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The hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. HEV is classified into eight genotypes, labeled HEV-1 through HEV-8. Genotypes 1 and 2 exclusively infect humans, while genotypes 3, 4, and 7 can infect both humans and animals. In contrast, genotypes 5, 6, and 8 are restricted to infecting animals. While most individuals with a strong immune system experience a self-limiting infection, those who are immunosuppressed may develop chronic hepatitis. Pregnant women are particularly vulnerable to severe illness and mortality due to HEV infection. In addition to liver-related complications, HEV can also cause extrahepatic manifestations, including neurological disorders. The immune response is vital in determining the outcome of HEV infection. Deficiencies in T cells, NK cells, and antibody responses are linked to poor prognosis. Interestingly, HEV itself contains microRNAs that regulate its replication and modify the host's antiviral response. Diagnosis of HEV infection involves the detection of HEV RNA and anti-HEV IgM/IgG antibodies. Supportive care is the mainstay of treatment for acute infection, while chronic HEV infection may be cleared with the use of ribavirin and pegylated interferon. Prevention remains the best approach against HEV, focusing on sanitation infrastructure improvements and vaccination, with one vaccine already licensed in China. This comprehensive review provides insights into the spread, genotypes, prevalence, and clinical effects of HEV. Furthermore, it emphasizes the need for further research and attention to HEV, particularly in cases of acute hepatitis, especially among solid-organ transplant recipients., (© 2024. The Author(s).)

Background: The hepatitis E virus (HEV) can cause acute viral hepatitis with or without neurological manifestations, and occasionally progresses to chronic infection in immunocompromised individuals. The management of chronic HEV infection in cancer patients may be challenging due to the complex immunological constellation. Furthermore, the diagnostic workflow and the impact on quality of life of neurological HEV manifestations in immunocompromised patients have not been sufficiently delineated previously., Case Description: A 61-year-old male with systemically treated chronic lymphocytic leukemia (CLL) experienced a slowly progressive atrophy of the spinal cord due to a chronic HEV infection. Despite continuous antiviral treatment with ribavirin, the patient's neurological condition continued to deteriorate, particularly following subsequent attempts to treat CLL. Treatment with obinutuzumab resulted in acute bowel and urinary retention and a further deterioration of motor skills, prompting the discontinuation of obinutuzumab. The patient's neurological status improved after the administration of intravenous immunoglobulins., Conclusion: This case study provides a comprehensive long-term follow-up of a cancer patient with chronic HEV infection and associated CNS involvement, which resulted in progressive neurological disability over several years. The challenges faced in diagnosing new neurological symptoms in patients undergoing immunosuppressive cancer treatment underscore the need for an interdisciplinary diagnostic approach that includes HEV testing. We propose a diagnostic pathway for future validation in immunocompromised cohorts presenting with neurological symptoms, emphasizing its potential to enhance clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ritter, Yomade, Holtz, Deinhardt-Emmer, McLean, Hartinger, Bechwar, Schwab, Huss, Mawrin, Axer, Schrenk, Reuken and Mäurer.)

Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL ) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants., Competing Interests: The authors declare no conflict of interest.

Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach mortality rates up to 25% in pregnant women or become chronic in immunocompromised patients. Hepatitis E virus (HEV) infection have been associated with a range of extrahepatic manifestations, including a spectrum of neurological symptoms. Current therapy options are limited to non-specific antivirals like ribavirin, but recently, repurposed viral polymerase inhibitors like sofosbuvir and NITD008 were described to inhibit HEV replication. Here, we evaluated the efficacy of these drugs in various neuronal-derived cell lines to determine their potency outside the liver. Our findings indicate that both drugs, especially sofosbuvir, exhibited reduced efficacy in neuronal cells compared to hepatic cells. These results should be taken into account in the development of direct-acting antivirals for HEV and their potency at extrahepatic replication sites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Since the coronavirus disease 2019 (COVID-19) pandemic, immunocompromised individuals face an increased risk of HEV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection, posing a threat of liver failure and prolonged illness. A 69-year-old male, with a history of chronic lymphocytic leukemia, was co-infected with HEV and SARS-CoV-2. Given the progressive decline in liver function post-admission, steroid therapy was initiated, which led to treatment-related complications. Additionally, the patient experienced an aggravation of COVID-19 symptoms due to persistent SARS-CoV-2 infection, effectively managed through a combination of antiviral medications and corticosteroids. This case describes the intricate clinical trajectory and therapeutic approach for managing HEV and SARS-CoV-2 co-infection, underscoring the potential efficacy of short-term corticosteroid intervention alongside comprehensive antiviral treatment., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection., (© 2024. The Author(s).)

Hepatitis E virus (HEV) is prevalent worldwide and can cause persistent infection with severe morbidity. Antiviral treatment approaches can lead to the emergence of viral variants encoding escape mutations that may impede viral clearance. The frequency of these variants remains unknown in the human population as well as environment due to limited comprehensive data on HEV diversity. In this study, we investigated the HEV prevalence and diversity of circulating variants in environmental samples, that is, wastewater and rivers from North-Rhine Westphalia, Germany. HEV prevalence could be determined with 73% of samples tested positive for viral RNA via qRT-PCR. Using high-throughput sequencing, we were able to assess the overall genetic diversity in these samples and identified the presence of clinically relevant variants associated with drug resistance. In summary, monitoring variants from environmental samples could provide valuable insights into estimating HEV prevalence and identifying circulating variants that can impact treatment outcome., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC 50 value of vidofludimus calcium is 4.6-7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E., Competing Interests: Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

A 26-year-old Indian man who had arrived in Japan 24 days prior presented to our hospital with abdominal pain and a fever. A blood test revealed marked hepatic dysfunction, and imaging tests confirmed a diagnosis of acute hepatitis. The patient's liver function and coagulability deteriorated, and his general condition was poor. Given the possibility of fulminant hepatic failure, we initiated steroid pulse therapy. Following the initiation of steroid therapy, the patient's liver function and subjective symptoms rapidly improved. Testing revealed positive findings for IgA-hepatitis E virus, and a genetic analysis of hepatitis E identified genotype 1, which is not endemic to Japan, leading to a definitive diagnosis of imported hepatitis E infection from India. The successful response to steroid therapy highlights the potential benefit of this approach in managing severe cases of acute hepatitis E, a rare occurrence in Japan. This case underscores the importance of considering hepatitis E infection in individuals with a recent travel history to regions with high prevalence and the potential benefits of steroid therapy in managing severe cases of acute hepatitis E.

Background and Aims: Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter phase II pilot trial was carried out, evaluating the nucleotide analog sofosbuvir by treating nine chronically HEV-infected patients with sofosbuvir (Trial Number NCT03282474). During the study, antiviral therapy reduced virus RNA levels initially but did not lead to a sustained virologic response. Here, we characterize the changes in HEV intrahost populations during sofosbuvir treatment to identify the emergence of treatment-associated variants., Approach and Results: We performed high-throughput sequencing on RNA-dependent RNA polymerase sequences to characterize viral population dynamics in study participants. Subsequently, we used an HEV-based reporter replicon system to investigate sofosbuvir sensitivity in high-frequency variants. Most patients had heterogenous HEV populations, suggesting high adaptability to treatment-related selection pressures. We identified numerous amino acid alterations emerging during treatment and found that the EC 50 of patient-derived replicon constructs was up to ~12-fold higher than the wild-type control, suggesting that variants associated with lower drug sensitivity were selected during sofosbuvir treatment. In particular, a single amino acid substitution (A1343V) in the finger domain of ORF1 could reduce susceptibility to sofosbuvir significantly in 8 of 9 patients., Conclusions: In conclusion, viral population dynamics played a critical role during antiviral treatment. High population diversity during sofosbuvir treatment led to the selection of variants (especially A1343V) with lower sensitivity to the drug, uncovering a novel mechanism of resistance-associated variants during sofosbuvir treatment., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Primary membranous nephropathy (PMN) is a major cause of nephrotic syndrome in adults. Studies have shown that one-third of PMN cases undergo spontaneous remission, among which are some cases of infection-related complete remission. Herein, we report the case of a 57-year-old man who achieved complete remission of PMN shortly after the onset of acute hepatitis E infection. At the age of 55 years, the patient developed a nephrotic syndrome, and renal biopsy revealed membranous nephropathy, Ehrenreich-Churg stage 1. Treatment with prednisolone (PSL) reduced urinary protein from 7.8 g/gCre to approximately 1 g/gCre but did not lead to complete remission. However, 7 months after starting treatment, he developed an acute hepatitis E infection after consuming wild boar meat. Immediately after the onset of acute hepatitis E, the patient's urinary protein levels decreased to < 0.3 g/gCre. The PSL dose was subsequently reduced and discontinued after 2 years and 8 months, and complete remission was maintained thereafter. We considered that an increase in the number of regulatory T cells (Tregs) caused by acute hepatitis E infection was associated with PMN remission in this patient., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

The hepatitis E virus (HEV) is increasingly acknowledged as the primary cause of acute hepatitis. While most HEV infections are self-limiting, cases of chronic infection and fulminant hepatitis necessitate the administration of anti-HEV medications. However, there is a lack of specific antiviral drugs designed for HEV, and the currently available drug (ribavirin) has been associated with significant adverse effects. The development of innovative antiviral drugs involves targeting distinct steps within the viral life cycle: the early step (attachment and internalization), middle step (translation and RNA replication), and late step (virus particle formation and virion release). We recently established three HEV reporter systems, each covering one or two of these steps. Using these reporter systems, we identified various potential drug candidates that target different steps of the HEV life cycle. Through rigorous in vitro testing using our robust cell culture system with the genotype 3 HEV strain (JE03-1760F/P10), we confirmed the efficacy of these drugs, when used alone or in combination with existing anti-HEV drugs. This underscores their significance in the quest for an effective anti-HEV treatment. In the present review, we discuss the development of the three reporter systems, their applications in drug screening, and their potential to advance our understanding of the incompletely elucidated HEV life cycle.

The hepatitis E virus (HEV) is a major cause of hepatitis, with an estimated 3.3 million symptomatic cases annually. There is no HEV-specific treatment besides the off-label use of ribavirin and a vaccine is only available in China and Pakistan. To aid the development of therapeutic and preventive strategies, there is a need for convenient HEV infection models in small laboratory animals. To this end, we make use of the rat hepatitis E virus. Human infections with this virus have been reported in recent years, making it a relevant pathogen for the establishment of a small animal infection model. We here report that oral gavage of a feces suspension, containing a pre-defined viral RNA load, results in a reproducible synchronized infection in athymic nude rats. This route of administration mimics fecal-oral transmission in a standardized fashion. The suitability of the model to study the effect of antiviral drugs was assessed by using ribavirin, which significantly reduced viral loads in the feces, liver, and other tissues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

A healthy 24-year-old woman was admitted to the emergency department with acute hepatitis. She denied traveling, consumption of drugs, herbs, alcohol or medication other than the same oral contraceptive for years. The etiological work-up revealed positive Herpes Simplex Virus (HSV) 1+2 serology (IgG and IgM). Other viral serologies were negative, while Hepatitis E Virus (HEV) serology and viraemia were pending. Liver biopsy showed portal and lobular necroinflammatory activity without specific etiological findings. The remaining work-up was unremarkable. The patient developed jaundice. Acyclovir was started, considering a possible herpetic hepatitis, while waiting for HSV viraemia and immunohistochemistry in the liver biopsy, which later revealed to be negative. Despite therapy, hyperbilirubinemia and liver cytolysis worsened. At this point, HEV serology and viraemia came back positive. Ribavirin was started with rapid clinical and biochemical improvement. Liver enzymes were normal and HEV viraemia was negative after 12 weeks of ribavirin, remaining undetectable 3 months later.

Hepatitis E virus (HEV) is endemic in several developing countries of Africa and Asia. It mainly causes self-limiting waterborne infections, in either sporadic or outbreak form. Recently, HEV was shown to cause chronic infections in immunosuppressed individuals. Ribavirin and interferon, the current off-label treatment options for hepatitis E, have several side effects. Hence, there is a need for new drugs. We evaluated the antimalarial drug artesunate (ART) against genotype 1 HEV (HEV-1) and HEV-3 using a virus-replicon-based cell culture system. ART exhibited 59% and 43% inhibition of HEV-1 and HEV-3, respectively, at the highest nontoxic concentration. Computational molecular docking analysis showed that ART can bind to the helicase active site (affinity score, -7.4 kcal/mol), indicating its potential to affect ATP hydrolysis activity. An in vitro ATPase activity assay of the helicase indeed showed 24% and 55% inhibition at 19.5 µM (EC 50 ) and 78 µM concentrations of ART, respectively. Since ATP is a substrate of RNA-dependent RNA polymerase (RdRp) as well, we evaluated the effect of ART on the enzymatic activity of the viral polymerase. Interestingly, ART showed 26% and 40% inhibition of the RdRp polymerase activity at 19.5 µM and 78 µM concentrations of ART, respectively. It could be concluded from these findings that ART inhibited replication of both HEV-1 and HEV-3 by directly targeting the activities of the viral enzymes helicase and RdRp. Considering that ART is known to be safe in pregnant women, we think this antimalarial drug deserves further evaluation in animal models., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal-oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results.

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.

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/m 2 . 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 log 10 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., (© 2022. Japanese Society of Gastroenterology.)

Background & Aims: Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action., Methods: Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase., Results: We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage., Conclusions: In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals., Impact and Implications: Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis E Virus (HEV) infection is an emergent zoonotic disease, where chronic hepatitis E associated to solid organ transplant (SOT) recipients, related to genotype 3, is the clinical manifestation of major concern. In this setting, ribavirin (RBV) treatment is the only available therapy, though drug-resistant variants could emerge leading to a therapeutic failure. Crystallographic structures have not been reported for most of the HEV proteins, including the RNA-polymerase (RdRp). Therefore, the mechanism of action of RBV against HEV and the molecular interactions between this drug and RdRp are largely unknown. In this work, we aimed to model in silico the 3 D structure of a novel HEV3 RdRp (HEV&#95;C1&#95;Uy) from a chronically HEV infected-SOT recipient treated with RBV and to perform a molecular docking simulation between RBV triphosphate (RBVT), 7-methyl-guanosine-5'-triphosphate and the modelled protein. The models were generated using I-TASSER server and validated with multiple bioinformatics tools. The docking analysis were carried out with AutoDock Vina and LeDock software. We obtained a suitable model for HEV&#95;C1&#95;Uy (C-Score=-1.33, RMSD = 10.4 ± 4.6 Å). RBVT displayed a binding affinity of -7.6 ± 0.2 Kcal/mol by molecular docking, mediated by 6 hydrogen-bonds (Q195-O14, S198-O11, E257-O13, S260-O2, O3, S311-O11) between the finger's-palm-domains and a free binding energy of 31.26 ± 16.81 kcal/mol by molecular dynamics simulations. We identified the possible HEV RdRp interacting region for incoming nucleotides or analogs and provide novel insights that will contribute to better understand the molecular interactions of RBV and the enzyme and the mechanism of action of this antiviral drug.Communicated by Ramaswamy H. Sarma.

Introduction: Hepatitis E Virus (HEV) was initially thought to cause only acute infections, but the discovery of chronic hepatitis E in immunocompromised patients has profoundly changed our understanding of the virus., Areas Covered: We describe the physiopathology, diagnosis, and clinical management of chronic HEV infection. The virus can persist in nearly two-thirds of immunosuppressed patients. Reducing immunosuppression is the first immunomodulatory strategy to cure chronic hepatitis E. But this may not always be feasible or effective. Ribavirin monotherapy for 3 months has been recommended as first-line treatment for chronically infected patients. Ribavirin is around 80% effective at eradicating HEV in retrospective studies. Apart from ribavirin, interferon has been successfully used in liver transplants recipients, but if the patient does not respond, no other alternative drug is available. The vaccine available to prevent HEV infection is one available only in China., Expert Opinion: HEV infection is a major concern in immunocompromised patients. But the therapeutic arsenal is limited to ribavirin and interferon. Both produce several side effects and new drugs are urgently needed. Moreover, preventive strategies to limit HEV transmission and/or evolution to a chronic infection are also required.

Hepatitis E virus (HEV) is a major cause of acute hepatitis globally. Chronic and fulminant courses are observed especially in immunocompromised transplant recipients since administration of ribavirin (RBV) does not always lead to a sustained virologic response. By in vitro stimulation of NK cells through hepatoma cell lines inoculated with a full-length HEV and treatment with RBV, we analyzed the viral replication and cell response to further elucidate the mechanism of action of RBV on immune cells, especially NK cells, in the context of HEV infection. Co-culture of HEV-infected hepatoma cells with PBMCs and treatment with RBV both resulted in a decrease in viral replication, which in combination showed an additive effect. An analysis of NK cell functions after stimulation revealed evidence of reduced cytotoxicity by decreased TRAIL and CD107a degranulation. Simultaneously, IFN-ɣ production was significantly increased through the IL-12R pathway. Although there was no direct effect on the IL-12R subunits, downstream events starting with TYK-2 and subsequently pSTAT4 were upregulated. In conclusion, we showed that RBV has an immunomodulatory effect on the IL-12R pathway of NK cells via TYK-2. This subsequently leads to an enhanced IFN-ɣ response and thus, to an additive antiviral effect in the context of an in vitro HEV infection.

Introduction: The hepatitis E virus (HEV) represents an important cause of viral hepatitis and could cause chronic infections in immunocompromised patients. However, data about immunocompromised patients other than solid organ transplant recipients are limited., Methods: We identified patients from a laboratory database and retrospectively compiled and analyzed clinical as well as laboratory data in detail., Results: Overall, 22 severely immunosuppressed patients, excluding solid organ transplant recipients, were identified. Four patients did not experience viral clearance (one without and three despite ribavirin therapy). Three patients acquired the infection after allogeneic hematopoietic stem cell transplantation (alloHSCT) and recovered spontaneously, whereas another patient, infected prior to alloHSCT, developed a chronic infection. Four patients failed to clear HEV, resulting in fatal liver failure in 2 patients. The CD4+ cell counts increased in all but 1 patient attaining a sustained virological response (SVR), as compared to patients with clinical failure. Severe immunoglobulin deficiency did not appear to obviate the control of HEV. Six of ten (60%) patients with and nine of 12 (75%) patients without ribavirin therapy achieved an SVR., Conclusions: Upfront ribavirin therapy does not appear mandatory in patients without CD4+ lymphopenia, but a prolonged HEV replication carries the risk of liver failure. Our data suggest that chronic HEV infections could cause T-cell exhaustion, which might be overruled with ribavirin therapy., (© 2023 S. Karger AG, Basel.)

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., (© 2023. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

Background: In the 2016 ESPGHAN recommendations on how to deal with hepatitis E virus infection in immunocompromised children, patients treated with chemotherapy were not specifically mentioned., Observations: Two teenagers treated with chemotherapy for acute leukemia and medulloblastoma, respectively, were diagnosed with hepatic cytolysis. After numerous investigations hepatitis E was found, limiting the good progress of the chemotherapy treatment., Conclusion: In the case of liver cytolysis in immunocompromised children treated with chemotherapy, hepatitis E virus infection has to be promptly diagnosed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hepatitis E virus (HEV) infection is a frequent cause of acute viral hepatitis. Immunocompromised patients are at increased risk for viral infection and chronic courses of hepatitis. Whether patients with autoimmune diseases are at risk of developing clinically relevant hepatitis or even chronic liver disease after HEV infection is discussed controversially. ANCA-associated vasculitis is a rare autoimmune disease with potentially life-threatening organ involvement, thus requiring intensive immunosuppression with glucocorticoids, cyclophosphamide, or rituximab. As there are no reports available on the infection with HEV in patients with ANCA-associated vasculitis, clinical decision making in such cases is based on experiences from other disease entities. Therefore, in this study we analyzed the course of liver disease and the therapeutic management of autoimmune vasculitis in a retrospective cohort of five patients with ANCA-associated vasculitis and acute hepatitis E., Results: Four patients were on immunosuppressive maintenance therapy and one patient was on remission induction therapy with cyclophosphamide and high dose glucocorticoids. All patients had at least one potentially hepatotoxic co-medication at the time of hepatitis. Hepatitis-associated clinical symptoms were recorded in four of five patients. The course of hepatitis was characterized by strongly elevated transaminases, a temporary liver failure was observed in one case. The management of hepatitis E included cessation of the immunosuppressants in all patients, whereas oral glucocorticoids were not discontinued. Under this regime, all patients cleared the virus without additional anti-viral treatment. Liver enzymes normalized one month after they peaked. In the follow-up period of at least 1.5 years (range 1.5-12 years), no chronic liver disease was observed, although one patient died of cholangiocarcinoma with liver metastases some years after HEV infection. Vasculitis was not active in our patient cohort at the time of HEV infection. However, inflammatory flares occured in three of five patients after discontinuation of the immunosuppressive therapy. Immunosuppressants were paused for a median time of 4 weeks and after their resumption vasculitic disease activity was controlled in all patients., Conclusions: Acute HEV infection in patients with ANCA-associated vasculitis shows a favorable outcome of liver disease but bears the risk of inflammatory flares due to cessation of immunosuppression., (© 2022. The Author(s).)

Hepatitis E virus is increasingly being reported to cause chronic infection in immunocompromised patients. However, less is known about patients with an underlying hematologic disease. In particular, the impact of hepatitis E infection on oncological therapy has been poorly described. In this retrospective single-center study, we analyzed 35 hematologic patients with hepatitis E, including 20 patients under active oncological treatment and 15 patients who were in the posttreatment follow-up or under active surveillance. The primary aim was to describe the clinical courses with particular focus on any hepatitis E-related therapy modifications of cancer-directed therapy. In the majority (60%) of patients who were under active oncological treatment, hepatitis E-related therapy modifications were made, and 25% of deaths were due to progression of the hematologic disease. In patients receiving concomitant oncological treatment, no hepatitis Erelated deaths occurred. In contrast, two patients in the follow-up group died from hepatitis E-associated acute-onchronic liver failure. Chronic hepatitis E was observed in 34% of all cases and 43% received ribavirin therapy; of those, 27% achieved a sustained virological response. CD20-directed therapy was the only independent risk factor for developing chronic hepatitis E. We conclude that CD20-directed treatment at any time point is a risk factor for developing chronic hepatitis E. Nevertheless, since mortality from the progression of hematologic disease was higher than hepatitis E-related mortality, we suggest careful case-by-case decisions on modifications of cancer treatment. Patients in the posttreatment follow-up phase may also suffer from severe courses and hepatitis E chronicity occurs as frequently as in patients undergoing active therapy.

The changes occurring in viral quasispecies populations during infection have been monitored using diversity indices, nucleotide diversity, and several other indices to summarize the quasispecies structure in a single value. In this study, we present a method to partition quasispecies haplotypes into four fractions according to their fitness: the master haplotype, rare haplotypes at two levels (those present at <0.1%, and those at 0.1−1%), and a fourth fraction that we term emerging haplotypes, present at frequencies >1%, but less than that of the master haplotype. We propose that by determining the changes occurring in the volume of the four quasispecies fitness fractions together with those of the Hill number profile we will be able to visualize and analyze the molecular changes in the composition of a quasispecies with time. To develop this concept, we used three data sets: a technical clone of the complete SARS-CoV-2 spike gene, a subset of data previously used in a study of rare haplotypes, and data from a clinical follow-up study of a patient chronically infected with HEV and treated with ribavirin. The viral response to ribavirin mutagenic treatment was selection of a rich set of synonymous haplotypes. The mutation spectrum was very complex at the nucleotide level, but at the protein (phenotypic/functional) level the pattern differed, showing a highly prevalent master phenotype. We discuss the putative implications of this observation in relation to mutagenic antiviral treatment.

Hepatitis E virus (HEV) is the most prevalent hepatitis virus worldwide. Genotypes 3 (HEV3) and 4 (HEV4) as well as rat HEV can lead to chronic hepatitis E and cirrhosis in immunosuppressed patients. Within the last decade, several options for treating chronic hepatitis have been developed and have achieved a sustained virological response. However, there are still unmet needs such as optimizing immunosuppression to allow HEV clearance with or without ribavirin, as well as alternative therapies to ribavirin that are discussed in this paper.

Background: Transplant-related hepatitis E virus (HEV) infection is a rarely recognized phenomenon with significant clinical importance given its potential to result in chronic hepatitis posttransplant., Methods: We retrospectively evaluated HEV diagnosis and treatment after liver, kidney, and heart transplant in a single center. We identified patients diagnosed with HEV by serologic testing and evaluated their treatment regimens., Results: Fifteen transplant recipients (12 liver, 2 kidney, and 1 heart) presented with elevated liver enzymes and were positive for HEV IgM antibody. Liver enzymes normalized in 4 patients after being treated with ribavirin. One of the 4 patients had 2 recurrences with positive HEV RNA results following ribavirin treatment but recovered after 12 months of ribavirin therapy. After treatment with reduction in immunosuppression without antiviral treatment, 6 of 8 patients' liver enzymes normalized. One of these patients died of acute pancreatitis 2 months after testing positive for HEV IgM antibody., Conclusions: The potential for complications related to active HEV infections in transplant recipients necessitates prompt diagnosis and treatment to prevent irreversible damage. Diagnosis with HEV reverse transcriptase-polymerase chain reaction should follow a positive HEV IgM antibody test. This manuscript provides evidence that ribavirin antiviral therapy and reducing immunosuppression are effective treatments for HEV infections in liver, kidney, and heart transplant recipients, which has not been sufficiently investigated in the population of the United States. Larger multicenter studies are needed to confirm the risks and benefits of using ribavirin antiviral therapy as first-line therapy of HEV posttransplant., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The incidence of hepatitis E continues to increase and in immunocompromised patients can lead to chronic infection. Management of hepatitis E has evolved over time, with the first step being a reduction of immunosuppression followed by treatment with ribavirin. The European Association for the Study of Liver guidelines support treatment with ribavirin although the optimum dose and regime is unknown. This series reviews eight chronically infected cases treated between 2018 and 2021 in two UK centres (Ipswich Hospital and Addenbrooke's Hospital). Treatment response was defined primarily as sustained virological response at 12 weeks (SVR12) following the cessation of treatment and secondly as sustained virological response at 24 weeks (SVR24). The median dose of ribavirin given daily was 600 mg. The management of five of the eight cases was in line with the guidelines, and treatment was stopped after 12 weeks. Two of these five patients achieved SVR (40%). The remaining three cases were given a 24-week course based on clinical judgement, and all achieved SVR (100%). The three patients who relapsed received a second 24-week course of treatment and achieved SVR. Therefore, with a 24-week course, a 100% treatment success rate was attained. In chronic hepatitis E, a 24-week course of ribavirin would achieve optimum clearance rates with a single course of treatment. Ensuring the highest dose of ribavirin as possible (aiming to reach 800 mg daily) and attempts to reduce immunosuppressive therapy safely may also be relevant to achieving SVR., (© 2022 John Wiley & Sons Ltd.)

Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing countries, but it can also take a chronic course especially in immunocompromised patients. Its epidemiology after liver transplantation (LT) is hard to assess and treatment options are still explored. Between 2009 and 2020, literature reporting HEV prevalence and treatment in LT recipients was searched and a synthesis was attempted. Sixteen studies reported HEV prevalence in consecutive LT patients: HEV RNA positivity ranged between 0%-1.4% and 0%-7.7% for Western and Eastern cohorts, respectively. In studies published between 2009-2014 and 2015-2020, HEV RNA positivity ranged between 0.35%-1.3% (all European) and 0%-7.7% (European: 0%-1.4%), respectively. Five studies evaluated HEV prevalence in LT recipients with abnormal liver enzymes: HEV RNA positivity was 2.9% in studies published between 2009 and 2014 and from 3.5% to 20% in studies published between 2015 and 2020. Twenty-seven studies reported HEV treatment in LT recipients: sustained virologic response was achieved in 15% by immunosuppression reduction alone and in 83% of cases by ribavirin regiments. Chronic HEV infection is affecting LT recipients, mostly those with abnormal liver enzymes and in Eastern countries. HEV diagnoses should be based on PCR techniques. Successful treatment can be achieved with ribavirin in most cases., (© 2022 John Wiley & Sons Ltd.)

Hepatitis E virus (HEV) infections are a leading cause of acute viral hepatitis in humans and pose a considerable threat to public health. Current standard of care treatment is limited to the off-label use of nucleoside-analog ribavirin (RBV) and PEGylated interferon-α, both of which are associated with significant side effects and provide limited efficacy. In the past few years, a promising natural product compound class of eukaryotic initiation factor 4A (eIF4A) inhibitors (translation initiation inhibitors), called rocaglates, were identified as antiviral agents against RNA virus infections. In the present study, we evaluated a total of 205 synthetic rocaglate derivatives from the BU-CMD compound library for their antiviral properties against HEV. At least eleven compounds showed inhibitory activities against the HEV genotype 3 (HEV-3) subgenomic replicon below 30 nM (EC 50 value) as determined by Gaussia luciferase assay. Three amidino-rocaglates (ADRs) (CMLD012073, CMLD012118, and CMLD012612) possessed antiviral activity against HEV with EC 50 values between 1 and 9 nM. In addition, these three selected compounds inhibited subgenomic replicons of different genotypes (HEV-1 [Sar55], wild boar HEV-3 [83-2] and human HEV-3 [p6]) in a dose-dependent manner and at low nanomolar concentrations. Furthermore, tested ADRs tend to be better tolerated in primary hepatocytes than hepatoma cancer cell lines and combination treatment of CMLD012118 with RBV and interferon-α (IFN-α) showed that CMLD012118 acts additive to RBV and IFN-α treatment. In conclusion, our results indicate that ADRs, especially CMLD012073, CMLD012118, and CMLD012612 may prove to be potential therapeutic candidates for the treatment of HEV infections and may contribute to the discovery of pan-genotypic inhibitors in the future., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Hepatitis E virus (HEV) is a cause of significant morbidity and mortality, representing an important global public health problem. Immunocompetent patients with acute hepatitis E can clear the infection spontaneously; however, in approximately two thirds of cases, immunosuppressed patients, such as kidney transplant (KT) recipients, fail to clear the HEV infection and develop chronic hepatitis., Patients and Methods: We report 3 cases of HEV infection in KT patients. Two presented only with laboratory abnormalities and elevated liver enzymes, and 1 presented with symptomatic disease motivating hospital admission. None was able to clear the infection spontaneously, and they were all treated with ribavirin, accompanied with reduction of immunosuppressive drugs. Adverse effects of the treatment were reported in 2 patients, and in 1 case, a dose reduction was necessary. All patients responded to the treatment and have no current evidence of active disease. No alterations of basal kidney function during or related to the treatment were registered., Discussion: HEV screening in KT patients presenting with abnormal liver function of undetermined cause is fundamental, as it might have poorer outcomes in this specific population. The treatment with ribavirin seems to be safe and effective, although we must always be alert to potential side effects, maintaining a close follow-up of these patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hepatitis E virus (HEV) and hepatitis C virus (HCV) are both RNA viruses with a tropism for liver parenchyma but are also capable of extrahepatic manifestations. Hepatitis E is usually a viral acute fecal-oral transmitted and self-limiting disease presenting with malaise, jaundice, nausea and vomiting. Rarely, HEV causes a chronic infection in immunocompromised persons and severe fulminant hepatitis in pregnant women. Parenteral HCV infection is typically asymptomatic for decades until chronic complications, such as cirrhosis and cancer, occur. Despite being two very different viruses in terms of phylogenetic and clinical presentations, HEV and HCV show many similarities regarding possible transmission through organ transplantation and blood transfusion, pathogenesis (production of antinuclear antibodies and cryoglobulins) and response to treatment with some direct-acting antiviral drugs. Although both HEV and HCV are well studied individually, there is a lack of knowledge about coinfection and its consequences. The aim of this review is to analyze current literature by evaluating original articles and case reports and to hypothesize some interactions that can be useful for research and clinical practice., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interests for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hepatitis E virus (HEV) is an important cause of viral hepatitis worldwide and there is currently no FDA-approved anti-HEV drug. The commonly used drug ribavirin (RBV) could not achieve viral clearance in all patients and can induce drug resistance. Recent studies showed sofosbuvir (SOF) can inhibit HEV replication in vitro and has add-on effect when combined with RBV, but the clinical effect of SOF against HEV infection remains controversial and the dosage of SOF warrants further exploration. In this study, a rabbit model for acute HEV infection was used to evaluate the effect of SOF at different doses against HEV genotype 3 and 4, and to compare the antiviral effect of SOF-plus-RBV therapy with RBV monotherapy. Virological parameters on fecal, serological and intrahepatic level were tested by real-time PCR and ELISA. Liver function tests and histopathological assays were performed. Both 200 mg/d and 300 mg/d SOF treatment inhibits HEV replication with relieved liver inflammation and declined levels of fecal HEV RNA and antigenemia. 300 mg/d SOF eliminated HEV replication while a short viral rebound was observed after 200 mg/d SOF treatment. The SOF-plus-RBV therapy also showed stronger anti-HEV effect than RBV monotherapy. Our study suggests that high dose of SOF showed anti-HEV effect in the rabbit model. Moreover, the de novo SOF-plus-RBV therapy which eliminated acute HEV infection more efficiently than RBV monotherapy may serve as an alternative treatment strategy but warrants further preclinical and clinical study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Transmission of hepatitis E virus (HEV) within the healthcare setting is extremely rare. Additionally, the development of chronic HEV infection in association with severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) infection and/or its immunomodulatory therapy has not been reported previously., Aims: To describe the investigation and management of a nosocomial HEV transmission incident during the coronavirus disease 2019 (COVID-19) pandemic., Methods: Epidemiological and molecular investigation of two individuals hospitalised with COVID-19 who were both diagnosed with HEV infection., Results: Findings from our investigation were consistent with transmission of HEV from one patient with a community-acquired HEV infection to another individual (identical HEV sequences were identified in the two patients), most likely due to a breach in infection control practices whilst both patients shared a bed space on the intensive care unit (ICU). Chronic HEV infection requiring treatment with ribavirin developed in one patient with prolonged lymphopaenia attributable to COVID-19 and/or the immunomodulators received for its treatment. Further investigation did not identify transmission of HEV to any other patients or to healthcare workers., Conclusions: The extraordinary demands that the COVID-19 pandemic has placed on all aspects of healthcare, particularly within ICU settings, has greatly challenged the ability to consistently maintain optimal infection prevention and control practices. Under the significant pressures of the COVID-19 pandemic a highly unusual nosocomial HEV transmission incident occurred complicated further by progression to a chronic HEV infection in one patient., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies.

Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. There is growing concern about transfusion-transmitted HEV (TT-HEV) as an emerging global health problem. HEV can potentially result in chronic infection in immunocompromised patients, leading to a higher risk of liver cirrhosis and even death. Between 0.0013% and 0.281% of asymptomatic blood donors around the world have HEV viremia, and 0.27% to 60.5% have anti-HEV immunoglobulin G. HEV is infectious even at very low blood concentrations of the virus. Immunosuppressed patients who develop persistent hepatitis E infection should have their immunosuppressant regimen reduced; ribavirin may be considered as treatment. Pegylated interferon can be considered in those who are refractory or intolerant to ribavirin. Sofosbuvir, a nucleotide analog, showed modest antiviral activity in some clinical studies but sustained viral response was not achieved. Therefore, rescue treatment remains an unmet need. The need for HEV screening of all blood donations remains controversial. Universal screening has been adopted in some countries after consideration of risk and resource availability. Various pathogen reduction methods have also been proposed to reduce the risk of TT-HEV. Future studies are needed to define the incidence of transmission through transfusion, their clinical features, outcomes and prognosis., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: HEV infection is the most common cause of liver inflammation, but the pathogenic mechanisms remain largely unclear. We aim to explore whether HEV infection activates inflammasomes, crosstalk with antiviral interferon response, and the potential of therapeutic targeting., Approach and Results: We measured IL-1β secretion, the hallmark of inflammasome activation, in serum of HEV-infected patients and rabbits, and in cultured macrophage cell lines and primary monocyte-derived macrophages. We found that genotypes 3 and 4 HEV infection in rabbits elevated IL-1β production. A profound increase of IL-1β secretion was further observed in HEV-infected patients (1,733 ± 1,234 pg/mL; n = 70) compared to healthy persons (731 ± 701 pg/mL; n = 70). Given that macrophages are the drivers of inflammatory response, we found that inoculation with infectious HEV particles robustly triggered NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in primary macrophages and macrophage cell lines. We further revealed that the ORF2 capsid protein and the formed integral viral particles are responsible for activating inflammasome response. We also identified NF-κB signaling activation as a key upstream event of HEV-induced NLRP3 inflammasome response. Interestingly, inflammasome activation antagonizes interferon response to facilitate viral replication in macrophages. Pharmacological inhibitors and clinically used steroids can effectively target inflammasome activation. Combining steroids with ribavirin simultaneously inhibits HEV and inflammasome response without cross-interference., Conclusions: HEV infection strongly activates NLRP3 inflammasome activation in macrophages, which regulates host innate defense and pathogenesis. Therapeutic targeting of NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

A patient with rheumatoid arthritis (RA) was presented, who developed an infection with the hepatitis E virus (HEV) under treatment with the Janus kinase (JAK) 1 and 2 inhibitor baricitinib. In the 3‑month routine check-up the patient had clearly elevated transaminase levels with an inconspicuous physical examination. The investigations detected antibodies of IgM and IgG classes against HEV and an elevated C‑reactive protein (CRP) level as well as HEV-RNA by real-time PCR, which is indicative of a recent HEV infection. Baricitinib was immediately discontinued. The extensive anamnesis revealed that the patient had eaten beef tartar some days before the consultation, without the occurrence of gastrointestinal symptoms or fever. In the further course the patient completely recovered and the liver function tests and the CRP levels normalized within 3 months. Baricitinib was then restarted. So far only few reports have been published on HEV infections in RA patients who have been treated with JAK inhibitors., (© 2021. The Author(s).)

Safety evaluation for the hepatitis E virus (HEV) is required for plasma fractionation products. Plasma-derived HEV (pHEV) is quite unique in that it is associated with a lipid membrane, which, when stripped during manufacturing processes, induces morphological changes in the virus, making it difficult to select proper HEV phenotypes for clearance studies. We developed a convenient system for the preparation of a high titer cell culture-derived HEV (cHEV). In this system, PLC/PRF/5 cells transfected with the wild-type HEV genome generated lipid membrane-associated cHEV for a long period even after cryopreservation. We also examined how this lipid membrane-associated cHEV can be used to verify the robustness of pHEV removal via 19-nm nanofiltration. Sodium-deoxycholate and trypsin (NaDOC/T) treatment not only dissolved lipid but also digested membrane-associated proteins from pHEV and cHEV, making the resulting cHEV particle smaller in size than any pHEV phenotypes generated by ethanol or solvent-detergent treatment in this study. In both 19-nm and 35-nm nanofiltration, cHEV behaved identically to pHEV. These results indicate that cHEV is a useful resource for viral clearance studies in term of availability, and the use of NaDOC/T-treated cHEV ensured robust pHEV removal capacity via 19-nm nanofiltration., (Copyright © 2021 Elsevier B.V. All rights reserved.)