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Blázquez AB, Mingo-Casas P, Quesada E, Priego EM, Pérez-Perez MJ, Martín-Acebes MA. Lipid-targeting antiviral strategies: Current state and future perspectives. Antiviral Res 2025; 236:106103. [PMID: 39947433 DOI: 10.1016/j.antiviral.2025.106103] [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: 12/11/2024] [Revised: 01/26/2025] [Accepted: 02/10/2025] [Indexed: 02/23/2025]
Abstract
There is an urgent need for antiviral compounds effective against currently known and future viral threats. The development of host-targeting antivirals (HTAs) appears as an alternative strategy to fight viral infections minimizing the potential of resistant mutant development and potentially leading to the identification of broad-spectrum antiviral agents. Among the host factors explored for HTA strategy, lipids constitute an attractive target as many viruses, even genetically diverse, hijack specific lipids during their lifecycle. Multiple repurposing efforts have been performed to analyze the antiviral properties of lipid-targeting compounds. These studies include the analysis of the effects of cholesterol lowering drugs such as statins, cholesterol transport inhibitors, sphingolipid modulators, de novo lipogenesis inhibitors blocking fatty acid synthesis, compounds targeting glycerophospholipids or drugs interfering with lipid droplet metabolism. This review is focused on the current status of lipid-based or lipid-targeting antiviral strategies and their potential for the development of antiviral therapies, with special emphasis on those studies that have reached advanced stages of development such as efficacy studies in animal models or clinical trials. Whereas there is still a long way to go, multiple proof-of-concept studies and clinical evidence reinforce the therapeutic potential of these strategies warranting their further development into effective antiviral therapies.
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Affiliation(s)
- Ana-Belén Blázquez
- Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC), Madrid, Spain.
| | - Patricia Mingo-Casas
- Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC), Madrid, Spain; Universidad Autónoma de Madrid (UAM, Escuela de Doctorado), Spain
| | | | | | | | - Miguel A Martín-Acebes
- Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC), Madrid, Spain.
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Clinical effects of simvastatin in chronic hepatitis C patients receiving sofosbuvir/daclatasvir combination. A randomized, placebo-controlled, double-blinded study. Clin Exp Hepatol 2020; 6:99-105. [PMID: 32728626 PMCID: PMC7380473 DOI: 10.5114/ceh.2020.95566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/17/2020] [Indexed: 11/17/2022] Open
Abstract
Aim of the study Chronic hepatitis C (CHC) affects more than 71 million people worldwide. Many therapies containing different direct-acting antivirals (DAAs) are now used. However, lipid profile is considered an important outcome with DAAs. So, this study aimed to assess clinical effects of statins in CHC patients. Material and methods One hundred patients were recruited from Kobri El koba Armed Forces Hospital and randomly assigned to: the drug group (D;n = 50) receiving simvastatin 10 mg plus sofosbuvir 400 mg/daclatasvir 60 mg (SOF/DAC) daily for 12 weeks; and the placebo group (P; n = 50), receiving placebo plus the same (SOF/DAC) regimen. Sustained virological response at 12 weeks after treatment (SVR12), lipid profile, C-reactive protein (CRP) and fibrosis stage were assessed. Results One hundred treatment-naïve CHC patients completed 12 weeks of the protocol with no clinically significant side effects. There was an increase in SVR failure rate in P (10%) compared to D (only 2%) but not reaching statistical significant difference; SVR12 (p > 0.05). Logistic regression analysis showed that high baseline CRP, low baseline hemoglobin level and non-statin usage had an independent effect on increasing the probability of SVR failure in both groups; p = 0.03, p = 0.0028, p = 0.02, respectively. Conclusions Statins could have an irreplaceable role in successful treatment of CHC patients receiving sofosbuvir/daclatasvir.
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Suda G, Ito J, Nagasaka A, Yamamoto Y, Furuya K, Okamoto M, Terashita K, Kobayashi T, Tsunematsu I, Yoshida J, Meguro T, Ohara M, Kawagishi N, Kimura M, Umemura M, Izumi T, Tsukuda Y, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study. Hepatol Res 2018; 48:E146-E154. [PMID: 28722780 DOI: 10.1111/hepr.12938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/11/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. METHODS This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. RESULTS Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. CONCLUSIONS This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | | | | | | | | | - Katsumi Terashita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Kushiro Rosai Hospital, Kushiro, Japan
| | - Tomoe Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Tomakomai City Hospital, Tomakomai, Japan
| | | | | | | | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoko Tsukuda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Sapporo City General Hospital, Sapporo, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, 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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Kishta SS, Kishta SA, El-Shenawy R. Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents. F1000Res 2017; 5:223. [PMID: 27583130 PMCID: PMC4988296 DOI: 10.12688/f1000research.7970.3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/25/2017] [Indexed: 12/17/2022] Open
Abstract
Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (
e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.
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Affiliation(s)
- Sara Sobhy Kishta
- Medical Biotechnology Lab, Microbial Biotechnology Department, National Research Center, Egypt, Cairo, Egypt
| | | | - Reem El-Shenawy
- Medical Biotechnology Lab, Microbial Biotechnology Department, National Research Center, Egypt, Cairo, Egypt
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Janicko M, Drazilova S, Pella D, Fedacko J, Jarcuska P. Pleiotropic effects of statins in the diseases of the liver. World J Gastroenterol 2016; 22:6201-6213. [PMID: 27468210 PMCID: PMC4945979 DOI: 10.3748/wjg.v22.i27.6201] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Statins are a class of molecules that inhibit HMG CoA reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins’ potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma (HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies.
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Kohjima M, Kurokawa M, Enjoji M, Yoshimoto T, Nakamura T, Ohashi T, Fukuizumi K, Harada N, Murata Y, Matsunaga K, Kato M, Kotoh K, Nakamuta M. Analysis of renal function during telaprevir-based triple therapy for chronic hepatitis C. Exp Ther Med 2016; 11:1781-1787. [PMID: 27168803 DOI: 10.3892/etm.2016.3133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 11/05/2015] [Indexed: 12/23/2022] Open
Abstract
Telaprevir (TVR) is used for the treatment of chronic hepatitis C in a combination therapy with pegylated-interferon and ribavirin. Although renal dysfunction is one of the critical adverse outcomes of this treatment, little is known regarding the mechanism of its onset. The present study assessed the association of renal function with TVR dose and viral response. Hematological, biochemical, urinary and virological parameters of renal function were examined during the TVR-based triple therapy of patients infected with hepatitis C virus (HCV) genotype 1b. Serum creatinine levels were increased and the estimated glomerular filtration rate (eGFR) was decreased in every patient during TVR administration, but these values recovered to normal levels following cessation of TVR. Fractional excretion of sodium was <1% at days 3 and 7, appearing similar regardless of baseline renal function. Urinary β2-microglobulin levels were elevated and were significantly higher in patients with renal dysfunction, as compared with those not exhibiting renal dysfunction (P<0.05). The reduction in renal function was milder in patients treated with a reduced TVR dose, and these patients had a significantly lower risk of developing renal dysfunction (P<0.05). Using a multivariate analysis, TVR dose and eGFR at the initiation of treatment were identified as significant contributory factors in the development of renal dysfunction. Reduction in TVR dose did not lead to a significant increase in the viral kinetics of HCV or detrimental effects on the sustained viral response (SVR) rate. It is hypothesized that renal dysfunction during TVR treatment is caused by damage of the renal tubule, in addition to pre-renal dysfunction, and that reduction in TVR dose reduces the rate of renal dysfunction without causing a significant decrease in the SVR rate.
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Affiliation(s)
- Motoyuki Kohjima
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Miho Kurokawa
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Munechika Enjoji
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Tsuyoshi Yoshimoto
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tsukasa Nakamura
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tomoko Ohashi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Kunitaka Fukuizumi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Naohiko Harada
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Yusuke Murata
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Kazuhisa Matsunaga
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
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Kohjima M, Yoshimoto T, Enjoji M, Fukushima N, Fukuizumi K, Nakamura T, Kurokawa M, Fujimori N, Sasaki Y, Shimonaka Y, Murata Y, Koyama S, Kawabe K, Haraguchi K, Sumida Y, Harada N, Kato M, Kotoh K, Nakamuta M. Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver. World J Gastroenterol 2015; 21:3291-3299. [PMID: 25805936 PMCID: PMC4363759 DOI: 10.3748/wjg.v21.i11.3291] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 10/22/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between the iron-metabolism-related gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients.
METHODS: The hepatic expression profile of iron-metabolism-related genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolism-related genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry.
RESULTS: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron-regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes.
CONCLUSION: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.
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Bickler SW, Lizardo RE, De Maio A. The transition from a rural to an urban environment alters expression of the human Ebola virus receptor Neiman-Pick C1: implications for the current epidemic in West Africa. Cell Stress Chaperones 2015; 20:203-6. [PMID: 25477151 PMCID: PMC4326391 DOI: 10.1007/s12192-014-0557-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 11/06/2014] [Accepted: 11/11/2014] [Indexed: 01/06/2023] Open
Affiliation(s)
- Stephen W. Bickler
- />Center for Investigations of Health and Education Disparities, University of California San Diego, 9500 Gilman Drive, #0739, La Jolla, CA 92093-0739 USA
- />Department of Surgery, School of Medicine, University of California, La Jolla, CA 92093 USA
- />Division of Pediatric Surgery, Rady Children’s Hospital, San Diego, CA 92123 USA
| | - Radhames E. Lizardo
- />Center for Investigations of Health and Education Disparities, University of California San Diego, 9500 Gilman Drive, #0739, La Jolla, CA 92093-0739 USA
- />Department of Surgery, Naval Medical Center San Diego, San Diego, CA 92134 USA
- />Division of Pediatric Surgery, Rady Children’s Hospital, San Diego, CA 92123 USA
| | - Antonio De Maio
- />Center for Investigations of Health and Education Disparities, University of California San Diego, 9500 Gilman Drive, #0739, La Jolla, CA 92093-0739 USA
- />Department of Surgery, School of Medicine, University of California, La Jolla, CA 92093 USA
- />Department of Neurosciences, School of Medicine, University of California, La Jolla, CA 92093 USA
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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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Barrios V, Escobar C, Zamorano JL. Searching the place of pitavastatin in the current treatment of patients with dyslipidemia. Expert Rev Cardiovasc Ther 2014; 11:1597-612. [DOI: 10.1586/14779072.2013.844546] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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12
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Lotrich FE, Sears B, McNamara RK. Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids. J Psychosom Res 2013; 75:475-83. [PMID: 24182638 PMCID: PMC3817416 DOI: 10.1016/j.jpsychores.2013.07.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 07/15/2013] [Accepted: 07/17/2013] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Anger worsens in some patients during interferon-alpha (IFN-α) therapy. Elevated anger has also been associated with lower long-chain omega-3 (LCn-3) fatty acid levels. We examined whether fatty acids could influence vulnerability to anger during IFN-α exposure. METHODS Plasma arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) levels were determined prior to IFN-α therapy by mass spectroscopy. Repeated-measure analyses examined the relationship between AA/EPA+DHA and the subsequent development of labile anger and irritability in 82 subjects who prospectively completed the Anger, Irritability, and Assault Questionnaire (AIAQ) during the first eight weeks of IFN-α therapy. RESULTS Prior to IFN-α therapy, AA/EPA+DHA did not correlate with either labile anger or irritability. Pre-treatment AA/EPA+DHA did correlate with the subsequent maximal increase in labile anger during IFN-α therapy (r=0.33; p=0.005). Over time, labile anger increased more in subjects with above median AA/EPA+DHA ratios (p<0.05). Of the 17 subjects ultimately requiring psychiatric intervention for anger, 14/17 had above-median AA/EPA+DHA ratios (p=0.009). There was also an interaction with the tumor necrosis factor-alpha (TNF-α) promoter polymorphism (A-308G), such that only those with both elevated AA/EPA+DHA and the A allele had increased labile anger (p=0.001). In an additional 18 subjects, we conversely observed that selective serotonin reuptake inhibitor treatment was associated with increased irritability during IFN-α therapy. CONCLUSION LCn-3 fatty acid status may influence anger development during exposure to elevated inflammatory cytokines, and may interact with genetic risk for increased brain TNF-α. LCn-3 supplements may be one strategy for minimizing this adverse side effect of IFN-α.
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Affiliation(s)
- Francis E. Lotrich
- Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA,All correspondence concerning this manuscript should be addressed to Francis E. Lotrich, Department of Psychiatry, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213. Tel: (412) 246-6267;
| | - Barry Sears
- Inflammation Research Foundation, Marblehead, Massachusetts
| | - Robert K. McNamara
- Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH
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Hepatitis C virus, cholesterol and lipoproteins--impact for the viral life cycle and pathogenesis of liver disease. Viruses 2013; 5:1292-324. [PMID: 23698400 PMCID: PMC3712309 DOI: 10.3390/v5051292] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 04/10/2013] [Accepted: 04/27/2013] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects.
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