an efficacy of 100% (95% CI: 72.1—100.0). The persistence of the protection conferred by the vaccine was not studied [117].
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Hepatic and extra-hepatic manifestations of HEV
Conclusion HEV infection has different faces and is still underdiagnosed. It can be responsible for chronic infection, cirrhosis, and extra-hepatic manifestations. Ribavirin therapy is highly efficient at treating HEV infection. Further studies are required to better understand the different spectra of this disease, its mode of transmission, and to define its optimal management.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
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MINI REVIEW
Hepatitis E virus: Chronic infection, extra-hepatic manifestations, and treatment Nassim Kamar a,∗,b,c, Florence Abravanel b,c,d, Sebastien Lhomme b,c,d, Lionel Rostaing a,b,c, Jacques Izopet b,c,d a
Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France b Inserm U1043, IFR—BMT, CHU Purpan, Toulouse, France c Université Paul-Sabatier, Toulouse, France d Laboratory of Virology, CHU Purpan, Toulouse, France
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. It is an underdiagnosed disease because of the use of low-sensitivity serological assays; however, diagnostics tools, including nucleic-acid tests, have improved. HEV infection is usually an acute self-limiting disease, but causes chronic infection with rapidly progressive cirrhosis in adult and pediatric organ-transplant-patients. HEV infection evolves to chronic hepatitis in nearly 60% of HEV-infection solid-organ-transplant patients. HEV can also cause extra-hepatic manifestations, such as neurological symptoms and kidney injury. Reducing immunosuppression in transplant patients can lead to HEV clearance in one-third of patients with chronic hepatitis. The use of anti-viral therapies, such as pegylated-interferon and ribavirin, has been found to efficaciously treat HEV infection. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction
∗
Corresponding author. Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, 31059 Toulouse cedex 9, France. Tel.: +33 5 61 32 23 35; fax: +33 5 61 32 39 89. E-mail address: [email protected] (N. Kamar).
Hepatitis E virus (HEV) infection is a worldwide disease [1]. An improved understanding of the natural history of HEV infection has been achieved within the last decade. In this mini-review, we shall briefly describe the transmission modes, the virological tools for HEV diagnosis, and its
http://dx.doi.org/10.1016/j.clinre.2014.07.005 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.
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clinical course. We shall focus on chronic HEV infection, extra-hepatic manifestations, and HEV treatment.
Hepatitis E virus and its epidemiology HEV is a small non-enveloped virus with a size of 27—34 nanometers, and has a positive-sense, single-stranded RNA 7.2-kilobase-long genome, which is capped and polyadenylated at the 5 and 3 -termini, respectively [2,3]. It is now classified within the Hepaviridae family. The HEV genome contains three open reading frames (ORF). ORF1 encodes a protein of 1693 amino acids containing functional motifs and domains present in the non-structural proteins of other positive-stranded RNA viruses. ORF2 encodes the capsid protein, and ORF3 encodes a protein essential for virus egress. Comparative analyses of the nucleotide sequences of HEV strains have led to the identification of four major genotypes and several subtypes within each genotype known to affect humans [4]. Genotypes 1 and 2 are isolated only from humans and are mainly responsible for large waterborne epidemics and sporadic cases of acute hepatitis associated with high mortality rates among pregnant women in developing countries [5]. Genotype 1 includes strains from Asia and Africa, genotype 2 includes the Mexican strain and a few variants from Africa. Large HEV outbreaks reported from these areas have been associated with fecally contaminated drinking water [6]. Genotypes 3 and 4 are zoonotic, present in different animals, particularly feral and domestic pigs [7,8]. They are distributed in most parts of the world, including most developed countries. However, the animal reservoir of Hepeviridae is still the object of research. HEVrelated viruses have also been isolated from several other animal species including chickens [9], rats [10], rabbits [11], ferret [12], camels [13], and the cutthroat trout [14], All these strains appear to belong to previously unrecognized genotypes.
The detection of anti-HEV IgG is considered a sign of past exposure to HEV. However, several studies have highlighted the great differences in sensitivity of this serological test, which can affect estimates of seroprevalence [20—22].
Clinical course In developing countries, HEV causes a self-limiting illness, which lasts days to several weeks. Patients are generally young adults (15—30 years). Symptoms of hepatitis develop after an incubation period of two to six weeks: these include fever and nausea, followed by abdominal pain, vomiting, anorexia, malaise, and hepatomegaly. Jaundice occurs in about 40% of patients [23]. Greater mortality is seen in patients with chronic liver disease and pregnant women [24,25]: mortality rate is 25%, with most deaths occurring in the third trimester [24]. Pregnant women die of obstetric complications, including hemorrhage, eclampsia, or they develop fulminant hepatic failure. Stillbirths are common, as is vertical transmission to infants, which leads to increased neonatal morbidity and mortality [26,27]. The excess mortality in pregnancy caused by HEV genotypes 1 and 2 is not seen with genotypes 3 and 4. The pathophysiological mechanisms of HEV genotypes 1 and 2 are unknown. In developed countries, the clinical features of acute autochthonous hepatitis E caused by genotypes 3 and 4 are indistinguishable from those in developing countries, except that patients in developed countries are usually middleaged/elderly males [28]. Jaundice and asthenia are the most common symptoms [29]. HEV infection can be mistaken for drug-induced liver injury in 3—13% of patients with ‘‘criterion referenced’’ drug-induced liver injury [30,31]. Extra hepatic manifestations can also occur (see below). Immunosuppressed patients, mainly with a solid-organtransplant (SOT), are usually asymptomatic [32].
Chronic HEV infection HEV diagnosis Cases of acute hepatitis E are primarily diagnosed by detecting anti-HEV antibodies, mainly anti-HEV IgM, or by detecting viral RNA in the serum and/or feces during the acute phase of the disease [15]. A recent evaluation of two anti-HEV IgM tests, available in Europe, has shown that both anti-HEV IgM assays were highly specific and their sensitivity in immunocompetent patients was 97.5%, but was 85% in immunocompromised patients [16]. Several in-house conventional or real-time RT-PCRs were recently evaluated [17]: this study found that the sensitivities of the majority of assays differed greatly. Moreover, virus diversity influenced the performance of HEV RNA assays, indicating that an RT-PCR protocol based on ORF3 provides the most suitable tool for assaying HEV RNA [18]. Commercial assays for detecting HEV RNA have only recently become available. The Ceeram and Altona assays are both valid assays for detecting genotype 3 HEV RNA. They provide good analytical sensitivity with high reproducibility [19]. HEV RNA assays are a useful complement to serological methods for detecting and monitoring HEV infections, particularly in immunocompromised patients.
Within the last few years, it has been shown that genotype-3 HEV infection can lead to chronic hepatitis in immunosuppressed patients, i.e., SOT patients, stem-cell-transplant patients, patients infected by the human immunodeficiency virus (HIV), hematology patients receiving chemotherapy, and rheumatology patients receiving immunotherapy [33—35]. No chronic HEV infection has been reported in patients infected by genotypes 1, 2, or 4 HEV [36].
Chronic HEV infection in organ- and stem-cell-transplant patients In SOT patients, the prevalence and incidence of positive HEV RNA ranges from 0.9—3.2% [37—44]. In this population, the mode of HEV transmission is similar to the general population [45,46]. Only one case of HEV transmission via a liver-allograft has been reported [47]. Because of the high prevalence of HEV RNA among blood donors and the high proportion of organ-transplant patients who receive blood products in the peri-operative period, blood transfusion may be a mode of HEV transmission in this setting [48]. However, this hypothesis has yet to be proven.
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Hepatic and extra-hepatic manifestations of HEV In the published literature, chronic HEV infection has been defined as the persistence of detectable HEV RNA in the serum and/or the stools for at least six months. However, it has been shown that no spontaneous clearance of HEV infection is observed between three and six months after infection, suggesting that chronic HEV infection can be defined as persisting HEV replication beyond three months after infection [49]. Among adult SOT patients, HEV infection evolves to chronic HEV infection in nearly 60% of patients [32]. Strikingly, nearly 10% of SOT patients with HEV develop cirrhosis within a short period (3—5 years) after primary infection [32,50]. Chronic cases of HEV infection have been also observed in pediatric organ-transplant patients [51—53]. Chronic HEV infection seems to occur mainly in heavily immunosuppressed patients. Indeed, having a lower CD4-positive T-cell count, having a lower HEV-specific Tcell response, and receiving a potent immunosuppressive therapy have all been associated with chronic HEV infection [32,33,54]. The use of tacrolimus rather cyclosporine A has been also identified as an independent predictive factor for chronic HEV infection [32]. It has been suggested that the use of mycophenolic acid may have a protective effect against the evolution of chronic HEV infection [41]. Increased quasispecies heterogeneity in the capsid protein and the polyproline region is seen in patients with chronic infection compared to those with resolving hepatitis [55,56]. By means of univariate analysis, patients who have high liver-enzyme levels during HEV infection were more likely to have resolving hepatitis [32]. HEV reinfection and evolution to chronic hepatitis was observed in HEV seropositive SOT patients who had an anti-HEV IgG concentration < 7 WHO IU/mL [44]. Patients who received a transplant with ongoing HEV replication can develop chronic hepatitis [57]. Conversely, after HEV clearance, no HEV reactivation has been observed [58]. In stem-cell-transplant patients, the incidence of positive HEV RNA in the serum ranges between 0 and 2.4% [59—61]. The mode of transmission has not been fully studied. Recently, HEV RNA has been detected in a hematopoietic stem-cell donor [62]. Chronic HEV infections, leading in some patients to cirrhosis, have been reported in both adults and pediatric patients with a bone-marrow transplant [61—64]. Finally, two cases of HEV reactivation have been reported [61,65].
Chronic HEV infection in HIV patients Cases of chronic HEV infection have been described in HIVpositive patients, especially those with a low CD4-positive cell count (< 250/mm3 ) [66—69]. All strains of HEV belong to genotype 3. The seroprevalence of anti-HEV IgG amongst HIV-positive patients varies from 1.5—11.2%. The incidence of HEV infection, defined by detection of HEV RNA in the plasma, ranges from 0—1.3% [46]. The clinical and biological presentation is quite similar to that observed in SOT patients. HEV infection can also lead to cirrhosis in patients infected by HIV [70,71]. The modes of HEV acquisition are probably similar to those in SOT patients and the general population. The possibility of sexual transmission is controversial. A recent study suggests that men having sex with men could be at risk for HEV contamination [72]. It is likely
3 that anti-retroviral therapy-induced immune reconstitution may induce HEV clearance in HIV patients [73].
Chronic HEV infection in hematological patients Chronic HEV infection has been reported in hematological patients receiving chemotherapy [63,74—76]. The clinical and biological presentation is quite similar to that observed in SOT patients. Recently, an acute infection with HEV-3 was diagnosed in a patient with chronic lymphatic B-cell leukemia at six weeks after infusion of donor lymphocytes. The patient died at 39 days later from acute liver failure [77]. This case report prompted clinicians to screen such patients with elevated liver-enzyme levels for HEV RNA before stem-cell transplantation.
Extra-hepatic manifestations of HEV Several extra-hepatic manifestations of HEV have been reported.
Neurological symptoms Neurological manifestations are the most frequent extrahepatic manifestation associated with genotype 1 or 3 HEV [78]. The main neurological manifestations associated with HEV are: Guillain-Barré syndrome, neuralgic amyotrophy, acute transverse myelitis, and acute meningoencephalitis. These manifestations have been observed at acute or chronic phases. In a retrospective study that included organ-transplant-patients and immunocompetent patients, the incidence of neurological symptoms was 5.5% [79]. These symptoms were observed in SOT patients, HIVpatients, and immunocompetent patients [79]. In patients with chronic hepatitis E and neurological symptoms, HEV RNA has been found in the cerebrospinal fluid (CSF) [79]. Analysis of HEV RNA from the CSF shows that the variants differed from those observed at the same time point in the serum: this suggests the presence of neurotropic variants [80]. Other groups have also found HEV RNA in the CSF [81]. Very recently, a Dutch case-controlled study assessed the incidence of HEV infection among of 201 patients with Guillain—Barré syndrome and 201 control patients [82]. The prevalence of anti-HEV IgM was 5% in the Guillain—Barré group and 0.5% in the healthy control group [82]. HEV RNA was detected in the serum of 1.5% of patients with Guillain—Barré syndrome. However, HEV RNA was not detected in the CSF of any of these patients. Another UK—Dutch study assessed the incidence of HEV infection among 47 patients who had neuralgic amyotrophy. The incidence of HEV infection was 10% [83]. Interestingly, in both studies, liver-enzyme levels were only slightly increased [82,83]. Finally, one case of Guillain—Barré syndrome associated with severe myositis has been reported [84].
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Kidney injury In the first case report of acute HEV infection in a kidneytransplant patient, an increase in kidney function was observed [85]. One case of membranous glomerulonephritis has been also reported in an immunocompetent patient infected by genotype-1 HEV [86]. Recently, in a retrospective study, it has been shown that a decrease in glomerular filtration rate is observed during the acute phase of genotype-3 HEV infection in SOT patients [87]. In addition, at acute and chronic phases of HEV infection, some patients develop renal injury, such as membranoproliferative and membranous glomerulonephritis [87]. More recently, another case of membranous glomerulonephritis associated with HEV infection has been reported [88]. Interestingly, in this latter case, proteinuria regressed after ribavirin therapy induced HEV clearance. Finally, cryoglobulinemia was observed in 80% of patients with HEV replication, but then disappeared after HEV clearance [87].
Acute pancreatitis Several cases of acute pancreatitis have been described in patients infected by HEV-1 in its acute phase [89—91]. However, no cases of acute pancreatitis have been reported in patients infected by HEV genotypes 3 or 4 [92].
Hematological manifestations Some hematological manifestations, such as aplastic anemia [93] and severe thrombocytopenia, have been reported in patients infected by HEV [94,95]. Interestingly, a lower platelet count at HEV infection has been identified as a predictive factor for chronic hepatitis among SOT patients [32]. However, the relationship between HEV infection and platelet count is still unknown.
Treatment of HEV infection In SOT patients with chronic HEV infection, the reduction of immunosuppressants, especially those targeting T-cells, has achieved HEV clearance in one-third of patients [32,50]. Indeed, those who were cleared of the virus had a significantly lower tacrolimus trough level and needed a lower daily steroid dose compared to those who remained viremic [50]. In vitro, both calcineurin inhibitors and mTOR inhibitors have been found to promote HEV replication [96,97]. It has been shown that cyclophilins A and B inhibit replication of HEV [96]. By inhibiting cyclophilins A and B, cyclosporin A has promoted replication of HEV in subgenomic and infectious models [96]. High doses of tacrolimus have promoted infection of liver cells by HEV [96]. In vitro, it has been also shown that mTOR inhibitors facilitate HEV replication by inhibiting the PI3K—PKB—mTOR pathway, which limits HEV infection through the phosphorylated eIF4E-binding protein 1 (4E-BP1) [97]. Hence, reducing the dose of immunosuppressants that target T-cells can be considered as a first-line therapeutic option. In liver-transplant patients who remained viremic despite immunosuppressive therapy dose reduction and in a hemodialysis patient,
pegylated interferon was successfully used [98—100]. However, interferon therapy is contraindicated in heart-, lung-, and kidney-transplant patients because it increases the risk of acute rejection [101]. Hence, clinicians have assessed the efficacy of ribavirin alone. In several case reports and small series, ribavirin has been found to be efficient at treating SOT patients with chronic HEV infection [41,43,53,84,102—107]. More recently, this was confirmed in a large multicenter retrospective study [108]. Fifty-nine HEV-positive solid-organ-transplant patients were given ribavirin for 3 (1—18) months. Two-third of patients was given ribavirin for 3 months. The large majority of these patients had chronic hepatitis. The time between diagnosis and initiation of ribavirin was 9 (range: 1—82) months. The median initial dose of ribavirin was 600 (range: 29—1200) mg/d. A sustained virological response (SVR) was observed in 78% of patients: i.e., 74% among patients treated for ≤ 3 months and 85% among those who received ribavirin for > 3 months. Six of the 10 relapsers who were initially treated for three months, were re-treated for six months. Four of them were completely cleared of the virus, which raised the sustained virological rate to 85% [108]. Having a high lymphocyte count at the initiation of ribavirin therapy was the sole independent predictive factor for a SVR [108]. Anemia was the sole adverse event observed in this population. The mechanism of action of ribavirin against HEV is unknown. It has been suggested that ribavirin inhibits HEV replication through depletion of guanosine 5-triphosphate (GTP) [109]. Mycophenolic acid also depletes GTP pools via inhibition of inosine monophosphate dehydrogenase. In vitro, Wang et al. have shown that the combination of mycophenolic acid and ribavirin had a greater ability to inhibit HEV replication than mycophenolic acid or ribavirin alone [96]. However, this finding has not been confirmed in a clinical setting. In HIV-positive patients and patients with hematological disease and receiving chemotherapy, case reports show that interferon alone, ribavirin alone, or a combination of both have been efficient at treating HEV infection [110—113]. In patients presenting with severe acute HEV infection and acute-on-chronic cases, anti-viral therapy has been also used [114—116]. Nevertheless, no comparison between anti-viral therapy and no-therapy has been performed. Thus, the role of antiviral therapy in acute infection remains to be established. Finally, anti-viral therapy can be considered in patients developing severe extra-hepatic manifestations.
HEV vaccine Although effective vaccines have been developed, only one vaccine is validated by the Chinese health authorities, named HEV239. It is a recombinant vaccine based on the genotype-1 capsid protein expressed in Escherichia coli. In a phase-III trial conducted in China, more than 100,000 healthy people were randomized to receive either three doses of HEV 239 at 0, one and six months, or hepatitis B vaccine as a placebo. The vaccine was well tolerated and protected against hepatitis E, with an efficacy of 100% (95% CI: 72.1—100.0). The persistence of the protection conferred by the vaccine was not studied [117].
Please cite this article in press as: Kamar N, et al. Hepatitis E virus: Chronic infection, extra-hepatic manifestations, and treatment. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.005
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Conclusion HEV infection has different faces and is still underdiagnosed. It can be responsible for chronic infection, cirrhosis, and extra-hepatic manifestations. Ribavirin therapy is highly efficient at treating HEV infection. Further studies are required to better understand the different spectra of this disease, its mode of transmission, and to define its optimal management.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Please cite this article in press as: Kamar N, et al. Hepatitis E virus: Chronic infection, extra-hepatic manifestations, and treatment. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.07.005
