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Li Y, Kong L. A case of diffuse large B-cell lymphoma with decompensated alcohol-related liver cirrhosis treated successfully by chemoimmunotherapy. Clin Case Rep 2024; 12:e8820. [PMID: 38659497 PMCID: PMC11039811 DOI: 10.1002/ccr3.8820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 03/13/2024] [Accepted: 03/20/2024] [Indexed: 04/26/2024] Open
Abstract
Key Clinical Message This report describes a case of diffuse large B-cell lymphoma with MYD88 L265P and KM2DT mutation and decompensated alcohol-related liver cirrhosis. And the treatment is successful in this patient, who had multiple complications and poor prognostic factors. Abstract This report describes a case of diffuse large B-cell lymphoma with MYD88 L265P and KM2DT mutation and decompensated alcohol-related liver cirrhosis. The lymphoma showed a complete response with no MYD88 L265P mutation after four courses of combination chemotherapy. Lymphoma is one of the most common malignant tumors, but cases of DLBCL with cirrhosis are much rarer especially with alcohol-related cirrhosis. And we reviewed the relevant mechanisms. Although we did not find a definite association between the pathogenesis of the patient's alcohol-related cirrhosis and that of diffuse large B-cell lymphoma, the treatment is successful in this patient, who had multiple complications and poor prognostic factors.
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Affiliation(s)
- Yan Li
- Department of HaematologyHebei General HospitalShijiazhuangHebeiPeople's Republic of China
| | - Ling‐zhijie Kong
- Department of HaematologyHebei General HospitalShijiazhuangHebeiPeople's Republic of China
- Department of Graduate SchoolHebei North UniversityZhangjiakouHebeiPeople's Republic of China
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2
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Zhang Y, Guo W, Zhan Z, Bai O. Carcinogenic mechanisms of virus-associated lymphoma. Front Immunol 2024; 15:1361009. [PMID: 38482011 PMCID: PMC10932979 DOI: 10.3389/fimmu.2024.1361009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 02/12/2024] [Indexed: 04/17/2024] Open
Abstract
The development of lymphoma is a complex multistep process that integrates numerous experimental findings and clinical data that have not yet yielded a definitive explanation. Studies of oncogenic viruses can help to deepen insight into the pathogenesis of lymphoma, and identifying associations between lymphoma and viruses that are established and unidentified should lead to cellular and pharmacologically targeted antiviral strategies for treating malignant lymphoma. This review focuses on the pathogenesis of lymphomas associated with hepatitis B and C, Epstein-Barr, and human immunodeficiency viruses as well as Kaposi sarcoma-associated herpesvirus to clarify the current status of basic information and recent advances in the development of virus-associated lymphomas.
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Affiliation(s)
| | | | | | - Ou Bai
- Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China
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3
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Wang SS. Epidemiology and etiology of diffuse large B-cell lymphoma. Semin Hematol 2023; 60:255-266. [PMID: 38242772 PMCID: PMC10962251 DOI: 10.1053/j.seminhematol.2023.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/15/2023] [Accepted: 11/21/2023] [Indexed: 01/21/2024]
Abstract
As the most common non-Hodgkin lymphoma subtype, diffuse large B-cell lymphoma (DLBCL) incidence patterns generally parallel that for NHL overall. Globally, DLBCL accounts for a third of all NHLs, ranging between 20% and 50% by country. Based on United States (U.S.) cancer registry data, age-standardized incidence rate for DLBCL was 7.2 per 100,000. DLBCL incidence rises with age and is generally higher in males than females; in the U.S., incidence is highest among non-Hispanic whites (9.2/100,000). Like NHL incidence, DLBCL incidence rose in the first half of the 20th century but has largely plateaued. However, there is some evidence that incidence rates are rising in areas of historically low rates, such as Asia; there are also estimates for rising DLBCL incidence in the near future due to the changing demographics in developed countries whose aging population is growing. Established risk factors for DLBCL include those that result in severe immune deficiency such as HIV/AIDS, inherited immunodeficiency syndromes, and organ transplant recipients. Factors that lead to chronic immune dysregulations are also established risk factors, and include a number of autoimmune conditions (eg, Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis), viral infections (eg, HIV, KSHV/HHV8, HCV, EBV), and obesity. Family history of NHL/DLBCL, personal history of cancer, and multiple genetic susceptibility loci are also well-established risk factors for DLBCL. There is strong evidence for multiple environmental exposures in DLBCL etiology, including exposure to trichloroethylene, benzene, and pesticides and herbicides, with recent associations noted with glyphosate. There is also strong evidence for associations with other viruses, such as HBV. Recent estimates suggest that obesity accounts for nearly a quarter of DLBCLs that develop, but despite recent gains in the understanding of DLBCL etiology, the majority of disease remain unexplained. An understanding of the host and environmental contributions to disease etiology, and concerted efforts to expand our understanding to multiple race/ethnic groups, will be essential for constructing clinically relevant risk prediction models and develop effective strategies for disease prevention.
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Affiliation(s)
- Sophia S Wang
- City of Hope Comprehensive Cancer Center, Duarte, CA.
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4
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Zhang W, Du F, Wang L, Bai T, Zhou X, Mei H. Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies. J Clin Transl Hepatol 2023; 11:1256-1266. [PMID: 37577221 PMCID: PMC10412707 DOI: 10.14218/jcth.2022.00079s] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/21/2023] [Accepted: 03/22/2023] [Indexed: 07/03/2023] Open
Abstract
Over the last decade, epidemiological studies have discovered a link between hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection's role in lymphoproliferative diseases. HBV infection was found to significantly enhance the incidence of NHL, according to the epidemiological data. The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocytes damage by the transitional entry of HCV. The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; (2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA. In fact, it is reasonable to consider direct-acting antivirals (DAAs) as first-line therapy for indolent HCV-associated B-NHL patients who do not require immediate chemotherapy. Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication. Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. The data on epidemiology, interventional studies, and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.
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Affiliation(s)
- Wenjing Zhang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Du
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Li Wang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tao Bai
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang Zhou
- Department of Internal Medicine II, Würzburg University Hospital, University of Würzburg, Würzburg, Germany
| | - Heng Mei
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Honma Y, Shibata M, Morino K, Koya Y, Hayashi T, Ogino N, Kusanaga M, Oe S, Miyagawa K, Abe S, Tabaru A, Harada M. Impact of Interferon-Free Direct-Acting Antivirals on the Incidence of Extrahepatic Malignancies in Patients with Chronic Hepatitis C. Dig Dis Sci 2023; 68:685-698. [PMID: 36100828 DOI: 10.1007/s10620-022-07686-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 08/29/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND The incidence of extrahepatic malignancies (EHMs) after hepatitis C virus (HCV) eradication by interferon (IFN)-based and IFN-free direct-acting antivirals (DAAs) treatment remains unclear. AIMS The aim was to evaluate the cumulative incidence of EHMs diagnosed for the first time after the antiviral treatments. METHODS We analyzed a total 527 patients with chronic HCV infection and without prior history of any malignancies who achieved sustained virological response by antiviral treatments, including IFN-based (n = 242) or IFN-free DAAs (n = 285). The baseline predictors for EHM occurrence were analyzed using Cox regression analysis. RESULTS Thirty-two patients were diagnosed with EHMs, 14 in IFN-based and 18 in IFN-free DAAs, respectively. The total duration of follow-up was 1,796 person-years in IFN-based and 823 person-years in IFN-free DAAs. The incidence of EHMs in IFN-based and IFN-free DAAs was 7.8 and 21.9 per 1,000 person-years, respectively. The cumulative incidence of EHMs was significantly higher in IFN-free DAAs than IFN-based (p = 0.002). IFN-free DAAs was a single independent predictor for incidence of EHMs (p = 0.012). As for gender, the incidence of EHMs was significantly higher in IFN-free DAAs only in the female cohort (p = 0.002). After propensity score matching, IFN-free DAAs was a single independent predictor for incidence of EHMs in the female patients (p = 0.045). CONCLUSIONS The incidence of EHMs after HCV eradication is higher in IFN-free DAAs than IFN-based regimens, especially in female patients. We should carefully follow-up not only HCC but also EHMs after IFN-free DAAs regimens.
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Affiliation(s)
- Yuichi Honma
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Michihiko Shibata
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Kahori Morino
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Yudai Koya
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
- Department of Gastroenterology, Moji Medical Center, 3-1 Higashiminato-machi, Moji-ku, Kitakyushu, 801-8502, Japan
| | - Tsuguru Hayashi
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Noriyoshi Ogino
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Masashi Kusanaga
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Shinji Oe
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Koichiro Miyagawa
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Shintaro Abe
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Akinari Tabaru
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
- Department of Gastroenterology, Wakamatsu Hospital of the University of Occupational and Environmental Health, 1-17-1 Hama-machi, Wakamatsu-ku, Kitakyushu, 800-0024, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
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Impact of eradication of hepatitis C virus on liver-related and -unrelated diseases: morbidity and mortality of chronic hepatitis C after SVR. J Gastroenterol 2022; 58:299-310. [PMID: 36585501 DOI: 10.1007/s00535-022-01940-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/05/2022] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus infection is characterized by chronic liver inflammation and fibrogenesis, leading to end-stage liver failure and hepatocellular carcinoma over the course of 20 to 30 years. It seems not only the chronicity of hepatitis C but also the presence of the virus in non-hepatic tissues creates a favorable environment for the potential development of pathogenic impacts on extrahepatic systems and organs. Numerous extra-hepatic manifestations have been reported in association with HCV infection, all of which can substantially affect morbidity, mortality, and quality of life. With the recent development of DAAs, antiviral treatment can cure almost all patients with HCV infection, even those intolerant of or unresponsive to IFN treatment, and several large multicenter studies have confirmed the association of DAA-induced SVR with reductions in liver-related and liver-unrelated complications, such as cardiovascular events, end stage renal disease, and so on. Because, in addition to liver-related diseases, extrahepatic lesions are threatening for patients, it is important to eradicate the virus before these progress and affect life prognosis; in other words, patients should be treated before reaching the point of no return. Tailored surveillance with biomarkers such as M2BPGi and Ang-2, which can be used to identify patients with an elevated risk of EHM, and early prevention or treatment for these patients could improve the morbidity, mortality and QOL. Advancement of both basic and clinical research in this field including the development of more precise biomarkers is highly anticipated.
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Jelicic J, Larsen TS, Fialla AD, Bukumiric Z, Andjelic B. Clinical Characteristics and Management of Patients With Concomitant Liver Cirrhosis and Lymphoma: A Systematic Review. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:e981-e991. [PMID: 35948478 DOI: 10.1016/j.clml.2022.07.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/07/2022] [Accepted: 07/14/2022] [Indexed: 06/15/2023]
Abstract
Over the years, a rising incidence of liver cirrhosis and lymphoma has been observed. Therefore, the risk of having cirrhosis as a comorbidity increases, thus challenging treatment approaches as data on the management of these patients is lacking. We performed a systematic review to summarize papers that analyzed patients with liver cirrhosis that occurred before and/or concomitantly to lymphoma. We identified 153 papers (230 patients) through Pubmed and/or Embase search. Publications comprised predominantly of case reports and/or case series. Most patients had HCV-related cirrhosis (62.6%), and aggressive lymphoma histology (59.6%). Data on liver status was available in 55.7% of all patients, with 46.1% having decompensated liver cirrhosis. These patients experienced more often treatment reductions and/or modifications, treatment side effects, and inferior survival than those with compensated cirrhosis (median 18 months vs. median not reached). Dose reductions and/or treatment modifications primarily due to concomitant liver disease were common. Moreover, liver toxicity was observed in 33.6% of patients with provided information on treatment side effects, ranging from mild toxicity to liver failure with fatal outcomes. Again, despite treatment modification/reduction, patients with decompensated liver cirrhosis developed hepatic toxicity more frequently than patients with compensated liver disease. Although patients suffering from cirrhosis and lymphoma can tolerate standard chemoimmunotherapy, a cautious multidisciplinary approach is needed to evaluate the risks and benefits.
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Affiliation(s)
- Jelena Jelicic
- Department of Hematology, Sygehus Lillebaelt, Vejle, Denmark; Department of Hematology, Odense University Hospital, Odense, Denmark.
| | - Thomas Stauffer Larsen
- Department of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Annette Dam Fialla
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Zoran Bukumiric
- Department of Statistics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Bosko Andjelic
- Department of Hematology, Blackpool Victoria Hospital, Lancashire Haematology Centre, Blackpool
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Mazzaro C, Bomben R, Gragnani L, Visentini M, Pozzato G, Pozzo F, Zucchetto A, Gattei V. Hepatitis C virus-associated B-cell lymphomas: The importance of the new direct antiviral agent therapy. Semin Hematol 2022; 59:177-182. [PMID: 36805885 DOI: 10.1053/j.seminhematol.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/23/2022] [Accepted: 11/27/2022] [Indexed: 11/30/2022]
Abstract
Hepatitis C virus (HCV) is a hepatotropic and lymphotropic virus, responsible for both chronic hepatitis and extra-hepatic manifestations. Multiple epidemiologic, clinical, biological, and molecular studies have suggested that HCV plays a causal role also in the development of several lymphoproliferative disorders, either benign, such as mixed cryoglobulinemia, or malignant, such as B-cell non-Hodgkin lymphomas (NHL). Chronic viral antigenic stimulation of B-lymphocytes plays a fundamental basic role from the onset of lymphoma to its final steps. In the past, several studies demonstrated that the association of pegylated interferon plus ribavirin was able to eradicate HCV, with subsequent regression of indolent B-cell low-grade NHL. Other studies have demonstrated that direct antiviral agents (DAAs) therapy have some efficacy in HCV-associated NHL, particularly in patients with low-grade NHL or marginal zone-lymphoma, but these results need to be confirmed in larger studies with longer follow-up. The response rate of antiviral therapy seems favorable also in high grade NHL when DAAs therapy is administered in combination with chemotherapy and therefore antiviral therapy should be considered as a first-line approach in HCV-related NHL.
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Affiliation(s)
- Cesare Mazzaro
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy.
| | - Riccardo Bomben
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Laura Gragnani
- MASVE Interdepartmental Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, Firenze, Italy
| | - Marcella Visentini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Gabriele Pozzato
- Clinical and Surgical Sciences, University of Trieste, Trieste, Italy
| | - Federico Pozzo
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Antonella Zucchetto
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Valter Gattei
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
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Liu X, Cao X, Pang Y, Min F. Primary hepatic mucosa-associated lymphoid tissue lymphoma with HP and previous HBV infection: A case report and literature review. J Infect Chemother 2022; 28:1182-1188. [PMID: 35459609 DOI: 10.1016/j.jiac.2022.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/29/2022] [Accepted: 04/08/2022] [Indexed: 02/05/2023]
Abstract
Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare disease with low malignancy, and its aetiology is unclear. A 65-year-old man presented with abdominal pain. Hepatitis virus examination revealed a previous hepatitis B virus (HBV) infection, and a carbon-13 urea breath test result was positive for the patient. Abdominal contrast-enhanced computed tomography revealed a patch of abnormal density in the right posterior lobe of the liver. The patient underwent VI segment hepatectomy and was pathologically diagnosed with hepatic MALT lymphoma. After the operation, he received quadruple anti-Helicobacter pylori (HP) therapy and refused other treatments. He has been followed up by telephone for 20 months after discharge and is now in a stable condition. In this study, we counted 105 cases of hepatic MALT lymphomas reported in English or Chinese since 1995 and summarised the clinical characteristics and concomitant diseases in this condition. Based on the literature review, we speculated that chronic infectious diseases, especially viral infections (including hepatitis C virus (HCV) and HBV) and HP infection, are associated with the pathogenesis of primary hepatic MALT lymphoma. In addition, autoimmune diseases might also play a role in this condition.
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Affiliation(s)
- Xinyi Liu
- Department of Haematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, China
| | - Xuewei Cao
- Department of Rheumatology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Yuanyuan Pang
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, China
| | - Fengling Min
- Department of Haematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, China.
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Cacoub P, Comarmond C, Vieira M, Régnier P, Saadoun D. HCV-related lymphoproliferative disorders in the direct-acting antiviral era: From mixed cryoglobulinaemia to B-cell lymphoma. J Hepatol 2022; 76:174-185. [PMID: 34600000 DOI: 10.1016/j.jhep.2021.09.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/31/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023]
Abstract
HCV has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes specialise in producing immunoglobulins and, during chronic HCV infection, they can cause manifestations ranging from polyclonal hypergammaglobulinaemia without clinical repercussions, through mixed cryoglobulinaemic vasculitis to B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, of the pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the final steps before overt malignancy. This has direct implications for treatment strategies, which always include the use of direct-acting antivirals sometimes alongside immunosuppressants. The role of direct-acting antivirals has been well established in patients with cryoglobulinaemia vasculitis. However, their positive impact on B-cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.
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Affiliation(s)
- Patrice Cacoub
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France.
| | - Cloé Comarmond
- AP-HP, Lariboisière Hospital, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Matheus Vieira
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
| | - Paul Régnier
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
| | - David Saadoun
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
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11
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Darvishian M, Tang T, Wong S, Binka M, Yu A, Alvarez M, Alexander Velásquez García H, Adu PA, Jeong D, Bartlett S, Karamouzian M, Damascene Makuza J, Wong J, Ramji A, Woods R, Krajden M, Janjua N, Bhatti P. Chronic hepatitis C infection is associated with higher incidence of extrahepatic cancers in a Canadian population based cohort. Front Oncol 2022; 12:983238. [PMID: 36313680 PMCID: PMC9609415 DOI: 10.3389/fonc.2022.983238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Chronic infection with hepatitis C virus (HCV) is an established risk factor for liver cancer. Although several epidemiologic studies have evaluated the risk of extrahepatic malignancies among people living with HCV, due to various study limitations, results have been heterogeneous. METHODS We used data from the British Columbia Hepatitis Testers Cohort (BC-HTC), which includes all individuals tested for HCV in the Province since 1990. We assessed hepatic and extrahepatic cancer incidence using data from BC Cancer Registry. Standardized incidence ratios (SIR) comparing to the general population of BC were calculated for each cancer site from 1990 to 2016. RESULTS In total, 56,823 and 1,207,357 individuals tested positive and negative for HCV, respectively. Median age at cancer diagnosis among people with and without HCV infection was 59 (interquartile range (IQR): 53-65) and 63 years (IQR: 54-74), respectively. As compared to people living without HCV, a greater proportion of people living with HCV-infection were men (66.7% vs. 44.7%, P-value <0.0001), had comorbidities (25.0% vs. 16.3%, P-value <0.0001) and were socially deprived (35.9% vs. 25.0%, P-value <0.0001). The SIRs for liver (SIR 33.09; 95% CI 29.80-36.39), anal (SIR: 2.57; 95% CI 1.52-3.63), oesophagus (SIR: 2.00; 95% CI 1.17-2.82), larynx (SIR: 3.24; 95% CI 1.21-5.27), lung (SIR: 2.20; 95% CI 1.82-2.58), and oral (SIR: 1.78; 95% CI 1.33-2.23) cancers were significantly higher among individuals living with HCV. The SIRs for bile duct and pancreatic cancers were significantly elevated among both individuals living with (SIR; 95% CI: 2.20; 1.27-3.14; 2.18; 1.57-2.79, respectively) and without HCV (SIR; 95% CI: 2.12; 1.88-2.36; 1.20; 1.11-1.28, respectively). DISCUSSION/CONCLUSION In this study, HCV infection was associated with increased incidence of several extrahepatic cancers. The elevated incidence of multiple cancers among negative HCV testers highlights the potential contributions of screening bias and increased cancer risks associated with factors driving acquisition of infection among this population compared to the general population. Early HCV diagnosis and treatment as well as public health prevention strategies are needed to reduce the risk of extrahepatic cancers among people living with HCV and potentially populations who are at higher risk of HCV infection.
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Affiliation(s)
- Maryam Darvishian
- Cancer Prevention, BC Cancer, Vancouver, BC, Canada
- Cancer Control Research, BC Cancer Research Centre, Vancouver, BC, Canada
- *Correspondence: Maryam Darvishian,
| | - Terry Tang
- Cancer Prevention, BC Cancer, Vancouver, BC, Canada
| | - Stanley Wong
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
| | - Mawuena Binka
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Amanda Yu
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
| | - Maria Alvarez
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
| | | | - Prince Asumadu Adu
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Dahn Jeong
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Sofia Bartlett
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
| | - Mohammad Karamouzian
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
- Department of Epidemiology, School of Public Health, Brown University, Providence, RI, United States
- Human Immunodeficiency Virus (HIV)/Sexually Transmitted Infection (STI) Surveillance Research Center, and World Health Organization (WHO) Collaborating Center for Human Immunodeficiency Virus (HIV) Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Jean Damascene Makuza
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Jason Wong
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
| | - Alnoor Ramji
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Ryan Woods
- Cancer Prevention, BC Cancer, Vancouver, BC, Canada
- Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada
| | - Mel Krajden
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Naveed Janjua
- Clinical Prevention Services, BC Centre for Disease Control, Vancouver, BC, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Parveen Bhatti
- Cancer Prevention, BC Cancer, Vancouver, BC, Canada
- Cancer Control Research, BC Cancer Research Centre, Vancouver, BC, Canada
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12
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Mazzaro C, Quartuccio L, Adinolfi LE, Roccatello D, Pozzato G, Nevola R, Tonizzo M, Gitto S, Andreone P, Gattei V. A Review on Extrahepatic Manifestations of Chronic Hepatitis C Virus Infection and the Impact of Direct-Acting Antiviral Therapy. Viruses 2021; 13:2249. [PMID: 34835054 PMCID: PMC8619859 DOI: 10.3390/v13112249] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 02/06/2023] Open
Abstract
Extrahepatic manifestations are a feature of chronic hepatitis C virus (HCV) infection. In the course of chronic HCV infection, about 70% of patients have one or more extrahepatic manifestations. The latter are often the first and only clinical sign of infection. Experimental and clinical data support a causal association for many extrahepatic manifestations and HCV infection, which include mixed cryoglobulinemia, non-Hodgkin lymphomas (NHL), cardiovascular disease, insulin resistance, type 2 diabetes, neurological and psychiatric disease and other rheumatic diseases. All these extrahepatic conditions influence the morbidity, quality of life and mortality of HCV-infected patients. Currently, interferon-free therapeutic regimens with direct-acting antiviral agents (DAA) offer the possibility of treatment to almost the entire infected population, irrespective of stage of cirrhosis and associated serious comorbidities, always maintaining a high efficacy and tolerability. Several studies have shown a close association between HCV clearance by DAAs and an improvement or reduction in the risk of extrahepatic manifestations. Patients with HCV after a sustained virologic response (SVR) by DAA treatment have a lower risk than non-responders of developing cryoglobulinemic vasculitis and B-cell non-Hodgkin's lymphomas. Furthermore, the SVR by DAA also reduces the risk of acute coronary syndrome, cardiovascular disease, insulin resistance and type 2 diabetes, and it improves atherosclerosis. HCV clearance by DAA also improves the quality of life and survival of patients with chronic HCV infection with associated extrahepatic diseases. Thus, DAAs should be initiated as early as possible in HCV patients with extrahepatic manifestations.
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Affiliation(s)
- Cesare Mazzaro
- Clinical Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy;
| | - Luca Quartuccio
- Rheumatology Clinic Department of Medicine (DAME), ASUFC, University of Udine, 34100 Udine, Italy;
| | - Luigi Elio Adinolfi
- Unit Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, 80100 Naples, Italy; (L.E.A.); (R.N.)
| | - Dario Roccatello
- Unit of Nefrology and Dialysis, Department of Clinical and Biological Sciences, San Giovanni Bosco Hospital, University of Turin,10092 Turin, Italy;
| | - Gabriele Pozzato
- Department of Clinical and Surgical Sciences, Maggiore Hospital University of Trieste, 34121 Trieste, Italy;
| | - Riccardo Nevola
- Unit Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, 80100 Naples, Italy; (L.E.A.); (R.N.)
| | - Maurizio Tonizzo
- Department of Internal Medicine Pordenone General Hospital, 33170 Pordenone, Italy;
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50100 Florence, Italy;
| | - Pietro Andreone
- Unit of Internal Medicine and Metabolic Medicine, University Hospital Moidena and Reggio Emilia, 41100 Modena, Italy;
| | - Valter Gattei
- Clinical Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy;
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13
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Torre P, Aglitti A, Masarone M, Persico M. Viral hepatitis: Milestones, unresolved issues, and future goals. World J Gastroenterol 2021; 27:4603-4638. [PMID: 34366625 PMCID: PMC8326259 DOI: 10.3748/wjg.v27.i28.4603] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
In this review the current overall knowledge on hepatitis A, B, C, D, and E will be discussed. These diseases are all characterized by liver inflammation but have significant differences in distribution, transmission routes, and outcomes. Hepatitis B virus and hepatitis C virus are transmitted by exposure to infected blood, and in addition to acute infection, they can cause chronic hepatitis, which in turn can evolve into cirrhosis. It is estimated that more than 300 million people suffer from chronic hepatitis B or C worldwide. Hepatitis D virus, which is also transmitted by blood, only affects hepatitis B virus infected people, and this dual infection results in worse liver-related outcomes. Hepatitis A and E spread via the fecal-oral route, which corresponds mainly to the ingestion of food or water contaminated with infected stools. However, in developed countries hepatitis E is predominantly a zoonosis. Although hepatitis A virus and hepatitis E virus are usually responsible for a self-limiting hepatitis, a serious, rarely fatal illness is also possible, and in immunosuppressed patients, such as organ transplant recipients, hepatitis E virus infection can become chronic. The description of goals achieved, unresolved issues, and the latest research on this topic may make it possible to speculate on future scenarios in the world of viral hepatitis.
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Affiliation(s)
- Pietro Torre
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
| | - Andrea Aglitti
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
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14
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Alkrekshi A, Kassem A, Park C, Tse W. Risk of Non-Hodgkin's Lymphoma in HCV Patients in the United States Between 2013 and 2020: A Population-Based Study. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:e832-e838. [PMID: 34330674 DOI: 10.1016/j.clml.2021.06.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/09/2021] [Accepted: 06/19/2021] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) is a significant healthcare problem affecting ~1% of the United States population. Meta-analyses of epidemiological studies reported a strong association between non-Hodgkin's lymphoma (NHL) and HCV. Direct oncogenic properties of HCV proteins and chronic antigenic stimulation are possible etiologies. We explored if NHL's prevalence has changed since older HCV therapy based on interferon that shared antiviral and anti-lymphoma properties was replaced with interferon-free direct-acting antivirals (DAA). We reviewed data from a nationwide database (Explorys, IBM) that aggregates records from 26 health-care-systems. We identified patients with chronic hepatitis C infection between June 2013 and June 2020. The control group was gender, race, and age-matched HCV-negative population. Statistical analysis used the odds ratio (OR) with P value <.001 for significance. There were 940 cases of NHL of 129,970 patients in the HCV group versus 107,480 cases of NHL of 37,961,970 in the control cohort [OR 2.6, 95% confidence interval (CI) 2.4-2.7]. A positive association was present for chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, non-Hodgkin T-cell lymphoma, and primary cutaneous T-cell lymphoma. There were no differences in Mantle cell lymphoma. The increased risk of HCV-associated lymphoma was persistent across genders, Caucasians and African-Americans, and age groups. While the risk of NHL in the HCV-negative population was higher in Caucasians than African-Americans (OR 1.8, 95% CI 1.7-1.8), the risk of HCV-associated NHL was not different. Further prospective studies examining the risk of HCV-associated lymphoma following DAA are warranted.
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Affiliation(s)
- Akram Alkrekshi
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH.
| | - Ahmad Kassem
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH
| | - Changsu Park
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH
| | - William Tse
- Department of Hematology and Oncology, The MetroHealth System campus of Case Western Reserve University, Cleveland, OH
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15
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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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16
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Ciancio A. Impact of Direct Antiviral Agents (DAAs) on B-cell Non Hodgkin's Lymphoma in patients with chronic hepatitis C. Minerva Gastroenterol (Torino) 2021; 67:227-233. [PMID: 33856146 DOI: 10.23736/s2724-5985.21.02834-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The relationship between HCV infection and extrahepatic manifestations has been demonstrated by epidemiological, clinical, immunological and pathological studies. Patients with HCV infection have an increased risk of morbidity and mortality related to these non-liver diseases. For these reasons, HCV chronic infection should be considered a systemic disease in which extrahepatic manifestations increase the severity of the disease. HCV-extrahepatic manifestations may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Over the past 5 years, treatment of chronic HCV infection in patients with hematologic malignancies has evolved rapidly and effective and safe direct-acting antivirals (DAAs) have become the standardof-care treatment. The choice of regimens with DAAs should be individualized after thorough assessment for potential hematologic toxic effects and drug-drug interactions. Elimination of HCV from infected cancer patients confers virologic, hepatic, and oncologic benefits.
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Affiliation(s)
- Alessia Ciancio
- Dipartimento di Scienze Mediche, Scuola di Medicina, Università degli Studi di Torino, Turin, Italy -
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17
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Affiliation(s)
- Patrice Cacoub
- From the Department of Internal Medicine and Clinical Immunology, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Centre de Référence des Maladies Auto-Immunes Systémiques Rares and Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose Inflammatoire, Institut National de la Santé et de la Recherche Médicale UMR S 959, Centre National de la Recherche Scientifique FRE3632, and the Inflammation-Immunopathology-Biotherapy Department, Sorbonne Université - all in Paris
| | - David Saadoun
- From the Department of Internal Medicine and Clinical Immunology, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Centre de Référence des Maladies Auto-Immunes Systémiques Rares and Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose Inflammatoire, Institut National de la Santé et de la Recherche Médicale UMR S 959, Centre National de la Recherche Scientifique FRE3632, and the Inflammation-Immunopathology-Biotherapy Department, Sorbonne Université - all in Paris
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18
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Nesterova E, Tanaschuk E, Abdurakhmanov D, Gemdzhian E, Kravchenko S, Mangasarova Y, Krasilnikova I, Bagova M. Safe and effective treatment of follicular lymphoma in patients with
HCV
‐infection. Hematol Oncol 2020; 38:604-606. [DOI: 10.1002/hon.2751] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/06/2020] [Accepted: 05/24/2020] [Indexed: 01/03/2023]
Affiliation(s)
| | | | | | - Eduard Gemdzhian
- National Research Center for Hematology Moscow Russian Federation
| | | | - Yana Mangasarova
- National Research Center for Hematology Moscow Russian Federation
| | | | - Madina Bagova
- National Research Center for Hematology Moscow Russian Federation
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19
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Sakai H, Miwa T, Ikoma Y, Hanai T, Nakamura N, Imai K, Kitagawa J, Shirakami Y, Kanemura N, Suetsugu A, Takai K, Shiraki M, Shimizu M. Development of diffuse large B-cell lymphoma after sofosbuvir-ledipasvir treatment for chronic hepatitis C: A case report and literature review. Mol Clin Oncol 2020; 13:1. [PMID: 32754315 PMCID: PMC7391802 DOI: 10.3892/mco.2020.2071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Recently, treatments for chronic hepatitis C virus (HCV) infection have significantly improved by the development of direct-acting antiviral agents (DAAs) and almost all patients with HCV can complete antiviral treatment without apparent adverse events. Malignant lymphoma, particularly B-cell non-Hodgkin's lymphoma, is one of the extrahepatic manifestations associated with chronic HCV infection. The effectiveness of anti-HCV therapy with DAAs for B-cell non-Hodgkin's lymphoma has been demonstrated in recent reports, whereas late-onset B-cell non-Hodgkin's lymphoma after HCV eradication with DAAs has occasionally been reported. In the present study, a 77-year-old man with chronic hepatitis C and intermediate liver cancer risk received sofosbuvir-ledipasvir treatment for 12 weeks. Two months following the end of antiviral therapy, he had achieved sustained virologic response for 8 weeks. However, the patient occasionally found swelling of the right cervical lymph nodes without any subjective symptoms. Lymph node biopsy revealed diffuse large B-cell lymphoma and whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography showed increased FDG uptake in the right cervical, right submandibular, mediastinal and mesenteric lymph nodes. The patient received six courses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and achieved complete response at 8 months after chemotherapy initiation. Thus, the development of lymphoid malignancies may arise, even after HCV eradication with DAAs. Therefore, clinicians should be aware of such risks during and after antiviral treatment with DAAs.
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Affiliation(s)
- Hiroyasu Sakai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Takao Miwa
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yoshikazu Ikoma
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Nobuhiko Nakamura
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Kenji Imai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Junichi Kitagawa
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yohei Shirakami
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Nobuhiro Kanemura
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Koji Takai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Makoto Shiraki
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
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20
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Villaume MT, Patel D, Lopez C, Patel V, Diggs P, Harmsen H, Thompson MA, Morgan D. Dural Marginal Zone Lymphoma in a Patient With a Hepatitis C Virus Infection. World J Oncol 2020; 11:122-125. [PMID: 32494320 PMCID: PMC7239576 DOI: 10.14740/wjon1285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 04/21/2020] [Indexed: 12/01/2022] Open
Abstract
Primary dural marginal zone lymphomas (MZLs) are exceptionally rare, with fewer than 100 cases reported to date. While the association between hepatitis C virus (HCV) infection and lymphoma is well established, it is unclear if this association extends to all anatomic sites. Here we report a case of dural MZL in a 61-year-old woman with an HCV infection. To our knowledge, this is the first report of a dural MZL associated with an HCV infection in an immunocompetent patient and was successfully treated with radiotherapy and rituximab. As such, future cases of primary MZL found in the dura should prompt consideration of co-infection with microbials such as HCV and upfront treatment with anti-virals should be considered.
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Affiliation(s)
- Matthew T Villaume
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dilan Patel
- Department of Hematology and Bone Marrow Transplant, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christine Lopez
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Vivek Patel
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Pauleatha Diggs
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Hannah Harmsen
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mary Ann Thompson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - David Morgan
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Hematology and Bone Marrow Transplant, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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21
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Azevedo MM, Pina-Vaz C, Baltazar F. Microbes and Cancer: Friends or Faux? Int J Mol Sci 2020; 21:ijms21093115. [PMID: 32354115 PMCID: PMC7247677 DOI: 10.3390/ijms21093115] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/23/2020] [Accepted: 04/26/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the most aggressive and deadly diseases in the world, representing the second leading cause of death. It is a multifactorial disease, in which genetic alterations play a key role, but several environmental factors also contribute to its development and progression. Infections induced by certain viruses, bacteria, fungi and parasites constitute risk factors for cancer, being chronic infection associated to the development of certain types of cancer. On the other hand, susceptibility to infectious diseases is higher in cancer patients. The state of the host immune system plays a crucial role in the susceptibility to both infection and cancer. Importantly, immunosuppressive cancer treatments increase the risk of infection, by decreasing the host defenses. Furthermore, alterations in the host microbiota is also a key factor in the susceptibility to develop cancer. More recently, the identification of a tumor microbiota, in which bacteria establish a symbiotic relationship with cancer cells, opened a new area of research. There is evidence demonstrating that the interaction between bacteria and cancer cells can modulate the anticancer drug response and toxicity. The present review focuses on the interaction between microbes and cancer, specifically aiming to: (1) review the main infectious agents associated with development of cancer and the role of microbiota in cancer susceptibility; (2) highlight the higher vulnerability of cancer patients to acquire infectious diseases; (3) document the relationship between cancer cells and tissue microbiota; (4) describe the role of intratumoral bacteria in the response and toxicity to cancer therapy.
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Affiliation(s)
- Maria Manuel Azevedo
- Department of Microbiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- CINTESIS, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Agrupamento de Escolas D. Maria II, 4760-067 V.N. Famalicão, Portugal
- Correspondence: ; Tel.: +351-22-551-36
| | - Cidália Pina-Vaz
- Department of Microbiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- CINTESIS, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4835-258 Guimarães, Portugal
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22
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Nyberg AH, Sadikova E, Cheetham C, Chiang KM, Shi JX, Caparosa S, Younossi ZM, Nyberg LM. Increased cancer rates in patients with chronic hepatitis C. Liver Int 2020; 40:685-693. [PMID: 31755208 DOI: 10.1111/liv.14305] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023]
Abstract
AIMS As previous reports show an association of chronic hepatitis C (HCV) with hepatocellular carcinoma (HCC) and non-liver cancers, we examine the association of HCV with liver cancer and non-liver cancers. METHODS Retrospective cross-sectional study at Kaiser Permanente Southern California (KPSC) evaluating HCV and non-HCV patients from 1 January 2008 to 12 December 2012. Cancer diagnoses were obtained from the KPSC-SEER-affiliated registry. Logistic regression analyses were used for rate ratios and time-to-event analyses were performed using Cox proportional hazards models, adjusted for age, gender, race, smoking and cirrhosis. Cancer rate ratios were stratified by tobacco, alcohol abuse, diabetes and body mass index (BMI). RESULTS The initial population and final population of multivariable analysis were N = 5 332 903 and N = 2 080 335 respectively. Cancer burden (all sites) was significantly higher in HCV than in non-HCV patients and HCV patients had a high rate of liver cancer. When liver cancer was excluded, cancer rates remained significantly increased in HCV. Unadjusted cancer rates were significantly higher in HCV compared to non-HCV for oesophageal, stomach, colorectal, pancreas, myeloma, non-Hodgkin's lymphoma, head/neck, lung, renal and prostate cancer. After stratification for alcohol abuse, tobacco, diabetes and BMI, increased cancer rates remained significant for all cancer sites, liver cancer and non-Hodgkin's lymphoma. Multivariable analyses demonstrated a strong correlation between cirrhosis and cancer. Tobacco use and diabetes were also associated with cancer. In the absence of cirrhosis, HCV, tobacco use and diabetes significantly increased the cancer risk. Mediation analyses showed that cirrhosis was responsible for a large proportion on the effect of HCV on cancer risk. CONCLUSION This study supports the concept of HCV as a systemic illness and treating HCV regardless of disease severity and prior to progression to cirrhosis.
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Affiliation(s)
- Anders H Nyberg
- Hepatology Research, Kaiser Permanente Southern California, San Diego, CA, USA
| | | | | | - Kevin M Chiang
- Pharmacy Analytical Services, Kaiser Permanente Southern California, Downey, CA, USA
| | - Jiaxiao X Shi
- Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
| | - Susan Caparosa
- Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
| | - Zobair M Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA
| | - Lisa M Nyberg
- Hepatology Research, Kaiser Permanente Southern California, San Diego, CA, USA
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Hepatitis C virus and risk of extrahepatic malignancies: a case-control study. Sci Rep 2019; 9:19444. [PMID: 31857595 PMCID: PMC6923417 DOI: 10.1038/s41598-019-55249-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Epidemiological studies have demonstrated an increased risk of non-Hodgkin lymphoma (NHL) in patients with chronic hepatitis C virus (HCV) infection. Therefore, we investigated the risk of extrahepatic malignancies associated with HCV infection. Inpatients diagnosed with lymphoma, breast, thyroid, kidney, or pancreatic cancer (research group, n = 17,925) as well as inpatients with no malignancies (control group, n = 16,580) matched by gender and age were enrolled from The First Affiliated Hospital of Nanjing Medical University between January 2008 and December 2016. A case-control study was conducted by retrospective analysis. The difference in HCV prevalence was analyzed between the research group and the control group. Also, the research group was compared to the 2006 National Hepatitis C sero-survey in China. A total of 86 cases were positive for anti-HCV in the research group. Compared with the control group (103 cases were anti-HCV positive), no significant associations between extrahepatic malignancies and HCV infection were observed. Meanwhile, compared to the 2006 National Hepatitis C sero-survey, we observed a significant association between the chronic lymphoma leukemia/small lymphocytic lymphoma (CLL/SLL) and HCV seropositivity in females in the research group aged 1–59 years old (OR = 14.69; 95% CI, 1.94–111.01). HCV infection had a potential association with CLL/SLL in females aged 1–59 years old. Our study did not confirm an association between HCV infection and the risk of extrahepatic malignancies. In regions with a low HCV prevalence, the association between HCV infection and extrahepatic malignancies needs further investigation.
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24
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Ioannou GN, Green PK, Berry K, Graf SA. Eradication of Hepatitis C Virus Is Associated With Reduction in Hematologic Malignancies: Major Differences Between Interferon and Direct-Acting Antivirals. Hepatol Commun 2019; 3:1124-1136. [PMID: 31388632 PMCID: PMC6671776 DOI: 10.1002/hep4.1389] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 05/17/2019] [Indexed: 12/15/2022] Open
Abstract
It is unclear whether eradication of hepatitis C virus (HCV) leads to a reduction in the risk of hematologic malignancies. We aimed to determine the impact of sustained virologic response (SVR) induced by either direct-acting antivirals (DAAs) or interferon (IFN) on the risk of hematologic malignancies. We identified 69,581 patients who initiated antiviral treatment in the Veterans Affairs national health care system from January 1, 1999, to December 31, 2015, including 40,410 (58%) IFN-only regimens, 4,546 (6.5%) DAA + IFN regimens, and 24,625 (35%) DAA-only regimens. We retrospectively followed patients to identify incident cases of hematologic malignancies or monoclonal gammopathy of unknown significance (MGUS), a premalignant precursor of multiple myeloma. Among patients treated with IFN, SVR was significantly associated with a reduction in the risk of lymphoma (adjusted hazard ratio [AHR], 0.70; 95% confidence interval [CI], 0.51-0.97), multiple myeloma (AHR, 0.40; 95% CI, 0.20-0.77), MGUS (AHR, 0.65; 95% CI, 0.42-0.99), or all hematologic malignancies and MGUS combined (AHR, 0.67; 95% CI, 0.53-0.84) over a mean follow-up of 10.6 years. In contrast, among patients treated with DAA, SVR was not associated with the risk of lymphoma, multiple myeloma, MGUS, or all hematologic malignancies and MGUS combined (AHR, 1.08; 95% CI, 0.66-1.78) during a mean follow-up of 2.9 years. Neither IFN-induced SVR nor DAA-induced SVR was associated with risk of colon cancer or prostate cancer, which were chosen a priori as comparison/control malignancies. Conclusion: We describe novel strong associations between IFN-induced SVR and lymphoma, multiple myeloma, MGUS, and all hematologic malignancies combined. Surprisingly, these associations were not observed with DAA-induced SVR.
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Affiliation(s)
- George N. Ioannou
- Division of Gastroenterology, Department of MedicineVeterans Affairs Puget Sound Health Care System and University of WashingtonSeattleWA
- Research and DevelopmentVeterans Affairs Puget Sound Health Care SystemSeattleWA
| | - Pamela K. Green
- Research and DevelopmentVeterans Affairs Puget Sound Health Care SystemSeattleWA
| | - Kristin Berry
- Research and DevelopmentVeterans Affairs Puget Sound Health Care SystemSeattleWA
| | - Solomon A. Graf
- Division of Oncology, Department of MedicineVeterans Affairs Puget Sound Health Care System and University of WashingtonSeattleWA
- Clinical Research DivisionFred Hutch Cancer Research CenterSeattleWA
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25
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Masarone M, Persico M. Hepatitis C virus infection and non-hepatocellular malignancies in the DAA era: A systematic review and meta-analysis. Liver Int 2019; 39:1292-1306. [PMID: 30983083 DOI: 10.1111/liv.14119] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/12/2019] [Accepted: 04/05/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Direct antiviral agents have greatly improved therapeutic options for chronic hepatitis C. Indeed, former "difficult-to-treat" patients can now be treated and can achieve sustained response. Hepatitis C virus (HCV) is associated with hepatocellular carcinoma and with B-cell non-Hodgkin lymphoma (B-NHL). Other malignancies have been reported to be associated with HCV infection albeit with various grades of evidence. Antineoplastic treatment is often reduced or suspended in HCV-positive cancer patients to avoid "HCV reactivation." In this setting, antiviral therapy combined with antineoplastic protocols may improve the outcome. For this reason, we conducted a systematic review and a meta-analysis to update the association between HCV infection and non-hepatocellular malignancies, and to shed light on the effects exerted by antiviral treatment on the natural history of oncological diseases. METHODS Relevant studies were identified by searching PUBMED, EMBASE and MEDLINE up to 1 August 2018. Pooled risk estimates were calculated with random-effects models according to PRISMA guidelines. RESULTS A total of 58 studies were included in the analysis: 27 studies of the association between HCV and B-NHL(OR 3.36; 95% CI 2.40-4.72;P < 0.00001);13 studies of the association between sustained virological response and progression-free survival (PFS) in B-NHL patients(OR 9.34; 95% CI 4.90-17.79; P < 0.00001); 13 studies of the association between HCV and intrahepatic-cholangio-carcinoma (OR 3.95;95% CI 2.25-6.94; P < 0.00001); and 5 studies of the association between HCV infection and pancreatic adeno-carcinoma(OR 1.60; 95% CI:1.25-2.04; P = 0.0002). CONCLUSIONS This study updates the strong association between B-NHL and HCV infection, confirms the association between HCV and non-hepatocellular tumours, and demonstrates a very strong association between viral eradication and a better outcome of HCV-positive B-NHL.
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Affiliation(s)
- Mario Masarone
- Internal Medicine and Hepatology Unit, University of Salerno, Salerno, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, University of Salerno, Salerno, Italy
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26
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Kuna L, Jakab J, Smolic R, Wu GY, Smolic M. HCV Extrahepatic Manifestations. J Clin Transl Hepatol 2019; 7:172-182. [PMID: 31293918 PMCID: PMC6609844 DOI: 10.14218/jcth.2018.00049] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 02/21/2019] [Accepted: 03/17/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) has been shown to affect many tissues other than liver. However, of the many extrahepatic manifestations (EMs) that have been associated with HCV, including cryoglobulinemia, lymphoma, insulin resistance, type 2 diabetes and neurological disorders, only a few have been shown to be directly related to HCV infection of extrahepatic tissues. HCV-triggered immune-mediated mechanisms account for most of the EMs. It is estimated that up to 74% of patients with chronic hepatitis C can develop at least one EM. All HCV patients with EMs should be considered for antiviral therapy, although not all will resolve with sustained virological response.
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Affiliation(s)
- Lucija Kuna
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Jelena Jakab
- Department of Pathophysiology and Physiology with Immunology, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Internal Medicine, Faculty of Medicine, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Robert Smolic
- Department of Pathophysiology and Physiology with Immunology, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - George Y Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, Osijek, Croatia
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27
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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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Gutiérrez-Saborido D, Gutiérrez-Valencia A, González Domenech CM, López Ruz MÁ, Raffo Márquez M, Omar M, Girón-González JA. Incidence of lymphoma in HIV-HCV-infected patients. Modifications in function of the anti-hepatitis C virus therapy. Ann Hematol 2019; 98:1953-1959. [PMID: 31025161 DOI: 10.1007/s00277-019-03700-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 04/15/2019] [Indexed: 12/13/2022]
Abstract
The change in the incidence of lymphomas in function of the presence or absence of sustained virological response after anti-hepatitis C therapy in a cohort of human immunodeficiency (HIV)-hepatitis C (HCV) viruses coinfected patients was analyzed. A prospective cohort of 755 HIV-HCV coinfected patients who received their first anti-HCV therapy, based on interferon + ribavirin schemas, was evaluated. Incidence and histologic types of lymphomas were analyzed in two periods: (1) before administration of anti-HCV therapy and (2) after anti-HCV therapy. The association between lymphoma incidence and demographic, HIV- (minimum CD4+ cell count and CD4+ cell count at diagnosis of lymphoma, antiretroviral therapy, maximal HIV load and HIV load at diagnosis of lymphoma) and HCV-related variables (HCV load, genotype, sustained viral response to anti-HCV therapy) were analyzed. A total of 13 lymphomas [incidence rate (95% confidence interval), 0.72 (0.33-1.11) × 1000 person-years, time from HIV diagnosis to lymphoma diagnosis (median, interquartile range), 15 (11-19) years] were diagnosed. Nine of them were non-Hodgkin and four Hodgkin lymphomas. The median CD4+ T cell count at diagnosis of lymphoma was 457/mm3, with only two cases with values lower than 200/mm3. The incidence rate of non-Hodgkin lymphomas was similar pre- and post-anti HCV therapy [0.33 (0.00-0.65) vs 0.68 (0.08-1.26) × 1000 person-years, respectively, p > 0.05]. Patients with sustained virologic HCV response showed similar incidence rate of lymphomas than that of those without anti-HCV response. In conclusion, anti-HCV therapy does not modify the incidence rate of lymphomas in HIV-HCV coinfected patients.
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Affiliation(s)
- Daniel Gutiérrez-Saborido
- Unidad de Enfermedades Infecciosas. Hospital Universitario Puerta del Mar. Facultad de Medicina, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Avda Ana de Viya s/n, 11009, Cádiz, Spain
| | - Alicia Gutiérrez-Valencia
- Enfermedades Infecciosas, Microbiología y Medicina Preventiva. Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Carmen María González Domenech
- Hospital Universitario Virgen de la Victoria, Málaga. Departamento de Microbiología, Facultad de Farmacia, Universidad de Granada, Granada, Spain
| | - Miguel Ángel López Ruz
- Unidad Enfermedades Infecciosas, Facultad de Medicina. IBS, Hospital Universitario Virgen Nieves, Granada, Spain
| | | | - Mohamed Omar
- Unidad de Enfermedades Infecciosas, Complejo Hospitalario de Jaén, Jaén, Spain
| | - José Antonio Girón-González
- Unidad de Enfermedades Infecciosas. Hospital Universitario Puerta del Mar. Facultad de Medicina, Instituto para la Investigación e Innovación en Ciencias Biomédicas de Cádiz (INiBICA), Universidad de Cádiz, Avda Ana de Viya s/n, 11009, Cádiz, Spain.
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Shimono J, Miyoshi H, Arakawa F, Yamada K, Sugio T, Miyawaki K, Eto T, Miyagishima T, Kato K, Nagafuji K, Akashi K, Teshima T, Ohshima K. Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma. Ann Hematol 2019; 98:1197-1207. [PMID: 30729289 DOI: 10.1007/s00277-019-03628-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 01/29/2019] [Indexed: 11/26/2022]
Abstract
The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.
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Affiliation(s)
- Joji Shimono
- Department of Pathology, Kurume University, School of Medicine, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Hiroaki Miyoshi
- Department of Pathology, Kurume University, School of Medicine, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan.
| | - Fumiko Arakawa
- Department of Pathology, Kurume University, School of Medicine, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan
| | - Kyohei Yamada
- Department of Pathology, Kurume University, School of Medicine, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan
| | - Takeshi Sugio
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | | | - Koji Kato
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Koji Nagafuji
- Department of Hematology, Kurume University, School of Medicine, Kurume, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Koichi Ohshima
- Department of Pathology, Kurume University, School of Medicine, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan
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Su TH, Liu CJ, Tseng TC, Chou SW, Liu CH, Yang HC, Wu SJ, Chen PJ, Chen DS, Chen CL, Kao JH. Early antiviral therapy reduces the risk of lymphoma in patients with chronic hepatitis C infection. Aliment Pharmacol Ther 2019; 49:331-339. [PMID: 30592071 DOI: 10.1111/apt.15101] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 01/26/2018] [Accepted: 11/27/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic hepatitis C infection is linked to lymphoma development. AIM To investigate whether antiviral therapy prevents the risk of HCV-related lymphoma. METHODS Patients diagnosed with chronic hepatitis C were retrieved from the Taiwan National Health Insurance Research Database during 2004-2012. We included patients who received pegylated interferon and ribavirin (PegIFN/RBV) antiviral therapy for ≥24 weeks (PegIFN/RBV cohort) or hepatoprotectants for ≥90 days without antiviral therapy (HCV-untreated cohort). Both cohorts were matched by age, sex, and comorbidities through propensity scores and followed for newly diagnosed lymphoma or non-Hodgkin's lymphoma (NHL). RESULTS In total, 24 133 patients were included in both the PegIFN/RBV and HCV-untreated cohort. The lymphoma incidence was significantly higher in the untreated than in the treated cohort (66.48 vs 43.34 per 100 000 person-years, P = 0.029). After adjusting for confounders, the patients who received PegIFN/RBV therapy were at a lower risk of developing lymphoma compared with the untreated patients (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.43-0.96, P = 0.030). Moreover, this beneficial effect was mainly observed in patients with chronic hepatitis C <60 years old with a relative risk reduction of 51% for all lymphoma (HR: 0.49, 95% CI: 0.29-0.82, P = 0.007) and 48% for non-Hodgkin's lymphoma (HR: 0.52, 95% CI: 0.30-0.91, P = 0.022). The risk of all lymphoma or non-Hodgkin's lymphoma development after antiviral therapy was lowered to that of subjects without HCV. CONCLUSIONS PegIFN/RBV-based antiviral therapy significantly reduced the risk of lymphoma, especially non-Hodgkin's lymphoma; the reduction was mostly among patients <60 years old. Early antiviral therapy for chronic hepatitis C is suggested.
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Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Wan Chou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shang-Ju Wu
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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31
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Ioannou GN, Feld JJ. What Are the Benefits of a Sustained Virologic Response to Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection? Gastroenterology 2019; 156:446-460.e2. [PMID: 30367836 DOI: 10.1053/j.gastro.2018.10.033] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 09/26/2018] [Accepted: 10/03/2018] [Indexed: 02/06/2023]
Abstract
Direct-acting antiviral (DAA) regimens are safe and effective at eradicating hepatitis C virus (HCV) infection. Unfortunately, DAAs remain expensive, so treatment of all HCV-infected patients would substantially affect health care costs. It is therefore important to continue to assess the hepatic and extrahepatic benefits of a DAA-induced sustained virologic response (SVR). A DAA-induced SVR reduces a patient's risk of cirrhosis and hepatocellular carcinoma and extrahepatic manifestations of HCV infection; there are also data to indicate that an SVR can reduce mortality. SVR is a relevant clinical end point, but further analyses are required to confirm its importance among diverse HCV-infected populations and to document the public health benefits of HCV elimination at the population level. We review the evidence for the benefits associated with SVRs in different clinical settings and challenges to data collection.
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Affiliation(s)
- George N Ioannou
- Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington; Department of Medicine, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington; Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, Washington.
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada
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Cacoub P, Comarmond C. Considering hepatitis C virus infection as a systemic disease. Semin Dial 2018; 32:99-107. [PMID: 30549107 DOI: 10.1111/sdi.12758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection has been demonstrated to result in several adverse hepatic outcomes and has been associated with a number of important extrahepatic manifestations. The scope of extrahepatic clinical possibilities includes systemic diseases such as vasculitis and lymphoproliferative disorders, cardiovascular disease, myalgia, arthritis, and sicca syndrome. These end-organ effects of HCV may dominate the clinical course beyond the hepatic complications and significantly worsen the long-term prognosis of infected patients. Until several years ago, the standard of care for the treatment of HCV infection had been interferon-alpha-based regimens, which not only had limited effectiveness in achieving a cure but were often poorly tolerated, especially in patients with kidney disease. In those HCV-infected patients with significant systemic manifestations, the interferon-based regimens were problematic given their association with a wide variety of toxicities. The development of highly effective direct-acting antiviral agents to treat HCV infection presented an opportunity to improve the HCV care cascade with the eradication of HCV in most infected patients and by reducing the burden of both hepatic and extrahepatic complications.
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Affiliation(s)
- Patrice Cacoub
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Cloé Comarmond
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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Clinical practice: hepatitis C virus infection, cryoglobulinemia and cryoglobulinemic vasculitis. Clin Exp Med 2018; 19:1-21. [PMID: 30430284 DOI: 10.1007/s10238-018-0536-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 10/25/2018] [Indexed: 02/06/2023]
Abstract
Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 °C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as cryoglobulinemic vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non-Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-α alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible.
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Shahini E, Iannone A, Romagno D, Armandi A, Carparelli S, Principi M, Viggiani MT, Ierardi E, Di Leo A, Barone M. Clinical relevance of serum non-organ-specific antibodies in patients with HCV infection receiving direct-acting antiviral therapy. Aliment Pharmacol Ther 2018; 48:1138-1145. [PMID: 30375693 DOI: 10.1111/apt.14999] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 07/26/2018] [Accepted: 09/05/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is associated with production of different serum non-organ-specific antibodies (NOSA) and risk for developing autoimmune disorders. The clinical significance of these phenomena is not fully understood. AIM To assess non-organ-specific antibodies before and 24 weeks after the end of therapy with direct-acting antivirals in patients with HCV-related infection, to better clarify the clinical relevance of these antibodies in terms of treatment response and prognostic value. METHODS Patients enrolled (191) were considered non-organ-specific antibody-positive for titres ≥1:40 on at least two determinations before treatment. RESULTS At baseline, 46 patients were positive and 145 were negative for autoantibodies. The prevalence of autoimmune thyroiditis was significantly higher in non-organ-specific antibody-positive group than non-organ-specific antibody-negative group (P = 0.02). HCV-RNA 24 weeks after the end of antiviral therapy was 100% negative in patients with antibodies positivity and 98.6% in antibody-negative patients (P = 1.0). In the former group, autoantibodies disappeared in 30 of 46 patients (65.2%). On multivariate analysis, non-organ-specific antibody-negativity was significantly reduced in patients with hepatic hilar lymphadenopathy (OR = 0.17; 95% CI 0.02-0.94, P = 0.04). None of the adverse events occurring during antiviral therapy was related to autoimmune disorders. CONCLUSIONS Hepatitis C virus clearance frequently reduces non-organ-specific antibody positivity suggesting that they represent an epiphenomenon of the viral infection. However, in patients who did not become negative, long-term monitoring would establish whether they could hide an underlying process that may progress into a clear autoimmune or rheumatologic disease. (Trial registration number: NCT03566966).
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Andrea Iannone
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Domenico Romagno
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Angelo Armandi
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Sonia Carparelli
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Mariabeatrice Principi
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Maria Teresa Viggiani
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Enzo Ierardi
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Alfredo Di Leo
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
| | - Michele Barone
- Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy
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Crespi M, Demarzo MG, Brunacci M, Pellegatta G, Ferrando F, Ballestrero A, Grillo F, Savarino V, Giannini EG. Improvement in Waldenström's Macroglobulinemia after Successful Treatment of HCV with Direct-acting Antivirals. Ann Hepatol 2018; 17:1072-1077. [PMID: 30600285 DOI: 10.5604/01.3001.0012.7208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Chronic hepatitis C (HCV) virus infection may be associated with several non-hepatic manifestations, mainly driven by chronic immune stimulation, such as mixed cryoglobulinemia and Non-Hodgkin's Lymphoma. This association has been proved by several meta-analyses and some interventional studies demonstrating that antiviral treatment may be effective in inducing HCV-associated lymphoma regression. The recent advent of direct acting antivirals (DAAs) in the therapeutic armamentarium of HCV infection made possible treatment of patients with advanced liver disease. Here we report on a rare association of a cirrhotic patient with HCV and Waldenström's Macroglobulinemia with severe cryoglobulinemia, who had already failed an interferon-based antiviral regimen, whose haematologic disease was ameliorated by HCV eradication following treatment with sofosbuvir and simeprevir with ribavirin, and where successful treatment was accompanied also by consistent improvement in liver function and parameters of portal hypertension.
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Affiliation(s)
- Mattia Crespi
- Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Maria Giulia Demarzo
- Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Matteo Brunacci
- Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Gaia Pellegatta
- Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Fabio Ferrando
- Internal Medicine and Oncology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Alberto Ballestrero
- Internal Medicine and Oncology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Federica Grillo
- Pathology Unit, Department of Surgical Sciences, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Vincenzo Savarino
- Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Edoardo G Giannini
- Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Oncogenic Signaling Induced by HCV Infection. Viruses 2018; 10:v10100538. [PMID: 30279347 PMCID: PMC6212953 DOI: 10.3390/v10100538] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/29/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
The liver is frequently exposed to toxins, metabolites, and oxidative stress, which can challenge organ function and genomic stability. Liver regeneration is therefore a highly regulated process involving several sequential signaling events. It is thus not surprising that individual oncogenic mutations in hepatocytes do not necessarily lead to cancer and that the genetic profiles of hepatocellular carcinomas (HCCs) are highly heterogeneous. Long-term infection with hepatitis C virus (HCV) creates an oncogenic environment by a combination of viral protein expression, persistent liver inflammation, oxidative stress, and chronically deregulated signaling events that cumulate as a tipping point for genetic stability. Although novel direct-acting antivirals (DAA)-based treatments efficiently eradicate HCV, the associated HCC risk cannot be fully eliminated by viral cure in patients with advanced liver disease. This suggests that HCV may persistently deregulate signaling pathways beyond viral cure and thereby continue to perturb cancer-relevant gene function. In this review, we summarize the current knowledge about oncogenic signaling pathways derailed by chronic HCV infection. This will not only help to understand the mechanisms of hepatocarcinogenesis but will also highlight potential chemopreventive strategies to help patients with a high-risk profile of developing HCC.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
- Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
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Zubkin ML, Chervinko VI, Ovchinnikov YV, Kryukov EV, Kotenko ON. [Chronic hepatitis C virus infection: An internist's opinion (Part 1)]. TERAPEVT ARKH 2018. [PMID: 28635859 DOI: 10.17116/terarkh2016886105-113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Hepatitis C virus (HCV) infection results in not only chronic hepatitis and subsequent complications as liver cirrhosis and hepatocellular carcinoma, but also in a significant number of other diseases, the so-called extrahepatic manifestations of chronic HCV infection. This is because of viral hepatotropicity and lymphotropicity. The most striking example of the course of chronic HCV infection, in which the infectious and inflammatory processes are concurrent with autoimmune disorders and carcinogenesis, is mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma. The pathogenesis of these diseases is based on the clonal expansion of B cells, which occurs under their prolonged stimulation with the virus or viral proteins. Part 1 of this review is devoted to the analysis of a correlation of chronic HCV infection with lymphoproliferative and autoimmune disorders, as well as its association with kidney injury.
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Affiliation(s)
- M L Zubkin
- G.N. Gabrichevsky Moscow Research Institute for Epidemiology and Microbiology, Russian Federal Service for Supervision of Consumer Rights Protection and Human Welfare, Moscow, Russia; Branch, S.M. Kirov Military Medical Academy, Moscow, Russia
| | - V I Chervinko
- Branch, S.M. Kirov Military Medical Academy, Moscow, Russia
| | | | - E V Kryukov
- N.N. Burdenko Main Military Clinical Hospital, Moscow, Russia
| | - O N Kotenko
- City Clinical Hospital Fifty-Two, Moscow Healthcare Department, Moscow, Russia
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Hegazy MT, Allam WR, Hussein MA, Zoheir N, Quartuccio L, El-Khamisy SF, Ragab G. Increased genomic instability following treatment with direct acting anti-hepatitis C virus drugs. EBioMedicine 2018; 35:106-113. [PMID: 30139628 PMCID: PMC6156732 DOI: 10.1016/j.ebiom.2018.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 08/04/2018] [Accepted: 08/05/2018] [Indexed: 12/04/2022] Open
Abstract
Mixed Cryoglobulinemic Vasculitis (MCV) is a prominent extra-hepatic manifestation of Hepatitis C virus (HCV) infection. HCV has been reported to cause B-cell disorders and genomic instability. Here, we investigated B-cell activation and genome stability in HCV-MCV patients receiving the direct antiviral agent, Sofosbuvir, at multiple centers in Egypt. Clinical manifestations in HCV-MCV patients were improved at the end of treatment (EOT), such as purpura (100%), articular manifestations (75%) and neuropathy (68%). Eighteen patients (56%) showed vasculitis relapse after EOT. BAFF and APRIL were higher at EOT and continued to increase one year following treatment onset. Chromosomal breaks were elevated at EOT compared to baseline levels and were sustained at 3 and 6 months post treatment. We report increased expression of DNA genome stability transcripts such as topoisomerase 1 and TDP1 in HCV-MCV patients after treatment, which continued to increase at 12 months from treatment onset. This data suggest that B-cell activation and DNA damage are important determinants of HCV-MCV treatment outcomes.
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Affiliation(s)
- Mohamed Tharwat Hegazy
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | | | - Mohamed A Hussein
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Naguib Zoheir
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Luca Quartuccio
- Clinic of Rheumatology, Department of Medical Area (DAME), University Hospital "Santa Maria della Misericordia", University of Udine, Udine, Italy
| | - Sherif F El-Khamisy
- Center for Genomics, Zewail City of Science and Technology, Giza, Egypt; Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK.
| | - Gaafar Ragab
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
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Abstract
Infectious agents, such as HCV, account for ∼15% of human cancers. HCV infects not only hepatocytes but also extrahepatic cells. Chronic HCV infection can induce chronic inflammation with qualitative and quantitative alterations of the immune repertoire and tissue microenvironment, which could induce various neoplasias. Epidemiological studies and meta-analyses suggest an increased rate of extrahepatic cancers in patients with chronic HCV infection along with a higher risk of intrahepatic cholangiocarcinoma, pancreatic cancer and non-Hodgkin lymphoma (NHL), highlighting the need to screen for HCV infection in patients with these cancers. Development of B cell NHL has been associated with HCV infection, with a relative risk of ∼1.5. Direct transformation related to the presence of the virus and chronic antigenic stimulation are the two major non-exclusive mechanisms involved in HCV-related lymphomagenesis. HCV infection alters survival of patients with lymphoma, and sustained virologic response (SVR) substantially improves prognosis. Antiviral treatments might induce remission of indolent lymphoma when SVR is achieved even without chemotherapy, emphasizing the role of HCV in lymphomagenesis in this context. However, studies are needed to provide prospective evidence of a causal relationship between chronic HCV infection and other extrahepatic cancers and to determine whether the risk of extrahepatic cancers is reduced with SVR. In this Review, we report on recent studies analysing the risk of extrahepatic cancers associated with chronic HCV infection. Although there is no doubt regarding the direct and indirect causality between HCV and NHL, an increased risk of other cancers is less clear, with the exception of cholangiocarcinoma.
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Ponziani FR, Miele L, Tortora A, Furnari M, Bodini G, Pompili M, Gasbarrini A, Giannini EG. Treatment of early stage chronic hepatitis C virus infection. Expert Rev Clin Pharmacol 2018; 11:519-524. [PMID: 29498556 DOI: 10.1080/17512433.2018.1447923] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
INTRODUCTION Treatment of Hepatitis C Virus (HCV) with direct acting antivirals (DAAs) is able to achieve the cure of infection in almost the totality of patients, independently of the characteristics of the individual and the virus, using short treatment schedules, and without the need of ribavirin. The high cost of DAAs is the main limiting factor for universal treatment of HCV. However, there is a strong evidence that treatment of infection at the early stage of disease may be the most rewarding approach. Areas covered: This review evaluates the aspects underlying the benefit of treating chronic HCV infection at the early stage of disease. It outlines the considerations that have to be taken into account when planning treatment in patients with HCV and minimal liver disease, assessing the positive reflex of viral eradication on several HCV-associated extra-hepatic conditions such as the risk of lymphoma, insulin-resistance and glycaemic control, and renal function. Lastly, it also covers the improvement of patients' quality of life and the pharmaco-economic aspects associated with early treatment. Expert commentary: Treatment of patients with HCV and minimal liver disease is associated with a beneficial, pleiotropic effect of viral eradication that goes beyond the simplistic consideration of the improvement in liver disease-related outcomes.
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Affiliation(s)
- Francesca Romana Ponziani
- a Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico "A. Gemelli" , Catholic University of Rome , Rome , Italy
| | - Luca Miele
- a Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico "A. Gemelli" , Catholic University of Rome , Rome , Italy
| | - Annalisa Tortora
- a Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico "A. Gemelli" , Catholic University of Rome , Rome , Italy
| | - Manuele Furnari
- b Gastroenterology Unit, Department of Internal Medicine , University of Genoa, IRCCS Ospedale Policlinico San Martino , Genoa , Italy
| | - Giorgia Bodini
- b Gastroenterology Unit, Department of Internal Medicine , University of Genoa, IRCCS Ospedale Policlinico San Martino , Genoa , Italy
| | - Maurizio Pompili
- a Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico "A. Gemelli" , Catholic University of Rome , Rome , Italy
| | - Antonio Gasbarrini
- a Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico "A. Gemelli" , Catholic University of Rome , Rome , Italy
| | - Edoardo Giovanni Giannini
- b Gastroenterology Unit, Department of Internal Medicine , University of Genoa, IRCCS Ospedale Policlinico San Martino , Genoa , Italy
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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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Andrade XA, Paz LH, Nassar M, Oramas DM, Fuentes HE, Kovarik P, Mishra S, Singh A. Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy. Acta Haematol 2018; 139:77-80. [PMID: 29393087 DOI: 10.1159/000484653] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 10/25/2017] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Hepatitis C infection is highly prevalent worldwide and has a well-known association with B-cell lymphoid malignancies. Antiviral therapy has successfully decreased the rate of liver cirrhosis and improved the outcome in patients with hepatitis C-associated lymphomas. However, although there are a few case reports of aggressive lymphomas after successful hepatitis C therapy, the mechanism behind this association remains unclear. CASE PRESENTATION We present the case of a 55-year-old man with chronic hepatitis C infection and liver cirrhosis who received antiviral therapy with sofosbuvir and ribavirin and achieved a sustained complete virological response. One year after successful therapy, there was an unexplained decline of his liver function and atypical liver nodularity, which led to the diagnosis of a primary liver diffuse large B-cell lymphoma. DISCUSSION We review the evidence supporting possible mechanisms of lymphomagenesis after successful hepatitis C therapy, particularly involving late "second-hit" mutations after viral-induced DNA damage and antiviral therapy facilitating the emergence of latent malignant B-cell clones by decreasing local inflammation and immune surveillance. More reports may help elucidate any association between hepatitis C antiviral therapy and late lymphoid malignancies.
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Affiliation(s)
- Xavier A Andrade
- Department of Medicine, John H. Stroger Jr. Hospital, Chicago, IL, USA
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Persico M, Aglitti A, Caruso R, De Renzo A, Selleri C, Califano C, Abenavoli L, Federico A, Masarone M. Efficacy and safety of new direct antiviral agents in hepatitis C virus-infected patients with diffuse large B-cell non-Hodgkin's lymphoma. Hepatology 2018; 67:48-55. [PMID: 28714143 DOI: 10.1002/hep.29364] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/29/2017] [Accepted: 07/07/2017] [Indexed: 12/18/2022]
Abstract
UNLABELLED The association of hepatitis C virus (HCV) with non-Hodgkin's lymphoma (NHL) has been demonstrated throughout the world. The new interferon-free direct antiviral agents (DAAs) showed high efficacy and safety, and preliminary data seem to confirm their activity on low-grade NHL. The question arises as whether or not-and how-to treat the HCV-positive patients suffering from diffuse large B-cell lymphomas (DLBCLs). The aim of this observational study was to evaluate whether DAA antiviral treatment of DLBCL/HCV-infected patients in concomitance with chemotherapy is a safe and effective option. Twenty (13 males and 7 females) HCV genotype 1b-positive subjects, undergoing chemotherapy for DLBCL, were enrolled between June 2015 and December 2015. After informed consent, all patients underwent antiviral therapy (AVT) with sofosbuvir/ledipasvir and chemotherapy (14 rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and 6 cyclophosphamide, doxorubicin, vincristine, and prednisone) for DLBCL. Complete hematological (Revised European-American Lymphoma classification, Ann Arbor, and International Prognostic Index [IPI] scores) and hepatological (viral markers, liver stiffness, and biochemical parameters) evaluations were made. A historical retrospective cohort of 101 DLBCL/HCV-positive patients not undergoing AVT was enrolled for comparison. DAA-treated and untreated patients were similar for sex distribution, IPI score, and NHL stage, and differed for age (older in treated), chemotherapy and use of AVT. Overall survival (OS) and disease-free survival (DFS) were evaluated among a 52-week of follow-up. No statistical difference was found in OS after 52 weeks (P = 0.122), whereas a statistically significant higher DFS was achieved in treated patients (P = 0.036). At the multivariate analysis, only IPI score and AVT were independently correlated with a better DFS. No differences in adverse events were reported. CONCLUSION DAA treatment in concomitance with chemotherapy was shown to be safe and effective in influencing remission of aggressive lymphomas in HCV patients. (Hepatology 2018;67:48-55).
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Affiliation(s)
- Marcello Persico
- Internal Medicine and Hepatology Unit, University of Salerno, Salerno, Italy
| | - Andrea Aglitti
- Internal Medicine and Hepatology Unit, University of Salerno, Salerno, Italy
| | - Rosa Caruso
- Internal Medicine and Hepatology Unit, University of Salerno, Salerno, Italy
| | - Amalia De Renzo
- Hematology Department, Federico Secondo University of Naples, Naples, Italy
| | | | - Catello Califano
- Hematology Department, Umberto I Hospital, Nocera Inferiore (Salerno), Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, University of Campania "Luigi Vanvitelli, Naples, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, University of Salerno, Salerno, Italy
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44
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Kanakry JA, Ambinder RF. Virus-Associated Lymphoma. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00083-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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45
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Ferri C, Feld JJ, Bondin M, Cacoub P. Expert opinion on managing chronic HCV in patients with non-Hodgkin lymphoma and other extrahepatic malignancies. Antivir Ther 2018; 23:23-33. [PMID: 30451149 DOI: 10.3851/imp3250] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2018] [Indexed: 02/07/2023]
Abstract
HCV is a carcinogen that is well established as a major risk factor for hepatocellular carcinoma. Evidence that HCV plays a role in the development of extrahepatic malignancies is less robust; however, epidemiological studies have consistently demonstrated an association between HCV infection and B-cell non-Hodgkin lymphoma (NHL). The strongest evidence for a link between HCV and tumourigenesis is the clear association between viral eradication, as indicated by achievement of sustained virological response, and remission of B-cell NHL. All-oral direct-acting antiviral-based therapies are effective in patients with HCV-associated NHL and well tolerated. For this reason, it is important that clinicians assess HCV-infected patients for HCV-associated extrahepatic malignancies so patients can receive timely diagnosis and treatment.
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Affiliation(s)
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | | | - Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France
- INSERM, UMR_S 959, F-75013, Paris, France
- CNRS, FRE3632, F-75005, Paris, France
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France
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Shimono J, Miyoshi H, Kato T, Sugio T, Miyawaki K, Kamimura T, Miyagishima T, Eto T, Imaizumi Y, Kato K, Nagafuji K, Akashi K, Seto M, Teshima T, Ohshima K. Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma. Oncotarget 2017; 9:1717-1725. [PMID: 29416725 PMCID: PMC5788593 DOI: 10.18632/oncotarget.23138] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 11/13/2017] [Indexed: 01/08/2023] Open
Abstract
Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin <120 g/l, elevated lactate dehydrogenase level, and high-risk categorization of Follicular Lymphoma International Prognostic Index (FLIPI) than in patients with HCV-negative FL. Overall survival and progression-free survival were poorer in patients with HCV-positive FL than in those with HCV-negative FL (p < 0.0001 and 0.006, respectively). Also, multivariate analysis revealed that positive HCV antibody was a poor prognostic factor of OS. In conclusion, HCV-positive FL has unique clinical features and may have a great impact on the overall survival of affected patients.
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Affiliation(s)
- Joji Shimono
- Department of Pathology, Kurume University, School of Medicine, Kurume, Japan.,Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Hiroaki Miyoshi
- Department of Pathology, Kurume University, School of Medicine, Kurume, Japan
| | - Takeharu Kato
- Department of Hematology, Sasebo City General Hospital, Sasebo, Japan.,Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Takeshi Sugio
- Department of Medicine and Biosystemic Science, Kyushu University Faculty of Medicine, Fukuoka, Japan
| | - Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Kyushu University Faculty of Medicine, Fukuoka, Japan
| | | | | | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Yoshitaka Imaizumi
- Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Koji Kato
- Department of Medicine and Biosystemic Science, Kyushu University Faculty of Medicine, Fukuoka, Japan
| | - Koji Nagafuji
- Department of Hematology, Kurume University, School of Medicine, Kurume, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Faculty of Medicine, Fukuoka, Japan
| | - Masao Seto
- Department of Pathology, Kurume University, School of Medicine, Kurume, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Koichi Ohshima
- Department of Pathology, Kurume University, School of Medicine, Kurume, Japan
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Torres HA, Shigle TL, Hammoudi N, Link JT, Samaniego F, Kaseb A, Mallet V. The oncologic burden of hepatitis C virus infection: A clinical perspective. CA Cancer J Clin 2017; 67:411-431. [PMID: 28683174 PMCID: PMC5591069 DOI: 10.3322/caac.21403] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 12/18/2022] Open
Abstract
Answer questions and earn CME/CNE Chronic hepatitis C virus (HCV) infection affects millions of people worldwide and is associated with cancer. Direct-acting antivirals (DAAs) have changed HCV treatment paradigms, but little is known about the management of HCV infection in patients with cancer. The substantial burden of HCV infection and the inconclusive evidence regarding its detection and management in patients with cancer prompted the authors to review the literature and formulate recommendations. Patients for whom HCV screening is recommended included all patients with hematologic malignancies, hematopoietic cell transplantation candidates, and patients with liver cancer. There is a lack of consensus-based recommendations for the identification of HCV-infected patients with other types of cancer, but physicians may at least consider screening patients who belong to groups at heightened risk of HCV infection, including those born during 1945 through 1965 and those at high risk for infection. Patients with evidence of HCV infection should be assessed by an expert to evaluate liver disease severity, comorbidities associated with HCV infection, and treatment opportunities. DAA therapy should be tailored on the basis of patient prognosis, type of cancer, cancer treatment plan, and hepatic and virologic parameters. HCV-infected patients with cancer who have cirrhosis (or even advanced fibrosis) and those at risk for liver disease progression, especially patients with HCV-associated comorbidities, should have ongoing follow-up, regardless of whether there is a sustained virologic response, to ensure timely detection and treatment of hepatocellular carcinoma. HCV infection and its treatment should not be considered contraindications to cancer treatment and should not delay the initiation of an urgent cancer therapy. CA Cancer J Clin 2017. © 2017 American Cancer Society. CA Cancer J Clin 2017;67:411-431. © 2017 American Cancer Society.
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Affiliation(s)
- Harrys A. Torres
- H. A. Torres: Department of Infectious Diseases, Infection Control
and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX,
USA
| | - Terri Lynn Shigle
- T. L. Shigle: Division of Pharmacy, Section of Clinical Pharmacy
Services, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nassim Hammoudi
- N. Hammoudi and V. Mallet: Université Paris
Descartes-Sorbonne Paris Cité; Assistance Publique-Hôpitaux de
Paris, Groupe Hospitalier Cochin Port Royal, Hepatology service; Institut National
de la Santé et de la Recherche Médicale unité 1223; Institut
Pasteur; all in Paris, France
| | - J. T. Link
- J. T. Link and A. Kaseb: Department of Gastrointestinal Medical
Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Felipe Samaniego
- F. Samaniego: Department of Lymphoma & Myeloma, The University
of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ahmed Kaseb
- J. T. Link and A. Kaseb: Department of Gastrointestinal Medical
Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vincent Mallet
- N. Hammoudi and V. Mallet: Université Paris
Descartes-Sorbonne Paris Cité; Assistance Publique-Hôpitaux de
Paris, Groupe Hospitalier Cochin Port Royal, Hepatology service; Institut National
de la Santé et de la Recherche Médicale unité 1223; Institut
Pasteur; all in Paris, France
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48
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van den Brand M, Scheijen B, Hess CJ, van Krieken JHJ, Groenen PJTA. Pathways towards indolent B-cell lymphoma - Etiology and therapeutic strategies. Blood Rev 2017; 31:426-435. [PMID: 28802906 DOI: 10.1016/j.blre.2017.08.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 05/07/2017] [Accepted: 08/04/2017] [Indexed: 02/06/2023]
Abstract
Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro-organisms, auto-immune diseases, and deregulated pathways caused by mutations. In particular, knowledge on the mutational landscape of indolent B-cell lymphomas has strongly increased in recent years and harbors great promise for more accurate decision making in the current wide range of therapeutic options. Despite this promise, only in chronic lymphocytic leukemia the detection of TP53 mutations and/or del17p currently have a direct effect on treatment decisions. Nevertheless, it is expected that in the near future the role of genetic testing will increase for prediction of response to targeted treatment as well as for more accurate prediction of prognosis in indolent B-cell lymphomas.
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MESH Headings
- Animals
- DNA Damage
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/etiology
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/microbiology
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Lymphoma, B-Cell/etiology
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/microbiology
- Lymphoma, B-Cell/therapy
- Lymphoma, B-Cell, Marginal Zone/etiology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/microbiology
- Lymphoma, B-Cell, Marginal Zone/therapy
- Lymphoma, Follicular/etiology
- Lymphoma, Follicular/genetics
- Lymphoma, Follicular/microbiology
- Lymphoma, Follicular/therapy
- Molecular Targeted Therapy/methods
- Mutation
- Signal Transduction
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Affiliation(s)
- Michiel van den Brand
- Department of Pathology, Radboud university medical center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands; Pathology-DNA, location Rijnstate, Wagnerlaan 55, 6815AD Arnhem, The Netherlands.
| | - Blanca Scheijen
- Department of Pathology, Radboud university medical center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands.
| | - Corine J Hess
- Department of Hematology, Radboud university medical center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands.
| | - J Han Jm van Krieken
- Department of Pathology, Radboud university medical center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands.
| | - Patricia J T A Groenen
- Department of Pathology, Radboud university medical center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands.
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Wong RJ, Saab S, Ahmed A. Extrahepatic Manifestations of Hepatitis C Virus After Liver Transplantation. Clin Liver Dis 2017; 21:595-606. [PMID: 28689596 DOI: 10.1016/j.cld.2017.03.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic hepatitis C virus (HCV) infection remains a leading cause of chronic liver disease in the United States. Although the hepatic impact of chronic HCV leading to cirrhosis and the need for liver transplantation is paramount, the extrahepatic manifestations of chronic HCV infection are equally important. In particular, a better understanding of the prevalence and impact of extrahepatic manifestations of chronic HCV infection in the post-liver transplant setting relies on understanding the interplay between the effects of chronic HCV infection in a posttransplant environment characterized by strong immunosuppression and the associated risks of this milieu.
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Affiliation(s)
- Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, 1411 East 31st Street, Highland Hospital - Highland Care Pavilion 5th Floor, Oakland, CA 94602, USA.
| | - Sammy Saab
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 200 UCLA Medical Plaza, Suite 214, Los Angeles, CA 90095, USA; Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, 200 UCLA Medical Plaza, Suite 214, Los Angeles, CA 90095, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 750 Welch Road, Suite # 210, Palo Alto, CA 94304, USA
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50
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Polo ML, Laufer N. Extrahepatic manifestations of HCV: the role of direct acting antivirals. Expert Rev Anti Infect Ther 2017; 15:737-746. [PMID: 28696154 DOI: 10.1080/14787210.2017.1354697] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations. This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions. Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.
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Affiliation(s)
- María Laura Polo
- a Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS) , Universidad de Buenos Aires- CONICET , Buenos Aires , Argentina
| | - Natalia Laufer
- a Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS) , Universidad de Buenos Aires- CONICET , Buenos Aires , Argentina
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