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Lin CY, Guu TW, Lai HC, Peng CY, Chiang JYJ, Chen HT, Li TC, Yang SY, Su KP, Chang JPC. Somatic pain associated with initiation of interferon-alpha (IFN-α) plus ribavirin (RBV) therapy in chronic HCV patients: A prospective study. Brain Behav Immun Health 2020; 2:100035. [PMID: 34589826 PMCID: PMC8474510 DOI: 10.1016/j.bbih.2019.100035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 12/21/2019] [Accepted: 12/28/2019] [Indexed: 12/12/2022] Open
Abstract
Objective This study is aimed to investigate the association between interferon-alpha (IFN-α) plus ribavirin (RBV) treatment and emergence of somatic pain symptoms in patients with hepatitis C virus (HCV) over a 24-week treatment. Method In this prospective cohort study, 297 patients with HCV were evaluated at baseline and 2nd, 4th, 8th, 12th, 16th, 20th, and 24th week with structured Mini-International Neuropsychiatric Interview for Major Depressive Disorder (MDD) diagnosis and the Neurotoxicity Rating Scale (NRS) for somatic symptoms. Results Eighty-seven out of the 297 patients (29%) developed IFN-α induced depression and had significantly higher somatic pain symptoms as early as the 2nd week and at all the assessment time points (p < .001). Most depressed patients perceived greatest somatic pain at the 8th week of treatment. Moreover, NRS somatic pain scores after initial therapy strongly correlated with NRS somatic pain scores at all other assessment time points (p < .001). Conclusion IFN-α therapy induce significant somatic pain as early as the 2nd week of treatment in HCV patients who later developed MDD. Thus, initial NRS somatic pain score after initiation of IFN-α treatment may serve as a reference for the susceptibility of the individual to IFN-α induced depression.
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Affiliation(s)
- Chih Ying Lin
- School of Medicine, China Medical University (CMU), Taichung, Taiwan
- Mind-Body Interface Lab (MBI-Lab) and Department of Psychiatry, CMUH, Taichung, Taiwan
| | - Ta-Wei Guu
- Department Psychiatry, CMU Beigang Hospital, Yunlin, Taiwan
- Mind-Body Interface Lab (MBI-Lab) and Department of Psychiatry, CMUH, Taichung, Taiwan
| | - Hsueh-Chou Lai
- School of Medicine, China Medical University (CMU), Taichung, Taiwan
- Departement of Hepatogastroenterology, China Medial University Hospital, Taichung, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University (CMU), Taichung, Taiwan
- Departement of Hepatogastroenterology, China Medial University Hospital, Taichung, Taiwan
| | - Jill Yi-Ju Chiang
- Mind-Body Interface Lab (MBI-Lab) and Department of Psychiatry, CMUH, Taichung, Taiwan
| | - Hui-Ting Chen
- Mind-Body Interface Lab (MBI-Lab) and Department of Psychiatry, CMUH, Taichung, Taiwan
| | - Tsai-Chung Li
- School of Medicine, China Medical University (CMU), Taichung, Taiwan
- China Medical University Graduate Institute of Biostatistics, Taiwan
| | - Shing-Yu Yang
- School of Medicine, China Medical University (CMU), Taichung, Taiwan
- China Medical University Graduate Institute of Biostatistics, Taiwan
| | - Kuan-Pin Su
- School of Medicine, China Medical University (CMU), Taichung, Taiwan
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
- Mind-Body Interface Lab (MBI-Lab) and Department of Psychiatry, CMUH, Taichung, Taiwan
| | - Jane Pei-Chen Chang
- School of Medicine, China Medical University (CMU), Taichung, Taiwan
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
- Mind-Body Interface Lab (MBI-Lab) and Department of Psychiatry, CMUH, Taichung, Taiwan
- Corresponding author. Department of Psychiatry, China Medical University Hospital, No. 2 Yu-Der Road, Taichung, 404, Taiwan.
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Balkhi SS, Hojati Z. The Comparison Between the Mutated HuIFN-β 27-101 and the Wild Type Interferon β: the Comprehensive In Silico Study to Evaluate the Effect of Mutations on IFN-β. Adv Pharm Bull 2019; 9:640-648. [PMID: 31857969 PMCID: PMC6912172 DOI: 10.15171/apb.2019.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 07/02/2019] [Accepted: 07/21/2019] [Indexed: 11/23/2022] Open
Abstract
Purpose: Interferon beta (IFN-β) is used to combat multiple sclerosis (MS) disease. Creating R27T and V101F mutations (mHuIFN-β-27 and mHuIFN-β-101) is one of the tasks performed to improve human interferon beta (HuIFN-β) half-life, function and expression. In this work, the impact of R27T and V101F mutations in recombinant IFN-β on its binding to interferon receptors were studied by molecular docking. Methods: This work was performed through in silico study. The simulation of mutation was performed using the online Rosetta Backrub software and checked using server verify3D. Comparison of access to the solvent of the amino acids in the structures created was performed using the asaview online server. Also, the effect of mutations on the fold of the protein was reviewed by the online HOPE server. The molecular docking was performed between HuIFN-β and the external region of IFNAR receptor using the online ClusPro2 protein-protein docking server. Results: The comparison of the values of the negative binding energy (ΔGbind) obtained from protein-protein molecular docking between IFNAR receptor and HuIFN-β, mHuIFN-β-27, mHuIFN-β-101 and mHuIFN-β-27-101 ligands did not show a significant difference, and these differences do not see any meaningful relationship between them (P > 0.9999). Conclusion: Regarding these results, it can be concluded that these mutations do not have a negative effect on the composition of the complex rHuIFN-β/IFNAR. So, they do not interfere with the binding of the IFN-β to the receptor. It is concluded that the quality of the rHuIFN-β is improved by introducing these two mutations.
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Affiliation(s)
- Sayed Sharif Balkhi
- Division of Genetics, Department of Biology, Faculty of Sciences, University of Isfahan, Postal Code: 81746-73441 Isfahan, Iran
| | - Zohreh Hojati
- Division of Genetics, Department of Biology, Faculty of Sciences, University of Isfahan, Postal Code: 81746-73441 Isfahan, Iran
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Boglione L, Cusato J, Cariti G, Di Perri G, D'Avolio A. Reasons to wait or to treat naive patients affected by chronic hepatitis C with low fibrosis stage and genotypes 2 or 3. Eur J Public Health 2018; 27:938-941. [PMID: 28340198 DOI: 10.1093/eurpub/ckx025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background New interferon (IFN)-free therapies are not currently available for all patients with chronic hepatitis C due to higher costs; in Italy, patients with genotype 2 (GT2) or GT3 without severe fibrosis can choose between wait or treatment with pegylated (PEG)-IFN and ribavirin. This study wants to examine the real rate of patients that accept or refused this therapy and the reasons related to decision. Methods This prospective, observational analysis was performed at our centre between January 2014 and June 2015. Epidemiological, social and clinical data were collected in medical records; reasons for treatment acceptance/refusal were recorded through a questionnaire. Eligible patients were: naïve, with genotypes 2 or 3, fibrosis stage F0-F2. Results In total 132 patients were included: 34 with GT2, 98 with GT3. Patients with GT3 were younger, with prevalent sex male and mostly with active intravenous drug use. 53 patients accepted the treatment option (40.1%): 12 with GT2 (22%), 41 GT3 (41.8%) (P < 0.001). 79 patients refused (59.8%): 22 with GT2 (64.7%), 57 with GT3 (58.2) (P < 0.001). Fear of side-effects (OR = 1.774; 95% CI = 1.089-2.117; P = 0.016) and active alcoholism (OR = 1.144; 95% CI = 1.012-2.006; P = 0.025) were predictive factors for treatment refusal in GT3, whereas the presence of extrahepatic manifestations in GT2 (OR = 1.911; 95% CI = 1.124-2.912; P = 0.019) and the will to eradicate the infection in GT3 (OR = 2.140; 95% CI = 1.120-3.445; P = 0.008) were predictive of treatment acceptance. Conclusions Dual therapy is the only option for these subjects; however the motivation of patients and major socio-economic conditions were strictly related to decision of acceptance or refusal.
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Affiliation(s)
- Lucio Boglione
- Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Jessica Cusato
- Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Giuseppe Cariti
- Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
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Boglione L, Cardellino CS, Cusato J, De Nicolò A, Cariti G, Di Perri G, D'Avolio A. Treatment with PEG-IFN and ribavirin in patients with chronic hepatitis C, low grade of hepatic fibrosis, genotype 1 and 4 and favorable IFNL3 genotype: A pharmacogenetic prospective study. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2017; 51:167-172. [PMID: 28315743 DOI: 10.1016/j.meegid.2017.03.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 03/08/2017] [Accepted: 03/14/2017] [Indexed: 12/12/2022]
Abstract
The new direct-acting antivirals agents (DAAs) rapidly changed the treatment approach in chronic hepatitis C (CHC); however, the interferon (IFN)-free therapies availability is currently different in some countries, due to higher costs of these drugs. Naïve treated patients, who are not eligible for IFN-free therapies, could be selected for standard dual treatment with pegylated (PEG)-IFN and ribavirin (RBV), through IFN lambda 3 gene polymorphisms and fibrosis stage evaluation. Inclusion criteria were: naïve treated CHC patients with GT1 or GT4, without major contraindication to PEG-IFN or RBV, with fibrosis stage F0-F2 and IFNL3 rs8099917/rs12979860 TT/CC genotypes. 65 patients were included in the study. Overall SVR was observed in 50 patients (76.9%); SVR rates among different genotypes were as follows: 15 with GT1a (71.4%), 27 with GT1b (79.4%) and 8 for GT4 (80%). The RBV cutoff at 2weeks of 1800ng/mL, predictor of RVR, was determined (p=0.003; sensibility=60.4%, specificity=88.2%, positive predictive value=88.9%, negative predictive value=100%). In multivariate analysis, factors significantly associated with treatment failure were living alone condition (OR=4.302; 95%IC=1.254-16.257; p=0.034) and RBV plasma level <1800ng/mL at 2weeks (OR=4.970; 95%IC=1.405-17.565; p=0.009). Considering a pharmacogenetic-guided approach, dual therapy with PEG-IFN and RBV can be considered a reliable option for patients ineligible for IFN-free treatments, who are motivated and well informed about all the aspects related to PEG-IFN administration.
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Affiliation(s)
- Lucio Boglione
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
| | - Chiara Simona Cardellino
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Jessica Cusato
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Amedeo De Nicolò
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giuseppe Cariti
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
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Li X, Li Y, Fang S, Su J, Jiang J, Liang B, Huang J, Zhou B, Zang N, Ho W, Li J, Li Y, Chen H, Ye L, Liang H. Downregulation of autophagy-related gene ATG5 and GABARAP expression by IFN-λ1 contributes to its anti-HCV activity in human hepatoma cells. Antiviral Res 2017; 140:83-94. [PMID: 28131804 DOI: 10.1016/j.antiviral.2017.01.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/23/2017] [Indexed: 02/07/2023]
Abstract
Type-III interferon (IFN-λ), the most recently discovered family of IFNs, shares common features with type I IFNs, but also has many distinctive activities. It is not clear that whether IFN-λ has additional antiviral mechanisms. In this study, we investigated the effects of IFN-λ on autophagy, a cellular process closely related to hepatitis C virus (HCV) infection in human hepatoma Huh7 cells. Our results showed that IFN-λ1 treatment inhibit autophagic activity in Huh7 cells, as evidenced by the decreased expression of microtubule-associated protein 1 light chain 3B (LC3B)-II and conversion of LC3B-I to LC3B-II, decreased formation of GFP-LC3 puncta and accumulation of autophagosomes. IFN-λ1 could also inhibit HCV-induced or tunicamycin (a known inducer of autophagy with similar mechanism to HCV infection) -induced LC3B-II expression and autophagosome formation. Through PCR array, real time RT PCR, and western blot, two autophagy-related genes, ATG5 and GABARAP, were identified and verified to be down-regulated by IFN-λ1 treatment, either in HCV-uninfected Huh7 cells or in HCV JFH-1-infected cells. Overexpression of ATG5 and/or GABARAP could partly recover the IFN-λ1-inhibited HCV replication. Mechanism research demonstrated that IFN-λ1 could induce the expression of miR-181a and miR-214 (targeting ATG5 and GABARAP respectively), by which down-regulates ATG5 and GABARAP expression. Taken together, our results indicate that suppression of the autophagy response by IFN-λ1 contributes to IFN-λ1 anti-HCV activity. The results also provide a theoretical basis for improving the effectiveness of IFN treatment of HCV infection through inhibition of the HCV-induced autophagy response.
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Affiliation(s)
- Xu Li
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yu Li
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Medical Insurance Department, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China
| | - Shoucai Fang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jinming Su
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Division of HIV/AIDS Control and Prevention, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, 530021, Guangxi, China
| | - Junjun Jiang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Bingyu Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jiegang Huang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Bo Zhou
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Ning Zang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Wenzhe Ho
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Jieliang Li
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Yiping Li
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hui Chen
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Geriatrics Digestion Department of Internal Medicine, The First Affiliated Hospital of GuangXi Medical University, Nanning, 530021, Guangxi, China
| | - Li Ye
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
| | - Hao Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
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Hathorn E, Elsharkawy AM. Management of hepatitis C genotype 4 in the directly acting antivirals era. BMJ Open Gastroenterol 2016; 3:e000112. [PMID: 27752338 PMCID: PMC5051320 DOI: 10.1136/bmjgast-2016-000112] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 08/10/2016] [Accepted: 09/07/2016] [Indexed: 12/14/2022] Open
Abstract
Genotype 4 chronic hepatitis C (G4 HCV) accounts for 13% of worldwide HCV infections; with 10 million people infected with the virus across the world. Up to the end of 2013, the only treatment option for G4 HCV was treatment with pegylated interferon and ribavirin for 24-48 weeks. Since late 2013, treatment of G4 HCV has been transformed by the licensing of many directly acting antiviral agents (DAA). It is an exciting time to be involved in the management of HCV generally and G4 particularly. Interferon-free DAA regimens are now a reality for G4 HCV. This review will highlight these developments and discuss the data behind the use of these drugs. It will also highlight future regimens that are likely to be available over the coming years.
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Affiliation(s)
- Emma Hathorn
- Liver Unit , University Hospitals Birmingham NHS Foundation Trust , Birmingham , UK
| | - Ahmed M Elsharkawy
- Liver Unit , University Hospitals Birmingham NHS Foundation Trust , Birmingham , UK
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7
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Maasoumy B, Vermehren J, Welker MW, Bremer B, Perner D, Höner Zu Siederdissen C, Deterding K, Lehmann P, Cloherty G, Reinhardt B, Pawlotsky JM, Manns MP, Zeuzem S, Cornberg M, Wedemeyer H, Sarrazin C. Clinical value of on-treatment HCV RNA levels during different sofosbuvir-based antiviral regimens. J Hepatol 2016; 65:473-82. [PMID: 27085252 DOI: 10.1016/j.jhep.2016.04.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 01/08/2016] [Accepted: 04/05/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The European Association for the Study of the Liver (EASL) guidelines recommend HCV RNA measurements at specific time points during sofosbuvir(SOF)-therapy. However, it remains unclear, how these results should be interpreted. We aimed to analyze whether on-treatment HCV RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays. METHODS Samples were collected from 298 patients (HCV genotypes; GT1-5) at weeks (w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two university clinics and tested for HCV RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin (RBV) 12/24 w (n=99), pegylated-interferon-alfa (PegIFN)/SOF/RBV 12 w (n=51), SOF/simeprevir (SMV)±RBV 12 w (n=69) or SOF/daclatasvir±RBV 12/24 w (n=79). RESULTS HCV RNA levels during the first 4weeks of SOF/RBV therapy were significantly lower in GT3 patients who achieved SVR compared with those who relapsed. All GT3 patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with ⩾45IU/ml (p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR: 100% vs. 29%; p=0.0002). In contrast, HCV RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens. Residual HCV RNA was frequently detected by ART at later stages of therapy. However, SVR rates remained high in these patients. At the end of SOF/SMV±RBV therapy HCV RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR. CONCLUSIONS HCV RNA levels assessed at week 2 of SOF/RBV therapy can predict relapse in GT3-patients. Detectable HCV RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension. LAY SUMMARY We analyzed the predictive value of hepatitis C virus (HCV) RNA levels measured at different time points for treatment efficacy. We found that the level of HCV RNA measured at week 2 of antiviral therapy can be used to predict treatment success in patients with HCV genotype 3 infection treated with sofosbuvir and ribavirin but not in patients treated with other sofosbuvir-based regimens. Low level HCV RNA is frequently detected by the RealTime HCV assay during later stages of antiviral therapy. However, this is not associated with reoccurrence of HCV RNA after the end of treatment.
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Affiliation(s)
- Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Johannes Vermehren
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Martin-Walter Welker
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Dany Perner
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | | | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Patrick Lehmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | | | | | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Stefan Zeuzem
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Christoph Sarrazin
- Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany.
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8
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Duarte-Rojo A, Fischer SE, Adeyi O, Zita D, Deneke MG, Selzner N, Chen L, Malespin M, Cotler SJ, McGilvray ID, Feld JJ. Protease inhibitors partially overcome the interferon nonresponse phenotype in patients with chronic hepatitis C. J Viral Hepat 2016; 23:340-7. [PMID: 26710754 DOI: 10.1111/jvh.12494] [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: 02/24/2015] [Accepted: 10/20/2015] [Indexed: 02/06/2023]
Abstract
The outcome of triple therapy with protease inhibitors (PI) depends on the intrinsic response to interferon. Interferon-stimulated gene (ISG) expression differs by cell type in the liver and is a strong predictor of interferon responsiveness. Patients who respond well to interferon have low/absent ISG expression in hepatocytes but significant ISG expression in macrophages. Nonresponders (NRs) show the opposite pattern. We aimed to determine the association between cell-type-specific ISG staining and treatment outcome with PI-based triple therapy. Liver biopsy tissue from consecutive patients treated with boceprevir or telaprevir with peginterferon and ribavirin was stained for myxovirus A (MxA). Staining was scored 0-3 in macrophages (M-MxA) and hepatocytes (H-MxA), and IL28B genotyping was performed. Of 56 patients included 41 achieved SVR (73%) (sustained virological response), 2 (4%) relapsed, 10 (18%) were NRs, and 3 (5%) were lost to follow-up. Median M-MxA staining was stronger and H-MxA staining was weaker in patients who achieved SVR. MxA staining correlated with IL28B genotype and with the HCV RNA decline during lead-in phase. However, unlike with dual therapy, the negative predictive value (NPV) of absent or weak M-MxA staining was poor (42%), while the positive predictive value improved (93%). Although by multivariable logistic regression M-MxA staining was significantly associated with SVR (OR 4.35, 1.32-14.28, P = 0.012), the predictive ability was inadequate to withhold therapy. The interaction between macrophages and hepatocytes plays a critical role in interferon responsiveness; however, the addition of a PI at least partially overcomes the interferon nonresponse phenotype making the predictive ability of ISG staining less clinically useful.
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Affiliation(s)
- A Duarte-Rojo
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - S E Fischer
- Department of Pathology, University of Toronto, Toronto, ON, Canada.,University Health Network, Toronto, ON, Canada
| | - O Adeyi
- Department of Pathology, University of Toronto, Toronto, ON, Canada.,University Health Network, Toronto, ON, Canada
| | - D Zita
- University Health Network, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada
| | - M G Deneke
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - N Selzner
- University Health Network, Toronto, ON, Canada
| | - L Chen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada.,Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada
| | - M Malespin
- Division of Hepatology, Loyola University Health System, Maywood, IL, USA
| | - S J Cotler
- Division of Hepatology, Loyola University Health System, Maywood, IL, USA
| | | | - J J Feld
- University Health Network, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada.,Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada
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9
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Isorce N, Testoni B, Locatelli M, Fresquet J, Rivoire M, Luangsay S, Zoulim F, Durantel D. Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus. Antiviral Res 2016; 130:36-45. [PMID: 26971407 DOI: 10.1016/j.antiviral.2016.03.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 03/08/2016] [Accepted: 03/09/2016] [Indexed: 12/12/2022]
Abstract
In HBV-infected patients, therapies with nucleoside analogues or IFNα remain ineffective in eradicating the infection. Our aim was to re-analyze the anti-HBV activity of a large panel of IFNs and cytokines in vitro using non-transformed cultured hepatocytes infected with HBV, to identify new immune-therapeutic options. HepaRG cells and primary human hepatocytes were infected with HBV and, when infection was established, treated with various concentrations of different IFNs or inflammatory cytokines. Viral parameters were evaluated by quantifying HBV nucleic acids by qPCR and Southern Blot, and secreted HBV antigens were evaluated using ELISA. The cytokines tested were type-I IFNs, IFNγ, type-III IFNs, TNFα, IL-6, IL-1β, IL-18 as well as nucleos(t)ide analogues tenofovir and ribavirin. Cytokines and drugs, with the exception of IL-18 and ribavirin, exhibited a suppressive effect on HBV replication at least as strong as, but often stronger than, IFNα. The cytokine presenting the highest effect on HBV DNA was IL-1β, which exerted its inhibition within picomolar range. Importantly, we noticed differential effects on other parameters (HBV RNA, HBeAg, HBsAg) between both IFNs and inflammatory cytokines, thus suggesting different mechanisms of action. The combination of IL-1β and already used therapies, i.e. IFNα or tenofovir, demonstrated a stronger or similar anti-HBV activity. IL-1β was found to have a very potent antiviral effect against HBV in vitro. HBV was previously shown to promptly inhibit IL-1β production in Kupffer cells. Strategies aiming at unlocking this inhibition and restoring local production of IL-1β may help to further inhibit HBV replication in vivo.
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Affiliation(s)
- Nathalie Isorce
- INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France
| | - Barbara Testoni
- INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France
| | - Maëlle Locatelli
- INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France
| | - Judith Fresquet
- INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France
| | | | - Souphalone Luangsay
- INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France
| | - Fabien Zoulim
- INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France; Hospices Civils de Lyon (HCL), Liver Departement of Croix-Rousse Hospital, 69002 Lyon, France; Institut Universitaire de France (IUF), 75005 Paris, France.
| | - David Durantel
- INSERM U1052, Cancer Research Centre of Lyon (CRCL), 69424 Lyon Cedex 03, France; University of Lyon, Université Claude Bernard (UCBL), UMR_S1052, 69008 Lyon, France; LabEx DEVweCAN, 69008 Lyon, France.
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10
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Fábregas BC, Vieira ÉLM, Moura AS, Carmo RA, Ávila RE, Abreu MNS, Prossin AR, Teixeira AL. A Follow-Up Study of 50 Chronic Hepatitis C Patients: Adiponectin as a Resilience Biomarker for Major Depression. Neuroimmunomodulation 2016; 23:88-97. [PMID: 27035148 DOI: 10.1159/000444531] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 02/05/2016] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Major depression (MD) is a condition associated with both hepatitis C virus (HCV) infection and pegylated interferon (IFN)-α treatment. IFN induces a depressive syndrome that is associated with an inflammatory profile. We aimed to investigate whether there is any specific alteration in plasma biomarkers associated with MD. METHODS HCV-monoinfected patients, with and without IFN treatment, were followed up for 18 months and went through structured psychiatric evaluation. We assessed plasma levels of brain-derived neurotrophic factor, tumor necrosis factor (TNF) and its soluble type 1 and type 2 receptors (sTNFR1 and sTNFR2, respectively), and adipokines (adiponectin, leptin and resistin) using ELISA. RESULTS Among the 50 patients included in the study, 14 were treated with IFN during the follow-up. Being older, not married, presenting higher body mass index, higher liver inflammatory activity, lower baseline adiponectin levels and use of IFN were associated with MD development. Higher levels of sTNFR1 during IFN treatment were associated with sustained virological response. The lack of a control group without HCV infection did not allow any assumption of a biomarker change exclusively due to the infection itself. CONCLUSION Adiponectin may be a resilience biomarker for MD in HCV-infected patients.
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Affiliation(s)
- Bruno C Fábregas
- Tropical Medicine Program, School of Medicine, Municipal Health Division/Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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11
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Perales C, Quer J, Gregori J, Esteban JI, Domingo E. Resistance of Hepatitis C Virus to Inhibitors: Complexity and Clinical Implications. Viruses 2015; 7:5746-66. [PMID: 26561827 PMCID: PMC4664975 DOI: 10.3390/v7112902] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 10/23/2015] [Accepted: 10/26/2015] [Indexed: 12/20/2022] Open
Abstract
Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic. We put the experimental observations in the context of quasi-species dynamics, in particular what the genetic and phenotypic barriers to resistance mean in terms of exploration of sequence space while HCV replicates in the liver of infected patients or in cell culture. Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined.
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Affiliation(s)
- Celia Perales
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Biologia Molecular "Severo Ochoa" (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
| | - Josep Quer
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
- Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
| | - Josep Gregori
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
- Roche Diagnostics SL, 08174 Sant Cugat del Vallès, Spain.
| | - Juan Ignacio Esteban
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
- Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
| | - Esteban Domingo
- Centro de Biologia Molecular "Severo Ochoa" (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
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12
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Isorce N, Lucifora J, Zoulim F, Durantel D. Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies. Antiviral Res 2015; 122:69-81. [PMID: 26275801 DOI: 10.1016/j.antiviral.2015.08.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 08/11/2015] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains a major challenge for clinicians, as there are only two types of approved therapies: interferon-alpha (IFN-α) or its pegylated form, Peg-IFN-α and nucleoside analogs (e.g. tenofovir, entecavir...). The first are used as finite-duration treatments of around 48-52 weeks, while the second must be taken life-long to prevent rebound. Other immune-modulators, including other types of recombinant IFNs and cytokines/chemokines, could be developed for treating chronic hepatitis B. Alternatively, strategies aimed either at restoring or favoring the endogenous production of IFNs, cytokines and/or chemokines, or at alleviating HBV-mediated inhibitory processes could also be envisaged. In this article, we review current investigational, preclinical and clinical efforts to implement immune-modulatory components in the therapy of chronic hepatitis B. This review forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B".
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Affiliation(s)
- Nathalie Isorce
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France
| | - Julie Lucifora
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France
| | - Fabien Zoulim
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France; Labex DEVweCAN, Lyon, France; Hospices Civils de Lyon (HCL), Croix-Rousse Hospital, Lyon, France
| | - David Durantel
- INSERM, U1052, CNRS UMR_5286, Cancer Research Centre of Lyon (CRCL), Lyon, France; University of Lyon, Université Claude Bernard (UCBL), Lyon, France; Labex DEVweCAN, Lyon, France.
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13
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Hilgenfeldt EG, Schlachterman A, Firpi RJ. Hepatitis C: Treatment of difficult to treat patients. World J Hepatol 2015; 7:1953-63. [PMID: 26244069 PMCID: PMC4517154 DOI: 10.4254/wjh.v7.i15.1953] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 05/29/2015] [Accepted: 07/16/2015] [Indexed: 02/06/2023] Open
Abstract
Over the past several years, more so recently, treatment options for hepatitis C virus (HCV) have seemed to exponentially grow. Up until recently, the regimen of pegylated interferon (peg-IFN) and ribavirin (RBV) stood as the standard of care. Direct acting antivirals, which target nonstructural proteins involved in replication and infection of HCV were first approved in 2011 as an addition to the peg-IFN and RBV regimen and with them have come increased sustained virological response rates (SVR). The previously reported 50%-70% SVR rates using the combination of peg-IFN and RBV are no longer the standard of care with direct acting antiviral (DAA) based regimens now achieving SVR of 70%-90%. Peg-IFN free as well as "all oral" regimens are also available. The current randomized controlled trials available show favorable SVRs in patients who are naive to treatment, non-cirrhotic, and not human immunodeficiency virus (HIV)-co-infected. What about patients who do not fit into these categories? In this review, we aim to discuss the currently approved and soon to be approved DAAs while focusing on their roles in patients that are treatment experienced, cirrhotic, or co-infected with HIV. In this discussion, review of the clinical trials leading to recent consensus guidelines as well as discussion of barriers to treatment will occur. A case will attempt will be made that social services, including financial support and drug/alcohol treatment, should be provided to all HCV infected patients to improve chances of cure and thus prevention of late stage sequela.
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Affiliation(s)
- Eric G Hilgenfeldt
- Eric G Hilgenfeldt, Department of Internal Medicine, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Alex Schlachterman
- Eric G Hilgenfeldt, Department of Internal Medicine, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Roberto J Firpi
- Eric G Hilgenfeldt, Department of Internal Medicine, University of Florida College of Medicine, Gainesville, FL 32610, United States
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14
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Liu B, Chen S, Guan Y, Chen L. Type III Interferon Induces Distinct SOCS1 Expression Pattern that Contributes to Delayed but Prolonged Activation of Jak/STAT Signaling Pathway: Implications for Treatment Non-Response in HCV Patients. PLoS One 2015; 10:e0133800. [PMID: 26193702 PMCID: PMC4508043 DOI: 10.1371/journal.pone.0133800] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 06/30/2015] [Indexed: 12/15/2022] Open
Abstract
Suppressor of cytokine signaling 1 (SOCS1) has long been thought to block type I interferon signaling. However, IFN-λ, a type III IFN with limited receptor expression in hepatic cells, efficiently inhibits HCV (Hepatitis C virus) replication in vivo with potentially less side effects than IFN-α. Previous studies demonstrated that type I and type III activated Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway differently, with delayed but prolonged activation by IFN-λ stimulation compared to IFNα/β. However, the molecular mechanisms underlying this observation is not well understood. Here, we found that there are distinct differences in SOCS1 expression patterns in Huh-7.5.1 cells following stimulation with IFN-α and IFN-λ. IFN-λ induced a faster but shorter expression of SOCS1. Furthermore, we confirmed that SOCS1 over-expression abrogates anti-HCV effect of both IFN-α and IFN-λ, leading to increased HCV RNA replication in both HCV replicon cells and JFH1 HCV culture system. In line with this, SOCS1 over-expression inhibited STAT1 phosphorylation, attenuated IFN-stimulated response elements (ISRE) reporter activity, and blocked IFN-stimulated genes (ISGs) expression. Finally, we measured SOCS1 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) with or without IFN-α treatment from 48 chronic hepatitis C patients and we found the baseline SOCS1 expression levels are higher in treatment non-responders than in responders before IFN-α treatment. Taken together, SOCS1 acts as a suppressor for both type I and type III IFNs and is negatively associated with sustained virological response (SVR) to IFN-based therapy in patients with HCV. More importantly, faster but shorter induction of SOCS1 by IFN-λ may contribute to delayed but prolonged activation of IFN signaling and ISG expression kinetics by type III IFN.
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Affiliation(s)
- Bing Liu
- The Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, People’s Republic of China
| | - Shan Chen
- The Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, People’s Republic of China
| | - Yujuan Guan
- Guangzhou No.8 People's Hospital, Guangzhou, China
| | - Limin Chen
- The Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, People’s Republic of China
- Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
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15
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Li HC, Lo SY. Hepatitis C virus: Virology, diagnosis and treatment. World J Hepatol 2015; 7:1377-1389. [PMID: 26052383 PMCID: PMC4450201 DOI: 10.4254/wjh.v7.i10.1377] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/22/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti-viral therapy and predict the likelihood of response. In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. However, this therapy is not ideal. To 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral, interferon-free, pan-genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these anti-viral treatments. However, not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus, an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection.
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16
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De Clercq E. Development of antiviral drugs for the treatment of hepatitis C at an accelerating pace. Rev Med Virol 2015; 25:254-67. [DOI: 10.1002/rmv.1842] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/04/2015] [Accepted: 05/05/2015] [Indexed: 02/06/2023]
Affiliation(s)
- Erik De Clercq
- Rega Institute for Medical Research; KU Leuven; Leuven Belgium
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17
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Herzer K, Papadopoulos-Köhn A, Achterfeld A, Canbay A, Piras-Straub K, Paul A, Walker A, Timm J, Gerken G. Management of telaprevir-based triple therapy for hepatitis C virus recurrence post liver transplant. World J Hepatol 2015; 7:1287-1296. [PMID: 26019745 PMCID: PMC4438504 DOI: 10.4254/wjh.v7.i9.1287] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 02/27/2015] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize management of telaprevir (TVR)-based triple therapy of hepatitis C virus (HCV) reinfection after liver transplantation (LT).
METHODS: We retrospectively analyzed safety and efficacy of telaprevir - based triple therapy in a single center cohort of 19 patients with HCV genotype (GT) 1 recurrence after LT, with respect to factors possibly predicting sustained viral response (SVR) or non-SVR. All patients were treated with TVR, pegylated (PEG) and ribavirine (RBV) for 12 wk followed by a dual phase with PEG/RBV for 12 wk in 7 patients and for 36 wk in 5 patients.
RESULTS: In total 11/19 (58%) of patients achieved a sustained response. All (11/11) SVR patients showed a rapid viral response at treatment weeks 4 and 11/14 rapid virological response (RVR) patients achieved SVR. Notably, all (7/7) patients who completed 48 wk of therapy and 80% (4/5) patients who completed 24 wk of therapy achieved SVR24. Treatment failure was significantly (P > 0.049) more frequent in GT1a infection (5/7) compared to GT1b (3/12) infection and was associated with emergence of resistance-associated mutations in the NS3 protease domain. Bilirubin level at baseline is also related to SVR (P > 0.030). None of the patients had to discontinue treatment due to side effects.
CONCLUSION: RVR, GT and bilirubin are clearly related to achievement of SVR. Providing a thorough patient selection and monitoring, a full course of TVR-based triple therapy in LT patients is feasible and achieves high SVR rates.
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18
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IFN-λ: A New Class of Interferon with Distinct Functions-Implications for Hepatitis C Virus Research. Gastroenterol Res Pract 2015; 2015:796461. [PMID: 26078754 PMCID: PMC4452855 DOI: 10.1155/2015/796461] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 04/06/2015] [Indexed: 12/14/2022] Open
Abstract
Pegylated interferon-α and ribavirin (PEG-IFN/RBV) is widely used to treat chronic hepatitis C virus infection with notorious adverse reactions since the broad expression of IFN-α receptors on all nucleated cells. Accordingly, a Type III IFN with restricted receptors distribution is much safer as an alternative for HCV therapy. In addition, single nucleotide polymorphisms (SNPs) near the human IFN-λ3 gene, IL-28B, correlate strongly with the ability to achieve a sustained virological response (SVR) to therapy with pegylated IFN-α plus ribavirin in patients infected with chronic hepatitis C. Furthermore, we also discuss the most recent findings: IFN-λ4 predicts treatment outcomes of HCV infection. In consideration of the apparent limitations of current HCV therapy, especially high failure rate and universal side effects, prediction of treatment outcomes prior to the initiation of treatment and developing new alternative drugs are two important goals in HCV research.
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19
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Pfeil AM, Reich O, Guerra IM, Cure S, Negro F, Müllhaupt B, Lavanchy D, Schwenkglenks M. Cost-effectiveness analysis of sofosbuvir compared to current standard treatment in Swiss patients with chronic hepatitis C. PLoS One 2015; 10:e0126984. [PMID: 25974722 PMCID: PMC4431849 DOI: 10.1371/journal.pone.0126984] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 04/09/2015] [Indexed: 12/17/2022] Open
Abstract
In clinical trials, sofosbuvir showed high antiviral activity in patients infected with hepatitis C virus (HCV) across all genotypes. We aimed to determine the cost-effectiveness of sofosbuvir-based treatment compared to current standard treatment in mono-infected patients with chronic hepatitis C (CHC) genotypes 1-4 in Switzerland. Cost-effectiveness was modelled from the perspective of the Swiss health care system using a lifetime Markov model. Incremental cost-effectiveness ratios (ICERs) used an endpoint of cost per quality-adjusted life year (QALY) gained. Treatment characteristics, quality of life, and transition probabilities were obtained from published literature. Country-specific model inputs such as patient characteristics, mortality and costs were obtained from Swiss sources. We performed extensive sensitivity analyses. Costs and effects were discounted at 3% (range: 0-5%) per year. Sofosbuvir-containing treatment in mixed cohorts of cirrhotic and non-cirrhotic patients with CHC genotypes 1-4 showed ICERs between CHF 10,337 and CHF 91,570 per QALY gained. In subgroup analyses, sofosbuvir dominated telaprevir- and boceprevir-containing treatment in treatment-naïve genotype 1 cirrhotic patients. ICERs of sofosbuvir were above CHF 100,000 per QALY in treatment-naïve, interferon eligible, non-cirrhotic patients infected with genotypes 2 or 3. In deterministic and probabilistic sensitivity analyses, results were generally robust. From a Swiss health care system perspective, treatment of mixed cohorts of cirrhotic and non-cirrhotic patients with CHC genotypes 1-4 with sofosbuvir-containing treatment versus standard treatment would be cost-effective if a threshold of CHF 100,000 per QALY was assumed.
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Affiliation(s)
- Alena M. Pfeil
- Institute of Pharmaceutical Medicine (ECPM), University of Basel, Basel, Switzerland
| | - Oliver Reich
- Department of Health Sciences, Helsana Group, Zurich, Switzerland
| | | | | | - Francesco Negro
- Divisions of Gastroenterology and Hepatology and of Clinical Pathology, University Hospital Geneva, Geneva, Switzerland
| | - Beat Müllhaupt
- Swiss HPB (Hepato-Pancreato-Biliary) Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, Zurich, Switzerland
| | - Daniel Lavanchy
- World Health Organization (WHO), African Union, Governments, Denges VD, Switzerland
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Jiang XH, Xie YT, Jiang B, Tang MY, Ma T, Peng H. Inhibition of expression of hepatitis C virus 1b genotype core and NS4B genes in HepG2 cells using artificial microRNAs. Mol Med Rep 2015; 12:1905-13. [PMID: 25847260 DOI: 10.3892/mmr.2015.3571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 02/05/2015] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to evaluate the silencing effect of artificial microRNAs (amiRNAs) against the hepatitis C virus (HCV) 1b (HCV1b) genotype core (C) and non-structural protein 4B (NS4B) genes. pDsRed-monomer-Core and pDsRed-monomer-NS4B plasmids, containing the target genes were constructed. A total of eight artificial micro RNA (amiRNA)-expressing plasmids, namely, pmiRE-C-mi1 to -mi4 and pmiRE-NS4B-mi1 to -mi4, were designed and constructed to interfere with various sites of the core and NS4B genes, and the amiRNA interfering plasmid and the corresponding target gene-expressing plasmid were co-transfected into HepG2 cells. At 48 h after transfection, HCV core and NS4B gene expression levels were detected using fluorescence microscopy, flow cytometry, reverse transcription quantitative polymerase chain reaction and western blot analysis. Fluorescence microscopy revealed that the target gene-transfected cells expressed red fluorescent protein, whereas the interfering plasmid-transfected cells exhibited expression of green fluorescent protein. The percentage of red fluorescent proteins and mean fluorescence intensity, as well as protein expression levels of the core and NS4B genes within the cells, which were co-transfected by the amiRNA interfering plasmid and the target gene, were significantly decreased. The results of the present study confirmed that amiRNAs may effectively and specifically inhibit the expression of HCV1b core and NS4B genes in HepG2 cells, potentially providing a novel therapeutic strategy for the treatment of HCV.
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Affiliation(s)
- Xiao-Hua Jiang
- Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, Hunan 410087, P.R. China
| | - Yu-Tao Xie
- Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, Hunan 410087, P.R. China
| | - Bo Jiang
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Meng-Ying Tang
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Tao Ma
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hua Peng
- Department of Infectious Diseases, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
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Çakır G, Küçükgüzel İ, Guhamazumder R, Tatar E, Manvar D, Basu A, Patel BA, Zia J, Talele TT, Kaushik-Basu N. Novel 4-Thiazolidinones as Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase. Arch Pharm (Weinheim) 2014; 348:10-22. [DOI: 10.1002/ardp.201400247] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 09/07/2014] [Accepted: 10/01/2014] [Indexed: 12/29/2022]
Affiliation(s)
- Gizem Çakır
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry; Marmara University; Haydarpaşa İstanbul Turkey
| | - İlkay Küçükgüzel
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry; Marmara University; Haydarpaşa İstanbul Turkey
| | - Rupa Guhamazumder
- Department of Biochemistry & Molecular Biology; New Jersey Medical School; The State University of New Jersey; Newark NJ USA
| | - Esra Tatar
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry; Marmara University; Haydarpaşa İstanbul Turkey
| | - Dinesh Manvar
- Department of Biochemistry & Molecular Biology; New Jersey Medical School; The State University of New Jersey; Newark NJ USA
| | - Amartya Basu
- Department of Biochemistry & Molecular Biology; New Jersey Medical School; The State University of New Jersey; Newark NJ USA
| | - Bhargav A. Patel
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences; St. John's University; Queens NY USA
| | - Javairia Zia
- Department of Biochemistry & Molecular Biology; New Jersey Medical School; The State University of New Jersey; Newark NJ USA
| | - Tanaji T. Talele
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences; St. John's University; Queens NY USA
| | - Neerja Kaushik-Basu
- Department of Biochemistry & Molecular Biology; New Jersey Medical School; The State University of New Jersey; Newark NJ USA
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22
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Maasoumy B, Hunyady B, Calvaruso V, Makara M, Vermehren J, Haragh A, Susser S, Bremer B, Cloherty G, Manns MP, Craxì A, Wedemeyer H, Sarrazin C. Performance of two HCV RNA assays during protease inhibitor-based triple therapy in patients with advanced liver fibrosis and cirrhosis. PLoS One 2014; 9:e110857. [PMID: 25389779 PMCID: PMC4229112 DOI: 10.1371/journal.pone.0110857] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 09/19/2014] [Indexed: 12/15/2022] Open
Abstract
Introduction On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance. Aim To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis. Methods We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays. Results Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR. Conclusion Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.
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Affiliation(s)
- Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Bela Hunyady
- Somogy County Kaposi Mor Teaching Hospital, Kaposvar, Hungary
- University of Pecs, Pecs, Hungary
| | - Vincenza Calvaruso
- Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Mihály Makara
- Outpatient Clinic, Saint Laszlo Hospital, Budapest, Hungary
| | - Johannes Vermehren
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
| | - Attila Haragh
- Somogy County Kaposi Mor Teaching Hospital, Kaposvar, Hungary
| | - Simone Susser
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Gavin Cloherty
- Abbott Molecular, Des Plaines, Illinois, United States of America
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Antonio Craxì
- Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Christoph Sarrazin
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
- * E-mail:
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23
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Wang J, Jiang D, Rao H, Yang R, Wang Y, Wei L. Association of interferon-γ-induced protein-10 serum levels with virological responses to PEG-interferon-based therapy in hepatitis C virus genotype 1 or 2 chronically infected Chinese patients. Scand J Gastroenterol 2014; 49:1349-58. [PMID: 25263691 DOI: 10.3109/00365521.2014.962609] [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] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Interferon (IFN)-γ-induced protein-10 (IP-10) serum level has been shown be associated with viral response in chronic hepatitis C (CHC) patients. However, little is known in Chinese population. We determined IP-10 serum levels in Chinese CHC patients undergoing PEG-IFN-based therapy. Predictive role of IP-10 level for virological responses was accessed. MATERIAL AND METHODS IP-10 serum levels were determined in 165 hepatitis C virus (HCV) genotype 1 and 33 genotype 2 patients. Multivariate analysis was performed to screen independent factors for sustained virological response (SVR) prediction. Predictive value of IP-10 level in combination with interleukin 28B (IL28B) genotype or rapid virological response was further investigated. RESULTS Our study showed that pretreatment IP-10 level was significantly higher in HCV genotype 1 patients. IP-10 levels were independently predictive for SVR with cut-off values of 250.60 pg/ml at baseline or 407.40 pg/ml at week 4. Positive predictive value (PPV) for SVR of low IP-10 level at baseline and IL28B CC genotype was 96.15% and negative predictive value (NPV) was 50.00%. PPV for SVR of low IP-10 level at week 4 and rapid viral response (RVR) was 95.24% and NPV was 50.00%. CONCLUSION Together our study indicated that higher IP-10 serum levels were associated with HCV genotype 1 CHC Chinese patients. IP-10 levels at baseline and week 4 were both predictive of SVR and improved predictive performances of IL28B genotype and RVR for SVR.
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Affiliation(s)
- Jianghua Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases , No.11, Xizhimen South Street, Beijing 100044 , China
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24
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Hoyo-Becerra C, Schlaak JF, Hermann DM. Insights from interferon-α-related depression for the pathogenesis of depression associated with inflammation. Brain Behav Immun 2014; 42:222-31. [PMID: 25066466 DOI: 10.1016/j.bbi.2014.06.200] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 06/26/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
Interferon-α (IFN-α) is a pleiotropic cytokine that is administered as a therapeutic in highly prevalent medical conditions such as chronic hepatitis C and B virus infection, melanoma and lymphoma. IFN-α induces, to a clinically relevant degree, concentration, memory, drive and mood disturbances in almost half of all patients. For this reason, IFN-α is increasingly being replaced by more specifically acting drugs. In the past decades, IFN-α has offered a valuable insight into the pathogenesis of major depression, particularly in settings associated with inflammation. IFN-α triggers immune responses, hypothalamo-pituitary-adrenal axis abnormalities and disturbances of brain metabolism resembling those in other depression states. IFN-α stimulates indoleamine-2,3 dioxygenase-1, activating the kynurenine pathway with reduced formation of the neurotransmitters serotonin and dopamine, excessive formation of the NMDA agonist quinolinic acid, and reduced formation of the NMDA antagonist kynurenic acid. In addition, IFN-α disturbs neurotrophic signaling and impedes neurite outgrowth, synaptic plasticity, endogenous neurogenesis and neuronal survival. Consequently, IFN-α-related depression may represent a model for the neurodegenerative changes that are noticed in late-life major depression. Indeed, the observation that brain responses in IFN-α-related depression resemble idiopathic depression is supported by the existence of common genetic signatures, among which of note, a number of neuronal survival and plasticity genes have been identified. In view of the high incidence of depressive symptoms, IFN-α-related depression is an attractive model for studying links between neuronal plasticity, neurodegeneration and depression. We predict that in the latter areas new targets for anti-depressant therapies could be identified, which may deepen our understanding of idiopathic major depression.
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Affiliation(s)
| | - Joerg F Schlaak
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
| | - Dirk M Hermann
- Department of Neurology, University Hospital Essen, Germany.
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Pawlotsky JM, Novruzov N, Baskiran A, Yetisir F, Unal B, Aydın C, Bayramov N, Kayaalp C, Yilmaz S. What are the pros and cons of the use of host-targeted agents against hepatitis C? Antiviral Res 2014; 105:22-5. [PMID: 24583032 PMCID: PMC7173253 DOI: 10.1016/j.antiviral.2014.02.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 02/13/2014] [Accepted: 02/14/2014] [Indexed: 12/12/2022]
Abstract
Host-targeted agents block hepatitis C virus production by interacting with host cell components. Blocking the interaction of a cell component involved in the HCV lifecycle results in blockade of viral production. Cyclophilin A inhibitors and antagonists of microRNA-122 have reached clinical development. Host-targeted agents represent ideal “backbones” for pangenotypic drug combinations. Research on host-targeted approaches to combat viral infections other than HCV should be encouraged. Hepatitis C virus (HCV) therapy is living a revolution. Host-targeted agents (HTAs) block HCV production by interacting with host cell components. Because they target conserved host proteins, not variable viral proteins, HTAs have the potential for pangenotypic antiviral activity and a high barrier to resistance. Only two HTAs have reached clinical development, including specific inhibitors of cyclophilin A peptidyl-prolyl cis/trans isomerase activity and antagonists of microRNA-122. Cyclophilin inhibitors have proven to be relatively well tolerated and can be confidently used as backbones of all-oral, interferon-free regimens. In addition, HTAs such as cyclophilin inhibitors offer opportunities for “panviral” approaches when they target mechanisms common to viruses of the same or different families. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”
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Affiliation(s)
- Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France.
| | - Namig Novruzov
- Inonu University, Liver Transplantation Institute, Malatya, Turkey; Central Customs Hospital, Baku, Azerbaijan
| | - Adil Baskiran
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | - Fahri Yetisir
- Department of General Surgery, Atatürk Research and Training Hospital, Ankara, Turkey; Inonu University, Liver Transplantation Institute, Malatya, Turkey.
| | - Bulent Unal
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | - Cemalettın Aydın
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | | | - Cuneyt Kayaalp
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | - Sezai Yilmaz
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
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