Hepatitis E virus infections.

Hepatitis E virus (HEV) infection is now endemic worldwide. Most patients with acute infection recover uneventfully. Outbreaks and sporadic cases, particularly in high-risk individuals are emerging increasingly. The patients with risk factors like pregnancy and pre-existing chronic liver disease, present with or progress rapidly to severe disease. Immuno-suppression in post-transplant patients is an additional risk factor. Standardized FDA-approved diagnostic tests are the need of the hour. Further studies are needed to establish guideline-based treatment regimen and outbreak preparedness for HEV to decrease global morbidity, mortality, and healthcare burden. Policies for screening donors and transplant cases are required.

Hepatitis E virus infects human testicular tissue and Sertoli cells.

Globally, hepatitis E virus (HEV) infections are prevalent. The finding of high viral loads and persistent viral shedding in ejaculate suggests that HEV replicates within the human male genital tract, but its target organ is unknown and appropriate models are lacking. We aimed to determine the HEV tropism in the human testis and its potential influence on male reproductive health. We conducted an ex vivo culture of human testis explants and in vitro culture of primary human Sertoli cells. Clinically derived HEV genotype 1 (HEV1) and HEV3 virions, as well as rat-derived HEV-C1, were used for inoculation. Transcriptomic analysis was performed on testis tissues collected from tacrolimus-treated rabbits with chronic HEV3 infection. Our findings reveal that HEV3, but not HEV1 or HEV-C1, can replicate in human testis explants and primary human Sertoli cells. Tacrolimus treatment significantly enhanced the replication efficiency of HEV3 in testis explants and enabled successful HEV1 infection in Sertoli cells. HEV3 infection disrupted the secretion of several soluble factors and altered the cytokine microenvironment within primary human Sertoli cells. Finally, intratesticular transcriptomic analysis of immunocompromised rabbits with chronic HEV infection indicated downregulation of genes associated with spermatogenesis. HEV can infect the human testicular tissues and Sertoli cells, with increased replication efficiency when exposed to tacrolimus treatment. These findings shed light on how HEV may persist in the ejaculate of patients with chronic hepatitis E and provide valuable ex vivo tools for studying countermeasures.

Hepatitis E virus infection in liver transplant recipients / 器官移植

Hepatitis E virus infection is a common cause of acute viral hepatitis. In recent years, the incidence of hepatitis E has shown an increasing trend, which has gradually become an important cause of acute viral hepatitis worldwide. Age, sex, intensity of immunosuppression and socio-economic factors are all risk factors for hepatitis E virus infection. Liver transplant recipients require long-term use of immunosuppressive drugs for anti rejection treatment, prone to hepatitis E virus infection and at the risk of liver fibrosis and cirrhosis due to immunosuppression status. Therefore, special attention should be paid to liver transplant recipients in clinical practice. Meantime, related risk factors should be identified to assist diagnosis and take stricter preventive measures. According to literature review, the etiological characteristics of hepatitis E virus and the epidemiological characteristics, clinical manifestations, diagnosis and treatment of hepatitis E virus infection in liver transplant recipients were reviewed, aiming to properly monitor, treat and prevent hepatitis E virus infection in liver transplant recipients in clinical practice, improving the prognosis of liver transplant recipients.

mTOR inhibitors a potential predisposing factor for chronic hepatitis E: Results from the prospective collaborative CHES study (Chronic Hepatitis EScreening in patients with immune impairment and increased transaminases levels) / Los inhibidores de mTOR como potencial factor predisponente para la hepatitis crónica E: resultados del estudio prospectivo colaborativo CHES (Chronic Hepatitis E Screening in patients with immune impairment and increased transaminases levels)

Background: Chronic hepatitis E virus (HEV) in persons with immune impairment has a progressive course leading to a rapid progression to liver cirrhosis. However, prospective data on chronic HEV is scarce. The aim of this study was to determine the prevalence and risk factors for chronic HEV infection in subjects with immune dysfunction and elevated liver enzymes. Patients and methods: CHES is a multicenter prospective study that included adults with elevated transaminases values for at least 6 months and any of these conditions: transplant recipients, HIV infection, haemodialysis, liver cirrhosis, and immunosuppressant therapy. Anti-HEV IgG/IgM (Wantai ELISA) and HEV-RNA by an automated highly sensitive assay (Roche diagnostics) were performed in all subjects. In addition, all participants answered an epidemiological survey. Results: Three hundred and eighty-one patients were included: 131 transplant recipients, 115 cirrhosis, 51 HIV-infected subjects, 87 on immunosuppressants, 4 hemodialysis. Overall, 210 subjects were on immunosuppressants. Anti-HEV IgG was found in 94 (25.6%) subjects with similar rates regardless of the cause for immune impairment. HEV-RNA was positive in 6 (1.6%), all of them transplant recipients, yielding a rate of chronic HEV of 5.8% among solid-organ recipients. In the transplant population, only therapy with mTOR inhibitors was independently associated with risk of chronic HEV, whereas also ALT values impacted in the general model. Conclusions: Despite previous abnormal transaminases values, chronic HEV was only observed among solid-organ recipients. In this population, the rate of chronic HEV was 5.8% and only therapy with mTOR inhibitors was independently associated with chronic hepatitis E. (AU)

Introducción: La infección crónica por el virus de la hepatitis E (VHE) en personas con disfunción inmunitaria tiene un curso progresivo conllevando una rápida progresión a cirrosis hepática. Sin embargo, los datos prospectivos a este respecto son escasos. El objetivo de este estudio fue determinar la prevalencia y factores de riesgo para la infección crónica VHE en sujetos con disfunción inmunitaria y elevación de enzimas hepáticos. Pacientes y métodos: CHES es un estudio prospectivo multicéntrico que incluyó adultos con transaminasas elevadas durante al menos 6 meses y alguno de estos factores: receptores de trasplante, infección por VIH, hemodiálisis, cirrosis hepática o tratamiento inmunosupresor. En todos los sujetos se realizaron IgG/IgM anti-VHE (Wantai Elisa) y ARN-VHE por una técnica super sensible (Roche Diagnostics). Además, todos los participantes contestaron una encuesta epidemiológica. Resultados: 381 pacientes fueron incluidos: 131 trasplantados, 115 cirróticos, 51 infectados por VIH, 87 bajo inmunosupresores, 4 hemodiálisis. En total, 210 sujetos recibían inmunosupresores. La IgG anti-VHE fue positiva en 94 (25,6%) sujetos, con tasas similares en todas la causas de disfunción inmunitaria. El ARN-VHE fue positivo en 6 (1,6%) pacientes, todos ellos trasplantados, siendo la tasa de infección crónica VHE en receptores de órgano sólido del 5,8%. En la población de trasplantados, solo el tratamiento con inhibidores de mTOR se asoció de forma independiente a la hepatitis crónica VHE, mientras que los niveles de ALT impactaron en el modelo general. Conclusiones: A pesar de los niveles anormales de transaminasas, solo se objetivó hepatitis crónica VHE en trasplantados de órgano sólido. En esta población, la tasa de hepatitis crónica VHE fue del 5,8% y solo el tratamiento con inhibidores de mTOR se asoció de forma independiente a la hepatitis crónica E. (AU)

Case Report: Chronic hepatitis E virus Infection in an individual without evidence for immune deficiency.

Chronic hepatitis E virus (HEV) infection occurs mainly in immunosuppressed populations. We describe an investigation of chronic HEV infection of genotype 3a in an individual without evidence for immune deficiency who presented hepatitis with significant HEV viremia and viral shedding. We monitored HEV RNA in plasma and stools, and assessed anti-HEV specific immune responses. The patient was without apparent immunodeficiency based on quantified results of white blood cell, lymphocyte, neutrophilic granulocyte, CD3+ T cell, CD4+ T cell, and CD8+ T cell counts and CD4/CD8 ratio, as well as total serum IgG, IgM, and IgA, which were in the normal range. Despite HEV specific cellular response and strong humoral immunity being observed, viral shedding persisted up to 109 IU/mL. After treatment with ribavirin combined with interferon, the indicators of liver function in the patient returned to normal, accompanied by complete suppression and clearance of HEV. These results indicate that HEV chronicity can also occur in individuals without evidence of immunodeficiency.

The Diagnosis, Pathophysiology, and Treatment of Chronic Hepatitis E Virus Infection-A Condition Affecting Immunocompromised Patients.

Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. Twenty million HEV infections worldwide are estimated each year. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced by HEV genotypes 3, 4, and 7-usually in immunocompromised patients such as transplant recipients. In addition, patients infected with HIV and those receiving chemotherapy for malignancy, along with patients with rheumatic disease and COVID-19, have recently been reported as having CHE. CHE can be easily misdiagnosed by usual diagnostic methods of antibody response, such as anti-HEV IgM or IgA, because of the low antibody response in the immunosuppressive condition. HEV RNA should be evaluated in these patients, and appropriate treatments-such as ribavirin-should be given to prevent progression to liver cirrhosis or liver failure. While still rare, cases of CHE in immunocompetent patients have been reported, and care must be taken not to overlook these instances. Herein, we conduct an overview of hepatitis E, including recent research developments and management of CHE, in order to improve our understanding of such cases. The early diagnosis and treatment of CHE should be performed to decrease instances of hepatitis-virus-related deaths around the world.

Treatment of Hepatitis E.

Hepatitis E virus (HEV) infections are the most common cause of acute hepatitis, but they can also take a chronic course. There is no specific therapy for acute hepatitis, and current treatment is supportive. Choosing ribavirin as the first-line therapy for chronic HEV is advisable, especially immunosuppressed individuals. Moreover, ribavirin therapy in the acute phase of infection provides major benefits for those at high risk of acute liver failure (ALF)/acute-on-chronic liver failure (ACLF). Pegylated interferon α has been used successfully for treatment of hepatitis E but is associated with major side effects. Cholestasis is one of the most common, but devastating, manifestations in hepatitis E. Current therapy for HEV aims to treat symptoms. Therapy generally involves several measures, such as vitamins, albumin, and plasma for supporting treatment, symptomatic treatment for cutaneous pruritus, ursodeoxycholic acid, Obeticholic acid, S-adenosylmethionine, etc. for removing jaundice. HEV infection during pregnancy and patients with underlying liver disease may develop liver failure. For these patients, active monitoring, standard care, and supportive treatment are the foundations. Ribavirin has successfully been used to prevent liver transplantation (LT). Prevention and treatment of complications are important for treatment of liver failure. Liver support devices are intended to support liver function until such time as native liver function recovers, or until LT. LT is widely considered as irreplaceable and definitive treatment for liver failure, particularly for patients who do not improve with supportive measures to sustain life.

Ribavirin Treatment Failure-Associated Mutation, Y1320H, in the RNA-Dependent RNA Polymerase of Genotype 3 Hepatitis E Virus (HEV) Enhances Virus Replication in a Rabbit HEV Infection Model.

Chronic hepatitis E virus (HEV) infection has become a significant clinical problem that requires treatment in immunocompromised individuals. In the absence of an HEV-specific antiviral, ribavirin (RBV) has been used off-label, but treatment failure may occur due to mutations in the viral RNA-dependent RNA polymerase (RdRp), including Y1320H, K1383N, and G1634R. Chronic hepatitis E is mostly caused by zoonotic genotype 3 HEV (HEV-3), and HEV variants from rabbits (HEV-3ra) are closely related to human HEV-3. Here, we explored whether HEV-3ra, along with its cognate host, can serve as a model to study RBV treatment failure-associated mutations observed in human HEV-3-infected patients. By utilizing the HEV-3ra infectious clone and indicator replicon, we generated multiple single mutants (Y1320H, K1383N, K1634G, and K1634R) and a double mutant (Y1320H/K1383N) and assessed the role of mutations on replication and antiviral activity of HEV-3ra in cell culture. Furthermore, we also compared the replication of the Y1320H mutant with the wild-type HEV-3ra in experimentally infected rabbits. Our in vitro analyses revealed that the effects of these mutations on rabbit HEV-3ra are altogether highly consistent with those on human HEV-3. Importantly, we found that the Y1320H enhances virus replication during the acute stage of HEV-3ra infection in rabbits, which corroborated our in vitro results showing an enhanced viral replication of Y1320H. Taken together, our data suggest that HEV-3ra and its cognate host is a useful and relevant naturally occurring homologous animal model to study the clinical relevance of antiviral-resistant mutations observed in human HEV-3 chronically-infected patients. IMPORTANCE HEV-3 causes chronic hepatitis E that requires antiviral therapy in immunosuppressed individuals. RBV is the main therapeutic option for chronic hepatitis E as an off-label use. Several amino acid changes, including Y1320H, K1383N, and G1634R, in the RdRp of human HEV-3 have reportedly been associated with RBV treatment failure in chronic hepatitis E patients. In this study, we utilized an HEV-3ra from rabbit and its cognate host to investigate the effect of these RBV treatment failure-associated HEV-3 RdRp mutations on viral replication efficiency and antiviral susceptibility. The in vitro data using rabbit HEV-3ra was highly comparable to those from human HEV-3. We demonstrated that the Y1320H mutation significantly enhanced HEV-3ra replication in cell culture and enhanced virus replication during the acute stage of HEV-3ra infection in rabbits. The rabbit HEV-3ra infection model should be useful in delineating the role of human HEV-3 RBV treatment failure-associated mutations in antiviral resistance.

mTOR inhibitors a potential predisposing factor for chronic hepatitis E: Results from the prospective collaborative CHES study (Chronic Hepatitis EScreening in patients with immune impairment and increased transaminases levels).

BACKGROUND: Chronic hepatitis E virus (HEV) in persons with immune impairment has a progressive course leading to a rapid progression to liver cirrhosis. However, prospective data on chronic HEV is scarce. The aim of this study was to determine the prevalence and risk factors for chronic HEV infection in subjects with immune dysfunction and elevated liver enzymes. PATIENTS AND METHODS: CHES is a multicenter prospective study that included adults with elevated transaminases values for at least 6 months and any of these conditions: transplant recipients, HIV infection, haemodialysis, liver cirrhosis, and immunosuppressant therapy. Anti-HEV IgG/IgM (Wantai ELISA) and HEV-RNA by an automated highly sensitive assay (Roche diagnostics) were performed in all subjects. In addition, all participants answered an epidemiological survey. RESULTS: Three hundred and eighty-one patients were included: 131 transplant recipients, 115 cirrhosis, 51 HIV-infected subjects, 87 on immunosuppressants, 4 hemodialysis. Overall, 210 subjects were on immunosuppressants. Anti-HEV IgG was found in 94 (25.6%) subjects with similar rates regardless of the cause for immune impairment. HEV-RNA was positive in 6 (1.6%), all of them transplant recipients, yielding a rate of chronic HEV of 5.8% among solid-organ recipients. In the transplant population, only therapy with mTOR inhibitors was independently associated with risk of chronic HEV, whereas also ALT values impacted in the general model. CONCLUSIONS: Despite previous abnormal transaminases values, chronic HEV was only observed among solid-organ recipients. In this population, the rate of chronic HEV was 5.8% and only therapy with mTOR inhibitors was independently associated with chronic hepatitis E.

Chronic hepatitis E in an elderly immunocompetent patient who achieved a sustained virologic response with ribavirin treatment.

A woman in her late 70 s was diagnosed with liver injury at a health examination. Despite treatment with ursodeoxycholic acid at a nearby hospital, her transaminase levels elevated in two peaks. She was transferred to our hospital 77 days after the health examination. She weighed 42 kg and had a low body mass index of 19.8 kg/m2. Viral markers, including immunoglobulin A (IgA) against hepatitis E virus (anti-HEV IgA), were negative. Drug-induced liver injury was negligible. We suspected autoimmune hepatitis because of the patient's female gender and positive antinuclear antibody. However, prednisolone and azathioprine failed to completely improve her hepatitis. On day 643, anti-HEV IgA was re-evaluated and found to be positive. She was diagnosed with autochthonous chronic hepatitis E because the virus strains in the preserved serum on day 77 and the serum on day 643 had identical nucleotide sequences (genotype 3a). Following prednisolone and azathioprine discontinuation, ribavirin (RBV) was administered for 3 months. HEV RNA disappeared and remained negative for more than 6 months after the cessation of RBV. The HEV RNA titer of 6.2 log10 copies/mL on day 77 was unusually high 2.5 months after the onset, suggesting that hepatitis E had already been chronic before immunosuppressive treatment for possible autoimmune hepatitis. After getting married at 23 years old, she had been a housewife and had no comorbidities that might deteriorate her immunity. Chronicity should be kept in mind when encountering HEV infection in elderly and underweight patients.

Sofosbuvir in the Treatment of Hepatitis E virus Infection: A Review of in vitro and in vivo Evidence.

Chronic hepatitis E virus (HEV) infection, which occurs almost exclusively in immunocompromised patients, if untreated may progress to cirrhosis and possibly hepatocellular carcinoma. The reduction of immunosuppression and/or administration of ribavirin is frequently curative but there remain many immunocompromised individuals whose HEV infection is refractory to these therapeutic strategies. Moreover, the haematological toxicity of ribavirin limits its use. Pegylated interferon has demonstrated success in a small number of patients with chronic HEV infection; however, the potentially increased risk of graft rejection associated with its use renders it unsuitable for many transplant recipients. Alternative therapeutic strategies are therefore required. This article reviews the in vitro and in vivo literature to date of the antiviral agent sofosbuvir (well established in the treatment of hepatitis C) in the treatment of HEV infection.

Characterization of Chronic Hepatitis E Virus Infection in Immunocompetent Rabbits.

Chronic hepatitis E virus (HEV) infection is frequently reported in immunocompromised patients, but has also been increasingly reported in non-immunocompromised individuals. We characterized the course of chronic HEV infection in immunocompetent rabbits. In two independent experiments, 40 specific-pathogen-free rabbits were infected with a rabbit HEV genotype 3 strain in serial diluted titers (108 to 104 copies/mL). Serum and fecal samples were collected weekly and were tested for HEV RNA, antigen, anti-HEV and liver enzymes. Rabbits that spontaneously cleared the infection before 10 weeks post-inoculation (wpi) were kept to the end of the study as recovery control. Liver tissues were collected from HEV-infected rabbits at 5, 10 and 26 wpi for histopathological analysis. Nineteen rabbits (47.5%) developed chronic HEV infection with persistent viraemia and fecal HEV shedding for >6 months. Seroconversion to anti-HEV was observed in 84.2% (16/19) of the chronically infected rabbits. Serum levels of aminotransferase were persistently elevated in most of the rabbits. Characterizations of chronic HEV infection in immunocompetent settings could be recapitulated in rabbits, which can serve as a valuable tool for future studies on pathogenesis.

Chronic Hepatitis E With Genotype 1-Masquerading as Allograft Rejection After LiverTransplantation.

Hepatitis E is one of the leading causes of acute viral hepatitis worldwide. Chronic infection with hepatitis E is less common and limited to immunosuppressed patients and is usually due to genotype 3 of the virus. Genotype 1, the most prevalent strain in the South Asian region, is seldom known to be associated with chronic hepatitis. Here we describe a case of chronic hepatitis E with genotype 1 in a post-liver transplant setting. In the index case, previously compensated cryptogenic cirrhosis was decompensated by an acute hepatitis E infection, which necessitated liver transplantation because of acute chronic liver failure. This later progressed to chronicity. This case may have significant implications in management, especially in the post-liver transplant setting.

Hepatitis E Virus Seroprevalence Among Liver Transplant Recipients with Persistent Elevation of Liver Enzymes: A Single Center Report.

BACKGROUND: Chronic hepatitis E infection has been reported in solid organ transplant recipients following acute hepatitis due to the compromised immune status. Almost all reports are from areas where hepatitis E virus (HEV) genotypes 3 and 4 are the dominant genotypes. This study was conducted to investigate the role of hepatitis E infection as an etiology for liver enzymes elevation in liver transplant recipients from the largest liver transplant program in Iran. METHODS: In a prospective study from June to December 2015, in a single liver transplantation center in Iran, all adult liver recipients who were investigated for the etiology of persistent elevation of liver enzymes were tested for HEV serology status. RESULTS: Of 122 patients included in the study, 19 (15.6%) were positive for HEV serology. Seropositive patients were significantly older than seronegative ones (mean age 43.79 vs. 31.58, P < 0.001); however, they were not different in other characteristics including sex distribution and mean of liver enzymes in each occasion. Liver biopsies were done in 16 HEV seropositive patients and none of the biopsies showed evidence for acute or chronic viral hepatitis. CONCLUSION: In this study, with 15.6% rate of HEV seropositivity in liver recipients with persistent elevation of liver enzymes, we were not able to confirm any clinical evidence for active acute or chronic hepatitis E infection. This could theoretically be attributed to the fact that the dominant prevalent HEV genotype in our endemic area is not associated with a chronic form of infection.

Time course alterations of virus sequences and immunoglobulin titers in a chronic hepatitis E patient.

AIM: Hepatitis E virus (HEV) can cause chronic infection in immunocompromised hosts. However, the dynamics of HEV during persistent infection is not well understood. To elucidate time course alterations in virus sequences and anti-HEV antibodies during persistent infection, we analyzed the HEV sequences and titers of anti-HEV antibodies from a chronic hepatitis E patient. METHODS: Serum samples were obtained from a chronic hepatitis E patient under corticosteroid therapy for neurological disease. The titers of anti-HEV antibodies (immunoglobulin A, immunoglobulin M, and immunoglobulin G) in serum samples were detected by enzyme immunoassay. The full or near-full nucleotide sequences of HEV isolated from consecutive serum samples were identified and compared. Phylogenetic analysis was also performed. RESULTS: Alterations of anti-HEV antibodies from a chronic hepatitis E patient were different from those previously reported in acute hepatitis E patients. The virus sequence was unchanged in the period without treatment, but nucleotide mutations were observed after ribavirin treatment was started. In addition, the sequence of this strain had extremely high identity to that isolated from swine liver in Japan. CONCLUSIONS: Virus mutations in HEV emerged after ribavirin treatment was started. Sequence analysis may useful for deciding the treatment strategy for chronic hepatitis E patients who did not eliminate the virus with 3 months of RBV treatment and inferring the origin of the infection. This report provides insights into the chronicity of hepatitis E, and the impact of persistent infection and ribavirin treatment on the emergence of virus mutations.

Sofosbuvir Add-on to Ribavirin Treatment for Chronic Hepatitis E Virus Infection in Solid Organ Transplant Recipients Does Not Result in Sustained Virological Response.

Ribavirin is effective for treating immunocompromised patients with chronic hepatitis E virus infection. However, ribavirin treatment is not always successful. We describe 3 solid organ transplant recipients treated with sofosbuvir and ribavirin after failing ribavirin monotherapy. Complete elimination of hepatitis E virus could not be achieved.

Defining virus-specific CD8+ TCR repertoires for therapeutic regeneration of T cells against chronic hepatitis E.

BACKGROUND & AIMS: Immunosuppressed patients with chronic hepatitis E virus infection (cHEV), who are ineligible or have failed current treatment with off-label ribavirin, are a potential target population for T cell-based therapy. T cell responses are important for viral control. Herein, we aimed to identify human leukocyte antigen (HLA)-A2 restricted HEV-specific CD8+ T cell epitopes and T cell receptors (TCR) targeting these epitopes, as the basis for a redirected TCR treatment approach for patients with cHEV. METHODS: HEV genotype 3 overlapping peptide pools were used to screen HEV-specific CD8+ T cell immune responses in HLA-A2+ patients with acute HEV infection and healthy donors, by intracellular cytokine staining. CD8+ T cells targeting the identified epitopes were sorted for sequencing of the TCR repertoires by next generation sequencing. Messenger RNA encoding these TCRs were introduced into lymphocytes of healthy donors and patients with cHEV through TCR redirection. TCR-engineered lymphocytes were evaluated for Dextramer®-binding capacity, target sensitivity and cytotoxicity against peptide-loaded T2 cells. RESULTS: HEV-specific responses were observed across open reading frame (ORF)1 and ORF2 of the HEV genome in patients with acute resolving HEV infection. HLA-A2-restricted HEV-specific CD8+ T cell epitopes targeting the HEV RNA helicase and RNA-dependent RNA polymerase were selected for functional studies. Introduction of HEV-specific TCRs into lymphocytes of immunocompetent donors and patients with chronic hepatitis E enabled the lymphocytes to bind HEV Dextramers, secrete multiple cytokines and exert cytotoxicity in a target-specific manner. CONCLUSION: We identified TCRs that target HEV-specific CD8+ T cell epitopes, and characterized their immune properties, which may have clinical potential in future T cell-based therapy. LAY SUMMARY: Patients who are immunosuppressed are vulnerable to developing chronic liver disease following infection with hepatitis E virus (HEV). To-date, there is no approved therapy for chronic hepatitis E. Interferon-α and ribavirin are off-label treatment options, but their applications are limited by side effects. Thus, immunotherapy, more specifically T cell-based therapy, may be an alternative approach. We designed T cell receptor-engineered T cells that effectively conferred immune cells, taken from patients with chronic hepatitis E, with the ability to recognize virus-specific epitopes and mediate killing of target cells in vitro.

Chronic Hepatitis E in Rheumatology and Internal Medicine Patients: A Retrospective Multicenter European Cohort Study.

Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim⁻Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.

Evaluation of an antigen assay for diagnosing acute and chronic hepatitis E genotype 4 infection.

BACKGROUND AND AIM: Results obtained from different hepatitis E virus (HEV) tests are usually inconsistent. The detection of serum HEV antigen (Ag) has been suggested to be more sensitive for the diagnosis of genotypes 1 and 3 HEV. METHODS: We compared the diagnostic accuracies of serum HEV Ag and HEV RNA by using 202 serum samples from patients suspected acute viral hepatitis. RESULTS: The HEV Ag assay was 100% specific. The lower detected levels of viremia ranged from 102 to 103  copies/mL. The sensitivity of the HEV Ag test was 90.5%. One of the 42 cases was negative for anti-HEV IgM, but HEV Ag was still detectable. The detectable period of HEV Ag was in concordance with the detectable period of HEV RNA. Serum HEV Ag was persistently detected in two cases of chronic hepatitis E, confirmed by the persistent presence of HEV RNA despite being negative for anti-HEV IgM. HEV Ag demonstrated good consistency with positive HEV RNA (k = 0.938, P < 0.001). Receiver operating characteristic analysis of HEV Ag suggested a second cut-off value of >0.095 to predict HEV patients with 95.24% sensitivity and 98.75% specificity, and the area under the curve was 0.9887, which was higher than that of three commercial anti-HEV IgM ELISA tests. CONCLUSIONS: The presence of HEV Ag has good consistency with HEV RNA in both acute and chronic genotype 4 hepatitis E. HEV Ag is a more promising serum marker to identify active genotype 4 HEV infection than anti-HEV IgM and HEV RNA.