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1
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Nguyen DP, Nguyen HX, Van Nguyen H, Dang LM, Nguyen MT, Minh Nguyen HT. On the steroids extracted from soft corals against the NS3/4A protease of hepatitis C virus. J Mol Graph Model 2025; 136:108936. [PMID: 39793475 DOI: 10.1016/j.jmgm.2024.108936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/16/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025]
Abstract
The Hepatitis C virus (HCV) causes a variety of liver diseases, making it a global health issue that affects millions of people in the world. The NS3/4A protease has been considered a common target for anti-HCV treatments using direct-acting antiviral agents and their derivatives. Of the natural products that have been proposed for novel therapeutic product alternatives, the soft coral compounds are found to contain steroids with various bioactive properties for effective HCV treatments. They are screened to search for HCV inhibitors using computational approaches to screen for potential HCV inhibitors from the extracts of soft corals. Among 188 steroids considered, the five top compounds are selected for evaluation of binding affinities and stabilities using molecular docking and dynamics simulations, as well as with absorption, distribution, metabolism, excretion, and toxicity to assess the drug's performance.
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Affiliation(s)
- Duy Phuong Nguyen
- Faculty of Chemistry and Center for Computational Science, Hanoi National University of Education, Hanoi, Viet Nam.
| | - Ha Xuan Nguyen
- Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, Hanoi, Viet Nam
| | - Hue Van Nguyen
- Faculty of Chemistry and Center for Computational Science, Hanoi National University of Education, Hanoi, Viet Nam
| | - Linh Mai Dang
- Faculty of Chemistry and Center for Computational Science, Hanoi National University of Education, Hanoi, Viet Nam
| | - Minh Tho Nguyen
- Laboratory for Chemical Computation and Modeling, Institute for Computational Science and Artificial Intelligence, Van Lang University, Ho Chi Minh City, Viet Nam; Faculty of Applied Technology, School of Technology, Van Lang University, Ho Chi Minh City, Viet Nam
| | - Hue Thi Minh Nguyen
- Faculty of Chemistry and Center for Computational Science, Hanoi National University of Education, Hanoi, Viet Nam; Institute of Natural Sciences, Hanoi National University of Education, Hanoi, Viet Nam
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2
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Hijazi AH, Al-Hamed FS, Tamimi F, Al-Maweri SA, Hamdan N, Psutka DJ, Ta P, Klieb H. Regenerative potential of platelet concentrates in chronic oral mucosal lesions. J Oral Biol Craniofac Res 2024; 14:216-221. [PMID: 38487393 PMCID: PMC10937318 DOI: 10.1016/j.jobcr.2024.02.007] [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: 09/07/2023] [Revised: 02/03/2024] [Accepted: 02/23/2024] [Indexed: 03/17/2024] Open
Abstract
Chronic oral mucosal diseases (COMDs) represent a significant challenge for clinicians and patients. They are commonly associated with chronic pain and negative effects on healing and patient's quality of life. Regenerative medicine including the use of biological autologous blood-derived substances (e.g., platelet concentrates [PCs]), has been reported to improve healing and reduce pain in orthopedic and maxillofacial surgeries as well as chronic oral mucosal diseases. In this review, we aim to describe the different types of PCs and their applications in the management of COMDs such as lichen planus, mucositis, pemphigus vulgaris, mucous membrane pemphigoid, and plasma cell mucositis, in terms of healing potential, pain control, and quality of life. Overall, PC applications seem to enhance healing and reduce pain in patients with COMDs. However, due to the small sample size and the lack of standardized clinical trials, further research is required to support these findings.
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Affiliation(s)
- Abdel-Hameed Hijazi
- Department of Oral Medicine, Periodontology, Oral Diagnosis and Oral Radiology, Faculty of Dentistry, Sinai University – Kantara Branch, Ismailia, 41636, Egypt
| | | | - Faleh Tamimi
- College of Dental Medicine, QU Health, Qatar University, Doha, Qatar
| | | | - Nader Hamdan
- School of Dentistry, University of Alberta, Edmonton, Canada
| | - David J. Psutka
- Faculty of Dentistry, University of Toronto, Ontario, Canada
- Senior Surgeon, Mount Sinai Hospital Center of Excellence for Advanced TMJ Reconstructive Surgery, Ontario, Canada
| | - Peter Ta
- Faculty of Dentistry, University of Toronto, Ontario, Canada
- Staff Surgeon, Sunnybrook Health Sciences Centre and Trillium Health Partners, Ontario, Canada
| | - Hagen Klieb
- Department of Oral and Maxillofacial Sciences, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada
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3
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Shokri S, Mahmoudvand S. The possibility of hepatitis C reactivation in COVID-19 patients treated with corticosteroids. Ann Hepatol 2022; 27:100704. [PMID: 35398269 PMCID: PMC8986273 DOI: 10.1016/j.aohep.2022.100704] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 03/26/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023]
Affiliation(s)
| | - Shahab Mahmoudvand
- Department of Virology, School of Medicine, Hamadan University of Medical Science, Hamadan, Iran.
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Kassem NM, Kassem HA, Ibrahim M, Zawam H, Hamada E. The clinical impact of hepatitis C virus infection in Egyptian multiple myeloma patients. J Egypt Natl Canc Inst 2020; 32:43. [PMID: 33244648 DOI: 10.1186/s43046-020-00054-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/18/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Multiple myeloma (MM) is a human B cell neoplasia characterized by the clonal proliferation of malignant plasma cells in the bone marrow. Worldwide, hepatitis C virus (HCV) infection is a public health problem. For MM patients, the clinical impact of preexisting HCV infection is still unclear. We aim to assess the clinical characteristics and the prevalence of the HCV infection in Egyptian MM patients. This observational study included 81 MM patients. HCV antibody assay was performed, and positive cases were confirmed using a reverse transcription-quantitative PCR (RT-PCR) method. RESULTS Fifteen (18.5%) patients were anti-HCV antibody positive. Only 6/15 (7.4%) patients were HCV RNA positive by RT-PCR. Liver affection in the form of hyperbilirubinemia with grade 4 adverse events was significantly higher in the anti-HCV positive/HCV RNA positive group versus anti HCV negative group (16.7% vs. 1.5%, p value = 0.005). The median HCV-RNA before the initiation of chemotherapy was 2.5 log IU/ml with mean ± SD = 4.25 ± 1.6 with no HCV reactivation. In the univariate and multivariate analysis, HCV infection was not an independent factor related to DFS. Low hemoglobin level < 10 g/dL (HR 0.59, 95% CI, 0.36-0.97, p value = 0.037) and abnormal serum total bilirubin level (HR 1.9, 95% CI 1.03-3.5, p value = 0.039) influenced DFS in the univariate analysis. However, in the multivariate analysis, serum calcium level greater than 12 mg/dL (HR 7.04, 95% CI 1.12-44.45, p value = 0.038) and abnormal serum total bilirubin level (HR 10.9, 95% CI 2.92-41.02, p value = < 0.001) remained statistically significant worse prognostic factors. CONCLUSION In conclusion, our study revealed the prevalence of HCV infection in Egyptian MM patients. Serologic tests at diagnosis are necessary to identify these patients, and confirmation of positive cases by molecular techniques should be mandatory, with regular follow-up for liver dysfunction. Finally, further larger studies explaining the molecular mechanisms linking HCV and the MM pathogenesis are warranted.
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Affiliation(s)
- Neemat M Kassem
- Clinical and Chemical Pathology Department, Kasr Al Ainy Centre of Clinical Oncology & Nuclear Medicine, School of Medicine, Cairo University, Cairo, Egypt
| | - Hebatallah A Kassem
- Clinical and Chemical Pathology Department, Kasr Al Ainy Centre of Clinical Oncology & Nuclear Medicine, School of Medicine, Cairo University, Cairo, Egypt.
| | - Magdy Ibrahim
- Gynecology & Obstetric Department, School of Medicine, Cairo University, Cairo, Egypt
| | - Hussam Zawam
- Clinical Oncology Department, School of Medicine, Cairo University, Cairo, Egypt
| | - Emad Hamada
- Clinical Oncology Department, School of Medicine, Cairo University, Cairo, Egypt
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5
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Putra J, Schiano TD, Fiel MI. Resolution of HCV-Autoimmune Hepatitis Overlap Syndrome With Antiviral TreatmentA Paired Liver Biopsy Study. Am J Clin Pathol 2019; 152:735-741. [PMID: 31310654 DOI: 10.1093/ajcp/aqz095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES To evaluate histologic changes occurring in patients having chronic hepatitis C and autoimmune hepatitis overlap (HCV-AIH), and who achieved virologic cure using direct-acting antiviral agents (DAA). METHODS Characteristics of HCV-AIH patients who underwent paired liver biopsies before and after receiving DAA treatment from 2011 to 2018 were evaluated. RESULTS Five HCV-AIH patients (three male; mean age, 60.4 years) underwent paired liver biopsies (average interval, 2.3 years) before and after achieving cure with DAA treatment. All patients showed virologic response, while four showed decreased inflammation, and three cases showed features of fibrosis regression. Immunohistochemical staining demonstrated significant decrease in plasma cell count in three patients (20.6 vs 11.9 plasma cells/high power field; P = .02, t test). CONCLUSIONS Histologic improvements in inflammation and fibrosis are noted in most HCV-AIH patients after DAA treatment, suggesting that the autoimmune component of the HCV-AIH overlap syndrome is merely a secondary phenomenon of viral infection.
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Affiliation(s)
- Juan Putra
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
- Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada
| | - Thomas D Schiano
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
- Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - M Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
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de Ruiter PE, Gadjradj Y, de Knegt RJ, Metselaar HJ, Ijzermans JNM, van der Laan LJW. Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid. World J Transplant 2018; 8:156-166. [PMID: 30211024 PMCID: PMC6134272 DOI: 10.5500/wjt.v8.i5.156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 06/14/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir.
METHODS The antiviral activity of daclatasvir (DCV) and asunaprevir (ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus (HCV) infection.
RESULTS Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid (MPA) showed additive antiviral effects combined with these direct acting antivirals (DAAs). MPA induces interferon-stimulated genes (ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis.
CONCLUSION Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.
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Affiliation(s)
- Petra E de Ruiter
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
| | - Yashna Gadjradj
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
| | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
| | - Herold J Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
| | - Jan NM Ijzermans
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
| | - Luc JW van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
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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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8
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Li Y, Li Y, Zhang L, Li W. Hepatitis C virus infection and risk of multiple myeloma: Evidence from a meta-analysis based on 17 case-control studies. J Viral Hepat 2017; 24:1151-1159. [PMID: 28656736 DOI: 10.1111/jvh.12742] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 06/06/2017] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is a leading cause of chronic liver damage and is associated with other diseases. Some studies reported that patients with HCV have a significantly increased risk of multiple myeloma while others do not report an association. We aimed to clarify the association between HCV and multiple myeloma and analyse the factors that affect the controversial conclusions through a meta-analysis. We conducted a systematic literature search of HCV and myeloma in the databases of PubMed/MEDLINE, Cochrane Library, EMBASE, Wanfang and China National Knowledge Infrastructure (CNKI) from inception to September 2016. Outcomes were expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). A positive correlation between HCV infection and risk of developing multiple myeloma was revealed (OR=2.67, 95% CI=1.35-5.26, P=.005) based on meta-analysis of 17 case-control observational studies. When the data were stratified by source of control, significant associations were observed in hospital-based studies, but not population-based studies. Further subgroup analyses showed increased risk of multiple myeloma in HCV patients when studies were conducted in high HCV prevalent countries, but not in low or moderate HCV prevalent countries. In addition, similar positive association was detected in studies performed in the East Asia and in intermediate-quality studies. In summary, the association of HCV infection with increased risk of multiple myeloma depended on several factors, including study design, quality and environmental HCV prevalence. Further large-scale, well-designed studies are needed to validate the role of HCV in the aetiology of multiple myeloma.
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Affiliation(s)
- Y Li
- Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Y Li
- Departments of Cardiology and Echocardiography, First Hospital of Jilin University, Changchun, China
| | - L Zhang
- Department of Nephrology, First Hospital of Jilin University, Changchun, China
| | - W Li
- Cancer Center, First Hospital of Jilin University, Changchun, China
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9
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Sabry D, Elamir A, Mahmoud RH, Abdelaziz AA, Fathy W. Role of LncRNA-AF085935, IL-10 and IL-17 in Rheumatoid Arthritis Patients With Chronic Hepatitis C. J Clin Med Res 2017; 9:416-425. [PMID: 28392862 PMCID: PMC5380175 DOI: 10.14740/jocmr2896w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The current study aimed at testing the effect of corticosteroid therapy on serum levels of interleukin-10 (IL-10) and IL-17 as well as lncRNA-AF085935 in patients of rheumatoid arthritis (RA) associated with hepatitis C virus (HCV) and evaluating the usefulness of using these parameters to predict the therapeutic efficacy of steroids in these patients. METHODS Thirty healthy control subjects and 65 chronic HCV patients with RA were included in our study. Patients were subjected to clinical examination, abdominal ultrasound, and liver biopsy and received 6-methyl-prednisolone (PDN) 16 mg/day for 48 weeks. Blood samples were collected from all subjects and serum was separated to assess IL-10 and IL-17 by ELISA and HCV RNA and lncRNA-AF085935 by qRT-PCR. RESULTS Our study revealed that there were significant increases in serum levels of IL-10, IL-17 and lncRNA-AF085935 in RA patients associated with HCV compared with healthy control subjects. Also there were significant increases in serum levels of IL-10 and HCV RNA and a significant decrease in serum level of IL-17 in patients after corticosteroid therapy, while lncRNA-AF085935 is not significantly changed. CONCLUSION LncRNA-AF085935 might be a useful candidate biomarker for the early detection of RA associated with HCV, providing potential new strategies for early screening and therapy of these patients. IL-17 is a non-invasive prognostic marker to predict the efficacy of corticosteroid therapy in RA patients associated with chronic hepatitis C.
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Affiliation(s)
- Dina Sabry
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Azza Elamir
- Medical Biochemistry Department, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Rania Hosny Mahmoud
- Medical Biochemistry Department, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Ahmed Ali Abdelaziz
- Rheumatology and Rehabilitation Department, Faculty of Medicine, Alazhar University, Cairo, Egypt
| | - Wael Fathy
- Tropical Medicine Department, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt
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10
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Tang KT, Chen YH, Lin CH, Chen DY. Methotrexate is not associated with increased liver cirrhosis in a population-based cohort of rheumatoid arthritis patients with chronic hepatitis C. Sci Rep 2016; 6:33104. [PMID: 27609026 PMCID: PMC5016832 DOI: 10.1038/srep33104] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 08/19/2016] [Indexed: 12/18/2022] Open
Abstract
A few studies have shown that methotrexate (MTX) use exacerbates liver fibrosis and even leads to liver cirrhosis in rheumatoid arthritis (RA) patients, although the risk is low compared to psoriatics. We therefore conducted a population-based cohort study to investigate the impact of long-term MTX use on the risk of chronic hepatitis C (CHC)-related cirrhosis among RA patients. We analyzed data from the National Health Insurance Research Database in Taiwan and identified 450 incident cases of RA among CHC patients (255 MTX users and 195 MTX non-users) from January 1, 1998 to December 31, 2007. After a median follow-up of more than 5 years since the diagnosis of CHC, a total of 55 (12%) patients developed liver cirrhosis. We did not find an increased risk of liver cirrhosis among CHC patients with long-term MTX use for RA. Furthermore, there was no occurrence of liver cirrhosis among the 43 MTX users with a cumulative dose ≧3 grams after 108 months of treatment. In conclusion, our data showed that long-term MTX use is not associated with an increased risk for liver cirrhosis among RA patients with CHC. However, these results should be interpreted with caution due to potential bias in the cohort.
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Affiliation(s)
- Kuo-Tung Tang
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, R.O.C.,Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, R.O.C
| | - Yi-Hsing Chen
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, R.O.C.,School of Medicine, National Yang-Ming University, Taipei, R.O.C
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, R.O.C
| | - Der-Yuan Chen
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, R.O.C.,School of Medicine, National Yang-Ming University, Taipei, R.O.C.,Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, R.O.C.,Institute of Biomedical Science, National Chung Hsing University, Taichung, R.O.C
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11
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Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. Antiviral Res 2016; 133:41-9. [PMID: 27468950 DOI: 10.1016/j.antiviral.2016.07.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 07/24/2016] [Indexed: 12/13/2022]
Abstract
Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 μg/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational.
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12
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Mahale P, Thomas SK, Kyvernitakis A, Torres HA. Management of Multiple Myeloma Complicated by Hepatitis C Virus Reactivation: The Role of New Antiviral Therapy. Open Forum Infect Dis 2015; 3:ofv211. [PMID: 26885541 PMCID: PMC4751339 DOI: 10.1093/ofid/ofv211] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 12/23/2015] [Indexed: 01/29/2023] Open
Abstract
Reactivation of chronic hepatitis C virus (HCV) infection has been reported in cancer patients receiving chemotherapy. In this study, we report the first case, to our knowledge, of thalidomide-induced acute exacerbation and reactivation of chronic HCV infection complicating management of multiple myeloma. Sofosbuvir-based antiviral therapy helped achieve viral clearance and normalization of liver enzymes, thus allowing access to future potentially life-saving chemotherapy agents.
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Affiliation(s)
- Parag Mahale
- Departments of Infectious Diseases, Infection Control, and Employee Health
| | - Sheeba K Thomas
- Lymphoma/Myeloma , The University of Texas MD Anderson Cancer Center , Houston, Texas
| | | | - Harrys A Torres
- Departments of Infectious Diseases, Infection Control, and Employee Health
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13
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de Ruiter PE, Boor PPC, de Jonge J, Metselaar HJ, Tilanus HW, Ijzermans JN, Kwekkeboom J, van der Laan LJW. Prednisolone does not affect direct-acting antivirals against hepatitis C, but inhibits interferon-alpha production by plasmacytoid dendritic cells. Transpl Infect Dis 2015; 17:707-15. [PMID: 26250892 DOI: 10.1111/tid.12430] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 07/07/2015] [Accepted: 07/17/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection compromises long-term outcomes of liver transplantation. Although glucocorticosteroid-based immunosuppression is commonly used, discussion is ongoing on the effect of prednisolone (Pred) on HCV recurrence and response to antiviral therapy post transplantation. Recently, new drugs (direct-acting antivirals) have been approved for the treatment of HCV, however, it remains unknown whether their antiviral activity is affected by Pred. The aim of this study was to investigate the effects of Pred on the antiviral activity of asunaprevir (Asu), daclatasvir (Dac), ribavirin (RBV), and interferon-alpha (IFN-α), and on plasmacytoid dendritic cells (PDCs), the main IFN-α-producing immune cells. METHODS The effects of Pred and antiviral compounds were tested in both a subgenomic and infectious HCV replication model. Furthermore, effects were tested on human PDCs stimulated with a Toll-like receptor-7 ligand. RESULT Pred did not directly affect HCV replication and did not inhibit the antiviral action of Asu, Dac, RBV, or IFN-α. Stimulated PDCs potently suppressed HCV replication. This suppression was reversed by treating PDCs with Pred. Pred significantly decreased IFN-α production by PDCs without affecting cell viability. When Asu and Dac were combined with PDCs, a significant cooperative antiviral effect was observed. CONCLUSION This study shows that Pred acts on the antiviral function of PDCs. Pred does not affect the antiviral action of Asu, Dac, RBV, or IFN-α. This implies that there is no contraindication to combine antiviral therapies with Pred in the post-transplantation management of HCV recurrence.
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Affiliation(s)
- P E de Ruiter
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - P P C Boor
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - J de Jonge
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - H J Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - H W Tilanus
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - J N Ijzermans
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - J Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - L J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
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Liu YY, Li CP, Huai MS, Fu XM, Cui Z, Fan LL, Zhang S, Liu Y, Ma J, Li G, Shen ZY. Comprehensive comparison of three different immunosuppressive regimens for liver transplant patients with hepatocellular carcinoma: steroid-free immunosuppression, induction immunosuppression and standard immunosuppression. PLoS One 2015; 10:e0120939. [PMID: 25816221 PMCID: PMC4376790 DOI: 10.1371/journal.pone.0120939] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 02/09/2015] [Indexed: 12/20/2022] Open
Abstract
The different choices of immunosuppression (IS) regimens influenced the outcomes of liver transplantation. Steroid was applied as a standard IS to prevent and treat rejections. However, steroid-related complications were increasingly prominent. This study compared the efficacy and safety of standard IS regimens with the efficacy and safety of steroid-free IS regimen and induction IS regimen in Chinese liver transplantation recipients for hepatocellular carcinoma (HCC). A total of 329 patients who underwent liver transplantation from January 2008 to December 2012 were retrospectively reviewed. Three different groups of patients received standard triple-drug IS regimen of steroid, tacrolimus (TAC) and mycophenolate mofetil (MMF) (triple-drug regimen group; n=57), induction-contained IS regimen of basiliximab, steroid, TAC and MMF (BS group; n=241), and induction-contained and steroid-free regimen of basiliximab, TAC and MMF (SF group; n=31), respectively. There were no significant differences in terms of patient, tumor-free and graft survival rates. The acute rejection rate and rejection time were equivalent in different groups. But compared with BS group, higher incidences of biliary complications (11.52% vs. 30.77%, p=0.013) and graft dysfunction (0.48% vs. 13.64%, p=0.003) were observed in SF group. Furthermore, compared with the two groups, incidence of pleural effusion was also higher in SF group (15.79%, 11.96% vs. 45.45%, respectively, both p<0.01). And a trend towards less proportion of De novo diabetes was revealed in SF group. Although it was found that patient, tumor-free and graft survival rates were equivalent among three IS regimens, higher incidences of complications were demonstrated in steroid-free regimen in patients for HCC. These findings suggested that steroid-free IS regimen has no clear advantages in comparison with standard IS regimens for liver transplant recipients with HCC and the postoperative complications should be treated with concentrated attention.
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Affiliation(s)
- Yuan-Yuan Liu
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Chang-Ping Li
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Ming-Sheng Huai
- Department of Transplantation, Tianjin First Center Hospital, 24 Fu-Kang Road, Nankai District, Tianjin, 300192, China
| | - Xiao-Meng Fu
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Zhuang Cui
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Lin-Lin Fan
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Shu Zhang
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Yuan Liu
- Follow-up Center, Department of Transplantation, Tianjin First Center Hospital, 24 Fu-Kang Road, Nankai District, Tianjin, 300192, China
| | - Jun Ma
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Guang Li
- Department of Biology, School of Basic Medical, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin, 300070, China
| | - Zhong-Yang Shen
- Department of Transplantation, Tianjin First Center Hospital, 24 Fu-Kang Road, Nankai District, Tianjin, 300192, China
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Shoreibah M, Anand BS, Singal AK. Alcoholic hepatitis and concomitant hepatitis C virus infection. World J Gastroenterol 2014; 20:11929-11934. [PMID: 25232227 PMCID: PMC4161778 DOI: 10.3748/wjg.v20.i34.11929] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/25/2014] [Accepted: 05/28/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection and alcohol abuse are two most important causes of chronic liver disease in the United States. Alcoholic hepatitis is a unique clinical syndrome among patients with chronic and active alcohol abuse with a potential for high short-term mortality. About 20% of patients presenting with alcoholic hepatitis have concomitant HCV infection. Mortality from alcoholic hepatitis is increased in the presence of concomitant hepatitis C due to synergistic interaction between HCV and alcohol in causing hepatocellular damage. Large prospective randomized studies are needed to develop guidelines on the use of corticosteroids among patients with alcoholic hepatitis and concomitant HCV infection. The impact of antiviral therapy on mortality and outcome in the setting of alcoholic hepatitis remains a novel area for future research.
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Wang Y, Zhou X, Debing Y, Chen K, Van Der Laan LJW, Neyts J, Janssen HLA, Metselaar HJ, Peppelenbosch MP, Pan Q. Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology 2014; 146:1775-83. [PMID: 24582714 DOI: 10.1053/j.gastro.2014.02.036] [Citation(s) in RCA: 141] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 11/27/2013] [Accepted: 02/19/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Many recipients of organ transplants develop chronic hepatitis, due to infection with the hepatitis E virus (HEV). Although chronic HEV infection is generally associated with immunosuppressive therapies, little is known about how different immunosuppressants affect HEV infection. METHODS A subgenomic HEV replication model, in which expression of a luciferase reporter gene is measured, and a full-length infection model were used. We studied the effects of different immunosuppressants, including steroids, calcineurin inhibitors (tacrolimus [FK506] and cyclosporin A), and mycophenolic acid (MPA, an inhibitor of inosine monophosphate dehydrogenase) on HEV replication in human hepatoma cell line Huh7. Expression of cyclophilins A and B (the targets of cyclosporin A) were knocked down using small hairpin RNAs. RESULTS Steroids had no significant effect on HEV replication. Cyclosporin A promoted replication of HEV in the subgenomic and infectious models. Knockdown of cyclophilin A and B increased levels of HEV genomic RNA by 4.0- ± 0.6-fold and 7.2- ± 1.9-fold, respectively (n = 6; P < .05). A high dose of FK506 promoted infection of liver cells with HEV. In contrast, MPA inhibited HEV replication. Incubation of cells with guanosine blocked the antiviral activity of MPA, indicating that the antiviral effects of this drug involve nucleotide depletion. The combination of MPA and ribavirin had a greater ability to inhibit HEV replication than MPA or ribavirin alone. CONCLUSIONS Cyclophilins A and B inhibit replication of HEV; this might explain the ability of cyclosporin A to promote HEV infection. On the other hand, the immunosuppressant MPA inhibits HEV replication. These findings should be considered when physicians select immunosuppressive therapies for recipients of organ transplants who are infected with HEV.
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Affiliation(s)
- Yijin Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands
| | - Xinying Zhou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands
| | - Yannick Debing
- Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Kan Chen
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands; Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China
| | - Luc J W Van Der Laan
- Department of Surgery, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands
| | - Johan Neyts
- Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands; Division of Gastroenterology, University Health Network, Toronto, Canada
| | - Herold J Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands.
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17
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Dhanasekaran R, Firpi RJ. Challenges of recurrent hepatitis C in the liver transplant patient. World J Gastroenterol 2014; 20:3391-3400. [PMID: 24707122 PMCID: PMC3974506 DOI: 10.3748/wjg.v20.i13.3391] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 11/22/2013] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis secondary to hepatitis C virus (HCV) is a very common indication for liver transplant. Unfortunately recurrence of HCV is almost universal in patients who are viremic at the time of transplant. The progression of fibrosis has been shown to be more rapid in the post-transplant patients than in the transplant naïve, hence treatment of recurrent HCV needs to be considered for all patients with documented recurrent HCV. Management of recurrent HCV is a challenging situation both for patients and physicians due to multiple reasons as discussed in this review. The standard HCV treatment with pegylated interferon and Ribavarin can be considered in these patients but it leads to a lower rate of sustained virologic clearance than in the non-transplanted population. Some of the main challenges associated with treating recurrent HCV in post-transplant patients include the presence of cytopenias; need to monitor drug-drug interactions and the increased incidence of renal compromise. In spite of these obstacles all patients with recurrent HCV should be considered for treatment since it is associated with improvement in survival and a delay in fibrosis progression. With the arrival of direct acting antiviral drugs there is renewed hope for better outcomes in the treatment of post-transplant HCV recurrence. This review evaluates current literature on this topic and identifies challenges associated with the management of post-transplant HCV recurrence.
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Chen K, Man K, Metselaar HJ, Janssen HLA, Peppelenbosch MP, Pan Q. Rationale of personalized immunosuppressive medication for hepatocellular carcinoma patients after liver transplantation. Liver Transpl 2014; 20:261-9. [PMID: 24376158 DOI: 10.1002/lt.23806] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 11/24/2013] [Indexed: 12/12/2022]
Abstract
Liver transplantation is the only potentially curative treatment for hepatocellular carcinoma (HCC) that is not eligible for surgical resection. However, disease recurrence is the main challenge to the success of this treatment. Immunosuppressants that are universally used after transplantation to prevent graft rejection could potentially have a significant impact on HCC recurrence. Nevertheless, current research is exclusively focused on mammalian target of rapamycin inhibitors, which are thought to be the only class of immunosuppressive agents that can reduce HCC recurrence. In fact, substantial evidence from the bench to the bedside indicates that other classes of immunosuppressants may also exert diverse effects; for example, inosine monophosphate dehydrogenase inhibitors potentially have antitumor effects. In this article, we aim to provide a comprehensive overview of the potential effects of different types of immunosuppressants on HCC recurrence and their mechanisms of action from both experimental and clinical perspectives. To ultimately improve the outcomes of HCC patients after transplantation, we propose a concept and approaches for developing personalized immunosuppressive medication to be used either as immunosuppression maintenance or during the prevention/treatment of HCC recurrence.
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Affiliation(s)
- Kan Chen
- Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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19
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Romero Gutiérrez M, del Campo Terrón S, Moreno Zamora A, Sánchez Ruano JJ, Artaza Varasa T, Bárcena Marugán R. Does low-dose prolonged steroid therapy affect the natural history of chronic hepatitis C? J Med Virol 2014; 86:758-64. [DOI: 10.1002/jmv.23889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2014] [Indexed: 01/05/2023]
Affiliation(s)
| | | | - Ana Moreno Zamora
- Infectious Diseases Service Hospital Universitario Ramón y Cajal; Madrid Spain
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20
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Nakasone H, Kurosawa S, Yakushijin K, Taniguchi S, Murata M, Ikegame K, Kobayashi T, Eto T, Miyamura K, Sakamaki H, Morishima Y, Nagamura T, Suzuki R, Fukuda T. Impact of hepatitis C virus infection on clinical outcome in recipients after allogeneic hematopoietic cell transplantation. Am J Hematol 2013; 88:477-84. [PMID: 23483626 DOI: 10.1002/ajh.23436] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Accepted: 03/05/2013] [Indexed: 01/12/2023]
Abstract
The impact of hepatitis C virus (HCV) infection on outcomes following allogeneic hematopoietic cell transplantation (HCT) remains a matter of debate. We have retrospectively examined the significance of HCV infection among recipients who received allogeneic HCT, using a Japan transplant outcome registry database between 2006 and 2009. Among 7,831 recipients, 136 were HCV-positive. The rate of hematopoietic recovery was lower in the HCV-positive group (neutrophil recovery of 500 × 10(6) /L or higher: 79% vs. 87% at Day 30, P = 0.087; platelet recovery of 50 × 10(9) /L or higher: 57% vs. 65% at Day 60, P = 0.012). The HCV-positive group had a significantly higher incidence of nonrelapse mortality 38% vs. 25% at 2 years, P < 0.01) and inferior overall survival (41% vs. 51% at 2 years, P < 0.01). A multivariate analysis revealed that HCV seropositivity was associated with an independent risk for higher nonrelapse mortality (hazard ratio: 1.65, P < 0.01) and inferior overall survival (hazard ratio: 1.39, P < 0.01). The incidences of death due to hepatic problems (8% vs. 2%, P < 0.01), bacterial infection (10% vs. 4%, P < 0.01), or graft failure (5% vs. 2%, P = 0.084) tended to be higher in the HCV-positive group. HCV infection had an adverse impact on the clinical outcome following HCT, especially in the setting of unrelated transplantation. Careful evaluation before embarking on HCT and intensive assessment against complications are warranted in HCV-infected recipients.
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Affiliation(s)
| | | | | | | | - Makoto Murata
- Department of Hematology and Oncology; Nagoya University Graduate School of Medicine; Nagoya; Japan
| | - Kazuhiro Ikegame
- Division of Hematology; Department of Internal Medicine; Hyogo College of Medicine; Nishinomiya; Japan
| | - Takeshi Kobayashi
- Hematology Division; Tokyo Metropolitan Cancer & Infectious Disease Center, Komagome Hospital; Tokyo; Japan
| | - Tetsuya Eto
- Department of Hematology; Hamanomachi Hospital; Fukuoka; Japan
| | - Koichi Miyamura
- Department of Hematology; Japanese Red Cross Nagoya First Hospital; Nagoya; Japan
| | - Hisashi Sakamaki
- Hematology Division; Tokyo Metropolitan Cancer & Infectious Disease Center, Komagome Hospital; Tokyo; Japan
| | - Yasuo Morishima
- Division of Epidemiology and Prevention; Aichi Cancer Center Research Institute; Nagoya; Japan
| | - Tokiko Nagamura
- Department of Cell Processing and Transfusion; Institute of Medical Science; University of Tokyo; Tokyo; Japan
| | - Ritsuro Suzuki
- Department of HSCT Data Management and Biostatistics; Nagoya University; Nagoya; Japan
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21
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Singal AK, Salameh H, Singal A, Jampana SC, Freeman DH, Anderson KE, Brunder D. Management practices of hepatitis C virus infected alcoholic hepatitis patients: A survey of physicians. World J Gastrointest Pharmacol Ther 2013; 4:16-22. [PMID: 23667769 PMCID: PMC3644613 DOI: 10.4292/wjgpt.v4.i2.16] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 03/27/2013] [Accepted: 04/11/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To survey gastroenterologists and hepatologists regarding their current views on treating hepatitis C virus (HCV) infected alcoholic hepatitis (AH) patients.
METHODS: A sixteen item questionnaire was electronically mailed to gastroenterologists and hepatologists. A reminder was sent after 2 mo to increase the response rate. Participation of respondents was confidential. Accessing secured web site to respond to the questionnaire was considered as informed consent. Responses received on the secured website were downloaded in an excel sheet for data analysis.
RESULTS: Analyzing 416 responses to 1556 (27% response rate) emails, 57% respondents (56% gastroenterologists) reported HCV prevalence > 20% amongst AH patients. Sixty nine percent often treated AH and 46% preferred corticosteroids (CS). Proportion of respondents with consensus (75% or more respondents agreeing on question) on specific management of HCV infected AH were: routine HCV testing (94%), HCV not changing response to CS (80%) or pentoxifylline (91%), no change in approach to treating HCV infected AH (75%). None of respondent variables: age, specialty, annual number of patients seen, and HCV prevalence could predict respondent to be in consensus on any of or all 4 questions. Further, only 4% would choose CS for treating HCV infected AH as opposed to 47% while treating HCV negative AH.
CONCLUSION: Gastroenterologists and hepatologists believe that AH patients be routinely checked for HCV. However, there is lack of consensus on choice of drug for treatment and outcome of HCV positive AH patients. Studies are needed to develop guidelines for management of HCV infected AH patients.
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22
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Zarrinpar A, Busuttil RW. Immunomodulating options for liver transplant patients. Expert Rev Clin Immunol 2013; 8:565-78; quiz 578. [PMID: 22992151 DOI: 10.1586/eci.12.47] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Much has changed since the early years of liver transplantation. Improvements in post-transplant survival are largely due to more selective and less toxic immunosuppression regimens and advances in operative and perioperative care. This has allowed liver transplantation to become an extremely successful treatment option for patients with endstage liver disease. Beginning with cyclosporine, a cyclic endecapeptide of fungal origin and the first of the calcineurin inhibitors to find widespread use, immunosuppressive regimens have evolved to include additional calcineurin inhibitors, steroids, mTOR inhibitors, antimetabolites and antibodies, mostly targeting T-cell activation. This review will present currently available immunosuppressive agents used in the perioperative period of liver transplantation, as well as maintenance treatments, tailoring therapeutic strategies for specific populations, and advances in immune monitoring and tolerance.
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Affiliation(s)
- Ali Zarrinpar
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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23
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Clinical Pharmacokinetics and Pharmacodynamics of Prednisolone and Prednisone in Solid Organ Transplantation. Clin Pharmacokinet 2012; 51:711-41. [DOI: 10.1007/s40262-012-0007-8] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Pan Q, Tilanus HW, Metselaar HJ, Janssen HLA, van der Laan LJW. Virus-drug interactions--molecular insight into immunosuppression and HCV. Nat Rev Gastroenterol Hepatol 2012; 9:355-62. [PMID: 22508161 PMCID: PMC7097508 DOI: 10.1038/nrgastro.2012.67] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver transplantation is an effective treatment for end-stage liver disease that is attributable to chronic HCV infection. However, long-term outcomes are compromised by universal virological recurrence in the graft. Reinfection that occurs after transplantation has increased resistance to current interferon-based antiviral therapy and often leads to accelerated development of cirrhosis. Important risk factors for severe HCV recurrence are linked to immunosuppression. Owing to the lack of good randomized, controlled trials, the optimal choice of immunosuppressants is still debated. By contrast, much progress has been made in the understanding of HCV biology and the antiviral action of interferons. These new insights have greatly expanded our knowledge of the molecular interplay between HCV and immunosuppressive drugs. In this article, we explore the effect of different immunosuppressants on the complex cellular events involved in HCV infection and interferon signalling. Potential implications for clinical practice and future drug development are discussed.
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Affiliation(s)
- Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Hugo W. Tilanus
- Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Herold J. Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Harry L. A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Luc J. W. van der Laan
- Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
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25
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Samonakis DN, Germani G, Burroughs AK. Immunosuppression and HCV recurrence after liver transplantation. J Hepatol 2012; 56:973-83. [PMID: 21963518 DOI: 10.1016/j.jhep.2011.06.031] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Revised: 05/27/2011] [Accepted: 06/01/2011] [Indexed: 02/06/2023]
Abstract
HCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens. From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency. There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6 months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed.
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Affiliation(s)
- Dimitrios N Samonakis
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital and UCL, London, UK
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26
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Zaydfudim V, Feurer ID, Landman MP, Moore DE, Wright JK, Pinson CW. Reduction in corticosteroids is associated with better health-related quality of life after liver transplantation. J Am Coll Surg 2011; 214:164-73. [PMID: 22137824 DOI: 10.1016/j.jamcollsurg.2011.10.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 10/09/2011] [Accepted: 10/10/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Corticosteroid use during post-transplant immunosuppression contributes to documented long-term complications in liver transplant recipients. However, the effects of steroids on post-transplant physical and mental health-related quality of life (HRQOL) have not been established. We aimed to test the association between steroid-based immunosuppression and post-transplant HRQOL in liver transplant recipients. STUDY DESIGN We performed a retrospective analysis of prospective, longitudinal HRQOL measured using the Short Form 36 Health Survey physical and mental component summary scores, Beck Anxiety Inventory, and Center for Epidemiologic Studies Depression Scale. Steroid use (none, low [<10 mg/d], high [≥10 mg/d]) and temporally associated acute rejection (within previous 6 weeks, previous 7 to 12 weeks, and never or >12 weeks before HRQOL measurement) were determined at every post-transplant HRQOL data point. Linear mixed-effects models tested the effects of contemporaneous steroid use and dosing on post-transplant HRQOL. RESULTS The sample included 186 adult liver transplant recipients (mean age 54 ± 8 years, 70% male) with pre- and at least 1 post-transplant HRQOL data point. Individual follow-up post-transplant averaged 21 ± 18 months (range 1 to 74 months). After controlling for pre-transplant HRQOL, time post-transplant, pre-transplant diagnosis group, and temporally associated episodes of rejection, post-transplant high-dose steroid use (≥10 mg/d) was associated with lower physical component summary (p < 0.001) and mental component summary (p = 0.049) scores and increased Beck Anxiety Inventory (p = 0.015) scores. Low-dose steroid use (<10 mg/d) was not associated with post-transplant HRQOL in any model (all p ≥ 0.28). CONCLUSIONS High-dose steroid use for post-transplant immunosuppression in liver transplant recipients was associated with reduced physical and mental HRQOL, and increased symptoms of anxiety. There was an association between better HRQOL and steroid reduction to <10 mg/d in liver transplant recipients during a broad follow-up period.
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Affiliation(s)
- Victor Zaydfudim
- Department of Surgery and Vanderbilt Transplant Center, Vanderbilt University Medical Center, Nashville, TN, USA.
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27
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Klintmalm GB, Davis GL, Teperman L, Netto GJ, Washburn K, Rudich SM, Pomfret EA, Vargas HE, Brown R, Eckhoff D, Pruett TL, Roberts J, Mulligan DC, Charlton MR, Heffron TG, Ham JM, Douglas DD, Sher L, Baliga PK, Kinkhabwala M, Koneru B, Abecassis M, Millis M, Jennings LW, Fasola CG. A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C. Liver Transpl 2011; 17:1394-403. [PMID: 21850690 DOI: 10.1002/lt.22417] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.
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Ji F, Li Z, Xue H, Liu L, Deng H. Simultaneous occurrence of pleural effusion and interstitial pneumonitis after treatment with pegylated interferon for hepatitis C virus infection. South Med J 2011; 104:140-142. [PMID: 21206334 DOI: 10.1097/smj.0b013e318206f8e3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Combination of pegylated interferon and ribavirin has been the standard program for hepatitis C virus (HCV) infection. Pulmonary complications, although uncommon, have been reported in association with the use of interferon, and pleural effusion is rare. We report the second case of pleural effusion and interstitial pneumonitis in a patient treated with pegylated interferon and ribavirin for chronic HCV infection. The respiratory symptoms of our patient continued to progress even though the treatment with pegylated interferon had been withdrawn, but the symptoms improved dramatically following treatment with steroids.
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Affiliation(s)
- Fanpu Ji
- Department of Infectious Disease, Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China.
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Ji FP, Li ZX, Deng H, Xue HA, Liu Y, Li M. Diagnosis and management of interstitial pneumonitis associated with interferon therapy for chronic hepatitis C. World J Gastroenterol 2010; 16:4394-4399. [PMID: 20845505 PMCID: PMC2941061 DOI: 10.3748/wjg.v16.i35.4394] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 05/24/2010] [Accepted: 05/31/2010] [Indexed: 02/06/2023] Open
Abstract
Interstitial pneumonitis (IP) is an uncommon pulmonary complication associated with interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection. Pneumonitis can occur at any stage of HCV treatment, ranging from 2 to 48 wk, usually in the first 12 wk. Its most common symptoms are dyspnoea, dry cough, fever, fatigue, arthralgia or myalgia, and anorexia, which are reversible in most cases after cessation of IFN therapy with a mean subsequent recovery time of 7.5 wk. Bronchoalveolar lavage in combination with chest high resolution computed tomography has a high diagnostic value. Prompt discontinuation of medication is the cornerstone, and corticosteroid therapy may not be essential for patients with mild-moderate pulmonary functional impairment. The severity of pulmonary injury is associated with the rapid development of IP. We suggest that methylprednisolone pulse therapy followed by low dose prednisolone for a short term is necessary to minimize the risk of fatal pulmonary damage if signs of significant pulmonary toxicity occur in earlier stage. Clinicians should be aware of the potential pulmonary complication related to the drug, so that an early and opportune diagnosis can be made.
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Acute hepatitis after autologous stem cell transplantation and rapid progression to liver cirrhosis. Eur J Gastroenterol Hepatol 2010; 22:1141-4. [PMID: 20463583 DOI: 10.1097/meg.0b013e32833a064a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A 51-year-old woman was diagnosed with a diffuse cerebral large cell lymphoma. During the period of a combined chemotherapy followed by autologous stem cell transplantation with multiple blood donations, an acute hepatitis without hepatitis C antibodies was diagnosed. Liver biopsy showed steatohepatitis, initially thought to be related to chemotherapy. Sixteen months after the transplantation, liver cirrhosis appeared with circulatory bypass. Retrospectively, testing of serum samples showed a hepatitis C infection. Infection with the hepatitis C virus (HCV) from a blood donation was excluded through retrospective testing for HCV-RNA of blood donors. Finally, the cause of infection remained elusive. Hepatitis serology is not a reliable test under immunosuppressive therapy. The course of progression to liver cirrhosis in the presented short period of 22 months after HCV infection is remarkable and has - to our knowledge - not been reported in literature before.
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Ciesek S, Steinmann E, Iken M, Ott M, Helfritz FA, Wappler I, Manns MP, Wedemeyer H, Pietschmann T. Glucocorticosteroids increase cell entry by hepatitis C virus. Gastroenterology 2010; 138:1875-84. [PMID: 20152835 DOI: 10.1053/j.gastro.2010.02.004] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2009] [Revised: 01/20/2010] [Accepted: 02/03/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Corticosteroids are used as immunosuppressants in patients with autoimmune disorders and transplant recipients. However, these drugs worsen hepatitis C virus (HCV) recurrence after liver transplantation, suggesting that they may directly exacerbate HCV infection. METHODS The influence of immunosuppressive drugs on HCV replication, assembly, and entry was assessed in Huh-7.5 cells and primary human hepatocytes using cell culture- and patient-derived HCV. Replication was quantified by immunofluorescence, luciferase assays, quantitative reverse-transcriptase polymerase chain reaction, or core enzyme-linked immunosorbent assays. Expression of HCV entry factors was evaluated by cell sorting and immunoblot analyses. RESULTS Glucocorticosteroids slightly reduced HCV RNA replication but increased efficiency of HCV entry by up to 10-fold. This was independent of HCV genotype but specific to HCV because vesicular stomatitis virus glycoprotein-dependent infection was not affected by these drugs. The increase in HCV entry was accompanied by up-regulation of messenger RNA and protein levels of occludin and the scavenger receptor class B type I-2 host cell proteins required for HCV infection; increase of entry by glucocorticosteroids was ablated by RU-486, an inhibitor of glucocorticosteroid signaling. Glucocorticosteroids increased propagation of cell culture-derived HCV approximately 5- to 10-fold in partially differentiated human hepatoma cells and increased infection of primary human hepatocytes by cell culture- and patient-derived HCV. CONCLUSIONS Glucocorticosteroides specifically increase HCV entry by up-regulating the cell entry factors occludin and scavenger receptor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due to increased HCV dissemination.
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Affiliation(s)
- Sandra Ciesek
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
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Nonventilatory strategies for patients with life-threatening 2009 H1N1 influenza and severe respiratory failure. Crit Care Med 2010; 38:e74-90. [PMID: 20035216 DOI: 10.1097/ccm.0b013e3181cc5373] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Severe respiratory failure (including acute lung injury and acute respiratory distress syndrome) caused by 2009 H1N1 influenza infection has been reported worldwide. Refractory hypoxemia is a common finding in these patients and can be challenging to manage. This review focuses on nonventilatory strategies in the advanced treatment of severe respiratory failure and refractory hypoxemia such as that seen in patients with severe acute respiratory distress syndrome attributable to 2009 H1N1 influenza. Specific modalities covered include conservative fluid management, prone positioning, inhaled nitric oxide, inhaled vasodilatory prostaglandins, and extracorporeal membrane oxygenation and life support. Pharmacologic strategies (including steroids) investigated for the treatment of severe respiratory failure are also reviewed.
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Manousou P, Samonakis D, Cholongitas E, Patch D, O'Beirne J, Dhillon AP, Rolles K, McCormick A, Hayes P, Burroughs AK. Outcome of recurrent hepatitis C virus after liver transplantation in a randomized trial of tacrolimus monotherapy versus triple therapy. Liver Transpl 2009; 15:1783-91. [PMID: 19938143 DOI: 10.1002/lt.21907] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Less potent immunosuppression is considered to reduce the severity of hepatitis C virus (HCV) recurrence after liver transplantation. An optimal regimen is unknown. We evaluated tacrolimus monotherapy versus triple therapy in a randomized trial of 103 first transplants for HCV cirrhosis. One hundred three patients who underwent transplantation for HCV were randomized to tacrolimus monotherapy (n = 54) or triple therapy with tacrolimus, azathioprine, and steroids (n = 49), which were tapered to zero by 3 to 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. The time to reach Ishak stage 4 was the predetermined endpoint. All factors documented in the literature as being associated with HCV recurrence and the allocated treatment were evaluated for reaching stage 4 and HVPG >or= 10 mm Hg. No significant preoperative, perioperative, or postoperative differences, including the frequency of biopsies between groups, were found. During a mean follow-up of 53.5 months, 9 monotherapy patients and 6 triple therapy patients died, and 5 monotherapy patients and 4 triple therapy patients underwent retransplantation. Stage 4 fibrosis was reached in 17 monotherapy patients and 10 triple therapy patients (P = 0.04), with slower fibrosis progression in the triple therapy patients (P = 0.048). Allocated therapy and histological acute hepatitis were independently associated with stage 4 fibrosis. HVPG increased to >or=10 mm Hg more rapidly in monotherapy patients versus triple therapy patients (P = 0.038). In conclusion, long-term maintenance immunosuppression with azathioprine and shorter term prednisolone with tacrolimus in HCV cirrhosis recipients resulted in a slower onset of histologically proven severe fibrosis and portal hypertension in comparison with tacrolimus alone, and this was independent of known factors affecting fibrosis.
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Affiliation(s)
- Pinelopi Manousou
- Royal Free Sheila Sherlock Liver Centre, Division of Surgery and Interventional Sciences, University College London, London, United Kingdom
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Abstract
Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease. Beginning with the revolutionary discovery of cyclosporine in the 1970s, immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors, anti-metabolites, mTOR inhibitors, steroids and antibody-based therapies. These agents target different sites in the T cell activation cascade, usually by inhibiting T cell activation or via T cell depletion. They are used as induction therapy in the immediate peri- and post-operative period, as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon.
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Shankar A, Alexander G. Liver transplantation for liver disease caused by hepatitis C virus infection. Br J Hosp Med (Lond) 2009; 70:95-100. [PMID: 19229150 DOI: 10.12968/hmed.2009.70.2.38908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hepatitis C is an important problem that often requires liver transplantation. However, outcomes have not improved in line with liver transplants for other indications. This article explores the issues surrounding this difficult area of transplant hepatology.
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Affiliation(s)
- Arun Shankar
- Department of Hepatology, Addenbrooke's Hospital, Cambridge
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36
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Huang HH, Hsieh CY. In Reply. J Clin Oncol 2008. [DOI: 10.1200/jco.2008.18.8276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Hsin-Hui Huang
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ching-Yun Hsieh
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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