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Zhu D, Du Y, Zhao M, Ablikim D, Huang H, Pan W, Zeng X, Xu C, Lu M, Sutter K, Dittmer U, Zheng X, Yang D, Liu J. Functional B cell deficiency promotes intrahepatic HBV replication and impairs the development of anti-HBV T cell responses. Hepatol Int 2025; 19:93-105. [PMID: 39630171 DOI: 10.1007/s12072-024-10753-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 11/10/2024] [Indexed: 02/23/2025]
Abstract
BACKGROUND The pivotal role of antibody-producing B cells in controlling hepatitis B virus (HBV) infection is well-established. However, the antiviral role of B cells extends beyond antibody production, which has been insufficiently studied for HBV infection. METHODS Using an HBV hydrodynamic injection (HDI) mouse model with B cell depletion or functional blockade, we detected HBV infection markers and assessed T cell function through enzyme-linked immunosorbent assay, RT-PCR and flow cytometry. RESULTS We observed significantly delayed serum and intrahepatic HBV clearance in permanently B cell-deficient and transiently B cell-depleted mice as well as mice with a functional B cell blockade. Blocking B cell function prior to or soon after HBV HDI resulted in delayed HBV clearance indicating that B cells contribute to initiating anti-HBV immune responses after following HBV exposure. Additionally, we also found an early activation of B cells following HBV exposure, characterized by an upregulation of MHC-II, CXCR5, and PD-1. Critically, the proliferation and activation of both CD4 + and CD8 + T cells were impaired after B cell depletion prior to HBV challenge. Consistently, depleting B cells reduced the generation of Th1, Th2, and Th17 cells in the spleen and hindered HBV-specific CD8 + T cell responses in the liver. Along these lines, the HBV-exposed B cells were more efficient in inducing HBcAg-specific CD8 + T cell responses in vitro. CONCLUSIONS Collectively, our data indicate that B cells, in addition to antibody production, are essential for the development of anti-HBV cellular responses and intrahepatic HBV clearance during the early stage of HBV antigen exposure.
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Affiliation(s)
- Dan Zhu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yanqin Du
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengxiao Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dilhumare Ablikim
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hongming Huang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wen Pan
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaoqing Zeng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chunli Xu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Kathrin Sutter
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Infectious Diseases and Immunity, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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2
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Dammacco F, Lauletta G, Vacca A. The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements. Clin Exp Med 2023; 23:255-272. [PMID: 35348938 PMCID: PMC8960698 DOI: 10.1007/s10238-022-00808-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 02/14/2022] [Indexed: 11/11/2022]
Abstract
Immunoglobulins that reversibly precipitate at temperatures below 37 °C are called cryoglobulins (CGs). Cryoglobulinemia often manifests as cryoglobulinemic vasculitis (CV), whose symptoms range in severity from purpuric eruptions to life-threatening features. The majority of CV patients are infected with hepatitis C virus (HCV), whereas lymphoproliferative disorders or connective tissue diseases (CTD) are commonly diagnosed among patients with CV of non-infectious origin. In the absence of detectable associated disease, cryoglobulinemia is classified as "essential" (EMC). All HCV-positive CV patients should be given direct-acting antiviral agents (DAAs) that are consistently able to induce a sustained virologic response (SVR). Glucocorticoids (GCs) can mitigate CV-associated vasculitis, but they have no role as maintenance therapy. Cyclophosphamide restrains the hyperactive phase(s) of the disease and the post-apheresis rebound of newly synthesized CGs. Its use has been largely replaced by rituximab (RTX) in patients unresponsive to DAAs, patients progressing to B-cell non-Hodgkin lymphoma (B-NHL) and patients in whom CV persists or reappears after clearance of HCV. Therapeutic apheresis is an emergency treatment for CV patients with hyperviscosity syndrome. HCV-positive CV patients are at an increased risk of developing NHL, but the achievement of SVR can effectively prevent HCV-related NHL or induce the remission of an already established lymphoma, even without chemotherapy. The treatment of patients with IgM or IgG monoclonal cryoglobulins and an underlying immunoproliferative disorder is based on the regimens adopted for patients with the same B-cell malignancies but without circulating CGs. For patients with CTD, GCs plus alkylating agents or RTX are similarly effective as first-line therapy and in the relapse/refractory setting. In patients with EMC, treatment should consist of GCs plus RTX, with the dose of GCs tapered as soon as possible to reduce the risk of infectious complications.
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Affiliation(s)
- Franco Dammacco
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, Polyclinic, Piazza Giulio Cesare, 11, 70124 Bari, Italy
| | - Gianfranco Lauletta
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, Polyclinic, Piazza Giulio Cesare, 11, 70124 Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, Polyclinic, Piazza Giulio Cesare, 11, 70124 Bari, Italy
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3
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Kanda T, Matsumoto N, Ishii T, Arima S, Shibuya S, Honda M, Sasaki-Tanaka R, Masuzaki R, Kanezawa S, Nishizawa T, Gon Y, Ogawa M, Kogure H. Chronic Hepatitis C: Acute Exacerbation and Alanine Aminotransferase Flare. Viruses 2023; 15:183. [PMID: 36680223 PMCID: PMC9861769 DOI: 10.3390/v15010183] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
The hepatitis C virus (HCV) causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma, as well as extrahepatic manifestations such as malignant lymphoma. Currently, direct-acting antiviral agents (DAAs) against HCV infection can lead to a sustained virological response (SVR) in almost all HCV-infected patients. In this review article, we discuss acute exacerbation and alanine aminotransferase (ALT) flare in patients with chronic HCV infection. Although acute liver failure caused by HCV infection is rare, careful attention should be paid to the cases with ALT elevation during the natural course of chronic HCV infection. HCV genotype 2 infection, the use of rituximab, and a higher dose of corticosteroid are factors associated with HCV acute exacerbation and ALT flare. Treatment regimens for cancer have been interrupted or changed due to ALT flare due to HCV infection in some patients undergoing chemotherapy for cancer. The pathogenesis of HCV acute exacerbation and ALT flare could involve cellular as well as humoral immune responses. In the DAA era, the earlier introduction of DAAs may prevent chronic HCV-infected patients with acute exacerbation and ALT flare from developing into a more severe form, although DAAs may not be effective for all of them.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tomotaka Ishii
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shuhei Arima
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shinji Shibuya
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masayuki Honda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shini Kanezawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tsukasa Nishizawa
- Division of Respiratory Medicine, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Yasuhiro Gon
- Division of Respiratory Medicine, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hirofumi Kogure
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
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Ogega CO, Skinner NE, Flyak AI, Clark KE, Board NL, Bjorkman PJ, Crowe JE, Cox AL, Ray SC, Bailey JR. B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. PLoS Pathog 2022; 18:e1010179. [PMID: 34990486 PMCID: PMC8769295 DOI: 10.1371/journal.ppat.1010179] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/19/2022] [Accepted: 12/07/2021] [Indexed: 11/25/2022] Open
Abstract
Antibodies targeting the hepatitis C virus (HCV) envelope glycoprotein E2 are associated with delayed disease progression, and these antibodies can also facilitate spontaneous clearance of infection in some individuals. However, many infected people demonstrate low titer and delayed anti-E2 antibody responses. Since a goal of HCV vaccine development is induction of high titers of anti-E2 antibodies, it is important to define the mechanisms underlying these suboptimal antibody responses. By staining lymphocytes with a cocktail of soluble E2 (sE2) glycoproteins, we detected HCV E2-specific (sE2+) B cells directly ex vivo at multiple acute infection timepoints in 29 HCV-infected subjects with a wide range of anti-E2 IgG titers, including 17 persistently infected subjects and 12 subjects with spontaneous clearance of infection. We performed multi-dimensional flow cytometric analysis of sE2+ and E2-nonspecific (sE2-) class-switched B cells (csBC). In sE2+ csBC from both persistence and clearance subjects, frequencies of resting memory B cells (rMBC) were reduced, frequencies of activated MBC (actMBC) and tissue-like MBC (tlMBC) were increased, and expression of FCRL5, an IgG receptor, was significantly upregulated. Across all subjects, plasma anti-E2 IgG levels were positively correlated with frequencies of sE2+ rMBC and sE2+ actMBC, while anti-E2 IgG levels were negatively correlated with levels of FCRL5 expression on sE2+ rMBC and PD-1 expression on sE2+ actMBC. Upregulation of FCRL5 on sE2+ rMBC and upregulation of PD-1 on sE2+ actMBC may limit anti-E2 antibody production in vivo. Strategies that limit upregulation of these molecules could potentially generate higher titers of protective antibodies against HCV or other pathogens. Antiviral immunity relies on production of protective immunoglobulin G (IgG) by B cells, but many hepatitis C virus (HCV)-infected individuals have very low levels of HCV-specific IgG in their serum. Elucidating mechanisms underlying this suboptimal IgG expression remains paramount in guiding therapeutic and vaccine strategies. In this study, we developed a highly specific method to capture HCV-specific B cells and characterized their surface protein expression. Two proteins analyzed were Fc receptor-like protein 5 (FCRL5), a cell surface receptor for IgG, and programmed cell death protein-1 (PD-1), a marker of lymphocyte activation and exhaustion. We measured serum levels of anti-HCV IgG in these subjects and demonstrated that overexpression of FCRL5 and PD-1 on memory B cells was associated with reduced anti-E2 IgG levels. This study uses HCV as a viral model, but the findings may be applicable to many viral infections, and they offer new potential targets to enhance antiviral IgG production.
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Affiliation(s)
- Clinton O. Ogega
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, Maryland, United States of America
| | - Nicole E. Skinner
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, Maryland, United States of America
| | - Andrew I. Flyak
- Division of Biology and Biological Engineering, California Institute of Technology; Pasadena, California, United States of America
| | - Kaitlyn E. Clark
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, Maryland, United States of America
| | - Nathan L. Board
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, Maryland, United States of America
| | - Pamela J. Bjorkman
- Division of Biology and Biological Engineering, California Institute of Technology; Pasadena, California, United States of America
| | - James E. Crowe
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center; Nashville, Tennessee, United States of America
- Department of Pediatrics, Vanderbilt University Medical Center; Nashville, Tennessee, United States of America
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center; Nashville, Tennessee, United States of America
| | - Andrea L. Cox
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, Maryland, United States of America
| | - Stuart C. Ray
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, Maryland, United States of America
| | - Justin R. Bailey
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, Maryland, United States of America
- * E-mail:
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5
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Miyashita K, Hongo Y, Nakashima A, Kato S, Kusano H, Morizono S, Higashi N. Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy. Intern Med 2021; 60:1533-1539. [PMID: 33191319 PMCID: PMC8188017 DOI: 10.2169/internalmedicine.4768-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
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Affiliation(s)
- Kaname Miyashita
- Department of Haematology, Saiseikai Fukuoka General Hospital, Japan
- Department of Hematology, National Hospital Organization Kyushu Cancer Center, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yui Hongo
- Department of Diabetes and Endocrinology, Saiseikai Fukuoka General Hospital, Japan
| | | | - Seiya Kato
- Division of Pathology, Saiseikai Fukuoka General Hospital, Japan
| | - Hironori Kusano
- Department of Pathology, Kurume University School of Medicine, Japan
| | - Shusuke Morizono
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
- Department of Hepatology, Saiseikai Fukuoka General Hospital, Japan
| | - Nobuhiko Higashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
- Department of Hepatology, Saiseikai Fukuoka General Hospital, Japan
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6
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Abstract
Antibody responses in hepatitis C virus (HCV) have been a rather mysterious research topic for many investigators working in the field. Chronic HCV infection is often associated with dysregulation of immune functions particularly in B cells, leading to abnormal lymphoproliferation or the production of autoantibodies that exacerbate inflammation and extrahepatic diseases. When considering the antiviral function of antibody, it was difficult to endorse its role in HCV protection, whereas T-cell response has been shown unequivocally critical for natural recovery. Recent breakthroughs in the study of HCV and antigen-specific antibody responses provide important insights into viral vulnerability to antibodies and the immunogenetic and structural properties of the neutralizing antibodies. The new knowledge reinvigorates HCV vaccine research by illuminating a new path for the rational design of vaccine antigens to elicit broadly neutralizing antibodies for protection.
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Affiliation(s)
- Mansun Law
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California 92109, USA
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7
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Buckland MS, Galloway JB, Fhogartaigh CN, Meredith L, Provine NM, Bloor S, Ogbe A, Zelek WM, Smielewska A, Yakovleva A, Mann T, Bergamaschi L, Turner L, Mescia F, Toonen EJM, Hackstein CP, Akther HD, Vieira VA, Ceron-Gutierrez L, Periselneris J, Kiani-Alikhan S, Grigoriadou S, Vaghela D, Lear SE, Török ME, Hamilton WL, Stockton J, Quick J, Nelson P, Hunter M, Coulter TI, Devlin L, Bradley JR, Smith KGC, Ouwehand WH, Estcourt L, Harvala H, Roberts DJ, Wilkinson IB, Screaton N, Loman N, Doffinger R, Lyons PA, Morgan BP, Goodfellow IG, Klenerman P, Lehner PJ, Matheson NJ, Thaventhiran JED. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report. Nat Commun 2020; 11:6385. [PMID: 33318491 PMCID: PMC7736571 DOI: 10.1038/s41467-020-19761-2] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 10/27/2020] [Indexed: 12/18/2022] Open
Abstract
The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.
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Affiliation(s)
- Matthew S Buckland
- Department of Clinical Immunology, Barts Health, London, UK.
- UCL GOSH Institute of Child Health Division of Infection and Immunity, Section of Cellular and Molecular Immunology, London, UK.
| | - James B Galloway
- Centre for Rheumatic Diseases, King's College London, London, UK
| | | | - Luke Meredith
- Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Nicholas M Provine
- Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford, OX1 3SY, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Stuart Bloor
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
| | - Ane Ogbe
- Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford, OX1 3SY, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Wioleta M Zelek
- Systems Immunity Institute and Dementia Research Institute, Cardiff University, Cardiff, UK
| | - Anna Smielewska
- Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Cambridge, UK
- PHE - Public Health England Laboratory, Cambridge. Box 236, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK
| | - Anna Yakovleva
- Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Tiffeney Mann
- Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QW, UK
| | - Laura Bergamaschi
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
| | - Lorinda Turner
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
| | - Frederica Mescia
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
| | - Erik J M Toonen
- R&D Department, Hycult Biotechnology, Frontstraat 2A, 5405 PB, Uden, The Netherlands
| | - Carl-Philipp Hackstein
- Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford, OX1 3SY, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Hossain Delowar Akther
- Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford, OX1 3SY, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Vinicius Adriano Vieira
- Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford, OX1 3SY, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | | | - Jimstan Periselneris
- Respiratory Department, King's College Hospital NHS Foundation Trust, UK. Department of Clinical Virology, Addenbrookes, UK
| | | | | | - Devan Vaghela
- Department of Infectious Diseases, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Sara E Lear
- Department of Immunology, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - M Estée Török
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Department of Microbiology, Cambridge, UK
| | - William L Hamilton
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Joanne Stockton
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK
| | - Josh Quick
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK
| | - Peter Nelson
- Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Michael Hunter
- Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Tanya I Coulter
- Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
- Regional Immunology Service, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Lisa Devlin
- Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
- Regional Immunology Service, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - John R Bradley
- NIHR BioResource and NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK
| | - Kenneth G C Smith
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
| | - Willem H Ouwehand
- Department of Haematology, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
- NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK
| | | | | | - David J Roberts
- NHS Blood and Transplant, Oxford, UK
- Radcliffe Department of Medicine and BRC Haematology Theme, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Ian B Wilkinson
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
| | | | - Nicholas Loman
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK
| | - Rainer Doffinger
- Respiratory Department, King's College Hospital NHS Foundation Trust, UK. Department of Clinical Virology, Addenbrookes, UK
| | - Paul A Lyons
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
| | - B Paul Morgan
- Systems Immunity Institute and Dementia Research Institute, Cardiff University, Cardiff, UK
| | - Ian G Goodfellow
- Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford, OX1 3SY, UK
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Paul J Lehner
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
- Department of Infectious Diseases, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Nicholas J Matheson
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
- Department of Infectious Diseases, Cambridge University Hospitals NHS Trust, Cambridge, UK.
- NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
| | - James E D Thaventhiran
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
- Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QW, UK.
- Cancer Research UK Cambridge Institute, Cambridge Biomedical Campus, Cambridge, UK.
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8
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Occhipinti V, Farina L, Viganò M, Capecchi M, Labanca S, Fanetti I, Corradini P, Rumi M. Concomitant therapy with direct-acting antivirals and chemoimmunotherapy in HCV-associated diffuse large B-cell lymphoma. Dig Liver Dis 2019; 51:719-723. [PMID: 30502232 DOI: 10.1016/j.dld.2018.10.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/11/2018] [Accepted: 10/23/2018] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin's Lymphomas (NHL) is well established. Antiviral therapy (AVT) is the first-line treatment for HCV-related indolent NHL whereas diffuse large B-cell lymphoma (DLBCL) requires immediate start of chemoimmunotherapy (CIT), usually deferring AVT. However, an early HCV elimination may reduce the risk of CIT-induced liver toxicity and consequent CIT interruption or withdrawal. To date few data are available on safety and efficacy of concomitant administration of direct-acting antivirals (DAA) and CIT in HCV-associated DLBCL. METHODS 7 consecutive patients (5 males, median age 65 years) with HCV infection (four genotype 2a/2c, two genotype 1b, one genotype 4; one patient with compensated cirrhosis) and DLBCL received different DAA regimens concurrently with CIT. RESULTS All patients completed the scheduled AVT and CIT with neither interruption nor withdrawal of the latter. One case of neutropenia was observed during concomitant therapy, no liver toxicity occurred. All patients achieved sustained virological response and complete DLBCL response (median follow-up of 12 months). CONCLUSIONS Concomitant administration of DAA and CIT for HCV-associated DLBCL is safe and may prevent CIT-induced liver toxicity. Large, prospective studies are needed to confirm these preliminary data and to assess prognostic implications.
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Affiliation(s)
| | - Lucia Farina
- Hematological Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Mauro Viganò
- Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy
| | - Marco Capecchi
- Hematological Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Sara Labanca
- Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy
| | - Ilaria Fanetti
- Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy
| | - Paolo Corradini
- Hematological Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Mariagrazia Rumi
- Hepatology Unit, San Giuseppe Hospital, University of Milan, Milan, Italy
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9
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Bunchorntavakul C, Mitrani R, Reddy KR. Advances in HCV and Cryoglobulinemic Vasculitis in the Era of DAAs: Are We at the End of the Road? J Clin Exp Hepatol 2018; 8:81-94. [PMID: 29743799 PMCID: PMC5938331 DOI: 10.1016/j.jceh.2017.11.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/30/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C Virus (HCV)-related Mixed Cryoglobulinemia (MC) is a unique condition with complex pathogenesis that involves HCV antigen-driven B-lymphocyte clonal proliferation and mutagenesis. Clinical spectrum of MC ranges from asymptomatic state to clinically-apparent vasculitis involving multiple organs. In the era of Direct-Acting Antiviral (DAA) therapy, patients with HCV-related MC achieve high rates of viral clearance that is commonly accompanied by an improvement in clinical symptoms as well as immunological profiles. Rituximab, either alone or in combination with DAA, has also been shown to be effective. Nevertheless, there have been limited and somewhat conflicting data, particularly over the long-term, regarding the rate and degree of clinical response of MC following DAA therapy. It appears that we have come quite a long way in the last decade with this condition. As with non-MC related HCV, undoubtedly long term outcome data will be forthcoming over the next few years. As we move forward successful therapy of HCV is not likely to be a challenge in contrast to access to therapy.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
| | - Robert Mitrani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K. Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
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10
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Abstract
Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.
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11
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Lin JW, Chang ML, Hsu CW, Chen YC, Liang KH, Huang YH, Lin CC, Yeh CT. Acute exacerbation of hepatitis C in hepatocellular carcinoma patients receiving chemotherapy. J Med Virol 2016; 89:153-160. [PMID: 27273118 DOI: 10.1002/jmv.24595] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2016] [Indexed: 02/06/2023]
Abstract
Acute hepatitis C exacerbations can occur in cancer patients carrying hepatitis C virus (HCV) when receiving systemic chemotherapy. However, clinical studies evaluating these complications remain rare due to the lack of clinically proven effective and tolerable anti-HCV treatments at late cancer stages. Furthermore, no data were available regarding hepatitis C exacerbation in advanced hepatocellular carcinoma (HCC) patients receiving chemotherapy. To address this issue, 48 patients with HCV-related advanced HCC, who underwent systemic chemotherapy using 5- fluorouracil, cisplatin, and mitoxantrone from 2008 to 2014 were analyzed. Nine patients developed acute hepatitis exacerbations defined by HCV-RNA elevation ≥10-fold and alanine transaminase (ALT) elevation ≥5-fold of the upper normal limit. Six were genotype 1b and 3 were genotype 2. Three patterns of clinical courses were observed including single episode of exacerbation (n = 5), fluctuated flares (n = 3), and delayed exacerbation (n = 1). Hepatic failure developed in five patients. Patients with acute exacerbations were less likely to have pretreatment ascites (11.1% vs. 53.8%; P = 0.028) and displayed a lower baseline ALT (44.1 ± 28.5 U/L vs. 72.6 ± 19.2 U/L; P = 0.007). Paradoxically, despite a high risk of hepatic failure, occurrence of hepatitis C exacerbation was associated with a favorable overall survival (P = 0.027; 22.8 vs. 5.4 months). In conclusion, hepatitis C exacerbation can occur in HCC patients receiving chemotherapy, leading to liver failure. However, the flare was associated with a better overall survival, possibly due to its association with a better baseline liver function. J. Med. Virol. 89:153-160, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ji-Wei Lin
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Ming-Ling Chang
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yi-Cheng Chen
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Chen-Chun Lin
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. .,Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
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12
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Liu L, Nardo D, Li E, Wang GP. CD4+ T-cell recovery with suppressive ART-induced rapid sequence evolution in hepatitis C virus envelope but not NS3. AIDS 2016; 30:691-700. [PMID: 26645605 DOI: 10.1097/qad.0000000000000997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES CD4 T-cell depletion from HIV infection leads to a global decline in anti-hepatitis C virus (HCV) envelope neutralizing antibody (nAb) response, which may play a role in accelerating liver fibrosis. An increase in anti-HCV nAb titers has been reported during antiretroviral therapy (ART) but its impact on HCV remains poorly understood. The objective of this study is to determine the effects of ART on long-term HCV evolution. DESIGN AND METHODS We examined HCV quasispecies structure and long-term evolution in HIV/HCV coinfected patients with ART-induced CD4 T-cell recovery, and compared with patients with CD4 T-cell depletion from delayed ART. We applied a single-variant sequencing (SVS) method to construct authentic viral quasispecies and compared sequence evolution in HCV envelope, the primary target for humoral immune responses, and NS3, a target for cellular immunity, between the two cohorts. RESULTS The SVS method corrected biases known to skew the proportions of viral variants, revealing authentic HCV quasispeices structures. We observed higher rates of HCV envelope sequence evolution in patients with ART-induced CD4 T-cell recovery, compared with patients with CD4 T-cell depletion from delayed ART (P = 0.03). Evolutionary rates for NS3 were considerably lower than the rates for envelope (P < 0.01), with no significant difference observed between the two groups. CONCLUSION ART-induced CD4 T-cell recovery results in rapid sequence evolution in HCV envelope, but not in NS3. These results suggest that suppressive ART disproportionally enhances HCV-specific humoral responses more than cellular responses, resulting in rapid sequence evolution in HCV envelope but not NS3.
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13
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Tarr AW, Khera T, Hueging K, Sheldon J, Steinmann E, Pietschmann T, Brown RJP. Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design. Viruses 2015; 7:3995-4046. [PMID: 26193307 PMCID: PMC4517138 DOI: 10.3390/v7072809] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/19/2015] [Accepted: 07/08/2015] [Indexed: 12/13/2022] Open
Abstract
In the 26 years since the discovery of Hepatitis C virus (HCV) a major global research effort has illuminated many aspects of the viral life cycle, facilitating the development of targeted antivirals. Recently, effective direct-acting antiviral (DAA) regimens with >90% cure rates have become available for treatment of chronic HCV infection in developed nations, representing a significant advance towards global eradication. However, the high cost of these treatments results in highly restricted access in developing nations, where the disease burden is greatest. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in at risk groups and resource constrained settings due to limited surveillance. Consequently a prophylactic vaccine is much needed. The HCV envelope glycoproteins E1 and E2 are located on the surface of viral lipid envelope, facilitate viral entry and are the targets for host immunity, in addition to other functions. Unfortunately, the extreme global genetic and antigenic diversity exhibited by the HCV glycoproteins represents a significant obstacle to vaccine development. Here we review current knowledge of HCV envelope protein structure, integrating knowledge of genetic, antigenic and functional diversity to inform rational immunogen design.
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Affiliation(s)
- Alexander W Tarr
- School of Life Sciences, Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK.
| | - Tanvi Khera
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Kathrin Hueging
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Julie Sheldon
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Eike Steinmann
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
| | - Thomas Pietschmann
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig 38124, Germany.
| | - Richard J P Brown
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centrefor Infection Research (HZI), Hannover D-30625, Germany.
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14
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Cordero-Coma M, Salazar-Méndez R, Yilmaz T. Treatment of severe non-infectious uveitis in high-risk conditions (Part 2): systemic infections; management and safety issues. Expert Opin Drug Saf 2015; 14:1353-71. [PMID: 26118392 DOI: 10.1517/14740338.2015.1061992] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Management of patients with severe immune-mediated uveitis requires the use of immunosuppressive (IS) drugs in selected cases. This may be particularly challenging in certain patients with associated conditions, which may increase the risk of side effects or modify guidelines for the use of such drugs. Chronic viral and mycobacterial infections in the setting of non-infectious uveitis create a number of diagnostic but also therapeutic dilemmas to clinicians because they can be exacerbated by IS therapies with detrimental effects. AREAS COVERED In this review, we will focus on very specific chronic infections that can be affected by IS therapies: human immunodeficiency virus infection, chronic hepatitis virus infection and tuberculosis. The main aim of this review is to provide an updated and comprehensive practical guide for practitioners regarding the therapeutic decision-making and management of patients with non-infectious uveitis affected by the aforementioned infectious conditions. EXPERT OPINION Clinicians should be aware of the risk of viral and mycobacterial reactivation of an underlying infection during IS therapy. However, most of these conditions do not represent an absolute contraindication if one were able to apply an appropriate prior screening and close monitoring of such therapy.
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Affiliation(s)
- Miguel Cordero-Coma
- a 1 University of León, Instituto Biomedicina (IBIOMED), University Hospital of León , León, Spain +34 654403609 ; +34 987 233322 ;
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15
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de Jong YP, Dorner M, Mommersteeg MC, Xiao JW, Balazs AB, Robbins JB, Winer BY, Gerges S, Vega K, Labitt RN, Donovan BM, Giang E, Krishnan A, Chiriboga L, Charlton MR, Burton DR, Baltimore D, Law M, Rice CM, Ploss A. Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci Transl Med 2015; 6:254ra129. [PMID: 25232181 DOI: 10.1126/scitranslmed.3009512] [Citation(s) in RCA: 177] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs-AR3A, AR3B, and AR4A-delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection.
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Affiliation(s)
- Ype P de Jong
- Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA. Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
| | - Marcus Dorner
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Michiel C Mommersteeg
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Jing W Xiao
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | | | - Justin B Robbins
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Benjamin Y Winer
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Sherif Gerges
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Kevin Vega
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Rachael N Labitt
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Bridget M Donovan
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Erick Giang
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Anuradha Krishnan
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Luis Chiriboga
- Department of Pathology, New York University Medical Center, New York, NY 10016, USA
| | - Michael R Charlton
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Dennis R Burton
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - David Baltimore
- Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
| | - Mansun Law
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Charles M Rice
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Alexander Ploss
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
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16
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Bailey JR, Dowd KA, Snider AE, Osburn WO, Mehta SH, Kirk GD, Thomas DL, Ray SC. CD4+ T-Cell-Dependent Reduction in Hepatitis C Virus-Specific Neutralizing Antibody Responses After Coinfection With Human Immunodeficiency Virus. J Infect Dis 2015; 212:914-23. [PMID: 25754978 DOI: 10.1093/infdis/jiv139] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 02/26/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Human immunodeficiency virus (HIV) infection leads to lower rates of hepatitis C virus (HCV) clearance after acute infection, higher HCV viremia, and accelerated progression of HCV-related fibrosis. The mechanisms underlying this acceleration of HCV progression by HIV are poorly understood, but HIV-induced dysfunction in the anti-HCV humoral immune response may play a role. METHODS To define the effect of HIV coinfection on the anti-HCV antibody response, we measured anti-HCV envelope binding antibody titers, neutralizing antibody (nAb) titers, and nAb breadth of serum from HCV-infected subjects isolated longitudinally before and after incident HIV infection. RESULTS A significant reduction in HCV envelope-specific binding antibody and nAb titers was detected in subjects with CD4(+) T-cell counts <350/mm(3) after HIV infection, and subjects with CD4(+) T-cell counts <200/mm(3) also showed a reduction in nAb breadth. Subjects who maintained CD4(+) T-cell counts ≥350/mm(3) displayed little to no decline in antibody levels. CONCLUSIONS Depletion of CD4(+) T cells by HIV infection results in a global decline in the anti-HCV envelope antibody response, including binding antibody titers, nAb titers, and nAb breadth.
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Affiliation(s)
| | - Kimberly A Dowd
- Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Anna E Snider
- Division of Infectious Diseases, Department of Medicine
| | | | - Shruti H Mehta
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
| | - Gregory D Kirk
- Division of Infectious Diseases, Department of Medicine Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
| | | | - Stuart C Ray
- Division of Infectious Diseases, Department of Medicine Department of Oncology, Johns Hopkins University School of Medicine
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17
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Vannata B, Zucca E. Hepatitis C virus-associated B-cell non-Hodgkin lymphomas. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2014; 2014:590-598. [PMID: 25696916 DOI: 10.1182/asheducation-2014.1.590] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Epidemiological studies have demonstrated an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. However, the strength of the association shows great geographic discrepancies, with higher relative risk in countries with high HCV prevalence. It remains unclear whether additional environmental and genetic factors are involved or if the international variability is simply a consequence of the variable infection prevalence. Therefore, a causal relationship remains controversial. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used, and the year of publication. The most convincing proof is the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after HCV eradication with IFN and ribavirin. However, the molecular mechanisms of the HCV-induced lymphomagenesis are mainly hypothetical. According to the model considered to be most plausible, lymphoma growth is a consequence of the continuous antigenic stimulation of the B-cell immunologic response induced by the chronic viral infection. This review summarizes the current epidemiological and biological evidence of a role of HCV in lymphomagenesis, describing the putative mechanisms for a causative relationship. The clinical characteristics and management difficulties of the HCV-associated lymphomas are also discussed. HCV treatment with IFN cannot be given safely in concomitance with cytotoxic lymphoma treatment because of hematological and liver toxicity. However, novel and better tolerated antiviral regimens are under development and will hopefully make the treatment of both lymphoma and hepatitis easier in the future.
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Affiliation(s)
- Barbara Vannata
- Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Emanuele Zucca
- Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
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18
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Chen TT, Chiu CF, Yang TY, Lin CC, Sargeant AM, Yeh SP, Liao YM, Bai LY. Hepatitis C infection is associated with hepatic toxicity but does not compromise the survival of patients with diffuse large B cell lymphoma treated with rituximab-based chemotherapy. Leuk Res 2014; 39:151-6. [PMID: 25524176 DOI: 10.1016/j.leukres.2014.11.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 11/20/2014] [Accepted: 11/22/2014] [Indexed: 02/07/2023]
Abstract
The influence of hepatitis C virus (HCV) infection on the outcome of patients with diffuse large B cell lymphoma (DLBCL) treated with rituximab-based chemotherapy is controversial. We retrospectively analyzed the characteristics and clinical outcomes of 168 patients with DLBCL diagnosed between January 2005 and December 2011. Twenty-nine patients who were HCV-positive before lymphoma treatment were compared with 139 patients who did not have HCV infection. The median follow-up duration was 3.0 (0.07-8.02) years. HCV infection resulted in more hepatic toxicity in both univariate (p=0.001) and multivariate (p=0.003) analyses. In addition, HCV-positive DLBCL patients were more likely to have treatment delay (20.1% vs. 0.7%, p<0.001). For patients who developed hepatic toxicity during immunochemotherapy, HCV-positive patients had significantly higher folds of aspartate aminotransferase elevation (p=0.042) and total bilirubin elevation (p=0.012) compared with those who were HCV negative. However, HCV did not influence the 5-year progression-free survival rate (p=0.412) or 5-year overall survival rate (p=0.410). In conclusion, HCV infection is associated with increased hepatic toxicity and delayed chemotherapy without compromised survival in DLBCL patients treated with rituximab-based chemotherapy.
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Affiliation(s)
- Tzu-Ting Chen
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - Chang-Fang Chiu
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan; Cancer Center, China Medical University Hospital, Taichung 40402, Taiwan; College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Tse-Yen Yang
- Molecular and Genomic Epidemiology Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan; Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
| | - Ching-Chan Lin
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - Aaron M Sargeant
- Charles River Laboratories, Preclinical Services, Spencerville, OH 45887, USA
| | - Su-Peng Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan; College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Yu-Min Liao
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - Li-Yuan Bai
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan; College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan.
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19
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Visco C, Finotto S. Hepatitis C virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment. World J Gastroenterol 2014; 20:11054-11061. [PMID: 25170194 PMCID: PMC4145748 DOI: 10.3748/wjg.v20.i32.11054] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 02/25/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
A significant association between hepatitis C virus (HCV) infection and B-cell lymphoma has been reported by epidemiological studies, most of them describing a strong relationship between indolent lymphomas and HCV. Furthermore, the curative potential of antiviral therapy on HCV related indolent lymphomas supports a specific role for the virus in lymphomagenesis. These observations are reinforced by numerous laboratory experiments that led to several hypothetical models of B-cell transformation by HCV. Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype in the western countries, has been associated to HCV infection despite its aggressive nature. This association seems particularly prominent in some geographical areas. Clinical presentation of HCV-associated DLBCL has consistently been reported to differ from the HCV-negative counterpart. Nevertheless, histopathology, tolerance to standard-of-care chemo-immunotherapy (R-CHOP or CHOP-like regimens) and final outcome of HCV-positive DLBCL patients is still matter of debate. Addition of rituximab has been described to enhance viral replication but the probability of severe hepatic complications remains low, with some exceptions (i.e., hepatitis B virus or immune immunodeficiency virus co-infected patients, presence of grade > 2 transaminases elevation, cirrhosis or hepatocarcinoma). HCV viral load in this setting is not necessarily directly associated with liver damage. Overall, treatment of HCV associated DLBCL should be performed in an interdisciplinary approach with hepatologists and hematologists with close monitoring of liver function. Available reports reveal that the final outcome of HCV-positive DLBCL that receive standard immunochemotherapy is not inferior to their HCV-negative counterpart. This review summarizes data on epidemiology, pathogenesis and therapeutic approach on HCV-associated DLBCL. Several issues that are matter of debate like clinical management of patients with transaminase elevation, criteria for discontinuing or starting immuno-chemotherapy, as well as the exact role of monoclonal antibodies will be analyzed.
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MESH Headings
- Animals
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antiviral Agents/therapeutic use
- Cell Transformation, Viral
- Drug Resistance, Neoplasm
- Hepacivirus/drug effects
- Hepacivirus/pathogenicity
- Hepatitis C/diagnosis
- Hepatitis C/drug therapy
- Hepatitis C/epidemiology
- Hepatitis C/virology
- Humans
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/epidemiology
- Lymphoma, Large B-Cell, Diffuse/virology
- Treatment Outcome
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Salah-Eldin MA, Ebrahim MA, El-Sadda W. Clinical outcome of HCV-positive patients with diffuse large B-cell lymphoma treated with rituximab-based chemotherapy. Ann Hematol 2014; 93:1903-11. [PMID: 24951125 DOI: 10.1007/s00277-014-2138-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 06/08/2014] [Indexed: 12/16/2022]
Abstract
The influence of rituximab therapy on prognosis and hepatic toxicity (HT) in patients with hepatitis C virus (HCV)-positive diffuse large B-cell lymphoma (DLBCL) is unclear. Thus, we assessed HT and clinical outcome in patients with DLBCL and HCV infection who received rituximab-containing immunochemotherapy. We carried out a prospective analysis on a total of 280 HCV-positive patients with DLBCL, 200 of whom received chemotherapy plus rituximab (R-CHT), 80 received chemotherapy (CHT)-only. Survival outcomes and HT were compared according to rituximab administration. The median follow-up was 41 months. Addition of rituximab did not significantly affect prognosis (median progression-free survival, 40 vs 35 months, P = 0.26; median overall survival, 51 vs 43 months P = 0.09). Of 200 patients who received rituximab, 53 (26.5 %) had severe HT (grade 3-4), compared with 11 of 80 (13.75 %) patients who received rituximab-free regimens (P = 0.033). Among patients treated with rituximab, 50 patients (25 %) did not complete planned course of therapy, 14 patients because of hepatic toxicity and 36 patients because of progressive disease. Pretreatment liver function impairment was predictive of severe HT. These results raise concerns regarding the routine use of rituximab with chemotherapy in individuals with HCV-positive DLBCL. However, more studies are warranted before a definitive conclusion can be made.
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Affiliation(s)
- Manal A Salah-Eldin
- Department of Medical Oncology, Oncology Center, Mansoura University, Mansoura, Egypt,
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21
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Yazici O, Şendur MAN, Aksoy S. Hepatitis C virus reactivation in cancer patients in the era of targeted therapies. World J Gastroenterol 2014; 20:6716-6724. [PMID: 24944464 PMCID: PMC4051913 DOI: 10.3748/wjg.v20.i22.6716] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 12/26/2013] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
The purpose of this review is to summarize the evidence of hepatitis C reactivation in cancer patients in the era of targeted therapies. Targeted therapies are novel therapeutics frequently used in cancer patients. During treatment with targeted therapies, viral replication is one of the major problems that can occur. The PubMed database, ASCO, and ASCO Gastrointestinal Cancer Symposium abstracts were searched up until September 15, 2013 using the following search keywords: “targeted therapies, rituximab, alemtuzumab, brentuximab, hepatitis, hepatitis C reactivation, tyrosine kinase inhibitors, imatinib, mammalian target of rapamycin (mTOR) inhibitors, everolimus, anti-HER therapies, trastuzumab, pertuzumab, lapatinib, anti-epidermal growth factor receptor therapies, cetuximab, panitumumab, and ipilimumab”. Papers considered relevant for the aim of this review were selected by the authors. The data about rituximab-induced hepatic flare in hepatitis C virus (HCV) positive patients is controversial. However, there is the possibility of life-threatening hepatic flare that can develop after HCV ribonucleic acid (HCV-RNA) viral load increases. Routine follow-up of liver function tests should be advised. Especially in high-risk patients, such as those with baseline chronic active hepatitis and cirrhosis, and where there are plans to administer rituximab concomitantly with corticosteroids, it is advised to have close follow-up of HCV viral load. The data is insufficient to make accurate statements about the association of alemtuzumab therapy and HCV reactivation. However, alemtuzumab may cause deep immunosuppression. Due to this, it is better to follow up with liver function tests and HCV RNA levels during alemtuzumab therapy. Brentuximab has effects on antibody dependent cellular toxicity and may decrease humoral immunity. Thus, we believe that during brentuximab treatment of HCV infected patients, clinicians may encounter hepatitis C reactivation. There have been no reported cases of hepatitis C reactivation with imatinib therapy. However, there are many reports of hepatitis B reactivation with imatinib treatment. Based on the evidence of hepatitis B reactivation with imatinib and the effects of imatinib on immune system functions, we suggest that imatinib therapy might be a risk factor for HCV reactivation. Anti-human epidermal growth factor receptor 2 therapies are not associated with hepatic flare in HCV infected patients. Post-transplant studies reported that mTOR was safely administered to patients with active hepatitis C without causing hepatic flare. Cetuximab and panitumumab have not been associated with HCV reactivation. Two cases of HCV infected melanoma were safely treated with ipilimumab without any HCV reactivation or hepatic flare. Targeted therapies are a new and emerging area of oncology treatment modalities. While treating HCV infected cancer patients, clinicians should be mindful of the immunosuppressive properties of targeted therapies. Further randomized trials are needed to establish algorithms for this issue.
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Zaky AH, Bakry R, El-sayed MI, Elwanis MA, Nabih O. Impact of treatment-related toxicity on outcome of HCV-positive diffuse large B-cell lymphoma in rituximab era. ACTA ACUST UNITED AC 2014; 19:412-6. [PMID: 24620947 DOI: 10.1179/1607845413y.0000000147] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
UNLABELLED NOVELTY AND IMPACT: This first study compares the survival of HCV-positive DLBCL treated with and without rituximab which showed in toxicity and the outcome. BACKGROUND The effect of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era is unclear. The treatment and the outcome of patients with DLBCL and HCV infection are still a matter of debate. METHODS We analyzed 137 DLBCL patients positive to HCV, treated with chemotherapy regimens include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab. Survival outcomes and hepatic toxicity were compared in DLBCL patients positive to HCV infection according to CHOP ± rituximab. RESULT Our result showed that the group of patients treated with R-CHOP has significant high incidence of hepatic toxicity grade (3-4) (28 vs. 18%, P value 0.001) and worse progression-free survival (55 vs. 80%, P value 0.002) in comparison with the group treated with CHOP, and also there is significant difference between both groups in overall survival. This first study compares the survival of HCV-positive DLBCL treated with and without rituximab which showed significant differences. CONCLUSION We conclude that HCV-positive patients with DLBCL treated with rituximab plus CHOP have high incidence in hepatic toxicity. Specific protocols evaluating antiviral therapy should be designed for these patients.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Murine-Derived/administration & dosage
- Antibodies, Monoclonal, Murine-Derived/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Chemical and Drug Induced Liver Injury/etiology
- Chemical and Drug Induced Liver Injury/mortality
- Cyclophosphamide/administration & dosage
- Disease Progression
- Disease-Free Survival
- Doxorubicin/administration & dosage
- Female
- Hepacivirus/physiology
- Hepatitis C/drug therapy
- Hepatitis C/virology
- Host-Pathogen Interactions/drug effects
- Humans
- Kaplan-Meier Estimate
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/virology
- Male
- Middle Aged
- Outcome Assessment, Health Care/methods
- Outcome Assessment, Health Care/statistics & numerical data
- Prednisone/administration & dosage
- Prognosis
- Rituximab
- Survival Rate
- Vincristine/administration & dosage
- Young Adult
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Yang SH, Hsu C, Cheng AL, Kuo SH. Anti-CD20 monoclonal antibodies and associated viral hepatitis in hematological diseases. World J Hematol 2014; 3:29. [DOI: 10.5315/wjh.v3.i2.29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 01/27/2014] [Accepted: 03/18/2014] [Indexed: 02/05/2023] Open
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Affiliation(s)
- Franco Dammacco
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
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25
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Sagnelli E, Pisaturo M, Sagnelli C, Coppola N. Rituximab-based treatment, HCV replication, and hepatic flares. Clin Dev Immunol 2012; 2012:945950. [PMID: 22919406 PMCID: PMC3420110 DOI: 10.1155/2012/945950] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 06/20/2012] [Indexed: 12/13/2022]
Abstract
Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only a few small studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.
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Affiliation(s)
- Evangelista Sagnelli
- Section of Infectious Diseases, Department of Public Medicine, Second University of Naples, 80131 Naples, Italy.
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26
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Clinical outcome in diffuse large B-cell lymphoma with hepatitis C virus infection in the rituximab era: A single center experience. Oncol Rep 2012; 28:835-40. [DOI: 10.3892/or.2012.1883] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 05/14/2012] [Indexed: 11/05/2022] Open
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27
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Marignani M, Fonzo MD, Begini P, Gigante E, Deli I, Pellicelli AM, Gallina S, de Santis E, Delle Fave G, Cox MC. ‘Les liaisons dangereuses’: Hepatitis C, Rituximab and B-cell non-Hodgkin’s lymphomas. World J Gastrointest Pharmacol Ther 2012; 3:21-8. [PMID: 22577616 PMCID: PMC3348959 DOI: 10.4292/wjgpt.v3.i2.21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 09/27/2011] [Accepted: 08/10/2011] [Indexed: 02/06/2023] Open
Abstract
Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin’s lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with Rituximab-containing regimens. In this paper we review the recent data regarding the effects of Rituximab in NHL patients with HCV infection. We also added a section devoted to improving communication between oncohaematologists and hepatologists. Furthermore, we propose a common methodological ground to study hepatic toxicity emerging during chemotherapy.
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Affiliation(s)
- Massimo Marignani
- Massimo Marignani, Michela di Fonzo, Paola Begini, Elia Gigante, Ilaria Deli, Sara Gallina, Emanuela de Santis, Gianfranco Delle Fave, Department of Digestive and Liver Disease, School of Medicine and Psychology University "Sapienza", Azienda Ospedaliera S. Andrea, Via Grottarossa, 1035-1039, 00189 Rome, Italy
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28
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Toshikuni N, Maeda T, Ueda Y. Do hepatitis C Virus genotypes influence liver dysfunction following rituximab-containing regimens in patients with diffuse large B cell lymphoma? Acta Haematol 2012; 127:178-81. [PMID: 22343527 DOI: 10.1159/000335622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 12/05/2011] [Indexed: 11/19/2022]
MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Alanine Transaminase/metabolism
- Antibodies, Monoclonal, Murine-Derived/therapeutic use
- Antigens, CD20/immunology
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Drug Therapy, Combination
- Female
- Genotype
- Hepacivirus/genetics
- Hepatitis C/complications
- Hepatitis C/pathology
- Humans
- Liver/drug effects
- Liver/metabolism
- Liver/physiopathology
- Lymphoma, Large B-Cell, Diffuse/complications
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Male
- Middle Aged
- RNA, Viral/analysis
- Risk Factors
- Rituximab
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Affiliation(s)
- Nobuyuki Toshikuni
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Japan.
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29
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Stamataki Z, Tilakaratne S, Adams DH, McKeating JA. Rituximab treatment in hepatitis C infection: an in vitro model to study the impact of B cell depletion on virus infectivity. PLoS One 2011; 6:e25789. [PMID: 21991396 PMCID: PMC3184166 DOI: 10.1371/journal.pone.0025789] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Accepted: 09/10/2011] [Indexed: 11/25/2022] Open
Abstract
Hepatitis C virus (HCV) infected patients with vasculitis are often treated with the B-cell-depleting anti-CD20 antibody rituximab. Treatment reduces the cryoglobulins that cause vasculitis, yet it also leads to a transient increase in liver enzymes and HCV genomic RNA in the periphery. The mechanism underlying the increased viral load is unclear and both direct and indirect roles have been proposed for B cells in HCV infection. We previously reported that HCV can associate with B cells and can trans-infect hepatocytes. We established an in vitro assay to study the effect(s) of rituximab on B cell-associated HCV infectivity. Rituximab-mediated lysis of B cells in vitro increases the level of infectious HCV released from B cells. Our results, using a model where virus does not replicate in B cells, recapitulate observations seen in patients and may explain in part the rapid increase in blood HCV RNA observed after rituximab treatment.
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Affiliation(s)
- Zania Stamataki
- Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom.
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30
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31
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Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood 2010; 116:5119-25. [PMID: 20823454 DOI: 10.1182/blood-2010-06-289231] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.
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32
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Pegylated interferon-α, ribavirin, and rituximab combined therapy of hepatitis C virus–related mixed cryoglobulinemia: a long-term study. Blood 2010; 116:343-53. [DOI: 10.1182/blood-2009-10-245878] [Citation(s) in RCA: 166] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AbstractThis study illustrates the use and efficacy of a combination of pegylated interferon-α (Peg-IFN-α) and ribavirin (RBV), with or without rituximab (RTX), in hepatitis C virus (HCV)–related mixed cryoglobulinemia (MC). Twenty-two patients with HCV-related MC received Peg-IFN-α (2a: 180 μg or 2b: 1.5 μg/kg) weekly plus RBV (1000 or 1200 mg) daily for 48 weeks, and RTX (375 mg/m2) once a week for 1 month followed by two 5-monthly infusions (termed PIRR). Fifteen additional patients received Peg-IFN-α/RBV with the same modalities as the PIRR schedule. Complete response was achieved in 54.5% (12/22) and in 33.3% (5/15) of patients who received PIRR and Peg-IFN-α/RBV, respectively (P < .05). Clearance of HCV RNA and conversion of B-cell populations from oligoclonal to polyclonal in liver, bone marrow, and peripheral blood was maintained for up to 3 years in 10 of 12 (83.3%) and in 2 of 5 (40%) patients receiving PIRR and Peg-IFN-α/RBV, respectively (P < .01). Cryoproteins in 22.7% (5/22) of patients with PIRR and in 33.3% (5/15) with Peg-IFN-α/RBV persisted despite sustained HCV RNA clearance. No response occurred in remaining 5 patients of both groups. PIRR therapy is well tolerated and more effective than Peg-IFN-α/RBV combination in HCV-related MC. Its effect may last for more than 3 years.
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33
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Pitini V, Sturniolo G, Arrigo C, Leonardi S, Pino S, Altavilla G. HCV genotype 2 as a risk factor for reactivation in patients with B-cell lymphoma undergoing rituximab combination chemotherapy. Br J Haematol 2010; 150:116-8. [PMID: 20230413 DOI: 10.1111/j.1365-2141.2010.08154.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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34
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Acute wrist and foot drop associated with hepatitis C virus related mixed cryoglobulinemia: Rapid response to treatment with rituximab. J Clin Virol 2010; 47:69-71. [DOI: 10.1016/j.jcv.2009.10.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Revised: 09/29/2009] [Accepted: 10/06/2009] [Indexed: 01/04/2023]
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Abstract
In this review we discuss the clinical manifestations, pathogenesis, and treatment of hepatitis C virus (HCV)-related cryoglobulinemia. HCV is a major cause of liver-related morbidity and is increasingly recognized as an instigator of B-cell lymphoproliferative disorders such as mixed cryoglobulinemia and non-Hodgkin lymphoma. Cryoglobulinemia is characterized by the clonal expansion of rheumatoid factor-expressing B cells in the liver, lymph nodes, and peripheral blood, resulting in the presence of cryoglobulins in the circulation. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor, polyclonal IgG, and HCV RNA that precipitate and deposit on vascular endothelium, causing vasculitis in organs such as the skin, kidneys, and peripheral nerves. A subset of patients develops a low-grade lymphoma composed of B cells that are immunophenotypically similar to the expanded B cells seen in cryoglobulinemia. HCV-related B-cell lymphoproliferative disorders likely comprise a spectrum of disease, ranging from asymptomatic clonal B-cell expansions to pathogenic cryoglobulinemia and lymphoma. It is unclear how B cells become dysregulated during the course of chronic HCV infection, and continued patient-centered research is necessary to elucidate the pathogenesis of HCV-related B-cell dysregulation.
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Affiliation(s)
- Edgar D Charles
- Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.
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36
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Tsai MK, Yang CY, Wu MS, Lee PH. Application of rituximab to hepatitis C-positive, ABO-incompatible renal transplantation. Int J Artif Organs 2009; 32:308-9. [PMID: 19569040 DOI: 10.1177/039139880903200508] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A safety issue has been noted in applying rituximab to renal transplant patients with HCV infection, as a hepatitis C virus (HCV) flare-up and lethal cholestatic hepatitis C occurred in a renal transplant patient treated with rituximab for lymphoproliferative disorder. As double-filtration plasmapheresis (DFPP) and cyclosporine were reported to reduce hepatitis C viremia, we performed ABO-incompatible renal transplantation in two patients with positive HCV RNA by using rituximab, DFPP and cyclosporine-based immunosuppressant. The HCV RNA level was 3.3 x 10(5) IU/mL for Case 1 and 1.2 x 10(3) IU/mL for Case 2 before DFPP. After DFPP and renal transplantation, Case 1 had stable ALT levels and a transient decrease in HCV RNA to 7.9 x 10(4) IU/mL at 1 month followed by a gradual increase to 7.6 x 10(6) at 12 months, but Case 2 had a dramatic and persistent elevation of HCV RNA to 7.7 x 10(6) from 1 week to 12 months accompanied by elevated ALT levels. The serum creatinine levels were 1.5 mg/dL for Case 1 and 1.9 mg/dL for Case 2 at 12 months. Although cholestatic hepatitis C did not occur in our patients, who received rituximab for ABO-incompatible renal transplantation, the antiviral effect of cyclosporine and DFPP did not seem evident.
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Affiliation(s)
- Meng-Kun Tsai
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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37
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Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab therapy--rare but there! Leuk Lymphoma 2009; 50:1083-95. [PMID: 19399690 DOI: 10.1080/10428190902934944] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Rituximab, an anti CD20 monoclonal antibody, has now become a cornerstone in the treatment of many CD20 positive hematological malignancies and a variety of autoimmune disorders. In contrast to the acute allergic and cytokine associated reactions, late adverse events of rituximab are indeed uncommon but at the same time probably under-reported. In this review, we detail late adverse events reported since its use in hemato-oncological neoplasias and other disorders. These adverse events include the development of late-onset neutropenia, defects of immune reconstitution with associated immune compromise, infections, progressive multifocal leukoencephalopathy, reactivation of hepatitis, intestinal perforation and interstitial pneumonitis. Possible mechanisms involved in rituximab-associated complications and the pathogenesis of these adverse effects are reviewed and discussed. Evidence based graded recommendations for the management of these adverse effects are proposed.
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Affiliation(s)
- Ron Ram
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
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38
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McDonald V, Leandro M. Rituximab in non-haematological disorders of adults and its mode of action. Br J Haematol 2009; 146:233-46. [DOI: 10.1111/j.1365-2141.2009.07718.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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39
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Zarife MAS, Reis EAG, Carmo TMA, Lopes GB, Brandão ECM, Silva HR, Santana N, Martins-Filho OA, Reis MG. Increased frequency of CD56Bright NK-cells, CD3-CD16+CD56- NK-cells and activated CD4+T-cells or B-cells in parallel with CD4+CDC25High T-cells control potentially viremia in blood donors with HCV. J Med Virol 2008; 81:49-59. [PMID: 19031471 DOI: 10.1002/jmv.21340] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
A detailed phenotypic analysis of major and minor circulating lymphocyte subsets is described in potential blood donors with markers of hepatitis C virus (HCV), including non-viremic and viremic groups. Although there were no changes in the hematological profile of either group, increased the levels of pre-NK cells (CD3-CD16+CD56-) and a lower frequency of mature NK cells (CD3-CD16+CD56+) characterized innate immunity in the non-viremic group. Both non-viremic and viremic groups displayed significantly increased levels of CD56(Bright) NK cells. Furthermore, this subset was significantly elevated in the viremic subgroup with a low viral load. In addition, an increase in the NKT2 subset was observed only in this subgroup. An enhanced frequency of activated CD4+ T-cells (CD4+HLA-DR+) was a characteristic feature of the non-viremic group, whereas elevated CD19+ B-cells and CD19+CD86+ cell populations were the major phenotypic features of the viremic group, particularly in individuals with a low viral load. Although CD4+CD25High T-cells were significantly elevated in both the viremic and non-viremic groups, it was particularly evident in the viremic low viral load subgroup. A parallel increase in CD4+CD25High T-cells, pre-NK, and activated CD4+ T-cells was observed in the non-viremic group, whereas a parallel increase in CD4+CD25High T-cells and CD19+ B-cells was characteristic of the low viral load subgroup. These findings suggest that CD56Bright NK cells, together with pre-NK cells and activated CD4+ T-cells in combination with CD4+CD25High T-cells, might play an important role in controlling viremia. Elevated CD56(Bright) NK cells, B-cell responses and a T-regulated immunological profile appeared to be associated with a low viral load.
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Chakravarty EF. Viral infection and reactivation in autoimmune disease. ACTA ACUST UNITED AC 2008; 58:2949-57. [DOI: 10.1002/art.23883] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Saadoun D, Resche-Rigon M, Sene D, Perard L, Karras A, Cacoub P. Rituximab combined with Peg-interferon-ribavirin in refractory hepatitis C virus-associated cryoglobulinaemia vasculitis. Ann Rheum Dis 2008; 67:1431-6. [PMID: 18178690 DOI: 10.1136/ard.2007.081653] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES To report the results of a pilot study using rituximab combined with Peg-interferon (IFN) alpha2b-ribavirin in severe refractory hepatitis C virus (HCV) related mixed cryoglobulinaemia (MC) vasculitis. METHODS Sixteen consecutive patients with severe HCV-MC vasculitis that were resistant (n = 11) or relapser (n = 5) to a previous combination treatment with standard (n = 10) or Peg-IFNalpha2b (n = 6) plus ribavirin were included. They were treated with rituximab (375 mg/m2 intravenously weekly for 4 weeks) combined with Peg-IFNalpha2b (1.5 mug/kg per week subcutaneously) plus ribavirin (600-1200 mg/day orally) for 12 months. RESULTS Fifteen patients (93.7%) showed clinical improvement, 10 of whom (62.5%) were clinical complete responders (CR). HCV RNA and serum cryoglobulin became undetectable in all the clinical CR. Peripheral blood B cell depletion was achieved in all patients (CD19+ cells, 111 (SD 32)/mm3 at baseline versus 2(2)/mm3 after the fourth infusion of rituximab) with reconstitution starting at the end of antiviral treatment. Compared with clinical CR, the partial or non-responders had a 3.6 times longer duration of vasculitis prior to treatment and a lower rate of early virological response. Treatment was well tolerated with no infectious complications. After a mean follow-up of 19.4 (SD 3.6) months, two patients experienced clinical relapse associated with a simultaneous reappearance of HCV RNA and cryoglobulin and an increase in the number of B cells. CONCLUSIONS Rituximab combined with Peg-IFNalpha2b-ribavirin represents a safe and effective treatment option in severe refractory HCV-MC vasculitis.
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Affiliation(s)
- D Saadoun
- Pierre et Marie Curie-Paris 6, University 1, CNRS, UMR 7087, Paris, F-75013 France.
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Huang HH, Hsieh CY. In Reply. J Clin Oncol 2008. [DOI: 10.1200/jco.2008.18.8276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Hsin-Hui Huang
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ching-Yun Hsieh
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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Tsutsumi Y, Ichiki K, Shiratori S, Kawamura T, Tanaka J, Asaka M, Imamura M, Masauzi N. Changes in hepatitis C virus antibody titer and viral RNA load in non-Hodgkin's lymphoma patients after rituximab chemotherapy. Int J Lab Hematol 2008; 31:468-70. [PMID: 18294236 PMCID: PMC2728889 DOI: 10.1111/j.1751-553x.2008.01034.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Murine-Derived
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/adverse effects
- Antineoplastic Agents/therapeutic use
- Female
- Hepacivirus/immunology
- Hepatitis C Antibodies/blood
- Humans
- Lymphoma, Non-Hodgkin/drug therapy
- Lymphoma, Non-Hodgkin/immunology
- Lymphoma, Non-Hodgkin/virology
- Male
- Middle Aged
- RNA, Viral/blood
- Rituximab
- Viral Load
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Affiliation(s)
- Y Tsutsumi
- Department of Internal Medicine, Hakodate Municipal HospitalHakodate
| | - K Ichiki
- Department of Internal Medicine, Hakodate Municipal HospitalHakodate
| | - S Shiratori
- Department of Internal Medicine, Hakodate Municipal HospitalHakodate
| | - T Kawamura
- Department of Internal Medicine, Hakodate Municipal HospitalHakodate
| | - J Tanaka
- Departments of Hematology and Oncology, Hokkaido University Graduate School of MedicineSapporo, Japan
| | - M Asaka
- Gastroenterology, Hokkaido University Graduate School of MedicineSapporo, Japan E-mail:
| | - M Imamura
- Departments of Hematology and Oncology, Hokkaido University Graduate School of MedicineSapporo, Japan
| | - N Masauzi
- Department of Internal Medicine, Hakodate Municipal HospitalHakodate
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Risks of immunosuppressive therapies including biologic agents in patients with rheumatic diseases and co-existing chronic viral infections. Curr Opin Rheumatol 2008; 19:619-25. [PMID: 17917544 DOI: 10.1097/bor.0b013e3282f05b63] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW A number of chronic viral infections could be reactivated by immunosuppressive agents used in rheumatic diseases. In this review, we will focus on the complex effect of immunosuppressive agents, including biologic agents, on the natural course of chronic viral infections as well as an approach to the prevention and management of therapy-induced viral reactivation. RECENT FINDINGS Chronic viral infections that are affected by immunosuppression in the setting of an underlying rheumatic disease include those due to hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, and latent infections from Epstein-Barr virus, JC virus, or varicella zoster virus. The most recent data of the effects of immunosuppressive agents are reviewed, with special emphasis on the effects of biologic therapies (anti-tumor necrosis factor, anti-B cell), on these viral agents. SUMMARY Clinicians should be aware of the risk for viral reactivation of an underlying chronic viral infection during immunosuppressive therapy. Despite the existence of such risk, the presence of chronic viral infection is not a contraindication to immunosuppressive therapy, given that appropriate pretherapy screening and close monitoring is applied.
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Dizdar O, Tapan U, Aksoy S, Harputluoglu H, Kilickap S, Barista I. Liver dysfunction after chemotherapy in lymphoma patients infected with hepatitis C. Eur J Haematol 2008; 80:381-5. [PMID: 18221389 DOI: 10.1111/j.1600-0609.2008.01039.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Reactivation of hepatitis B virus (HBV) infection in asymptomatic hepatitis B surface antigen carriers undergoing chemotherapy or immunosuppressive therapy is a well-documented complication. However, data on the consequence of chemotherapy on the course of hepatitis C virus (HCV) infection in HCV+ patients have been controversial. Here, we review the current knowledge about the complications related to HCV in lymphoma patients receiving chemotherapy/immunosuppressive therapy. Although less frequent than HBV, these complications occur in a subset of patients with mortality rates up to 45%. Therefore, baseline screening for HBV and HCV before initiation of chemotherapy is crucial. High-risk patients having chronic active hepatitis, high baseline HCV viral load, HBV co-infection and receiving cytotoxic drugs, corticosteroids and rituximab (particularly if combined) should be closely monitored for serum transaminase, bilirubin and HCV RNA levels.
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Affiliation(s)
- Omer Dizdar
- Division of Medical Oncology, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara, Turkey.
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Bibliography. Current world literature. Myositis and myopathies. Curr Opin Rheumatol 2007; 19:651-3. [PMID: 17917548 DOI: 10.1097/bor.0b013e3282f20347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Rituximab Off Label Use for Difficult-To-Treat Auto-Immune Diseases: Reappraisal of Benefits and Risks. Clin Rev Allergy Immunol 2007; 34:103-10. [DOI: 10.1007/s12016-007-8020-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Visentini M, Granata M, Veneziano ML, Borghese F, Carlesimo M, Pimpinelli F, Fiorilli M, Casato M. Efficacy of low-dose rituximab for mixed cryoglobulinemia. Clin Immunol 2007; 125:30-3. [PMID: 17692572 DOI: 10.1016/j.clim.2007.06.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2007] [Revised: 05/21/2007] [Accepted: 06/25/2007] [Indexed: 10/23/2022]
Abstract
Rituximab at 375 mg/m(2) x 4 is effective for refractory HCV-related mixed cryoglobulinemia. We conducted a pilot study to assess the efficacy of a lower dosage, 250 mg/m(2) x 2. Six consecutive patients with mixed cryoglobulinemia were treated. All patients had severe or life-threatening disease manifestations, including necrotizing skin ulcers, renal disease, hyperviscosity or intestinal vasculitis. Four of five evaluable patients (excluding one early death) had >80% decrease of cryocrit and remission of vasculitis at the end of a 22- to 55-week (median 40) follow-up. The non-responder failed to respond to additional rituximab treatment, suggesting intrinsic resistance rather than insufficient dosage as the cause of treatment failure. No sustained increase of HCV viremia after rituximab was observed. Rituximab at 250 mg/m(2) x 2 may be as effective as at 375 mg/m(2) x 4 for treating mixed cryoglobulinemia. Larger studies are required to assess the efficacy of low-dose rituximab.
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Affiliation(s)
- Marcella Visentini
- Department of Clinical Immunology, University of Rome La Sapienza, Viale dell'Università 37, 00185, Rome, Italy
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