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Yu CH, Cai LZ, Zhang X, Zhu GX, Zhong J, Xu XF. Chronic viral hepatitis B complicated by hepatitis E virus infection. Hepatobiliary Pancreat Dis Int 2025; 24:334-336. [PMID: 39244509 DOI: 10.1016/j.hbpd.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 08/26/2024] [Indexed: 09/09/2024]
Affiliation(s)
- Chun-Hua Yu
- Department of Health Management Center, Hangzhou First People's Hospital, Hangzhou 310006, China
| | - Ling-Zhi Cai
- Department of Breast Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China
| | - Xue Zhang
- Department of Infectious Diseases, Hangzhou First People's Hospital, Hangzhou 310006, China
| | - Guo-Xian Zhu
- Department of Infectious Diseases, Hangzhou First People's Hospital, Hangzhou 310006, China
| | - Jing Zhong
- Department of Operating Room, Xiangshan First People's Hospital Medical and Health Group, Ningbo 315700, China
| | - Xiang-Fei Xu
- Department of Infectious Diseases, Hangzhou First People's Hospital, Hangzhou 310006, China.
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Ugbaja SC, Mushebenge AGA, Kumalo H, Ngcobo M, Gqaleni N. Potential Benefits of In Silico Methods: A Promising Alternative in Natural Compound's Drug Discovery and Repurposing for HBV Therapy. Pharmaceuticals (Basel) 2025; 18:419. [PMID: 40143195 PMCID: PMC11944881 DOI: 10.3390/ph18030419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 01/30/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Hepatitis B virus (HBV) is an important global public health issue. The World Health Organization (WHO) 2024 Global Hepatitis Report estimated that the global prevalence of people living with HBV infection is 254 million, with an estimated prevalence incidence of 1.2 million new HBV infections yearly. Previous studies have shown that natural compounds have antiviral inhibition potentials. In silico methods such as molecular docking, virtual screening, pharmacophore modeling, quantitative structure-activity relationship (QSAR), and molecular dynamic simulations have been successfully applied in identifying bioactive compounds with strong binding energies in HBV treatment targets. The COVID-19 pandemic necessitated the importance of repurposing already approved drugs using in silico methods. This study is aimed at unveiling the benefits of in silico techniques as a potential alternative in natural compounds' drug discovery and repurposing for HBV therapy. Relevant articles from PubMed, Google Scholar, and Web of Science were retrieved and analyzed. Furthermore, this study comprehensively reviewed the literature containing identified bioactive compounds with strong inhibition of essential HBV proteins. Notably, hesperidin, quercetin, kaempferol, myricetin, and flavonoids have shown strong binding energies for hepatitis B surface antigen (HBsAg). The investigation reveals that in silico drug discovery methods offer an understanding of the mechanisms of action, reveal previously overlooked viral targets (including PreS1 Domain of HBsAg and cccDNA (Covalently Closed Circular DNA) regulators, and facilitate the creation of specific inhibitors. The integration of in silico, in vitro, and in vivo techniques is essential for the discovery of new drugs for HBV therapy. The insights further highlight the importance of natural compounds and in silico methods as targets in drug discovery for HBV therapy. Moreover, the combination of natural compounds, an in silico approach, and drug repurposing improves the chances of personalized and precision medicine in HBV treatment. Therefore, we recommend drug repurposing strategies that combine in vitro, in vivo, and in silico approaches to facilitate the discovery of effective HBV drugs.
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Affiliation(s)
- Samuel Chima Ugbaja
- Discipline of Traditional Medicine, School of Nursing and Public Health, University of KwaZulu Natal, Durban 4000, South Africa;
| | - Aganze Gloire-Aimé Mushebenge
- Department of Pharmacology, University of the Free State, Bloemfontein Campus, Bloemfontein 9301, South Africa;
- Faculty of Pharmaceutical Sciences, University of Lubumbashi, Lubumbashi 1825, Democratic Republic of the Congo
| | - Hezekiel Kumalo
- Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa;
| | - Mlungisi Ngcobo
- Discipline of Traditional Medicine, School of Nursing and Public Health, University of KwaZulu Natal, Durban 4000, South Africa;
| | - Nceba Gqaleni
- Discipline of Traditional Medicine, School of Nursing and Public Health, University of KwaZulu Natal, Durban 4000, South Africa;
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Gömer A, Dinkelborg K, Klöhn M, Jagst M, Wißing MH, Frericks N, Nörenberg P, Behrendt P, Cornberg M, Wedemeyer H, Steinmann E, Maasoumy B, Todt D. Dynamic evolution of the sofosbuvir-associated variant A1343V in HEV-infected patients under concomitant sofosbuvir-ribavirin treatment. JHEP Rep 2024; 6:100989. [PMID: 38434938 PMCID: PMC10906529 DOI: 10.1016/j.jhepr.2023.100989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 11/14/2023] [Accepted: 12/11/2023] [Indexed: 03/05/2024] Open
Abstract
Background & Aims In the absence of a hepatitis E virus (HEV)-specific antiviral treatment, sofosbuvir has recently been shown to have antiviral activity against HEV in vivo. However, a variant, A1343V, that is strongly associated with viral relapse impedes treatment success. In this study, we investigated the occurrence of variants during sofosbuvir and ribavirin treatment in vivo and assessed the sensitivity of resistance-associated variants to concurrent treatment in cell culture. Methods Two patients with chronic HEV infection that did not clear infection under ribavirin treatment were subsequently treated with a combination of sofosbuvir and ribavirin. We determined response to treatment by measuring liver enzymes and viral load in blood and stool. Moreover, we analyzed viral evolution using polymerase-targeted high-throughput sequencing and assessed replication fitness of resistance-associated variants using a HEV replicon system. Results Combination treatment was successful in decreasing viral load towards the limit of quantification. However, during treatment sustained virological response was not achieved. Variants associated with sofosbuvir or ribavirin treatment emerged during treatment, including A1343V and G1634R. Moreover, A1343V, as a single or double mutation with G1634R, was associated with sofosbuvir resistance during concomitant treatment in vitro. Conclusions These results highlight the importance of variant profiling during antiviral treatment of patients with chronic infection. Understanding how intra-host viral evolution impedes treatment success will help guide the design of next-generation antivirals. Impact and implications The lack of hepatitis E virus (HEV)-specific antivirals to treat chronic infection remains a serious health burden. Although ribavirin, interferon and sofosbuvir have been reported as anti-HEV drugs, not all patients are eligible for treatment or clear infection, since resistant-associated variants can rapidly emerge. In this study, we analyzed the efficacy of sofosbuvir and ribavirin combination treatment in terms of HEV suppression, the emergence of resistance-associated variants and their ability to escape treatment inhibition in vitro. Our results provide novel insights into evolutionary dynamics of HEV during treatment and thus will help guide the design of next-generation antivirals.
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Affiliation(s)
- André Gömer
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Katja Dinkelborg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
- German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Michelle Jagst
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
| | | | - Nicola Frericks
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Pia Nörenberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
- German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
- German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany
- Excellence Cluster 2155 RESIST, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
- German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany
- Excellence Cluster 2155 RESIST, Hannover Medical School, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
- German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
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Gömer A, Klöhn M, Jagst M, Nocke MK, Pischke S, Horvatits T, Schulze zur Wiesch J, Müller T, Hardtke S, Cornberg M, Wedemeyer H, Behrendt P, Steinmann E, Todt D. Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients. Hepatology 2023; 78:1882-1895. [PMID: 37334496 PMCID: PMC10653298 DOI: 10.1097/hep.0000000000000514] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/21/2023] [Indexed: 06/20/2023]
Abstract
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.
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Affiliation(s)
- André Gömer
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Michelle Jagst
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Maximilian K. Nocke
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Sven Pischke
- Medical Clinic and Polyclinic, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck-Borstel-Riems, Germany
| | - Thomas Horvatits
- Medical Clinic and Polyclinic, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck-Borstel-Riems, Germany
- Gastromedics Health Center, Eisenstadt, Austria
| | - Julian Schulze zur Wiesch
- Medical Clinic and Polyclinic, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck-Borstel-Riems, Germany
| | - Tobias Müller
- Department of Gastroenterology and Hepatology, Charité Campus Virchow-Klinikum (CVK), Berlin, Germany
| | - Svenja Hardtke
- German Center for Infection Research (DZIF); HepNet Study-House/German Liver Foundation (DLS), Hannover, Germany
- Institute for Infections Research and Vaccine, University Medical Centre Hamburg Eppendorf, Hamburg, Germany
| | - Markus Cornberg
- German Center for Infection Research (DZIF); HepNet Study-House/German Liver Foundation (DLS), Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Germany
- German Center for Infection Research (DZIF); Partner Site Hannover Braunschweig, Germany
- Center for Individualized Infection Medicine (CiiM), Hannover, Germany
| | - Heiner Wedemeyer
- German Center for Infection Research (DZIF); HepNet Study-House/German Liver Foundation (DLS), Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Germany
- German Center for Infection Research (DZIF); Partner Site Hannover Braunschweig, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Germany
- German Center for Infection Research (DZIF); Partner Site Hannover Braunschweig, Germany
- Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- German Centre for Infection Research (DZIF), Bochum, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
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Marascio N, Rotundo S, Quirino A, Matera G, Liberto MC, Costa C, Russo A, Trecarichi EM, Torti C. Similarities, differences, and possible interactions between hepatitis E and hepatitis C viruses: Relevance for research and clinical practice. World J Gastroenterol 2022; 28:1226-1238. [PMID: 35431515 PMCID: PMC8968488 DOI: 10.3748/wjg.v28.i12.1226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/06/2022] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Nadia Marascio
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Salvatore Rotundo
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Angela Quirino
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Giovanni Matera
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Maria Carla Liberto
- Department of Health Sciences, Unit of Microbiology, University “Magna Graecia” of Catanzaro, Catanzaro 88100, Italy
| | - Chiara Costa
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Alessandro Russo
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Enrico Maria Trecarichi
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
| | - Carlo Torti
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, "Magna Graecia" University of Catanzaro, Catanzaro 88100, Italy
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Viral Interference of Hepatitis C and E Virus Replication in Novel Experimental Co-Infection Systems. Cells 2022; 11:cells11060927. [PMID: 35326378 PMCID: PMC8946046 DOI: 10.3390/cells11060927] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/04/2022] [Accepted: 03/04/2022] [Indexed: 12/04/2022] Open
Abstract
Background: Hepatitis C virus (HCV) constitutes a global health problem, while hepatitis E virus (HEV) is the major cause of acute viral hepatitis globally. HCV/HEV co-infections have been poorly characterized, as they are hampered by the lack of robust HEV cell culture systems. This study developed experimental models to study HCV/HEV co-infections and investigate viral interference in cells and humanized mice. Methods: We used state-of-the art human hepatocytes tissue culture models to assess HEV and HCV replication in co- or super-transfection settings. Findings were confirmed by co- and super-infection experiments in human hepatocytes and in vivo in human liver chimeric mice. Results: HEV was inhibited by concurrent HCV replication in human hepatocytes. This exclusion phenotype was linked to the protease activity of HCV. These findings were corroborated by the fact that in HEV on HCV super-infected mice, HEV viral loads were reduced in individual mice. Similarly, HCV on HEV super-infected mice showed reduced HCV viral loads. Conclusion: Direct interference of both viruses with HCV NS3/4A as the determinant was observed. In vivo, we detected reduced replication of both viruses after super-infection in individual mice. These findings provide new insights into the pathogenesis of HCV-HEV co-infections and should contribute to its clinical management in the future.
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Liang Z, Shu J, He Q, Zhang F, Dai L, Wang L, Lu F, Wang L. High dose sofosbuvir and sofosbuvir-plus-ribavirin therapy inhibit Hepatitis E Virus (HEV) replication in a rabbit model for acute HEV infection. Antiviral Res 2022; 199:105274. [PMID: 35247472 DOI: 10.1016/j.antiviral.2022.105274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022]
Abstract
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 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, viremia 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 better 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.
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Affiliation(s)
- Zhaochao Liang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jingyi Shu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fan Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lizhong Dai
- Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China.
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China.
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8
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Lampejo T. Sofosbuvir in the Treatment of Hepatitis E virus Infection: A Review of in vitro and in vivo Evidence. J Clin Exp Hepatol 2022; 12:1225-1237. [PMID: 35814503 PMCID: PMC9257862 DOI: 10.1016/j.jceh.2022.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/16/2022] [Indexed: 12/12/2022] Open
Abstract
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.
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9
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Nasir M, Wu GY. HEV and HBV Dual Infection: A Review. J Clin Transl Hepatol 2020; 8:313-321. [PMID: 33083255 PMCID: PMC7562801 DOI: 10.14218/jcth.2020.00030] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/29/2020] [Accepted: 06/07/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatitis E virus (HEV) is a global health problem, affecting about 20 million people worldwide. There is significant overlap of hepatitis B virus (HBV) and HEV endemicity in many Asian countries where dual infections with HEV and HBV can occur. Though the clinical course of HEV is largely self-limited, HEV superinfection in patients with chronic hepatitis B (CHB) can result in acute exacerbation of underlying CHB. HEV superinfection in patients with CHB-related cirrhosis has been identified as a risk factor for decompensated cirrhosis and an independent predictor of mortality. Whereas acute HEV infection in pregnancy can cause fulminant liver failure, the few studies on pregnant patients with dual HBV and HEV infection have shown a subclinical course. Immunosuppression is a risk factor for the development of chronic HEV infection, which can be managed by decreasing the dose of immune-suppressants and administering ribavirin. Vaccination for HEV has been developed and is in use in China but its efficacy in patients with CHB has yet to be established in the USA. In this review, we appraise studies on dual infection with HEV and HBV, including the effect of HEV superinfection and coinfection in CHB, management strategies used and the role of active vaccination in the prevention of HEV.
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Affiliation(s)
- Myra Nasir
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Myra Nasir, Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. Tel: +1-860-470-6616, E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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10
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Zhu M, Zhang X. Effect of IL-18 on intrauterine infection of HBV in mice on cell molecular level. Saudi J Biol Sci 2020; 27:1685-1690. [PMID: 32489312 PMCID: PMC7254044 DOI: 10.1016/j.sjbs.2020.04.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/15/2020] [Accepted: 04/15/2020] [Indexed: 11/26/2022] Open
Abstract
Objective The objective of this study is to investigate the effect of IL-18 on intrauterine infection of HBV (Hepatitis B Virus) in mice based on cellular and molecular level, and to analyze its mechanism, as well as the relationship between IL-18 and intrauterine infection of HBV. Methods Pregnant rats are taken as the study subjects and divided into two groups according to infection and non-infection, namely the study group and the control group. Firstly, the peripheral blood of rats and the blood of newborn mice are collected for the determination of hepatitis B in two-and-a-half pairs. Then, the levels of interleukin-18 (IL-18), interferon-γ (IFN-γ) and interleukin-4 (IL-4) in peripheral serum are detected by ELISA (Enzyme Linked Immunosorbent Assay). Finally, the two groups of horizontal values are compared and analyzed. The effect of IL-18 on intrauterine infection of HBV in mice is investigated based on the level of cell and molecular. Results The levels of IL-18, IFN-γ, IL-4 and IFN-γ/IL-4 in the two groups are compared and analyzed. The levels of IL-18, IFN-γ and IFN-γ/IL-4 in the study group are significantly lower than those in the control group, with statistical significance. However, the level of IL-4 in the study group is higher than that in the control group, with statistical significance. Conclusion It is found that the decrease of HL-type specific response and the enhancement of Th2-type specific response in pregnant mice are closely related to HBV intrauterine infection. Moreover, the decrease of IL-18 secretion in peripheral blood may cause intrauterine infection of HBV. This study can make people better realize the mechanism of HBV intrauterine infection, and effectively help clinical prevention and treatment of intrauterine infection.
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Affiliation(s)
| | - Xiaoqi Zhang
- Corresponding author at: Obstetrical Department, Hanzhong Central Hospital of Shaanxi Province, No.22 Kangfu Road, Hantai District, Hanzhong, 723000 Shaanxi Province, China.
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Rivero-Juarez A, Vallejo N, Lopez-Lopez P, Díaz-Mareque AI, Frias M, Vallejo A, Caballero-Gómez J, Rodríguez-Velasco M, Molina E, Aguilera A. Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients. Microorganisms 2019; 8:E51. [PMID: 31888090 PMCID: PMC7022260 DOI: 10.3390/microorganisms8010051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/23/2019] [Accepted: 12/23/2019] [Indexed: 02/06/2023] Open
Abstract
The hepatitis E virus (HEV) is the major cause of acute hepatitis of viral origin worldwide. Despite its usual course as an asymptomatic self-limited hepatitis, there are highly susceptible populations, such as those with underlying immunosuppression, which could develop chronic hepatitis. In this situation, implementation of therapy is mandatory in the sense to facilitate viral clearance. Currently, there are no specific drugs approved for HEV infection, but ribavirin (RBV), the drug of choice, is used for off-label treatment. Here, we present two cases of chronic HEV infection in transplant patients, reviewing and discussing the therapeutic approach available in the literature. The use of RBV for the treatment of an HEV infection in organ transplant patients seems to be effective. The recommendation of 12 weeks of therapy is adequate in terms of efficacy. Nevertheless, there are important issues that urgently need to be assessed, such as optimal duration of therapy and drug dosage.
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Affiliation(s)
- Antonio Rivero-Juarez
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
| | - Nicolau Vallejo
- Digestive Unit, Complexo Hospitalario Universitario de Santiago, 15705 Santiago de Compostela, Spain; (N.V.); (E.M.)
| | - Pedro Lopez-Lopez
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
| | - Ana Isabel Díaz-Mareque
- Nephrology Unit, Complexo Hospitalario Universitario de Santiago, 15705 Santiago de Compostela, Spain;
| | - Mario Frias
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
| | - Aldara Vallejo
- Microbiology Unit, Complexo Hospitalario Universitario de Santiago, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; (A.V.); (M.R.-V.); (A.A.)
| | - Javier Caballero-Gómez
- Infectious Diseases Unit, Clinical Virology and Zoonoses research group, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14006 Cordoba, Spain; (P.L.-L.); (M.F.); (J.C.-G.)
- Animal Health Department, University of Cordoba-Agrifood Excellence International Campus (ceiA3), 15705 Cordoba, Spain
| | - María Rodríguez-Velasco
- Microbiology Unit, Complexo Hospitalario Universitario de Santiago, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; (A.V.); (M.R.-V.); (A.A.)
| | - Esther Molina
- Digestive Unit, Complexo Hospitalario Universitario de Santiago, 15705 Santiago de Compostela, Spain; (N.V.); (E.M.)
| | - Antonio Aguilera
- Microbiology Unit, Complexo Hospitalario Universitario de Santiago, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; (A.V.); (M.R.-V.); (A.A.)
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