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Chang ML, Chang SW, Chen SC, Chien RN, Hsu CL, Chang MY, Fann CSJ. Genetic Association of Hepatitis C-Related Mixed Cryoglobulinemia: A 10-Year Prospective Study of Asians Treated with Antivirals. Viruses 2021; 13:464. [PMID: 33799903 PMCID: PMC7998980 DOI: 10.3390/v13030464] [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] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 12/16/2022] Open
Abstract
Genetic profiles of hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) in Asians remain elusive. A 10-year prospective cohort study was conducted with 1043 consecutive HCV Ab-positive Taiwanese surveyed with 13 single nucleotide polymorphisms (SNPs). Of 1043, 589 (56.5%) had baseline MC, 934 (89.5%) had positive HCV RNA, 796 completed anti-HCV therapy, and 715 had sustained virological responses (SVRs). SNP associations were surveyed withgenotypic, allelic, trend, permutation and multivariate analyses. At baseline, higher male sex and MC rates were noted in HCV RNA-positive than RNA-negative patients; higher female sex and positive HCV RNA rates but lower HCV RNA levels were noted in patients with than those without MC. Baseline associations were: HLA II-rs9461776 A allele, IFNL3-rs12979860 T allele, SERPINE1-rs6976053 C allele and MC with HCV RNA positivity; IFNL3-rs12979860 C allele, ARNTL-rs6486122 T allele and HCV RNA positivity with baseline MC. In SVR patients, RETN-rs1423096 C allele and SERPINE1-rs6976053 T allele were associated with 24-week and 10-year post-therapy MC, respectively. Conclusions: HCV RNA, IFNL3-rs12979860 and ARNTL-rs6486122 were associated with baseline MC; RETN-rs1423096 and SERPINE1-rs6976053 were associated with short- and long-term post-therapy MC in SVR patients, respectively. Links with HCV RNA and immune-associated SNPs suggest MC an immune reaction to expel HCV.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
| | - Su-Wei Chang
- Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyua 333423, Taiwan;
- Division of Allergy, Asthma, and Rheumatology, Department of Paediatrics, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University, Taipei 11031, Taiwan;
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
| | - Chia-Lin Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan;
| | - Ming-Yu Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
- Division of Pediatric Neurologic Medicine, Chang Gung Children’s Hospital, Taoyuan 333423, Taiwan
- Division of Pediatrics, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Cathy S. J. Fann
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan;
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Cusato J, Boglione L, De Nicolò A, Cardellino CS, Carcieri C, Cariti G, Di Perri G, D'Avolio A. Pharmacogenetic analysis of hepatitis C virus related mixed cryoglobulinemia. Pharmacogenomics 2017; 18:607-611. [PMID: 28453396 DOI: 10.2217/pgs-2016-0040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM Mixed cryoglobulinemia (MC) is an extra hepatic hepatitis C virus related problem and different studies suggested genetics' role in predicting this complication. We evaluated the influence of SNPs in IL-28B, SLC29A1, SLC28A2, NT5C2, HNF4 and ABCB1 genes in MC prediction. PATIENTS & METHODS SNPs were evaluated through real-time PCR. RESULTS ABCB1 (gene encoding P-glycoprotein) 3435C>T SNP was associated with MC presence (p = 0.034): related to T allele carriers (CC vs CT/TT), we reached a p-value of 0.013. In the logistic regression analysis baseline viral load >600.000 IU/ml (p < 001), IL28B rs8099917/rs12979860 TT/CC (p < 0.001), NT5 (gene encoding for 5' nucleotidase) 153 TC (p = 0.012) and ABCB1 3435 CT/TT (p = 0.034) genotypes predicted MC presence. CONCLUSION These data could help clinicians to identify patients with higher probability to show MC extra hepatic complication.
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Affiliation(s)
- Jessica Cusato
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Lucio Boglione
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Amedeo De Nicolò
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Chiara Simona Cardellino
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Chiara Carcieri
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Giuseppe Cariti
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Antonio D'Avolio
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
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Bellanti F, Lauletta G, Villani R, Lipsi MR, Natalicchio MI, Sansonno D, Vendemiale G, Serviddio G. Combined Effects of 2 Interleukin 28B Polymorphisms on the Therapeutic Outcome of Hepatitis C Patients With Circulating Cryoglobulins. Medicine (Baltimore) 2015; 94:e1409. [PMID: 26334898 PMCID: PMC4616511 DOI: 10.1097/md.0000000000001409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 07/24/2015] [Accepted: 07/24/2015] [Indexed: 02/05/2023] Open
Abstract
Chronic hepatitis C is commonly associated with extrahepatic manifestations. Cryoglobulins are observed in 40% to 60% of such patients and their presence seems to modify response to therapy. The new antivirals are greatly improving the sustained virological response (SVR); however, their high cost limits the use, leaving pegylated interferon plus ribavirin (PR) still the standard-of-care therapy worldwide. Since PR therapy is burdened with several side effects, pretreatment predictions of patients who are unlikely to respond to this regimen may avoid ineffective treatment. Variants of the interleukin-28B (IL28B) gene correlate with an SVR to PR, and combined IL28B polymorphisms may improve the prediction of treatment outcome.The potential role of both rs8099917 and rs12979860 IL28B single nucleotide polymorphisms (SNPs) combined with presence of cryoglobulins in predicting SVR to PR in hepatitis C virus (HCV)-chronically infected patients was analyzed in the present study.Single and combined IL28B SNPs (rs12979860 and rs8099917) were analyzed in 64 chronic HCV patients treated with PR showing circulating cryoglobulins and compared to 108 noncryoglobulinemic subjects to verify the predictive value on the SVR.The association of rs12979860CC or rs8099917TT with SVR was confirmed in the noncryoglobulinemic group but not in cryoglobulinemic patients. Moreover, the combined determination of both SNPs improved the prediction of SVR in noncryoglobulinemic patients but not in the cryoglobulinemic subgroup.We report that both single and combined determination of IL28B rs12979860 and rs8099917 SNPs in chronic HCV patients with circulating cryoglobulins treated with PR may have a reduced predictive value of SVR.
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Affiliation(s)
- Francesco Bellanti
- From the Department of Medical and Surgical Sciences, C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, University of Foggia, Foggia, Italy (FB, RV, GV, GS); Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy (GL, DS); and Department of Clinical Pathology, II Laboratory, Section of Cytogenetic and Molecular Biology, University Hospital "Ospedali Riuniti", Foggia, Italy (MRL, MIN)
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Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D, Fallahi P, Antonelli A, Ferri C. Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection. Expert Rev Clin Immunol 2015; 11:15-31. [PMID: 25534977 DOI: 10.1586/1744666x.2015.997214] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.
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Affiliation(s)
- Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Boglione L, Cusato J, Allegra S, Cariti G, Di Perri G, D'Avolio A. Role of IL28B genotyping in patients with hepatitis C virus-associated mixed cryoglobulinemia and response to PEG-IFN and ribavirin treatment. Arch Virol 2015; 160:2009-17. [PMID: 26060059 DOI: 10.1007/s00705-015-2482-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 05/30/2015] [Indexed: 12/11/2022]
Abstract
The role of interleukin (IL) 28B in the treatment of chronic hepatitis C (CHC) has recently been examined in many studies, while a possible relationship between IL28B and the presence of mixed cryoglobulinemia (MC) remains to be clarified. In this study, we analyzed the influence of IL28B rs8099917/rs12979860 on the presence of MC and the role in treatment with PEG-IFN. We retrospectively examined 541 patients affected by CHC who were treated with pegylated interferon (PEG-IFN) and ribavirin from 2003 to 2012. We included all treatment-naïve patients without other viral co-infections or major contraindications to the PEG-IFN and ribavirin standard of care. One hundred seventy-five patients (32.3 %) had MC; 49 of these (33.3 %) had symptomatic MC. The IL28B rs8099917/rs12979860 TT/CC genotype was the most frequent in MC-positive patients with sustained virological response (SVR) (p < 0.001), while the TG/TC genotype was most frequent in non-SVR (p < 0.001). The TT/CC genotype was found to be the main positive predictive factor of MC in HCV patients (OR = 11.914; IQR = 7.092-18.776; p < 0.001); HCV genotype 2/3 was the strongest positive predictive factor of SVR (OR = 10.448; IQR = 8.352-21.561; p < 0.001); IL28B rs8099917/rs12979860 TT/CC was a better predictive factor than rs12979860 CC alone (OR = 9.829 vs. 2.663). Negative predictive factors were Metavir score F3-F4 (OR = 0.625; IQR = 0.416-0.779; p = 0.008), insulin-resistance (OR = 0.315; IQR = 0.224-0.585; p < 0.001) and presence of symptoms (OR = 0.716; IQR = 0.492-0.855; p < 0.001). IL28B rs8099917/rs12979860 is useful in the treatment of MC-positive HCV patients with PEG-IFN and ribavirin; the TT/CC genotype is associated with SVR, the TG/TC with non-SVR; TT/CC is also predictive of MC in HCV patients.
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Affiliation(s)
- Lucio Boglione
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy,
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Gragnani L, Fognani E, Piluso A, Boldrini B, Urraro T, Fabbrizzi A, Stasi C, Ranieri J, Monti M, Arena U, Iannacone C, Laffi G, Zignego AL. Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study. Hepatology 2015; 61:1145-1153. [PMID: 25431357 DOI: 10.1002/hep.27623] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 11/21/2014] [Indexed: 12/15/2022]
Abstract
UNLABELLED Limited data are available about the efficacy of antiviral treatment in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC), especially concerning the long-term effects of HCV eradication. The aim of this study was to evaluate the influence of MC on the virological response and the long-term effects of viral eradication on MC. We prospectively enrolled 424 HCV(+) patients belonging to the following groups: MC syndrome (MCS)-HCV (121 patients with symptomatic MC), MC-HCV (132 patients with asymptomatic MC), and HCV (158 patients without MC). Pegylated interferon plus ribavirin treatment was administered according to standard protocols. Posttreatment follow-up ranged from 35 to 124 months (mean 92.5 months). A significant difference was observed in the rate of sustained virological response between the HCV group and both the MC-HCV (P = 0.009) and MC-HCV+MCS-HCV (P = 0.014) groups. Multivariate logistic regression analysis identified cryoglobulinemia as an independent prognostic factor of nonresponse. The clinical-immunological response in MCS-HCV correlated with the virological one. All patients with sustained virological response also experienced a sustained clinical response, either complete or partial. In the majority of sustained virological response patients all MCS symptoms persistently disappeared (36 patients, 57%); in only two (3%) did definite MCS persist. All virological nonresponders were also clinical nonresponders, in spite of a transient improvement in some cases. No evolution to lymphoma was observed. For the first time we have evaluated both the effects of interferon-based therapy on HCV patients with and without MC and with and without symptoms, as well as the long-term effects of viral eradication on MC. CONCLUSION MC is a negative prognostic factor of virological response. Clearance of HCV led to persistent resolution or improvement of MCS, strongly suggesting the need for a next generation of highly effective antiviral drugs.
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Affiliation(s)
- Laura Gragnani
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Stasi C, Piluso A, Arena U, Salomoni E, Montalto P, Monti M, Boldrini B, Corti G, Marra F, Laffi G, Milani S, Zignego AL. Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy: A prospective pilot study. World J Gastroenterol 2015; 21:3013-3019. [PMID: 25780300 PMCID: PMC4356922 DOI: 10.3748/wjg.v21.i10.3013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 10/14/2014] [Accepted: 12/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the association between liver stiffness (LS) prior to the initiation of dual/triple therapy and viral response. METHODS LS was measured in all patients before treatment was administered. The therapeutic approach was based on hepatic, virological, and immunological evaluations and considered the fact that patients with severe fibrosis (F3) or compensated cirrhosis (F4) in Child-Pugh class A are the primary candidates for triple therapy. In total, 65 hepatitis C virus (HCV) patients were treated with Peg-interferon/ribavirin (Peg-IFN/RBV); 24 patients were classified as genotypes 1/4 (36.92%), and 41 patients were classified as genotypes 2/3 (63.08%) (dual therapy). In addition, 20 HCV treatment-experienced genotype 1 patients were treated with PegIFN-RBV and boceprevir (triple therapy). Wilcoxon rank-sum tests were used to compare the groups. RESULTS LS significantly differed between dual therapy and triple therapy (P = 0.002). The mean LS value before dual therapy treatment was 8.61 ± 5.79 kPa and was significantly different between patients achieving a sustained virologic response (SVR) 24 weeks after therapy and those who did not (7.23 ± 5.18 kPa vs 11.72 ± 5.99 kPa, respectively, P = 0.0003). The relative risk of non-response to therapy was 4.45 (95%CI: 2.32-8.55). The attributable risk of non-response to therapy was 49%. The mean LS value before triple therapy treatment was 13.29 ± 8.57 kPa and was significantly different between patients achieving and not achieving SVR24 (9.41 ± 5.05 vs 19.11 ± 9.74, respectively; P = 0.008). The relative risk of non-response to therapy was 5.57% (95%CI: 1.50-20.65). The attributable risk of non-response to therapy (70%) was increased compared with dual therapy patients. Pre-treatment stiffness > 12 kPa was significantly associated with non-SVR (P < 0.025) in both groups. CONCLUSION Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either dual or triple anti-HCV therapy.
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Combined treatment with antiviral therapy and rituximab in patients with mixed cryoglobulinemia: review of the literature and report of a case using direct antiviral agents-based antihepatitis C virus therapy. Case Reports Immunol 2015; 2015:816424. [PMID: 25815218 PMCID: PMC4359800 DOI: 10.1155/2015/816424] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 01/09/2015] [Accepted: 01/20/2015] [Indexed: 12/15/2022] Open
Abstract
Mixed cryoglobulinemia (MC) is an autoimmune/B-cell lymphoproliferative disorder associated with Hepatitis C Virus (HCV) infection, manifesting as a systemic vasculitis. In the last decade, antiviral treatment (AT) with pegylated interferon (Peg-IFN) plus ribavirin (RBV) was considered the first therapeutic option for HCV-MC. In MC patients ineligible or not responsive to antivirals, the anti-CD20 monoclonal antibody rituximab (RTX) is effective. A combined AT plus RTX was also suggested. Since the introduction of direct acting antivirals (DAAs), few data were published about MC and no data about a combined schedule. Here, we report a complete remission of MC after a sustained virological response following a combined RTX/Peg-IFN+RBV+DAA (boceprevir) treatment and review the literature about the combined RTX/AT.
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Esmaeilzadeh A, Erfanmanesh M, Ghasemi S, Mohammadi F. Serological assay and genotyping of hepatitis C virus in infected patients in zanjan province. HEPATITIS MONTHLY 2014; 14:e17323. [PMID: 25368655 PMCID: PMC4214121 DOI: 10.5812/hepatmon.17323] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/22/2014] [Accepted: 05/23/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis C Virus (HCV), a public health problem, is an enveloped, single-stranded RNA virus and a member of the Hepacivirus genus of the Flaviviridae family. Liver cancer, cirrhosis, and end-stage liver are the outcomes of chronic infection with HCV. HCV isolates show significant heterogeneity in genetics around the world. Therefore, determining HCV genotypes is a vital step in determining prognosis and planning therapeutic strategies. OBJECTIVES As distribution of HCV genotypes is different in various geographical regions and HCV genotyping of patients has not been investigated in Zanjan City, this study was designed for the first time, to determine HCV genotypes in the region and to promote the impact of the treatment. MATERIALS AND METHODS Serum samples of 136 patients were collected and analyzed for anti-HCV antibodies using ELISA (The enzyme-linked immunosorbent assay) method. Then, positive samples were exposed to RT-PCR, which was performed under standard condition. Afterwards, they investigated for genotyping using allele-specific PCR (AS-PCR), and HCV genotype 2.0 line probe assay (LiPA). RESULTS Samples indicated 216 bp bands on 2% agarose gel. Analyses of the results demonstrated that the most dominant subtype was 3a with frequency of 38.26% in Zanjan Province followed by subtypes of 1b, 1a, 2, and 4 with frequencies of 25.73%, 22.05%, 5.14%, and 4.41%, respectively. The frequency of unknown HCV genotypes was 4.41%. CONCLUSIONS According to the results, it was found that HCV high prevalent genotype in Zanjan is subtype 3a. Analysis of the results provides identification of certain HCV genotypes, and these valuable findings could affect the type and duration of the treatment.
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Affiliation(s)
- Abdolreza Esmaeilzadeh
- Department of Immunolory, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, IR Iran
- Cancer Gene Therapy Research Center, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, IR Iran
- Corresponding Author: Abdolreza Esmaeilzadeh, Department of Immunology, Zanjan University of Medical Sciences, Mahdavi Blvd., Zanjan, IR Iran. Tel: +98-2433440301, Fax: +98-2433449553, E-mail:
| | - Maryam Erfanmanesh
- Young Researchers Club, Zanjan Branch, Islamic Azad University, Zanjan, IR Iran
| | - Sousan Ghasemi
- Medical Laboratory, Shaheed Beheshti General Hospital, Zanjan University of Medical Sciences, Zanjan, IR Iran
| | - Farzaneh Mohammadi
- Department of Immunolory, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, IR Iran
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Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: a prospective, controlled pilot study. Dig Liver Dis 2014; 46:833-7. [PMID: 24953206 DOI: 10.1016/j.dld.2014.05.017] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 05/12/2014] [Accepted: 05/20/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Mixed cryoglobulinaemia is strongly related to hepatitis C virus infection. Treatment with peg-interferon and ribavirin has been indicated as first-line therapy for mild/moderate hepatitis C virus-related mixed cryoglobulinaemia. AIM To evaluate the safety and efficacy of triple boceprevir-based antiviral therapy in patients with or without mixed cryoglobulinaemia previously treated with peg-interferon and ribavirin, and with advanced liver disease. METHODS Thirty-five hepatitis C virus-positive patients (17 with asymptomatic mixed cryoglobulinaemia, 5 with symptomatic mixed cryoglobulinaemia, and 11 without mixed cryoglobulinaemia) were treated with triple boceprevir-based antiviral therapy. RESULTS In 19/22 cryoglobulinaemic subjects (86%), the addition of boceprevir induced cryocrit disappearance. Cryocrit behaviour was related to virological response, with improvement of symptoms upon undetectable viraemia and reappearance after virological breakthrough. The rate of sustained virological response was lower in cryoglobulinaemic patients than in patients without mixed cryoglobulinaemia (23.8% vs 70% respectively, p=0.01). CONCLUSION Boceprevir-based therapy was safe and effective in cryoglobulinaemic patients. The correlation between direct inhibition of hepatitis C virus replication and clinical improvement in mixed cryoglobulinaemic patients is definitive proof of the key pathogenetic role played by viral replication. Further studies are needed to confirm and clarify the reduced virological response in patients with mixed cryoglobulinaemia.
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De Re V, Gragnani L, Fognani E, Piluso A, Izzo F, Mangia A, Crovatto M, Gava G, Casarin P, Sansonno D, Racanelli V, De Vita S, Pioltelli P, Caggiari L, De Zorzi M, Berretta M, Gini A, Zucchetto A, Buonaguro FM, De Paoli P, Zignego AL. Impact of immunogenetic IL28B polymorphism on natural outcome of HCV infection. BIOMED RESEARCH INTERNATIONAL 2014; 2014:710642. [PMID: 24707497 PMCID: PMC3955679 DOI: 10.1155/2014/710642] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/19/2013] [Accepted: 11/20/2013] [Indexed: 01/20/2023]
Abstract
With the aim of investigating whether interleukin 28B gene (IL28B) rs1297860 polymorphism is associated with different hepatitis C (HCV) infection statuses, we compared IL28B allelic distribution in an Italian case series of 1050 patients with chronic infection and different outcomes, 47 individuals who spontaneously cleared HCV, and 178 blood donors. Furthermore, we compared IL28B variants among 3882 Caucasian patients with chronic infection, 397 with spontaneous clearance, and 1366 blood donors reported in PubMed. Overall data confirmed a relation between IL28B C allele and HCV spontaneous clearance. Furthermore, we found that IL28B T allele had a weak relation with chronic HCV progression to hepatocellular carcinoma. Study findings are in accordance with the hepatocellular carcinogenic model where IL28B TT genotype, by promoting a persistent chronic hepatitis which leads to both hepatocyte injury and chronic inflammation, could facilitate HCC development. Conversely, patients with lymphoproliferative disorders had not any significantly different IL28B rs1297860 allelic distribution than those with chronic HCV, but, like all chronic HCV-related diseases, they showed a lower CC frequency than patients who spontaneously cleared HCV. Study results confirmed the model of persistent HCV infection as a risk factor for the pathogenesis of both liver and lymphoproliferative disorders.
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Affiliation(s)
- Valli De Re
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
| | - Elisa Fognani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
| | - Alessia Piluso
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
| | - Francesco Izzo
- Hepatobiliary Unit, National Cancer Institute “Fondazione Pascale”, 80138 Naples, Italy
| | - Alessandra Mangia
- Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, Italy
| | - Marina Crovatto
- Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, 33170 Pordenone, Italy
| | - Graziella Gava
- Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, 33170 Pordenone, Italy
| | - Pietro Casarin
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, 33170 Pordenone, Italy
| | - Domenico Sansonno
- Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70121 Bari, Italy
| | - Vito Racanelli
- Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70121 Bari, Italy
| | - Salvatore De Vita
- Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital Santa Maria della Misericordia, 33100 Udine, Italy
| | - Pietro Pioltelli
- Hematology and Transplant Unit, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Laura Caggiari
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | - Mariangela De Zorzi
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | | | - Andrea Gini
- Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, 33081 Aviano, Italy
| | - Antonella Zucchetto
- Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, 33081 Aviano, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology, National Cancer Institute “Fondazione Pascale”, 80138 Naples, Italy
| | - Paolo De Paoli
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | - Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
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12
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Stasi C, Triboli E, Arena U, Urraro T, Petrarca A, Gragnani L, Laffi G, Zignego AL. Assessment of liver stiffness in patients with HCV and mixed cryoglobulinemia undergoing rituximab treatment. J Transl Med 2014; 12:21. [PMID: 24456582 PMCID: PMC3906886 DOI: 10.1186/1479-5876-12-21] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 12/09/2013] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients. MATERIALS AND METHODS Fourteen consecutive patients (10 F, 4 M; mean age 60.43 ± 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. RESULTS MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. CONCLUSION This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion.
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Affiliation(s)
- Cristina Stasi
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Elisa Triboli
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Umberto Arena
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Teresa Urraro
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Antonio Petrarca
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Giacomo Laffi
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses MASVE, University of Florence, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
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13
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Sansonno D, Russi S, Serviddio G, Conteduca V, D'Andrea G, Sansonno L, Pavone F, Lauletta G, Mariggiò MA, Dammacco F. Interleukin 28B gene polymorphisms in hepatitis C virus-related cryoglobulinemic vasculitis. J Rheumatol 2014; 41:91-8. [PMID: 24293567 DOI: 10.3899/jrheum.130527] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Single-nucleotide polymorphisms (SNP) in the interleukin 28B (IL-28B) gene region are strongly predictive of the response of infected patients to antiviral therapy for hepatitis C virus (HCV). We sought to determine the prevalence of SNP IL-28B rs12979860 C/C and non-C/C (C/T plus T/T) genotypes in HCV-related cryoglobulinemic vasculitis (CV), as compared with HCV-positive patients without CV. We also searched for their association with peculiar clinical manifestations of CV and potential influence on the complete response (virological, molecular, and immunological) to the therapy. METHODS The study cohort comprised 159 and 172 HCV-infected patients with and without CV, respectively, prospectively followed starting from 1990. SNP rs12979860 genotyping was performed by Taq-Man allelic discrimination. In 106 patients (66.6%) with CV, the profile of circulating B cell clonalities was determined as well. All patients with CV were treated with pegylated interferon-α/ribavirin-based antiviral therapy. RESULTS The T/T IL-28B genotype was more common in patients with CV than in those without (17% vs 8.1%, p = 0.02). In patients with CV, compared with non-C/C variants, the IL-28B C/C genotype was associated with a higher rate of complete response (52.6% vs 39.2%, p = 0.13), whereas a treatment response of 61.4% was demonstrated when solely virological response was considered (p = 0.008). A higher frequency of expanded B cell clonalities in the circulation (84.2% vs 55.9%; p = 0.005), kidney involvement (21% vs 2.9%; p = 0.003), and B cell non-Hodgkin lymphoma (17.5% vs 6.8%; p = 0.048), were also observed. CONCLUSION In HCV-positive patients with CV, the IL-28B C/C genotype is distinguished biologically by a higher frequency of restriction of B cell response and clinically by a higher risk of cryoglobulinemic nephropathy and B cell malignancies, while acting as an independent predictor of a sustained virological response to antiviral therapy. In addition, we found that IL-28B T/T variant was more prevalent in patients with CV than in those without.
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Affiliation(s)
- Domenico Sansonno
- From the Section of Internal Medicine and Clinical Oncology, Laboratory of General Pathology and Experimental Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari; Section of Internal Medicine, Department of Medical Sciences, and Section of Medical Genetics, Department of Biomedical Sciences, University of Foggia, Foggia, Italy
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14
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Gragnani L, Fognani E, Piluso A, Zignego AL. Hepatitis C virus-related mixed cryoglobulinemia: Is genetics to blame? World J Gastroenterol 2013; 19:8910-8915. [PMID: 24379615 PMCID: PMC3870543 DOI: 10.3748/wjg.v19.i47.8910] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/28/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Mixed cryoglobulinemia (MC) is the extrahepatic manifestation most strictly correlated with hepatitis C virus (HCV) infection; it is a benign autoimmune and lymphoproliferative disorder that evolves to lymphoma in 5%-10% of cases. MC is reputed to be a multistep and multifactorial process whose pathogenicity is still poorly understood. It is still unknown why only some chronically infected HCV patients develop MC and only some of these exhibit systemic symptoms (MC syndrome). Several studies have investigated the pathogenetic basis of MC and the most recent ones suggest that the virus is able to trigger such a disorder only in the presence of genetic factors that are still unknown. Here, we try to clarify the complex relationship between HCV-related MC and the host’s genetic background. The data that we report are heterogeneous and sometimes even conflicting. Therefore, large, multicenter studies are clearly needed. The identification of a characteristic genetic signature of cryoglobulinemic patients would be an important step toward a personalized approach in their clinical care. The new wide-ranging genomics technologies will hopefully help to resolve these complex issues.
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Fognani E, Giannini C, Piluso A, Gragnani L, Monti M, Caini P, Ranieri J, Urraro T, Triboli E, Laffi G, Zignego AL. Role of microRNA profile modifications in hepatitis C virus-related mixed cryoglobulinemia. PLoS One 2013; 8:e62965. [PMID: 23650540 PMCID: PMC3641090 DOI: 10.1371/journal.pone.0062965] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 03/26/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin’s lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV-associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV-related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders.
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Affiliation(s)
- Elisa Fognani
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Carlo Giannini
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessia Piluso
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Laura Gragnani
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Monica Monti
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Patrizio Caini
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Jessica Ranieri
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Teresa Urraro
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Elisa Triboli
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giacomo Laffi
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- * E-mail:
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