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Wang J, Qiu K, Zhou S, Gan Y, Jiang K, Wang D, Wang H. Risk factors for hepatocellular carcinoma: an umbrella review of systematic review and meta-analysis. Ann Med 2025; 57:2455539. [PMID: 39834076 PMCID: PMC11753015 DOI: 10.1080/07853890.2025.2455539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength. METHODS This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria. RESULTS We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk. CONCLUSIONS HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.
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Affiliation(s)
- Jie Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Kaijie Qiu
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Songsheng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Yichao Gan
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Keting Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Donghuan Wang
- Operations Department, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Haibiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
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Pham N, Benhammou JN. Statins in Chronic Liver Disease: Review of the Literature and Future Role. Semin Liver Dis 2024; 44:191-208. [PMID: 38701856 DOI: 10.1055/a-2319-0694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.
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Affiliation(s)
- Nguyen Pham
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jihane N Benhammou
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
- Veterans Affairs Greater Los Angeles, Los Angeles, California
- Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, California
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3
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Qin C, Xie T, Yeh WW, Savas AC, Feng P. Metabolic Enzymes in Viral Infection and Host Innate Immunity. Viruses 2023; 16:35. [PMID: 38257735 PMCID: PMC10820379 DOI: 10.3390/v16010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024] Open
Abstract
Metabolic enzymes are central players for cell metabolism and cell proliferation. These enzymes perform distinct functions in various cellular processes, such as cell metabolism and immune defense. Because viral infections inevitably trigger host immune activation, viruses have evolved diverse strategies to blunt or exploit the host immune response to enable viral replication. Meanwhile, viruses hijack key cellular metabolic enzymes to reprogram metabolism, which generates the necessary biomolecules for viral replication. An emerging theme arising from the metabolic studies of viral infection is that metabolic enzymes are key players of immune response and, conversely, immune components regulate cellular metabolism, revealing unexpected communication between these two fundamental processes that are otherwise disjointed. This review aims to summarize our present comprehension of the involvement of metabolic enzymes in viral infections and host immunity and to provide insights for potential antiviral therapy targeting metabolic enzymes.
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Affiliation(s)
- Chao Qin
- Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA
| | | | | | | | - Pinghui Feng
- Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA
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Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact. Biomedicines 2023; 11:biomedicines11020271. [PMID: 36830808 PMCID: PMC9953247 DOI: 10.3390/biomedicines11020271] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.
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Mustafin R. Prospects for the use of statins in antiviral therapy. CLINICAL MICROBIOLOGY AND ANTIMICROBIAL CHEMOTHERAPY 2023; 25:56-67. [DOI: 10.36488/cmac.2023.1.56-67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Inhibitors of hydroxymethylglutaryl-CoA reductase, in addition to suppressing cholesterol synthesis, have an antiviral effect. Clinical studies have shown antiviral efficacy of statins against COVID-19, HCV, HBV, RSV, HIV, influenza viruses. The ability of statins to inhibit influenza viruses, COVID-19, RSV, HIV, as well as Ebola, Zika, Dengue, Coxsackie, rotaviruses, ADV, HDV, HHV was experimentally confirmed. Statins can also enhance the effects of antiviral drugs, making them more effective in treating infections. Therefore, the use of statins in the complex therapy of viral infections is promising. In addition, the role of influenza viruses, T-cell leukemia and herpesviruses, HIV, HBV, HCV, HPV in the development of atherosclerosis has been identified, so the use of statins in complex treatment is also necessary to correct endothelial dysfunction that occurs under the influence of viruses. Since the activity of retroelements that are evolutionarily related to exogenous viruses increases with aging, it has been suggested that retrotransposons can also be targets for statins. This is evidenced by a change in the expression of non-coding RNAs under the action of statins, since the key sources of non-coding RNAs are retroelements. This property may be an additional factor in the prescription of statins to increase life expectancy, in addition to the prevention and treatment of atherosclerosis, since pathological activation of retroelements are the causes of aging. Viruses, like retroelements, are involved in the pathogenesis of malignant neoplasms, in the treatment of which statins have shown their effectiveness and the ability to enhance the effect of anticancer drugs, overcoming chemoresistance (similar to the potentiation of antiviral drugs). One of the mechanisms of this activity of statins may be their effect on retroelements and viruses.
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Clark EH, Ahmed ST, Chang E, Chiao EY, White DL. Can statins lessen the burden of virus mediated cancers? Infect Agent Cancer 2022; 17:47. [PMID: 36058947 PMCID: PMC9441070 DOI: 10.1186/s13027-022-00460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Oncogenic viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), and Kaposi Sarcoma Herpes virus (KSHV) contribute to a significant proportion of the world's cancers. Given the sizeable burden of virus mediated cancers, development of strategies to prevent and/or treat these cancers is critical. While large population studies suggest that treatment with hydroxymethylglutaryl-CoA reductase inhibitors, commonly known as statins, may reduce the risk of many cancer types including HBV/HCV related hepatocellular carcinoma, few studies have specifically evaluated the impact of statin use in populations at risk for other types of virus mediated cancers. MAIN BODY Studies of populations with HBV and HCV suggest a protective, dose-dependent effect of statins on hepatocellular carcinoma risk and support the theory that statins may offer clinical benefit if used as chemoprophylactic agents to reduce liver cancer incidence. However, no population level data exists describing the impact of statins on populations with other oncogenic viral infections, such as HPV, EBV, and KSHV. CONCLUSION Further study of statin use in diverse, global populations with or at high risk for oncogenic viral infections is essential to determine the impact of statin therapy on virus mediated cancer risk.
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Affiliation(s)
- Eva H Clark
- Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA.
- Section of Pediatric Tropical Medicine, Baylor College of Medicin, Feigin Building Suite 550, Houston, TX, 77030, USA.
| | - Sarah T Ahmed
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elaine Chang
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elizabeth Y Chiao
- Departments of Epidemiology and General Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Donna L White
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
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7
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Wang Y, Wang W, Wang M, Shi J, Jia X, Dang S. A Meta-Analysis of Statin Use and Risk of Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2022; 2022:5389044. [PMID: 35356132 PMCID: PMC8958112 DOI: 10.1155/2022/5389044] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The use of statins is a potential protective factor against the development of hepatocellular carcinoma. Therefore, we conducted a meta-analysis to evaluate the contribution of statins to the risk of hepatocellular carcinoma. METHODS We searched for PubMed and EMBASE through January 2021. RESULTS Thirty-two studies (eighteen cohort, eleven case-control, and three randomized controlled trials) reporting 56,838 cases of hepatocellular carcinoma in 4,963,518 persons were included. Statin users were less likely to develop hepatocellular carcinoma than nonusers (adjusted odds ratio, 0.58; 95% CI: 0.51-0.67). Stratified analysis showed that statins reduced the risk of hepatocellular carcinoma in Asian and Western populations (odds ratio, 0.54 vs. 0.60). Besides, statins have protective effects against hepatocellular carcinoma after hepatitis B virus (odds ratio, 0.44; 95% CI: 0.22-0.85) and hepatitis C virus infections (odds ratio, 0.53; 95% CI: 0.49-0.57). Statins have protective effects on people with chronic liver disease (odds ratio, 0.52; 95% CI: 0.40-0.68) and on the general population (odds ratio, 0.60; 95% CI: 0.50-0.72). Lipophilic statins can prevent hepatocellular carcinoma (odds ratio, 0.51, 95% CI: 0.46-0.57), while hydrophilic statins cannot (odds ratio, 0.77, 95% CI: 0.58-1.02). The single-drug analyses showed that simvastatin (odds ratio, 0.53, 95% CI: 0.48-0.59), atorvastatin (odds ratio, 0.54, 95% CI: 0.45-0.64), rosuvastatin (odds ratio, 0.55, 95% CI: 0.37-0.83), lovastatin (odds ratio, 0.30, 95% CI: 0.15-0.62), and pitavastatin (odds ratio, 0.36, 95% CI: 0.17-0.75) had significant benefits. Further studies have shown that those in the high-dose group experienced better effects in preventing hepatocellular carcinoma (adjusted hazard ratio, 0.38 vs. 0.55). Further research found that the combined use of aspirin did not increase the chemoprevention effect of liver cancer (odds ratio, 0.57; 95% CI: 0.40-0.81). In addition, the preventive effect of statins improved with the extension of follow-up time (odds ratio, 0.54 vs. 0.65). CONCLUSION Our meta-analysis shows that the use of statins is associated with a lower risk of liver cancer.
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Affiliation(s)
- Yikai Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Muqi Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Juanjuan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
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Valenti L, Pelusi S, Aghemo A, Gritti S, Pasulo L, Bianco C, Iegri C, Cologni G, Degasperi E, D'Ambrosio R, Del Poggio P, Soria A, Puoti M, Carderi I, Pigozzi MG, Carriero C, Spinetti A, Zuccaro V, Memoli M, Giorgini A, Viganò M, Rumi MG, Re T, Spinelli O, Colombo MC, Quirino T, Menzaghi B, Lorini G, Pan A, D'Arminio Monforte A, Buscarini E, Autolitano A, Bonfanti P, Terreni N, Aimo G, Mendeni M, Prati D, Lampertico P, Colombo M, Fagiuoli S. Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study. Hepatol Commun 2021; 6:867-877. [PMID: 34811949 PMCID: PMC8948549 DOI: 10.1002/hep4.1851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real‐life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE‐Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow‐up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03‐1.09) and diabetes (OR 2.01 [1.65‐2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35‐0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20‐3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16‐6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11‐0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi‐disciplinary management approach may improve cardiovascular and possibly liver‐related outcomes.
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Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Serena Pelusi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Alessio Aghemo
- Department of Internal Medicine and Hepatology, Humanitas University and Research Hospital, Rozzano, Italy
| | - Sara Gritti
- Fondazione Ricerca Ospedale di Bergamo, Papa Giovanni Hospital, Bergamo, Italy
| | - Luisa Pasulo
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
| | - Cristiana Bianco
- Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Claudia Iegri
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
| | - Giuliana Cologni
- Department of Internal Medicine, Papa Giovanni Hospital, Bergamo, Italy
| | - Elisabetta Degasperi
- Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Roberta D'Ambrosio
- Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Paolo Del Poggio
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Zingonia, Italy
| | - Alessandro Soria
- Division of Infectious Diseases, San Gerardo Hospital-ASST Monza, Monza, Italy
| | - Massimo Puoti
- Department of Infectious Diseases, Hepatitis Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | | | | | - Canio Carriero
- Department of Infectious Diseases, Spedali Civili Hospital-ASST Brescia, Brescia, Italy
| | - Angiola Spinetti
- Department of Infectious Diseases, Spedali Civili Hospital-ASST Brescia, Brescia, Italy
| | - Valentina Zuccaro
- Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia, Italy
| | - Massimo Memoli
- Liver Center, San Raffaele Scientific Institute IRCCS, Milano, Italy
| | - Alessia Giorgini
- Department of Gastroenterology and Hepatology, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Mauro Viganò
- Department of Gastroenterology and Hepatology, San Giuseppe Hospital, Milan, Italy
| | - Maria Grazia Rumi
- Department of Gastroenterology and Hepatology, San Giuseppe Hospital, Milan, Italy
| | - Tiziana Re
- Department of Gastroenterology and Hepatology, Legnano Hospital-ASST Milano Ovest, Milan, Italy
| | - Ombretta Spinelli
- Department of Gastroenterology and Hepatology, Lariana Como Hospital, Milan, Italy
| | - Maria Chiara Colombo
- Department of Gastroenterology and Hepatology, Lariana Como Hospital, Milan, Italy
| | - Tiziana Quirino
- Department of Gastroenterology and Hepatology, Busto Arsizio Hospital ASST Valle Olona, Milan, Italy
| | - Barbara Menzaghi
- Department of Gastroenterology and Hepatology, Busto Arsizio Hospital ASST Valle Olona, Milan, Italy
| | - Gianpaolo Lorini
- Department of Gastroenterology and Hepatology, ASST Franciacorta, Milan, Italy
| | - Angelo Pan
- Department of Internal Medicine, Ospedale di Cremona, Cremona, Italy
| | | | | | | | - Paolo Bonfanti
- Division of Infectious Diseases, ASST Lecco, Lecco, Italy
| | | | | | | | - Daniele Prati
- Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Pietro Lampertico
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy.,CRC "AM. and A. Migliavacca" Center for Liver Disease, Università degli Studi di Milano, Milano, Italy
| | - Massimo Colombo
- Liver Center, San Raffaele Scientific Institute IRCCS, Milano, Italy
| | - Stefano Fagiuoli
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
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Hsu CS, Liu WL, Li Q, Lowey B, Hertz L, Chao YC, Liang TJ, Chen DS, Kao JH. Hepatitis C virus genotypes 1-3 infections regulate lipogenic signaling and suppress cholesterol biosynthesis in hepatocytes. J Formos Med Assoc 2020; 119:1382-1395. [PMID: 32284164 PMCID: PMC11492201 DOI: 10.1016/j.jfma.2020.03.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/18/2020] [Accepted: 03/23/2020] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Patients with different hepatitis C virus (HCV) genotype infections are associated with varying metabolic disorders. Although alteration of lipid metabolism has been confirmed as a virus-induced metabolic derangement in chronic hepatitis C patients, the impact of various HCV genotypes on hepatic cholesterol metabolism remains elusive. In this study, we thus investigated the HCV genotype-specific lipogenic and cholesterol metabolism profiles in an in vitro cell culture system. METHODS We first conducted HCV cell culture system (HCVcc) assays by infecting Huh7.5.1 cells with multiple infection-competent HCV strains, including the genotype 2a JFH1 and JFH1-based intergenotypic recombinants 1b and 3a. We then examined the expression levels of various lipid and cholesterol-related genes. RESULTS The data showed that infection with individual HCV genotypes exerted unique gene expression regulatory effects on lipoproteins and cholesterol metabolism genes. Of note, all HCV strains suppressed cholesterol biosynthesis in hepatocytes through downregulating the expression of HMG-CoA reductase (HMGCR) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) - two essential enzymes for cholesterol biosynthesis. These HCV-mediated inhibitory effects could be reversed by treatment with sofosbuvir, a pangenotypic NS5B inhibitor. In addition, overexpression of HCV genotype 1b, 2a or 3a core protein significantly suppressed HMGCR mRNA transcription and translation, thus diminished cellular cholesterol biosynthesis. Nonetheless, the core protein had no effect on FDFT1 expression. CONCLUSION Although HCV infection regulates host lipid metabolism in a genotype-specific manner, its inhibition on hepatocellular cholesterogenic gene expression and total cholesterol biosynthesis is a common effect among HCV genotype 1b, 2a and 3a.
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Affiliation(s)
- Ching-Sheng Hsu
- Liver Diseases Research Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan; School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Wei-Liang Liu
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Qisheng Li
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Brianna Lowey
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Laura Hertz
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - You-Chen Chao
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Nankang, 11549, Taiwan
| | - Jia-Horng Kao
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
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10
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Graf C, Welzel T, Bogdanou D, Vermehren J, Beckel A, Bojunga J, Friedrich-Rust M, Dietz J, Kubesch A, Mondorf A, Fischer S, Lutz T, Stoffers P, Herrmann E, Poynard T, Zeuzem S, Dultz G, Mihm U. Hepatitis C Clearance by Direct-Acting Antivirals Impacts Glucose and Lipid Homeostasis. J Clin Med 2020; 9:E2702. [PMID: 32825571 PMCID: PMC7564474 DOI: 10.3390/jcm9092702] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. METHODS 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. RESULTS 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). CONCLUSION Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.
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Affiliation(s)
- Christiana Graf
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Tania Welzel
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Dimitra Bogdanou
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Johannes Vermehren
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Anita Beckel
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Jörg Bojunga
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Mireen Friedrich-Rust
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Julia Dietz
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Alica Kubesch
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Antonia Mondorf
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Sarah Fischer
- Infektiologikum, Center for Infectious Diseases, 60596 Frankfurt, Germany; (S.F.); (T.L.)
| | - Thomas Lutz
- Infektiologikum, Center for Infectious Diseases, 60596 Frankfurt, Germany; (S.F.); (T.L.)
| | - Philipp Stoffers
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, 60596 Frankfurt, Germany;
| | | | - Stefan Zeuzem
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Georg Dultz
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
| | - Ulrike Mihm
- Department of Internal Medicine, University Hospital Frankfurt, 60596 Frankfurt, Germany; (T.W.); (D.B.); (J.V.); (A.B.); (J.B.); (M.F.-R.); (J.D.); (A.K.); (A.M.); (P.S.); (S.Z.); (G.D.); (U.M.)
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11
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Tallorin L, Villareal VA, Hsia CY, Rodgers MA, Burri DJ, Pfeil MP, Llopis PM, Lindenbach BD, Yang PL. Hepatitis C virus NS3-4A protease regulates the lipid environment for RNA replication by cleaving host enzyme 24-dehydrocholesterol reductase. J Biol Chem 2020; 295:12426-12436. [PMID: 32641492 PMCID: PMC7458815 DOI: 10.1074/jbc.ra120.013455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Many RNA viruses create specialized membranes for genome replication by manipulating host lipid metabolism and trafficking, but in most cases, we do not know the molecular mechanisms responsible or how specific lipids may impact the associated membrane and viral process. For example, hepatitis C virus (HCV) causes a specific, large-fold increase in the steady-state abundance of intracellular desmosterol, an immediate precursor of cholesterol, resulting in increased fluidity of the membrane where HCV RNA replication occurs. Here, we establish the mechanism responsible for HCV's effect on intracellular desmosterol, whereby the HCV NS3-4A protease controls activity of 24-dehydrocholesterol reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol. Our cumulative evidence for the proposed mechanism includes immunofluorescence microscopy experiments showing co-occurrence of DHCR24 and HCV NS3-4A protease; formation of an additional, faster-migrating DHCR24 species (DHCR24*) in cells harboring a HCV subgenomic replicon RNA or ectopically expressing NS3-4A; and biochemical evidence that NS3-4A cleaves DHCR24 to produce DHCR24* in vitro and in vivo. We further demonstrate that NS3-4A cleaves DHCR24 between residues Cys91 and Thr92 and show that this reduces the intracellular conversion of desmosterol to cholesterol. Together, these studies demonstrate that NS3-4A directly cleaves DHCR24 and that this results in the enrichment of desmosterol in the membranes where NS3-4A and DHCR24 co-occur. Overall, this suggests a model in which HCV directly regulates the lipid environment for RNA replication through direct effects on the host lipid metabolism.
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Affiliation(s)
- Lorillee Tallorin
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Valerie A Villareal
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Chih-Yun Hsia
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Mary A Rodgers
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Dominique J Burri
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Marc-Philipp Pfeil
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Paula Montero Llopis
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Brett D Lindenbach
- Department of Microbial Pathogenesis, Yale Medical School, New Haven, Connecticut, USA
| | - Priscilla L Yang
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
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12
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Xun Z, Lin JP, Liu C, Huang JL, Shen Y, Xu SY, Wu WN, Ou QS. Association of serum total cholesterol with pegylated interferon-α treatment in HBeAg-positive chronic hepatitis B patients. Antivir Ther 2020; 24:85-93. [PMID: 30520414 DOI: 10.3851/imp3282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recent studies suggest that serum lipids are associated with pegylated interferon-alpha (PEG-IFN-α) treatment response in chronic hepatitis C patients. However, the role of serum lipids in influencing the outcome of HBV treatment is not well understood. This study aims to investigate the association of serum lipids with the response to interferon-alpha treatment for chronic hepatitis B (CHB) patients. METHODS We dynamically measured 11 clinical serum lipid parameters of 119 hepatitis B e antigen (HBeAg)-positive CHB patients, including 53 patients who achieved sustained response (SR) and 66 patients who achieved non-response (NR) induced by PEG-IFN-α treatment for 48 weeks. RESULTS The dynamic analysis showed that the baseline serum total cholesterol (TCHO) level was higher in the NR group than that in the SR group (P=0.004). Moreover, the correlation analysis demonstrated a significant positive correlation between TCHO and hepatitis B surface antigen (HBsAg) at baseline (P=0.009). In addition, CHB patients with high baseline TCHO levels exhibited higher HBV DNA, HBsAg, HBeAg and hepatitis B e antibody (HBeAb) levels during early treatment periods (weeks 0, 4, 12 and 24) than those with the low TCHO levels. Furthermore, the logistic regression analysis identified that baseline serum TCHO was a risk factor for NR achievement (OR=4.94; P=0.047). CONCLUSIONS Our results indicated that serum TCHO was associated with PEG-IFN-α therapeutic response in HBeAg-positive CHB patients which suggested that serum TCHO could be useful as an auxiliary clinical factor to predict poor efficacy of PEG-IFN-α therapy.
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Affiliation(s)
- Zhen Xun
- First Clinical College, Fujian Medical University, Fuzhou, China.,Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jin-Piao Lin
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Can Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jin-Lan Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ye Shen
- First Clinical College, Fujian Medical University, Fuzhou, China.,Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Si-Yi Xu
- First Clinical College, Fujian Medical University, Fuzhou, China.,Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Wen-Nan Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qi-Shui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Gene Diagnostic Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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13
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Wang CP, Kuhn J, Shah DP, Schmidt S, Lam YWF, MacCarthy D, Tenner L, Ramirez AG. Metformin modifies disparity in hepatocellular carcinoma incidence in men with type 2 diabetes but without chronic liver diseases. Cancer Med 2019; 8:3206-3215. [PMID: 30993905 PMCID: PMC6558591 DOI: 10.1002/cam4.2142] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 03/06/2019] [Accepted: 03/15/2019] [Indexed: 12/18/2022] Open
Abstract
Background We assessed racial/ethnic disparity in hepatocellular carcinoma (HCC) incidence among men with type 2 diabetes (T2D) but without chronic liver diseases (CLD), and whether metformin use modified the disparity. Methods Study cohort: the nationwide Veterans Administration Health Care System electronic medical records among 40‐89 years old men with T2D; without CLD, cancer, cardiovascular or renal diseases previously; insulin and thiazolidinedione naive. Logistic regression analyses compared HCC incidence between race/ethnicity groups under no metformin use adjusted for covariates and inverse propensity score weights (IPSW) for race/ethnicity. The generalizability technique integrated with IPSW was incorporated to compare covariates adjusted odds ratios (aOR) of HCC associated with metformin use among race/ethnicity groups. Results Study cohort: N = 84 433; 79.47% non‐Hispanic white (NHW), 15.5% non‐Hispanic African American (NHAA), 5.03% Hispanics; 36.76% metformin users; follow‐up 6.10 ± 2.87 years; age 67.8 ± 9.8 years, HbA1c 6.57 ± 0.98%; 0.14% HCC cases. Under no metformin use, HCC incidence was lower for NHAA vs NHW (aOR = 0.60 [0.40‐0.92]), similar between NHW and Hispanics. Metformin was associated with reduced HCC risk: aOR = 0.57 (0.40‐0.81) for NHW; aOR = 0.35 (0.25‐0.47) for NHAA; aOR = 0.31 (0.22‐0.43) for Hispanics. Metformin dose >1000 mg/d was neutral for NHW; less effective for NHAA (P = 0.02); more effective for Hispanics (P = 0.002). Conclusions In men with T2D but without CLD nor metformin use, HCC incidence was lower for NHAA compared to NHW or Hispanics; similar between NHW and Hispanics. Metformin use reduced HCC risk and modified the race/ethnicity disparity. Impact Metformin's heterogeneous HCC prevention effect elucidates potential interventions to modify HCC disparity in patients with T2D.
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Affiliation(s)
- Chen-Pin Wang
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
| | - John Kuhn
- Department of Pharmacology, UTHSCSA, San Antonio, Texas
| | - Dimpy P Shah
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas.,Institute for Health Promotion Research, UTHSCS, San Antonio, Texas
| | - Susanne Schmidt
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
| | | | - Daniel MacCarthy
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
| | | | - Amelie G Ramirez
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas.,Institute for Health Promotion Research, UTHSCS, San Antonio, Texas
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14
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Chida T, Kawata K, Ohta K, Matsunaga E, Ito J, Shimoyama S, Yamazaki S, Noritake H, Suzuki T, Suda T, Kobayashi Y. Rapid Changes in Serum Lipid Profiles during Combination Therapy with Daclatasvir and Asunaprevir in Patients Infected with Hepatitis C Virus Genotype 1b. Gut Liver 2018; 12:201-207. [PMID: 29212314 PMCID: PMC5832345 DOI: 10.5009/gnl17179] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 06/28/2017] [Accepted: 06/28/2017] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Changes in lipid profiles in patients infected with hepatitis C virus (HCV) during direct-acting antiviral therapy have been reported in recent years. However, the clinical aspects of disturbed lipid metabolism in chronic HCV infection have not been fully elucidated. Methods Dynamic changes in serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and apolipoprotein levels in patients infected with HCV genotype 1b were examined during combination therapy with daclatasvir (DCV) and asunaprevir (ASV). Results Total, LDL−, and HDL-cholesterol levels increased rapidly and persistently after week 4. Apolipoprotein (apo) A-I, apo B, apo C-II, and apo C-III levels were significantly higher at week 4 than at week 0. In contrast, apo A-II and apo E levels were significantly lower. The differences in LDL− and HDL-cholesterol levels were positively correlated with those of apo B and apo A-I, respectively. Interestingly, in patients with non-sustained virological response, these cholesterol levels decreased rapidly after viral breakthrough or viral relapse. Furthermore, similar changes were observed for apo A-I, apo B and apo C-III levels. Conclusions Clearance of HCV using combination therapy with DCV and ASV results in rapid changes in serum lipid profiles, suggesting an influence of HCV infection on disturbed lipid metabolism.
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Affiliation(s)
- Takeshi Chida
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuhito Kawata
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuyoshi Ohta
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Erika Matsunaga
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Jun Ito
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Shin Shimoyama
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoru Yamazaki
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hidenao Noritake
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takafumi Suda
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshimasa Kobayashi
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
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15
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Moctezuma-Velázquez C, Abraldes JG, Montano-Loza AJ. The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis. ACTA ACUST UNITED AC 2018; 16:226-240. [PMID: 29572618 DOI: 10.1007/s11938-018-0180-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Statins are drugs developed to treat hypercholesterolemia. Its use in patients with liver disease has been limited because one of its potential and most feared side effects is hepatotoxicity. However, there is robust evidence that supports the safety of statins in this population in the absence of severe liver dysfunction. In this review, we will summarize the efficacy and safety of statins in cirrhosis. RECENT FINDINGS Statins are effective in the treatment of dyslipidemia in patients with liver disease, because of their pleiotropic properties. These properties are independent of their effect on cholesterol levels, such as improving endothelial dysfunction or having antioxidant, antifibrotic, anti-inflammatory, antiproliferative, antiangiogenic, proapoptotic, or immunomodulation properties. Statins have been studied in other areas such as in treatment of portal hypertension, prevention of hepatocellular carcinoma, and/or protection against ischemia/reperfusion injury. Approved indications for statins in patients with cirrhosis are those of the general population, including dyslipidemia and increased cardiovascular risk. Compensated cirrhosis is not a contraindication. In patients with decompensated cirrhosis, statins should be prescribed with extreme caution at low doses, and with frequent monitoring of creatinine phosphokinase levels in order to detect adverse events in a timely fashion.
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Affiliation(s)
- Carlos Moctezuma-Velázquez
- Division of Gastroenterology and Liver Unit, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta, T6G 2X8, Canada
| | - Juan G Abraldes
- Division of Gastroenterology and Liver Unit, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta, T6G 2X8, Canada
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, 8540 112 Street NW, Zeidler Ledcor Centre, Room 1-20B, Edmonton, Alberta, T6G 2X8, Canada.
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16
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Crouchet E, Wrensch F, Schuster C, Zeisel MB, Baumert TF. Host-targeting therapies for hepatitis C virus infection: current developments and future applications. Therap Adv Gastroenterol 2018; 11:1756284818759483. [PMID: 29619090 PMCID: PMC5871046 DOI: 10.1177/1756284818759483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/15/2018] [Indexed: 02/04/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) worldwide. In the past few years, anti-HCV therapies have undergone a revolution with the approval of multiple direct-acting antivirals (DAAs), which enable interferon-free treatments with considerable improvement of sustained virologic response in patients. Today, DAAs have become the standard of care for HCV therapy. However, several limitations remain, which include access to therapy, treatment failure in a subset of patients and persistent risk of HCC development following cure in patients with advanced fibrosis. By targeting conserved host proteins involved in the HCV life cycle, host-targeting agents (HTAs) offer opportunities for pan-genotypic antiviral approaches with a high barrier to drug resistance. Moreover, when applied in combination with DAAs, HTAs could improve the management of difficult-to-treat patients by acting through a complementary mechanism of action. In this review, we summarize the different HTAs evaluated in preclinical and clinical development and discuss their potential role for anti-HCV therapies.
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Affiliation(s)
- Emilie Crouchet
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Florian Wrensch
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Catherine Schuster
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Mirjam B. Zeisel
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France
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17
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Jalilian S, Latifi SM, Makvandi M, Teimoori A, Azaran A, Parsanahad M, Kayedani G. The evaluation of interferon lambda 4 rs368234815 as a predictor factor in treated patients with chronic hepatitis C genotype 1a infection. Indian J Med Microbiol 2018; 35:262-268. [PMID: 28681817 DOI: 10.4103/ijmm.ijmm_16_309] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONTEXT Host factors including single-nucleotide polymorphisms (SNPs) in or near interferon lambda (IFNL) gene are the important factors in predicting response to treatment of chronic hepatitis C (CHC). AIMS The aim of this study was to determine the frequency and association of IFNL4 rs368234815 with IFNL3 SNPs rs12979860, rs8099917 and other factors including cholesterol, alanine aminotransferase, fibrosis, viral load, age and body mass index in genotype 1a treated CHC patients, to achieve rapid virologic response (RVR) and sustained virologic response (SVR). SUBJECTS AND METHODS A total of 71 hepatitis C virus genotype 1a patients were enrolled from 2013 to 2015. The genotypes of rs12979860, rs8099917 were identified by polymerase chain reaction (PCR) and restriction fragment length polymorphism while the genotype rs368234815 detected by amplification-refractory mutation system-PCR. RESULTS The rate of RVR and SVR were 43/71 (60.6%) and 46/71 (64.8%), respectively. To achieve an SVR in patients with rs368234815, TT/TT genotype 20/24 (83.3%) was found to be higher than other SNPs. The correlation coefficient of rs368234815 was strongly associated with rs12979860 (r = 0.788, P < 0.001). Multivariate logistic regression showed that the cholesterol (odds ratio [OR]: 0.205, confidence interval [CI] 95%: 0.047-0.891, P = 0.035), age (OR: 0.160, CI 95%: 0.035-0.730, P = 0.018), baseline viral load (OR: 0.167, CI 95%: 0.032-879, P < 0.035) and IFNL4 (OR: 5.453, CI 95%: 1.015-29.293, P < 0.048) could be independent predictors of SVR. CONCLUSIONS The results of these findings emphasise that factors such as age, cholesterol, baseline viral load and IFNL4 rs368234815 are better predictive factors and should be evaluated before CHC treatment.
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Affiliation(s)
- Shahram Jalilian
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Mahmoud Latifi
- Diabetes Research Centre, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Manoochehr Makvandi
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Teimoori
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Azarakhsh Azaran
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehdi Parsanahad
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Gholamabas Kayedani
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Parsa Nahad M, Makvandi M, Teimoori A, Jalilian S, Kayedani GA, Mahmoodi S. MDR1 gene C3435T polymorphism in chronic hepatitis C patients. Microb Pathog 2018; 114:63-67. [PMID: 29155127 DOI: 10.1016/j.micpath.2017.11.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 10/15/2017] [Accepted: 11/10/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND MDR1 is a highly polymorphic gene that encodes P-glycoprotein (P-gp). This protein anchor to the cell membrane and transports toxins, xenobiotic, chemicals, and drugs from the intracellular to extracellular and thus protect cells. Polymorphism of the MDR1 gene seems to be effective in gene expression and response to treatment. Since one of the main mechanisms of drug resistance is the removal of the drug from the cell by ATP-dependent efflux proteins, thus MDR1, single nucleotide polymorphism (SNP) C3435T can be used as a predictor for treatment outcomes. METHODS The peripheral blood-EDTA samples were collected from 71 patients with chronic hepatitis C. The total genomic DNA extraction was carried out. The PCR was performed for detection of the MDR1 gene in HCV patients and MDR1 gene polymorphism was genotyped by the PCR-RFLP method. RESULTS Out of 71 patients 52 (73.3%) were male, 19 (26.7%) female with mean age-min-max; 41.17 ± 8.3-(26-59). The distribution of MDR1 genotype in 48(67.6%) responders were CC 13 (27%), CT 34 (71%) and TT 1(2%), while MDR1 genotypes in 8 (11.3%) non responders were CC 2(25%), CT 1(12.5%) TT 5(62.5%) and in 15(21.1%) recurrence were 5 (33%) CC, 6 (40%) CT and 4 (27%) TT genotype. The patients with heterozygous CT (C3435T) genotype 34/48(71%) were found better response than non-responders with TT 5/8(62.5%) genotype (p < 0.05). CONCLUSION Our result reveals that 71% of the responders were CT genotypes (C3435T) and 62.5% of non-responders were TT genotype (T3435T). With aforementioned results, determination of different forms of SNPs in MDR1 gene should be considered as a predictor in the treatment of all chronic HCV patients. The homozygous TT genotype and high prevalence of T allele may be related to low antiviral response during combined therapy in treatment of chronic HCV patients.
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Affiliation(s)
- Mehdi Parsa Nahad
- Health Research Institute, Infectious and Tropical Diseases Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Manoochehr Makvandi
- Health Research Institute, Infectious and Tropical Diseases Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Ali Teimoori
- Health Research Institute, Infectious and Tropical Diseases Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shahram Jalilian
- Health Research Institute, Infectious and Tropical Diseases Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Gholam Abbas Kayedani
- Health Research Institute, Infectious and Tropical Diseases Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sara Mahmoodi
- Toxicology Department, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Nakamoto S, Imazeki F, Kanda T, Wu S, Nakamura M, Yasui S, Tawada A, Mikata R, Chiba T, Arai M, Yokosuka O, Shirasawa H. Association of IFNL3 Genotype with Hepatic Steatosis in Chronic Hepatitis C Patients Treated with Peginterferon and Ribavirin Combination Therapy. Int J Med Sci 2017; 14:1088-1093. [PMID: 29104462 PMCID: PMC5666539 DOI: 10.7150/ijms.20171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 07/05/2017] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Genetic variation near the interferon lambda 3 (IFNL3) is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis. AIMS We examined whether this genetic variation is associated with host lipids and treatment response. METHODS A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between IFNL3 genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of >5% steatosis in the liver specimen was defined as hepatic steatosis. RESULTS Forty patients (40%) had liver steatosis before therapy. Patients with IFNL3 minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher γ-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and IFNL3 major genotype (OR 0.13, p=0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, IFNL3 genotype was the most significant predictor, as per multivariate analysis. CONCLUSIONS Our results confirmed that IFNL3 genotype is associated with hepatic steatosis as well as IFN response.
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Affiliation(s)
- Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Japan
| | - Fumio Imazeki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Shuang Wu
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | | | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Rintaro Mikata
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Japan
| | - Hiroshi Shirasawa
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Japan
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The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017; 29:759-766. [PMID: 28240613 DOI: 10.1097/meg.0000000000000867] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Besides regulating lipid metabolism, statins have garnered considerable interest because of their antiviral and antineoplastic properties. The potential benefit of statins using in chronic hepatitis C (CHC) patients is not well described. This meta-analysis was carried out to quantitatively assess the efficacy of statins in improving the therapeutic effect and prognosis of patients with CHC. PATIENTS AND METHODS We searched electronic databases for relevant studies comparing the course of benefit in CHC patients with statins versus without statins. Risk estimates were pooled to assess the association of statins use with sustained virological response and the prognosis of CHC patients. RESULTS Twenty-three studies fulfilled the inclusion criteria. Meta-analysis of 16 homogeneous studies showed that the sustained virological response rate increased by 31% [relative risk (RR)=1.31; 95% confidence interval (CI): 1.23-1.39] in 12 791 CHC patients with statins as an adjuvant under the general antiviral therapy compared with those without this adjuvant therapy. Moreover, meta-analysis of seven studies suggested that statins was beneficial on several specific poor outcomes of CHC patients (RR=0.49; 95% CI: 0.42-0.56). CHC patients with statin use were found to be inversely associated with a 55% reduced risk of hepatocellular carcinoma (RR=0.45; 95% CI: 0.36-0.57) and 53% reduced risk of cirrhosis (RR=0.47; 95% CI: 0.33-0.67) as well as 44% reduced risk of mortality (RR=0.56; 95% CI: 0.46-0.69). However, significant heterogeneity and publication bias were present in some of our analyses. CONCLUSION Beneficial effects of statins use were found in the therapy and the prognosis of CHC patients. Further prospective studies are still needed to confirm these benefits.
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Vasudevan S, Kavimandan A, Kalra N, Nayak B, Thakur B, Das P, Gupta SD, Panda SK, Acharya SK. Demographic profile, host, disease & viral predictive factors of response in patients with chronic hepatitis C virus infection at a tertiary care hospital in north India. Indian J Med Res 2017; 143:331-40. [PMID: 27241647 PMCID: PMC4892080 DOI: 10.4103/0971-5916.182624] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background & objectives: Standard of care for chronic hepatitis C (CHC) in India is peginterferon and ribavirin (RBV). The response to treatment in real life stetting is unclear. The objectives of this study were to evaluate the demographic profile and assess the virological response and predictors of response in CHC patients. Methods: Consecutive patients with CHC were included in this study. Detailed clinical history, risk factors, and predictive factors of response were noted. Patients were treated with peginterferon α2b (1.5 µg/kg/wk) and RBV (12 mg/kg/day) for 6 to 18 months based on response. Results: A total of 211 patients were included in the analysis, mean age 40.6±12.3 yr, 144 (68%) were males and 71 (34%) had compensated cirrhosis. Commonest risk factor for acquiring CHC was previous transfusion and surgery (51%). Genotype 3 (72%) was most common followed by genotype 1 (23%). Overall sustained virologic response (SVR) was 64 per cent [95% CI 57.1%-70.4%]. The SVR was 66.5 per cent [95% CI 58.34-73.89%] for genotype 3 and 61.2 per cent [95% CI 46.23 to 74.80%] for genotype 1. Non-cirrhotics had better SVR rates compared to cirrhotics (76 vs 41%, P<0.001). On multivariate analysis, BMI ≥23 kg/m2, HOMA-IR ≥2, compliance (≤80%), and fibrosis >2 were predictors of low SVR. Interpretation & conclusions: Genotype 3 was the commonest HCV genotype. The commonest source of infection was previous transfusion and surgery. SVR rates for genotypes 3 were better than genotype 1 patients. Predictors of non-response were high BMI, insulin resistance, significant fibrosis and inadequate compliance.
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Affiliation(s)
- Sreejith Vasudevan
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Amit Kavimandan
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Nancy Kalra
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Bhaskar Thakur
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Subrat Kumar Panda
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Subrat Kumar Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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Abstract
Lipid lowering, particularly with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins"), reduces the risk of cardiovascular disease. Patients with chronic liver disease present challenges to the use of lipid medications. In the case of most liver disorders, the concern has been one of safety. There is evidence that most lipid-lowering medications can be used safely in many situations, although large outcomes trials are lacking. This review examines lipid physiology and cardiovascular risk in specific liver diseases and reviews the evidence for lipid lowering and the use of statins in chronic liver disease.
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Affiliation(s)
- Cynthia Herrick
- Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid, St Louis, MO 63110, USA.
| | - Samira Bahrainy
- VA Medical Center, Puget Sound, 1660 South Columbian Way, Seattle, WA 98104, USA
| | - Edward A Gill
- Harborview Medical Center, University of Washington School of Medicine, 325 Ninth Avenue, Box 359748, Seattle, WA 98104, USA
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Jeon CY, Goodman MT, Cook-Wiens G, Sundaram V. Statin Use and Survival with Early-Stage Hepatocellular Carcinoma. Cancer Epidemiol Biomarkers Prev 2016; 25:686-92. [PMID: 26908429 DOI: 10.1158/1055-9965.epi-15-1040] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 01/21/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Limited clinical and epidemiologic data suggest that statins may improve the outcomes of hepatocellular carcinoma (HCC), which has poor prognosis. METHODS We identified 1,036 stage I or II HCC patients, diagnosed between 2007 and 2009, through the linked Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims database. Of these, 363 patients were using statin either at the time of their HCC diagnosis or afterwards. We conducted multivariable Cox regression analysis to estimate the time-dependent effect of statin on survival. The analysis included age, sex, resection, transarterial chemoembolization, transplantation, cirrhosis, cardiovascular disease, diabetes, dyslipidemia, and hepatitis B and C. RESULTS Over a median follow-up time of 21 months, 584 HCC patients died. Statin users had a longer median survival compared with nonusers: 23.9 versus 18.9 months (P = 0.047). However, after accounting for immortal time bias and confounding, statin use was not associated with survival (HR, 0.98; 95% confidence interval, 0.80-1.20). The associations did not vary by hepatitis C or intensity of statin use. CONCLUSION Statin treatment after HCC diagnosis was not associated with survival in elderly patients with stage I/II disease. IMPACT Our study of nationally representative elderly patients with stage I or II HCC in the United States shows that statin treatment does not improve survival with liver cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 686-92. ©2016 AACR.
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Affiliation(s)
- Christie Y Jeon
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California. Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California.
| | - Marc T Goodman
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California. Department of Medicine, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Galen Cook-Wiens
- Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Vinay Sundaram
- Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California
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Blanco JR, Rivero-Juarez A. HCV genotype 3: a wolf in sheep's clothing. Expert Rev Anti Infect Ther 2016; 14:149-52. [PMID: 26635242 DOI: 10.1586/14787210.2016.1127757] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- José-R Blanco
- a Infectious Diseases Area , Hospital San Pedro - Center for Biomedical Research of La Rioja (CIBIR) , Logroño , Spain
| | - Antonio Rivero-Juarez
- b Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Córdoba , Spain
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25
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Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection. Viruses 2015; 7:5659-85. [PMID: 26540069 PMCID: PMC4664971 DOI: 10.3390/v7112898] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 09/25/2015] [Accepted: 10/19/2015] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.
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26
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Wright AP, Adusumalli S, Corey KE. Statin therapy in patients with cirrhosis. Frontline Gastroenterol 2015; 6:255-261. [PMID: 28839820 PMCID: PMC5369584 DOI: 10.1136/flgastro-2014-100500] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 07/24/2014] [Accepted: 07/25/2014] [Indexed: 02/04/2023] Open
Abstract
Cardiovascular disease is one of the leading causes of death among patients with cirrhosis and following liver transplantation. Although 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors ('statins') reduce the risk of cardiovascular events, fears about hepatotoxicity have historically led to underuse in patients with liver disease. In addition, the pharmacokinetics of statins can be significantly altered in cirrhosis, creating challenges with their use in liver disease. However, emerging data from randomised controlled trials and observational studies suggest that statin therapy appears to be safe and effective in patients with chronic liver disease and compensated cirrhosis. The cardiovascular risk benefits as well as the potential pleiotropic benefits of statins warrants strong consideration of use of statin therapy in patients with cirrhosis.
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Affiliation(s)
- Andrew P Wright
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA,Harvard Medical School, Boston, Massachusetts, USA
| | - Srinath Adusumalli
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA,Harvard Medical School, Boston, Massachusetts, USA
| | - Kathleen E Corey
- Harvard Medical School, Boston, Massachusetts, USA,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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Pandya P, Rzouq F, Oni O. Sustained virologic response and other potential genotype-specific roles of statins among patients with hepatitis C-related chronic liver diseases. Clin Res Hepatol Gastroenterol 2015; 39:555-65. [PMID: 25835493 DOI: 10.1016/j.clinre.2015.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 01/18/2015] [Accepted: 02/05/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND While statins have shown antiviral effects in different studies, few data are available about their effect among different HCV genotypes. AIM To evaluate the effect of concomitant statin use on sustained virologic response (SVR) and other treatment outcomes among patients with HCV genotypes 1-3. METHOD Using US Department of Veterans Affairs database, multivariate (MV), propensity score matched (PSM) and repeated measures mixed model analyses were performed on patients who received combination therapy with Peg-IFN and Ribavirin for treatment of HCV genotypes 1-3 between October 2001-December 2011. Concomitant statin users were matched with non-users in each genotype and SVR rates were compared. Changes in serum ALT during treatment was assessed. RESULTS Of 37,611 treated patients, 236 genotype 1 (GT1), 78 genotype 2 (GT2) and 23 genotype 3 (GT3) statin users and non-users were used for PSM. SVR among GT1 patients was 22.8% (overall), significantly higher among statin users (26.3% vs. 19.5% P<0.01 from PSM; OR=1.49 CI 1.06-2.08 P=0.02 from MV). No significant impact of statin use was observed among GT2 (overall SVR - 55.8%, statin users vs. non-users - 53.9% vs. 57.7%, P=0.32), and GT3 (overall SVR - 58.7%, statin users vs. non-users - 60.9% vs. 56.2%, P=0.39) patients. Higher baseline LDL was positively associated with SVR while statin use reduced ALT during treatment in GT1 patients. CONCLUSION In view of additional benefits of statins, and the prohibitive cost of newer HCV therapies, statins could be a potential assist for hard-to-treat GT1 patients especially in resource-poor settings.
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Affiliation(s)
- Prashant Pandya
- Kansas City VA Medical Center, Department of Gastroenterology (Hepatology Division), Kansas City, MO, USA; University of Kansas Medical Center, Department of Internal Medicine, Kansas City, KS, USA
| | - Fadi Rzouq
- University of Kansas Medical Center, Department of Internal Medicine, Kansas City, KS, USA
| | - Olurinde Oni
- Kansas City VA Medical Center, Hepatology Research Unit, Kansas City, MO, USA.
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Simon TG, Butt AA. Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes. World J Gastroenterol 2015; 21:8293-8303. [PMID: 26217081 PMCID: PMC4507099 DOI: 10.3748/wjg.v21.i27.8293] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 04/17/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.
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29
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Saigal S, Choudhary NS, Saraf N, Gautam D, Lipi L, Rastogi A, Goja S, Menon PB, Bhangui P, Ramachandra SK, Soin AS. Genotype 3 and higher low-density lipoprotein levels are predictors of good response to treatment of recurrent hepatitis C following living donor liver transplantation. Indian J Gastroenterol 2015; 34:305-9. [PMID: 26394853 DOI: 10.1007/s12664-015-0578-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 07/03/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Treatment of recurrent hepatitis C after liver transplantation is associated with poor sustained virological response (SVR) in genotype 1, and data on genotype 3 is limited to small numbers. We report one of the largest series of genotype 3 patients treated for recurrent hepatitis C following living donor liver transplantation (LDLT). METHODS From January 2002 to November 2013, of 1349 transplants, 359 patients had hepatitis C. Patients with histological recurrence were treated with pegylated interferon in escalating dose regimen for 48 weeks and weight-based ribavirin. Virological response was defined as rapid virological response (RVR-4 weeks), early virological response (EVR-12 weeks), end of treatment response (ETR-48 weeks), and SVR (24 weeks after end of treatment). SVR and no-SVR groups were compared for age, sex, body mass index (BMI), diabetes, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, ferritin, genotype, and hepatitis C virus (HCV) RNA levels before initiation of treatment. RESULTS The study included 67 patients who had at least 18 months of follow up after treatment initiation (45 males), aged 51 ± 6.3 years. Treatment was started after 16 months (median); baseline median RNA was 2.7 × 10(6) IU/mL. There was no significant difference between the SVR and no-SVR groups regarding age, sex ratio, follow up period, total cholesterol, triglycerides, HDL, BMI, prevalence of diabetes, HCV RNA, and ferritin levels. Genotype 3, RVR, EVR, ETR, and higher LDL levels were significantly associated with SVR. Genotype 3 had a significantly higher SVR rate of 71 % as compared to an SVR rate of only 14 % in genotype 1, p = 0.0003. Absence of RVR and EVR predicted treatment failure with a specificity of 88 % and 92 %, respectively. CONCLUSION Genotype 3 and higher LDL levels predict SVR in patients treated for hepatitis C recurrence following LDLT, whereas absence of RVR and EVR strongly predict treatment failure.
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Affiliation(s)
- Sanjiv Saigal
- Medanta Liver Institute, Gurgaon, Haryana, 122 001, India.
| | | | - Neeraj Saraf
- Medanta Liver Institute, Gurgaon, Haryana, 122 001, India
| | - Dheeraj Gautam
- Department of Histopathology, Medanta The Medicity, Gurgaon, Haryana, 122 001, India
| | - Lipika Lipi
- Department of Histopathology, Medanta The Medicity, Gurgaon, Haryana, 122 001, India
| | - Amit Rastogi
- Medanta Liver Institute, Gurgaon, Haryana, 122 001, India
| | - Sanjay Goja
- Medanta Liver Institute, Gurgaon, Haryana, 122 001, India
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Jiménez Macías FM, Barrero Alor F, Casado Monge PG, Ramos Lora M, Pujol de la Llave E, Ruíz-Frutos C. [Lipid kinetics during dual antiviral therapy in patients with chronic hepatitis C]. Med Clin (Barc) 2015; 144:536-43. [PMID: 24726260 DOI: 10.1016/j.medcli.2013.12.016] [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: 03/24/2013] [Revised: 12/17/2013] [Accepted: 12/18/2013] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND OBJECTIVE We analyzed baseline and kinetic characteristics of lipid metabolism during the first month of bitherapy in patients with chronic hepatitis C genotype 1 (CHC-1). PATIENTS AND METHODS A longitudinal, prospective study including 99 naïve CHC-1 patients with liver biopsy who were treated with bitherapy. Our patients were assigned to one of 5 different "degrees of lipid requirement" that we established depending on the degree of liver fibrosis, baseline viral load and infectivity ratio (ratio between the median level of triglycerides and high densitity lipoproteins-cholesterol during the first month). The goal was to achieve "a favorable lipid metabolism" (FLM) by establishing a necessary minimum level of low density lipoproteins (LDL)-cholesterol during this period for each one of them. We also analyzed the relationship with the rate of sustained virological response. RESULTS Patients with liver fibrosis F3-F4 who had higher baseline levels of LDL-cholesterol achieved higher rates of sustained virological response. Those patients who had a lower value of infectivity ratio and median levels of LDL-cholesterol during the first month of bitherapy also achieved higher rates of sustained virological response: SVR group 100 (23) mg/dl against non-SVR group: 89 (28) mg/dl; odds ratio 1.1; 95% confidence interval (1.0-1.2); P<.05, these differences being more significant for genotype IL-28B-CC (P=.013). Patients with sustained virological response had higher rates of FLM. CONCLUSIONS Not every patient with CHC-1 has the same lipid kinetics during the first month of bitherapy, and it is necessary to achieve a sustained virological response and/or a FLM to keep higher plasma levels of LDL-cholesterol during this period. Those subjects without FLM could benefit from statins.
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Affiliation(s)
| | - Fátima Barrero Alor
- Departamento de Biología Molecular y Bioquímica, Hospital Juan Ramón Jiménez, Huelva, España
| | | | | | | | - Carlos Ruíz-Frutos
- Departamento de Biología Ambiental y Salud Pública, Universidad de Huelva, Huelva, España
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Abe H, Tsubota A, Shimada N, Atsukawa M, Kato K, Takaguchi K, Asano T, Chuganji Y, Sakamoto C, Toyoda H, Kumada T, Ide T, Sata M, Aizawa Y. Factors associated with sustained virological response in 24-week telaprevir-based triple therapy for chronic hepatitis C genotype 1b patients with the IL28B minor genotype. Hepatol Res 2015; 45:387-396. [PMID: 24849518 DOI: 10.1111/hepr.12360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/11/2014] [Accepted: 05/15/2014] [Indexed: 02/08/2023]
Abstract
AIM Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. METHODS Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). RESULTS Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. CONCLUSION In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.
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Affiliation(s)
- Hiroshi Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan
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Solbach P, Westhaus S, Deest M, Herrmann E, Berg T, Manns MP, Ciesek S, Sarrazin C, von Hahn T. Oxidized Low-Density Lipoprotein Is a Novel Predictor of Interferon Responsiveness in Chronic Hepatitis C Infection. Cell Mol Gastroenterol Hepatol 2015; 1:285-294.e1. [PMID: 28210681 PMCID: PMC5301270 DOI: 10.1016/j.jcmgh.2015.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 03/03/2015] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) cell entry is mediated by several cell surface receptors, including scavenger receptor class B type I (SR-BI). Oxidized low density lipoprotein (oxLDL) inhibits the interaction between HCV and SR-BI in a noncompetitive manner. We tested whether serum oxLDL levels correlate with sustained virologic response (SVR) rates after interferon-based treatment of chronic hepatitis C. METHODS Baseline oxLDL was determined in 379 participants with chronic HCV genotype 1 infection from the INDIV-2 study using a commercial enzyme-linked immunosorbent assay. The mechanistic in vitro studies used full-length and subgenomic HCV genomes replicating in hepatoma cells. RESULTS In the multivariate analysis, oxLDL was found to be an independent predictor of SVR. Oxidized LDL did not correlate with markers of inflammation (alanine transaminase, ferritin), nor was serum oxLDL affected by exogenous interferon administration. Also, oxLDL did not alter the sensitivity of HCV replication to interferon. However, oxLDL was found to be a potent inhibitor of cell-to-cell spread of HCV between adjacent cells in vitro. It could thus reduce the rate at which new cells are infected by HCV through either the cell-free or cell-to-cell route. Finally, serum oxLDL was significantly associated with the estimated infected cell loss rate under treatment. CONCLUSIONS Oxidized LDL is a novel predictor of SVR after interferon-based therapy and may explain the previously observed association of LDL with SVR. Rather than being a marker of activated antiviral defenses it may improve chances of SVR by limiting spread of infection to naive cells through the cell-to-cell route.
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Key Words
- Cell-to-Cell Spread
- DAA, direct-acting antiviral drug
- DMEM, Dulbecco’s modified Eagle medium
- DTT, dithiothreitol
- HCV, hepatitis C virus
- HCVcc, cell culture–grown hepatitis C virus
- IPS1, interferon promoter stimulator-1
- ITX-5061, N-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-2-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]-2-oxoacetamide;hydrochloride
- LDL, low-density lipoprotein
- NLS, nuclear localization signal
- PBS, phosphate-buffered saline
- RBV, ribavirin
- RFP, red fluorescent protein
- ROC, receiver operating characteristic
- SR-BI
- SR-BI, scavenger receptor class B member I
- SVR
- SVR, sustained virologic response
- oxLDL
- oxLDL, oxidized low-density lipoprotein
- peg-IFN, pegylated interferon α
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Affiliation(s)
- Philipp Solbach
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Sandra Westhaus
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Maximilian Deest
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany
| | - Thomas Berg
- Hepatology Section, Department of Gastroenterology and Rheumatology, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Sandra Ciesek
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Christoph Sarrazin
- German Center for Infection Research (DZIF), Hannover, Germany,Medical Clinic I, Zentrum der Inneren Medizin, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany
| | - Thomas von Hahn
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany,Correspondence Address correspondence to: Thomas von Hahn, MD, Medizinische Hochschule Hannover, Institut für Molekularbiologie, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. fax: +49 511 532-4896.
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Meissner EG, Lee YJ, Osinusi A, Sims Z, Qin J, Sturdevant D, McHutchison J, Subramanian M, Sampson M, Naggie S, Patel K, Remaley AT, Masur H, Kottilil S. Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients. Hepatology 2015; 61:790-801. [PMID: 25203718 PMCID: PMC4340816 DOI: 10.1002/hep.27424] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 09/03/2014] [Indexed: 12/23/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response [SVR]; n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n=17 SVR; n=8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. CONCLUSION Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis.
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Affiliation(s)
- Eric G. Meissner
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yu-Jin Lee
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Anu Osinusi
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland Medical School, Baltimore, MD, USA
| | - Zayani Sims
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Jing Qin
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dan Sturdevant
- Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | | | | | - Maureen Sampson
- Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Susanna Naggie
- Duke University, Duke Clinical Research Institute, Durham, NC, USA
| | - Keyur Patel
- Duke University, Duke Clinical Research Institute, Durham, NC, USA
| | - Alan T. Remaley
- Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Henry Masur
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Shyam Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Kamo Y, Ichikawa T, Miyaaki H, Uchida S, Yamaguchi T, Shibata H, Honda T, Taura N, Isomoto H, Takeshima F, Nakao K. Significance of miRNA-122 in chronic hepatitis C patients with serotype 1 on interferon therapy. Hepatol Res 2015; 45:88-96. [PMID: 24612050 DOI: 10.1111/hepr.12317] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 01/23/2014] [Accepted: 02/13/2014] [Indexed: 12/18/2022]
Abstract
AIM Peginterferon (PEG IFN) and ribavirin combination therapy is a curative treatment for chronic hepatitis C virus (HCV) infection, and virological response to IFN therapy has been strongly associated with genetic variation in IL28B single nucleotide polymorphisms (SNP). Recently, miRNA122 (miR-122), which is the most abundant miRNA in the liver, has been reported to be important for the replication of HCV RNA. Therefore, we investigated the correlation of miR-122 expression with virological response to IFN and other clinical data. METHODS A total of 51 patients with HCV infection who were treated with IFN therapy at Nagasaki University Hospital from 2006 to 2011 were included in this study. We investigated the correlation of miR-122 expression in liver biopsy specimens with virological response to IFN therapy and other predictors of response, including IL28 SNP. RESULTS miR-122 expression did not correlate with IL28 SNP. However, a significant difference was observed in miR-122 expression between patients who showed a sustained virological response (SVR) and those who did not (P < 0.05). Multivariate analysis indicated that miR-122 is an independent predictor of SVR. CONCLUSION miR-122 expression could be a marker for predicting the outcome of IFN therapy. Therapies targeting miR-122 may have positive effects not only by directly inhibiting viral propagation but also by ameliorating cholesterol and lipid abnormalities.
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Affiliation(s)
- Yasuhiro Kamo
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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Lim T. Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy? Hepat Med 2014; 6:113-8. [PMID: 25506251 PMCID: PMC4259863 DOI: 10.2147/hmer.s60083] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV) infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy.
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Affiliation(s)
- Tr Lim
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, UK
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Vercauteren K, Mesalam AA, Leroux-Roels G, Meuleman P. Impact of lipids and lipoproteins on hepatitis C virus infection and virus neutralization. World J Gastroenterol 2014; 20:15975-91. [PMID: 25473151 PMCID: PMC4239485 DOI: 10.3748/wjg.v20.i43.15975] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 07/09/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infections represent a major global health problem. End-stage liver disease caused by chronic HCV infection is a major indication for liver transplantation. However, after transplantation the engrafted liver inevitably becomes infected by the circulating virus. Direct acting antivirals are not yet approved for use in liver transplant patients, and limited efficacy and severe side effects hamper the use of pegylated interferon combined with ribavirin in a post-transplant setting. Therefore, alternative therapeutic options need to be explored. Viral entry represents an attractive target for such therapeutic intervention. Understanding the mechanisms of viral entry is essential to define the viral and cellular factors involved. The HCV life cycle is dependent of and associated with lipoprotein physiology and the presence of lipoproteins has been correlated with altered antiviral efficacy of entry inhibitors. In this review, we summarise the current knowledge on how lipoprotein physiology influences the HCV life cycle. We focus especially on the influence of lipoproteins on antibodies that target HCV envelope proteins or antibodies that target the cellular receptors of the virus. This information can be particularly relevant for the prevention of HCV re-infection after liver transplantation.
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Niederau C, Mauss S, Schober A, Stoehr A, Zimmermann T, Waizmann M, Moog G, Pape S, Weber B, Isernhagen K, Sandow P, Bokemeyer B, Alshuth U, Steffens H, Hüppe D. Predictive factors for sustained virological response after treatment with pegylated interferon α-2a and ribavirin in patients infected with HCV genotypes 2 and 3. PLoS One 2014; 9:e107592. [PMID: 25238535 PMCID: PMC4169557 DOI: 10.1371/journal.pone.0107592] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 08/12/2014] [Indexed: 12/15/2022] Open
Abstract
Background Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management. Aims The present study looks for differences between the two genotypes and analyzes predictive factors for SVR. Methods Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012. Results When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, p = 0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis. Conclusions The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis. Trial Registration Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany ML21645 ClinicalTrials.gov NCT02106156
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Affiliation(s)
- Claus Niederau
- Clinic for Internal Medicine, St. Josef Hospital, Oberhausen, Germany
- * E-mail:
| | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
| | | | - Albrecht Stoehr
- ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany
| | - Tim Zimmermann
- 1st Medical Clinic, Dept. Gastroenterology and Hepatology, Johannes Gutenberg University of Mainz, Mainz, Germany
| | | | - Gero Moog
- Center of Gastroenterology, Kassel, Germany
| | - Stefan Pape
- Center of Gastroenterology, Paderborn, Germany
| | - Bernd Weber
- Competence Center for Addiction, Praxiszentrum Friedrichsplatz, Kassel, Germany
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Chang ML, Tsou YK, Hu TH, Lin CH, Lin WR, Sung CM, Chen TH, Cheng ML, Chang KC, Chiu CT, Yeh CT, Pang JHS, Shiao MS. Distinct patterns of the lipid alterations between genotype 1 and 2 chronic hepatitis C patients after viral clearance. PLoS One 2014; 9:e104783. [PMID: 25122116 PMCID: PMC4133245 DOI: 10.1371/journal.pone.0104783] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 07/12/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The hepatitis C virus (HCV) genotype-specific impacts on the host metabolic alterations remained inconclusive. METHODS A prospective study including 229 (118 genotype 1 (G1) and 111 G2) consecutive chronic HCV patients who had completed a course of anti-HCV treatment and underwent pre- and 24 weeks post-treatment surveys of metabolic profiles was conducted. Patients were stratified according to the therapeutic response, viral genotype and baseline insulin resistance (IR: homeostasis model assessments of IR (HOMA-IR) ≥ 2.5). Paired t-tests were used to compare the pre- and post-treatment variables. RESULTS Significant post-therapeutic increases in cholesterol, triglyceride, HDL, LDL, apolipoprotein A1 and apolipoprotein B were observed in patients with sustained virological response (SVR) but not in those without. Among those with SVR, post-therapeutic increases in HDL (p<0.001) and apolipoprotein A1 (p = 0.012) were only found in G2, whereas increased triglyceride/HDL (p = 0.01) ratios were only found in G1 patients. When stratified by baseline IR among those with SVR, a significant increase in post-treatment HDL (p = 0.019) and apolipoprotein A1 (p = 0.012) but a decrease in HOMA-IR (p = 0.04), C-peptide (p = 0.019) and hemoglobin A1c (p = 0.047) were found in patients with baseline IR; a significant increase in HOMA-IR (p = 0.002) was found in patients without baseline IR. The latter change was observed only in G1 (p = 0.01) but not G2 patients. Although the pre-treatment metabolic profiles of G1 and G2 patients were indifferent, G1 had higher post-treatment triglyceride/HDL ratios (p = 0.041) and triglyceride (p = 0.044) levels than G2 patients. CONCLUSIONS G2 benefit more than G1 patients from viral clearance in metabolic alterations, particularly in those without baseline IR.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Kuan Tsou
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Hui Lin
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wey-Ran Lin
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chang-Mu Sung
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tsung-Hsing Chen
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Mei-Ling Cheng
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Tang Chiu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jong-Hwei Su Pang
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Shi Shiao
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan
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Grammatikos G, Farnik H, Bon D, Böhlig A, Bader T, Berg T, Zeuzem S, Herrmann E. The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta-analysis. J Viral Hepat 2014; 21:533-41. [PMID: 24943517 DOI: 10.1111/jvh.12274] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 05/25/2014] [Indexed: 12/16/2022]
Abstract
Several studies investigating the role of statins and fibrates in chronic hepatitis C virus (HCV) infection offered so far conflicting evidence regarding the antiviral potency of these medications, whereas combination of these drugs with pegylated interferon and ribavirin improved in some trials therapeutic outcome. We conducted a literature search to identify trials that included monoinfected HCV patients, treated with statins or fibrates as monotherapy with the primary end point of our meta-analysis being the quantitative change of HCV-RNA induced by these medications. Logarithmic changes of the viral load (ΔlogVL) and confidence intervals (CIs) were calculated according to the DerSimonian-Laird estimate. Statistical heterogeneity was assessed with the I² statistic. We identified eight observational studies that evaluated the potency of bezafibrate and different statins as monotherapy to induce a significant reduction of HCV-RNA in HCV-monoinfected patients (n = 281). Overall, a significant reduction of viral load with mean 0.19 [log10 IU/mL] (95%-confidence interval, (CI) 0.11-0.28) could be observed when antihyperlipidemic medications were administered. Bezafibrate featured the highest antiviral efficacy (0.45 log10 reduction, 95%-CI, 0.17-0.72) among all medications and fluvastatin (0.20 log10 reduction, 95%-CI, 0.09-0.31) among all statins tested. Based on meta-analysis, fibrates and statins induce a reduction of HCV viral load. We suggest that the addition of statins and fibrates to antiviral regimes, especially in HCV patients with concomitant dyslipidemia, could beside the established reduction of cardiovascular risk increase the potency of antiviral therapy.
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Affiliation(s)
- G Grammatikos
- University Hospital Frankfurt, Frankfurt am Main, Germany
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Sargolzaee Aval F, Behnaz N, Raoufy MR, Alavian SM. Predicting the outcomes of combination therapy in patients with chronic hepatitis C using artificial neural network. HEPATITIS MONTHLY 2014; 14:e17028. [PMID: 24976838 PMCID: PMC4071357 DOI: 10.5812/hepatmon.17028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 02/15/2014] [Accepted: 04/05/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Treatment with Peginterferon Alpha-2b plus Ribavirin is the current standard therapy for chronic hepatitis C (CHC). However, many host related and viral parameters are associated with different outcomes of combination therapy. OBJECTIVES The aim of this study was to develop an artificial neural network (ANN) model to predetermine individual responses to therapy based on patient's demographics and laboratory data. PATIENTS AND METHODS This case-control study was conducted in Tehran, Iran, on 139 patients divided into sustained virologic response (SVR) (n = 50), relapse (n = 50) and non-response (n = 39) groups according to their response to combination therapy for 48 weeks. The ANN was trained 300 times (epochs) using clinical data. To test the ANN performance, the part of data that was selected randomly and not used in training process was entered to the ANN and the outputs were compared with real data. RESULTS Hemoglobin (P < 0.001), cholesterol (P = 0.001) and IL-28b genotype (P = 0.002) values had significant differences between the three groups. Significant predictive factor(s) for each group were hemoglobin for SVR (OR: 1.517; 95% CI: 1.233-1.868; P < 0.001), IL-28b genotype for relapse (OR: 0.577; 95% CI: 0.339-0.981; P = 0.041) and hemoglobin (OR: 0.824; 95% CI: 0.693-0.980; P = 0.017) and IL-28b genotype (OR: 2.584; 95% CI: 1.430-4.668;P = 0.001) for non-response. The accuracy of ANN to predict SVR, relapse and non-response were 93%, 90%, and 90%, respectively. CONCLUSIONS Using baseline laboratory data and host characteristics, ANN has been shown as an accurate model to predict treatment outcome, which can lead to appropriate decision making and decrease the frequency of ineffective treatment in patients with chronic hepatitis C virus (HCV) infection.
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Affiliation(s)
| | - Nazanin Behnaz
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Nazanin Behnaz, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Velenjak St., Shahid Chamran Highway, Tehran, IR Iran. Tel: +98-9127979580, E-mail:
| | - Mohamad Reza Raoufy
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, IR Iran
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Sheridan DA, Bridge SH, Crossey MME, Felmlee DJ, Fenwick FI, Thomas HC, Neely RDG, Taylor-Robinson SD, Bassendine MF. Omega-3 fatty acids and/or fluvastatin in hepatitis C prior non-responders to combination antiviral therapy - a pilot randomised clinical trial. Liver Int 2014; 34:737-47. [PMID: 24118830 DOI: 10.1111/liv.12316] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Accepted: 08/29/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) utilises cholesterol and lipoprotein metabolism for replication and infectivity. Statins and omega-3 (n-3) polyunsaturated fatty acids (PUFA) have been shown to have antiviral properties in vitro. This open label pilot study evaluated the efficacy of fluvastatin (Lescol(®) 40-80 mg) and n-3 PUFA (Omacor(®) 1 g and 2-4 g) on HCV-RNA and lipoviral particles (LVP) in difficult to treat prior non-responders. METHODS Patients (n = 60) were randomly allocated in a factorial design to: no active drug; low-dose n-3 PUFA; high-dose n-3 PUFA; fluvastatin; low-dose n-3 PUFA + fluvastatin; or high-dose n-3 PUFA + fluvastatin. 50/60 completed study drugs for 12 weeks and followed up to week 24. Comparison was made between fluvastatin (n = 24) vs no fluvastatin (n = 26) and n-3 PUFA high-dose (n = 17) vs low-dose (n = 17) vs none (n = 16). The primary outcomes were change in total HCV-RNA, LVP and ALT at week 12 compared with baseline. Secondary outcome was change in interferon-gamma-inducible protein-10 (IP10) as a measure of interferon activation. RESULTS 35% had compensated cirrhosis and 45% were prior null responders. There was no significant change in total HCV RNA, LVP, non-LVP or LVP ratio in patients receiving fluvastatin or n-3 PUFAs. ALT was not significantly different in those treated with fluvastatin or n-3 PUFAs. 12 weeks of low-dose n-3 PUFA decreased median IP10 concentration by -39 pg/ml (-111, 7.0 pg/ml Q1-Q3). CONCLUSIONS Fluvastatin and n-3 PUFAs have no effect on plasma HCV-RNA or LVP. The effect of low-dose n-3 PUFA on IP10 warrants further prospective evaluation as a supplemental therapy to enhance interferon sensitivity.
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Affiliation(s)
- David A Sheridan
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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Van Thiel DH, George M, Attar BM, Ramadori G, Ion-Nedelcu N. Plasma triglyceride levels may modulate hepatitis C viral replication. Dig Dis Sci 2014; 59:881-5. [PMID: 24563239 DOI: 10.1007/s10620-014-3079-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 02/11/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND Plasma and hepatic lipid abnormalities are frequent in hepatitis C infected individuals. METHODS Plasma lipid and medical records profiles were prospectively obtained in 130 consecutive individuals seen by a single hepatologist in a university liver disease clinic. The relationships between viral load, genotype, plasma lipid fractions, HDL, LDL particle number and particle size were examined. RESULTS Of 130 individuals studied, 74 had hepatitis C while 15 had NAFLD/NASH and 30 had alcohol related liver disease. The LDL particle number and LDL-C levels did not differ between those with and without hepatitis C although the number of small LDL particles was greater in those with hepatitis C infection. The HDL-C and total cholesterol levels were greater in those without hepatitis C than those with hepatitis C (P = 0.009). In contrast, the serum triglyceride level was greater in the hepatitis C viral group (P = 0.013). Importantly, the hepatitis C viral load regardless of the genotype correlated directly with the triglyceride and VLDL levels with r values of 0.73 and 0.84, respectively. CONCLUSIONS There are: (1) important differences in lipid classes, number and the size of lipid particles exist between hepatitis C virus infected and noninfected liver disease groups, (2) the serum total triglyceride and the LDL levels correlate significantly with the hepatitis C viral load and, (3) Serum triglyceride level may play an important role in viral replication. These data further suggest that therapies directed at lowering plasma triglyceride levels may enhance the efficacy of current antiviral treatment regimens.
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Gatselis NK, Zachou K, Saitis A, Samara M, Dalekos GN. Individualization of chronic hepatitis C treatment according to the host characteristics. World J Gastroenterol 2014; 20:2839-53. [PMID: 24659876 PMCID: PMC3961989 DOI: 10.3748/wjg.v20.i11.2839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/19/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem that affects more than 170 million people worldwide. It is a major cause of cirrhosis and hepatocellular carcinoma, making the virus the most common cause of liver failure and transplantation. The standard-of-care treatment for chronic hepatitis C (CHC) has been changed during the last decade and direct acting antiviral drugs have already been used. Besides, understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment. Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection. The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
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Toshikuni N, Arisawa T, Tsutsumi M. Hepatitis C-related liver cirrhosis - strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality. World J Gastroenterol 2014; 20:2876-2887. [PMID: 24659879 PMCID: PMC3961980 DOI: 10.3748/wjg.v20.i11.2876] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 01/13/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of β-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.
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Verpaalen B, Neyts J, Delang L. Are statins a viable option for the treatment of infections with the hepatitis C virus? Antiviral Res 2014; 105:92-9. [PMID: 24613180 DOI: 10.1016/j.antiviral.2014.02.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 02/20/2014] [Accepted: 02/24/2014] [Indexed: 12/11/2022]
Abstract
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are widely used for the treatment of hypercholesterolemia. Besides their cholesterol-lowering effect, statins have been reported to have antiviral activity against a variety of viruses, including hepatitis C virus (HCV). Several statins inhibit the in vitro replication of subgenomic HCV replicons and also suppress in vitro RNA replication of infectious HCV. The precise mechanism of the anti-HCV activity of statins has not yet been defined. Recent studies suggest that the antiviral effect may result from the inhibition of geranylgeranylation of cellular proteins, rather than the inhibition of cholesterol synthesis. Despite the antiviral effect observed in vitro, statin monotherapy seems to be insufficient for the treatment of chronic HCV infection. However, several prospective and retrospective studies have demonstrated that the addition of statins to IFN-α and ribavirin therapy increases SVR, RVR, and EVR rates without the occurrence of additional adverse events. These clinical data, together with the excellent safety profile and low cost, suggest that statins may play a role in HCV therapy until more potent and safe direct-acting antivirals become available. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Ben Verpaalen
- Rega Institute for Medical Research, KU Leuven, Belgium
| | - Johan Neyts
- Rega Institute for Medical Research, KU Leuven, Belgium.
| | - Leen Delang
- Rega Institute for Medical Research, KU Leuven, Belgium
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Ogawa E, Furusyo N, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Nakamuta M, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J. Influence of low-density lipoprotein cholesterol on virological response to telaprevir-based triple therapy for chronic HCV genotype 1b infection. Antiviral Res 2014; 104:102-9. [PMID: 24462955 DOI: 10.1016/j.antiviral.2014.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 01/06/2014] [Accepted: 01/12/2014] [Indexed: 12/12/2022]
Abstract
Elevated serum low-density lipoprotein cholesterol (LDL-C) level has been associated with sustained virological response (SVR) by chronic hepatitis C patients treated with pegylated-interferon (PEG-IFN) α and ribavirin (RBV). The aim of this study was to investigate the relation between the baseline LDL-C level and the treatment outcome from telaprevir (TVR)-based triple therapy. This prospective, multicenter study consisted of 241 treatment-experienced patients infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of PEG-IFNα2b and RBV. The SVR rate was 81.3% (196 of 241) by intention-to-treat analysis. Higher LDL-C level was strongly associated with SVR (P=1.3×10⁻⁸). The area under the receiver operating characteristic curve for predicting SVR was 0.78 and the cutoff value for the LDL-C level at baseline was 95 mg/dL. In multivariable logistic regression analysis of predictors of SVR, LDL-C ≥95 mg/dL (odds ratio [OR] 3.60, P=0.0238), α-fetoprotein ≤5.0 ng/mL (OR 5.06, P=0.0060), prior relapse to PEG-IFNα and RBV (OR 5.71, P=0.0008), and rapid virological response (HCV RNA undetectable at week 4) (OR 5.52, P=0.0010) were extracted as independent predictors of SVR. For prior partial and null responders, the SVR rates of the groups with LDL-C ≥95 mg/dL were significantly higher than those of the <95 mg/dL groups with IL28B TG/GG and pretreatment platelet count <150×10⁹/L (both P<0.05). The baseline LDL-C level exerted a potent influence on the SVR of treatment-experienced patients treated with TVR-based triple therapy, especially for prior partial and null responders to PEG-IFNα and RBV.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiji Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | | | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Yuichi Tanabe
- Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan
| | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
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Cheng FKF, Torres DM, Harrison SA. Hepatitis C and lipid metabolism, hepatic steatosis, and NAFLD: still important in the era of direct acting antiviral therapy? J Viral Hepat 2014; 21:1-8. [PMID: 24329852 DOI: 10.1111/jvh.12172] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) have an individual prevalence of 1.8-3% and at least 30%, respectively, in the United States. It is therefore not surprising that there is overlap between these two common chronic liver diseases, although the relationship appears to go beyond isolated co-existence. Hepatic steatosis is a common feature of CHC infection and can be related to both metabolic and viral specific factors. Steatosis in the setting of nongenotype 3 CHC has been predictive of response to therapy prior to the advent of the direct acting antiviral medications (DAAs). Similarly, lipid metabolism appears important in response to CHC treatment. The pathways for both lipid homeostasis and NAFLD as it pertains to CHC infection as well as the utilization of statin therapy in CHC infection will be reviewed with a focus on the relevance of these topics in the era of DAA therapy.
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Affiliation(s)
- F-K F Cheng
- Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Washington, DC, USA
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Ali N, Allam H, Bader T, May R, Basalingappa KM, Berry WL, Chandrakesan P, Qu D, Weygant N, Bronze MS, Umar S, Janknecht R, Sureban SM, Huycke M, Houchen CW. Fluvastatin interferes with hepatitis C virus replication via microtubule bundling and a doublecortin-like kinase-mediated mechanism. PLoS One 2013; 8:e80304. [PMID: 24260365 PMCID: PMC3833963 DOI: 10.1371/journal.pone.0080304] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 10/11/2013] [Indexed: 12/18/2022] Open
Abstract
Hepatitis C virus (HCV)-induced alterations in lipid metabolism and cellular protein expression contribute to viral pathogenesis. The mechanism of pleiotropic actions of cholesterol-lowering drugs, statins, against HCV and multiple cancers are not well understood. We investigated effects of fluvastatin (FLV) on microtubule-associated and cancer stem cell marker (CSC), doublecortin-like kinase 1 (DCLK1) during HCV-induced hepatocarcinogenesis. HCV replication models, cancer cell lines and normal human hepatocytes were used to investigate the antiviral and antitumor effects of statins. FLV treatment resulted in induction of microtubule bundling, cell-cycle arrest and alterations in cellular DCLK1 distribution in HCV-expressing hepatoma cells. These events adversely affected the survival of liver-derived tumor cells without affecting normal human hepatocytes. FLV downregulated HCV replication in cell culture where the ATP pool and cell viability were not compromised. Pravastatin did not exhibit these effects on HCV replication, microtubules and cancer cells. The levels of miR-122 that regulates liver homeostasis and provides HCV genomic stability remained at steady state whereas DCLK1 mRNA levels were considerably reduced during FLV treatment. We further demonstrated that HCV replication was increased with DCLK1 overexpression. In conclusion, unique effects of FLV on microtubules and their binding partner DCLK1 are likely to contribute to its anti-HCV and antitumor activities in addition to its known inhibitory effects on 3-hydroxy-3-methylglutary-CoA reductase (HMGCR).
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Affiliation(s)
- Naushad Ali
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Veterans Affairs Medical Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- * E-mail: (NA); (CWH)
| | - Heba Allam
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Microbiology and Immunology, National Liver Institute, Menoufiya University, Menoufiya, Egypt
| | - Ted Bader
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Veterans Affairs Medical Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Randal May
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Veterans Affairs Medical Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Kanthesh M. Basalingappa
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - William L. Berry
- Department of Cell Biology, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Parthasarathy Chandrakesan
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Dongfeng Qu
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Nathaniel Weygant
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Michael S. Bronze
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Shahid Umar
- Department of Molecular and Integrative Physiology, and Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Ralf Janknecht
- Department of Cell Biology, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Sripathi M. Sureban
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Veterans Affairs Medical Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Mark Huycke
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Veterans Affairs Medical Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Courtney W. Houchen
- Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Veterans Affairs Medical Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- * E-mail: (NA); (CWH)
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Di Lello FA, Caruz A, Rallon NI, Rivero-Juarez A, Neukam K, Barreiro P, Camacho A, García-Rey S, Rivero A, Soriano V, Cifuentes C, Macias J, Pineda JA. Effects of the genetic pattern defined by low-density lipoprotein receptor and IL28B genotypes on the outcome of hepatitis C virus infection. Eur J Clin Microbiol Infect Dis 2013; 32:1427-35. [PMID: 23715768 DOI: 10.1007/s10096-013-1894-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 05/07/2013] [Indexed: 02/06/2023]
Abstract
The aim of this study was to assess the impact of the genetic pattern (GP) defined by the single nucleotide polymorphisms (SNPs) rs14158 of low-density lipoprotein receptor (LDLR) and rs12979860 of interleukin-28B (IL28B) genes on the outcome and features of hepatitis C virus (HCV) infection in patients with and without human immunodeficiency virus (HIV) coinfection. 314 HIV/HCV-coinfected and 109 HCV-monoinfected patients treated with pegylated interferon (Peg-IFN) plus ribavirin (RBV), as well as 51 patients with HCV spontaneous clearance (SC), were included. Variations in both SNPs were determined by the TaqMan polymerase chain reaction (PCR) assay. In the 286 patients chronically infected by HCV genotypes 1 or 4, both rs14158 CC and rs12979860 CC were associated with a higher rate of sustained virological response (SVR), and these effects were complementary in both HCV-monoinfected and HIV/HCV-coinfected patients. Thus, 24 % of patients with rs14158/rs12979860 TT-TC/TT-TC, 33 % with TT-TC/CC, 44.2 % with CC/TT-TC, and 75.8 % harboring CC/CC attained SVR (p < 0.001). SC was associated with the IL28B genotype (66.7 % CC in SC vs. 42.6 % among those with chronic infection, p < 0.001) but not with the LDLR genotype. There was no association between GP and the plasma level of alanine aminotransferase (ALT) or the presence of advanced fibrosis. There is a complementary effect between the IL28B and LDLR genotypes on the probability of achieving SVR after Peg-IFN/RBV therapy in patients with HCV 1 or 4. Thus, the predictive value of IL28B genotype is modulated by the LDLR genotype in both HCV-monoinfected and HIV/HCV-coinfected patients. This complementary effect of both genotypes is also observed on the plasma levels of low-density lipoprotein cholesterol (LDL-C).
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Affiliation(s)
- F A Di Lello
- Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Avenida de Bellavista s/n, 41014, Seville, Spain
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