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Patil VS, Harish DR, Vetrivel U, Roy S, Deshpande SH, Hegde HV. Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective. Molecules 2022; 27:molecules27031076. [PMID: 35164341 PMCID: PMC8839135 DOI: 10.3390/molecules27031076] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/15/2022] [Accepted: 01/22/2022] [Indexed: 01/27/2023] Open
Abstract
Terminalia chebula Retz. forms a key component of traditional folk medicine and is also reported to possess antihepatitis C virus (HCV) and immunomodulatory activities. However, information on the intermolecular interactions of phytochemicals from this plant with HCV and human proteins are yet to be established. Thus, by this current study, we investigated the HCV NS3/4A inhibitory and host immune-modulatory activity of phytocompounds from T. chebula through in silico strategies involving network pharmacology and structural bioinformatics techniques. To start with, the phytochemical dataset of T. chebula was curated from biological databases and the published literature. Further, the target ability of the phytocompounds was predicted using BindingDB for both HCV NS3/4A and other probable host targets involved in the immune system. Further, the identified targets were docked to the phytochemical dataset using AutoDock Vina executed through the POAP pipeline. The resultant docked complexes with significant binding energy were subjected to 50 ns molecular dynamics (MD) simulation in order to infer the stability of complex formation. During network pharmacology analysis, the gene set pathway enrichment of host targets was performed using the STRING and Reactome pathway databases. Further, the biological network among compounds, proteins, and pathways was constructed using Cytoscape 3.6.1. Furthermore, the druglikeness, side effects, and toxicity of the phytocompounds were also predicted using the MolSoft, ADVERpred, and PreADMET methods, respectively. Out of 41 selected compounds, 10 were predicted to target HCV NS3/4A and also to possess druglike and nontoxic properties. Among these 10 molecules, Chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose exhibited potent HCV NS3/4A inhibitory activity, as these scored a lowest binding energy (BE) of −8.6 kcal/mol and −7.7 kcal/mol with 11 and 20 intermolecular interactions with active site residues, respectively. These findings are highly comparable with Asunaprevir (known inhibitor of HCV NS3/4A), which scored a BE of −7.4 kcal/mol with 20 key intermolecular interactions. MD studies also strongly suggest that chebulagic acid and 1,2,3,4,6-Pentagalloyl glucose as promising leads, as these molecules showed stable binding during 50 ns of production run. Further, the gene set enrichment and network analysis of 18 protein targets prioritized 10 compounds and were predicted to potentially modulate the host immune system, hemostasis, cytokine levels, interleukins signaling pathways, and platelet aggregation. On overall analysis, this present study predicts that tannins from T. chebula have a potential HCV NS3/4A inhibitory and host immune-modulatory activity. However, further experimental studies are required to confirm the efficacies.
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Affiliation(s)
- Vishal S. Patil
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
| | - Darasaguppe R. Harish
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Correspondence: (D.R.H.); (S.R.)
| | - Umashankar Vetrivel
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- ICMR-National Institute for Research in Tuberculosis, Chetpet, Chennai 600031, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Correspondence: (D.R.H.); (S.R.)
| | - Sanjay H. Deshpande
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
- Regional Centre for Biotechnology, NCR-Biotech Science Cluster, Faridabad 121001, India
| | - Harsha V. Hegde
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India; (V.S.P.); (U.V.); (S.H.D.); (H.V.H.)
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Brozzetti S, Tancredi M, Bini S, De Lucia C, Antimi J, D’Alterio C, De Sanctis GM, Furlan C, Malpassuti VC, Lucatelli P, Di Martino M, Bezzi M, Ciardi A, Pascale RM. HCC in the Era of Direct-Acting Antiviral Agents (DAAs): Surgical and Other Curative or Palliative Strategies in the Elderly. Cancers (Basel) 2021; 13:3025. [PMID: 34204186 PMCID: PMC8235445 DOI: 10.3390/cancers13123025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: "de novo occurrent HCC", "recurrent HCC", and "without HCC". Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: "de novo occurrent'' 18.13% and "recurrent'' 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% "de novo occurrent" HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies.
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Affiliation(s)
- Stefania Brozzetti
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Marsia Tancredi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Simone Bini
- Department of Translational and Precision Medicine, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy
| | - Chiara De Lucia
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Jessica Antimi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Chiara D’Alterio
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Giuseppe Maria De Sanctis
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | - Caterina Furlan
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | | | - Pierleone Lucatelli
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Michele Di Martino
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Mario Bezzi
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | - Rosa Maria Pascale
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy;
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Bianculli RH, Mase JD, Schulz MD. Antiviral Polymers: Past Approaches and Future Possibilities. Macromolecules 2020. [DOI: 10.1021/acs.macromol.0c01273] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Rachel H. Bianculli
- Department of Chemistry, Macromolecules Innovation Institute (MII), Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Jonathan D. Mase
- Department of Chemistry, Macromolecules Innovation Institute (MII), Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Michael D. Schulz
- Department of Chemistry, Macromolecules Innovation Institute (MII), Virginia Tech, Blacksburg, Virginia 24061, United States
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Pisaturo M, Starace M, Minichini C, De Pascalis S, Macera M, Occhiello L, Messina V, Sangiovanni V, Claar E, Precone D, Stornaiuolo G, Stanzione M, Gentile I, Brancaccio G, Martini S, Masiello A, Megna AS, Coppola C, Federico A, Sagnelli E, Persico M, Lanza AG, Marrone A, Gaeta GB, Coppola N. Patients with HCV genotype-1 who have failed a direct-acting antiviral regimen: virological characteristics and efficacy of retreatment. Antivir Ther 2020; 24:485-493. [PMID: 30758299 DOI: 10.3851/imp3296] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND This real-world clinical setting study characterized the virological patterns in genotype-1 patients failing interferon (IFN)-free regimens and evaluated the efficacy of re-treatment. METHODS A total of 73 consecutive patients failing IFN-free regimens were enrolled (17 genotype-1a and 56 -1b). At failure Sanger sequencing of NS3, NS5A and NS5B regions was performed by home-made protocols. RESULTS In patients having failed an NS3 inhibitor, the prevalence of NS3-RASs was higher in the 10 with genotype-1a than in the 24 with genotype-1b (80% versus 41.6%). In patients treated with an NS5A inhibitor, the prevalence of NS5A-RASs was very high in the 14 with genotype-1a and the 27 with genotype-1b (78.6% and 92.5%, respectively). In patients having failed sofosbuvir, the prevalence of NS5B-RASs was more frequently identified in the 45 with genotype-1b than in the 10 with genotype-1a (37.7% versus 10%). The prevalence of NS5B-RASs in patients having failed dasabuvir was high in both genotypes, 66.6% in the 6 with genotype-1a and 45.5% in the 11 with genotype-1b. The 6 patients re-treated with genotype-1a less frequently (50%) showed sustained virological response (SVR) than the 18 with genotype-1b (88.8%; P=0.07). SVR was more frequent in the 21 patients with an effective second-line direct-acting antiviral (DAA) regimen than the 3 without (90.4% versus 0%; P<0.005). CONCLUSIONS The prevalence of RASs was high in our real-world population. NS3, NS5A and NS5B sequencing seems mandatory in the choice of DAA re-treatment.
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Affiliation(s)
- Mariantonietta Pisaturo
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania L. Vanvitelli, Naples, Italy
| | - Mario Starace
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania L. Vanvitelli, Naples, Italy
| | - Carmine Minichini
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania L. Vanvitelli, Naples, Italy
| | - Stefania De Pascalis
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Margherita Macera
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Laura Occhiello
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania L. Vanvitelli, Naples, Italy
| | - Vincenzo Messina
- Infectious Diseases Unit, A.O. S Anna and S Sebastiano Caserta, Caserta, Italy
| | | | - Ernesto Claar
- Internal Medicine Unit, Evangelical Hospital Villa Betania, Naples, Italy
| | - Davide Precone
- Internal Medicine Unit A.O. Sarno, Sarno (SA)Campania L. Vanvitelli, & Infectious and Transplant Medicine, AORN Ospedali dei Colli- Monaldi Hospital, Naples, Italy
| | - Gianfranca Stornaiuolo
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Maria Stanzione
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Ivan Gentile
- Infectious Diseases Unit, University Federico II, Naples, Italy
| | - Giuseppina Brancaccio
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | | | | | | | | | - Alessandro Federico
- Internal Medicine and Hepatology Department of Clinical and Experimental Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Evangelista Sagnelli
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania L. Vanvitelli, Naples, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, PO G. Da Procida-AOU- San Giovanni and Ruggi D'Aragona, University of Salerno, Salerno Italy
| | | | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, University of Campania L. Vanvitelli, Naples, Italy
| | - Giovanni Battista Gaeta
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Nicola Coppola
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania L. Vanvitelli, Naples, Italy.,Infectious Diseases Unit, A.O. S Anna and S Sebastiano Caserta, Caserta, Italy
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Pisaturo M, Minichini C, Starace M, Caroprese M, Macera M, Brancaccio G, De Pascalis S, Santonicola A, Galeota Lanza A, Zampino R, Cotticelli G, Sagnelli E, Gaeta GB, Coppola N. Hepatitis C late relapse in patients with directly acting antiviral-related sustained virological response at week 12. Liver Int 2019; 39:844-853. [PMID: 30554459 DOI: 10.1111/liv.14025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 11/21/2018] [Accepted: 12/02/2018] [Indexed: 12/15/2022]
Abstract
AIM The aim of the present study was to identify, among the patients with failure to DAA regimen, those with a late relapse (after the achievement of a sustained virological response at week 12) and to characterize the clinical, epidemiological and virological features of these patients. MATERIAL AND METHODS A total of 129 HCV patients with non-response to an IFN-free regimen were enrolled. Sanger sequencing of NS3, NS5A and NS5B was performed at failure by home-made protocols. RESULTS Of the 129 patients enrolled, 8 (6.2%) experienced a breakthrough, 15 (11.7%) non-response, 99 (76.7%) a relapse by week 12 after the end of DAA therapy, and 7 (5.4%) a late relapse (after week 12; median 24 weeks, range 24-72). For two of the seven patients with a late relapse, a serum sample collected before the start of the DAA regimen was available; phylogenetic analysis showed no change in sequences of NS3, NS5A and NS5B regions, suggesting a reactivation of the initial HCV strain; for the remaining five patients, no serum collected before the DAA regimen was available, and thus, a re-infection cannot be excluded. CONCLUSIONS Although a late relapse is infrequent, the study suggests a post-treatment follow-up of 72 weeks.
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Affiliation(s)
- Mariantonietta Pisaturo
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Carmine Minichini
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Mario Starace
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Mara Caroprese
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Margherita Macera
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Giuseppina Brancaccio
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Stefania De Pascalis
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | | | | | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, University of Campania "L. Vanvitelli", Naples, Italy
| | - Gaetano Cotticelli
- Internal Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Evangelista Sagnelli
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Giovanni Battista Gaeta
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Nicola Coppola
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
- Infectious Diseases Unit, AO Caserta, Caserta, Italy
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Coppola N, Alessio L, Onorato L, Sagnelli C, Macera M, Sagnelli E, Pisaturo M. Epidemiology and management of hepatitis C virus infections in immigrant populations. Infect Dis Poverty 2019; 8:17. [PMID: 30871599 PMCID: PMC6419370 DOI: 10.1186/s40249-019-0528-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 02/26/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND At present, there is a continuous flow of immigrants from the south of the world to north-western countries. Often immigrants originate from areas of high-prevalence of viral hepatitis and pose a challenge to the healthcare systems of the host nations. Aims of this study is to evaluate the prevalence and virological and clinical characteristics of hepatitis C virus (HCV) infection in immigrants and the strategies to identify and take care of the immigrants infected with HCV. MAIN BODY We conducted an electronic literature search in several biomedical databases, including PubMed, Google Scholar, Scopus, Web of Science, using different combinations of key words: "HCV infection; chronic hepatitis C, immigrants; low-income countries". We included studies written in English indicating the epidemiological data of HCV infection in the immigrant population, studies that assessed the clinical presentation, clinical management and treatment with directly acting antiviral agent in immigrants, HCV infection is unevenly distributed in different countries, with worldwide prevalence in the general population ranging from 0.5 to 6.5%. In Western countries and Australia this rate ranges from 0.5 to 1.5%, and reaches 2.3% in countries of south-east Asia and eastern Mediterranean regions, 3.2% in China, 0.9% in India, 2.2% in Indonesia and 6.5% in Pakistan; in sub-Saharan Africa the prevalence of HCV infection varies from 4 to 9%. Immigrants and refugees from intermediate/high HCV endemic countries to less- or non-endemic areas are more likely to have an increased risk of HCV infection due to HCV exposure in their countries of origin. Because of the high HCV endemicity in immigrant populations and of the high efficacy of directly acting antiviral agent therapy, a campaign could be undertaken to eradicate the infection in this setting. CONCLUSIONS The healthcare authorities should support screening programs for immigrants, performed with the help of cultural mediators and including educational aspects to break down the barriers limiting access to treatments, which obtain the HCV clearance in 95% of cases and frequently prevent the development of liver cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania, Via: L. Armanni 5, 80131 Naples, Italy
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano di Caserta, 81100 Caserta, Italy
| | - Loredana Alessio
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano di Caserta, 81100 Caserta, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania, Via: L. Armanni 5, 80131 Naples, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania, Via: L. Armanni 5, 80131 Naples, Italy
| | - Margherita Macera
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania, Via: L. Armanni 5, 80131 Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania, Via: L. Armanni 5, 80131 Naples, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania, Via: L. Armanni 5, 80131 Naples, Italy
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano di Caserta, 81100 Caserta, Italy
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Sagnelli E, Starace M, Minichini C, Pisaturo M, Macera M, Sagnelli C, Coppola N. Resistance detection and re-treatment options in hepatitis C virus-related chronic liver diseases after DAA-treatment failure. Infection 2018; 46:761-783. [PMID: 30084057 DOI: 10.1007/s15010-018-1188-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 07/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Introduced in 2013-2014, the second- and third-wave directly acting antivirals (DAAs) have strongly enhanced the efficacy and tolerability of anti-HCV treatment, with a sustained virological response (SVR) in 90-95% of cases treated. The aim of this paper was to focus on the type and prevalence of viral strains with a reduced sensitivity to DAAs and on treatment choices for DAA-experienced patients. METHODS The Medline was searched for "HCV infection", "HCV treatment", "Directly acting antivirals","HCV resistance". RESULTS Most patients who did not achieve an SVR have been found to be infected with HCV mutant strains with a reduced susceptibility to these drugs. These mutants occur frequently in the NS5A region, with a moderate frequency in the NS3/4A regions and rarely in the NS5B region. Treatment-induced mutants resistant to NS5A DAAs persist for years after treatment discontinuation, whereas those resistant to the NS3 DAAs have a shorter duration. CONCLUSIONS Patients who have failed HCV treatment with DAA agents have several re-treatment options, but re-treatment selection may be intricate and resistance testing is recommended to optimize this choice. It is, therefore, important to bear in mind that the correct determination of HCV genotype and subtype and the identification of RASs are essential elements for choosing the optimal re-treatment. It is supposed that it is useful to give readers some other suggestions regarding therapeutic reprocessing.
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Affiliation(s)
- Evangelista Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy.
| | - Mario Starace
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Carmine Minichini
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Mariantonietta Pisaturo
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Margherita Macera
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Caterina Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Nicola Coppola
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
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Federico A, Dallio M, Caprio GG, de Sio I, Cotticelli G, Esposito P, Loguercio C. A Real-Life Study of New Antiviral Therapies in a High Prevalence Geographical Area for Hepatitis C Virus Infection. HEPATITIS MONTHLY 2018; In Press. [DOI: 10.5812/hepatmon.74224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Wahid B, Waqar M, Rasool N, Rehman Z, Saeed J, Wasim M, Khan MA, Ali A, Rafique S, Sajjad, Idrees M. Recent trends in molecular epidemiology of Hepatitis C virus in Mardan, KPK Pakistan. INFECTION GENETICS AND EVOLUTION 2018; 66:66-71. [PMID: 30201500 DOI: 10.1016/j.meegid.2018.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 09/05/2018] [Accepted: 09/06/2018] [Indexed: 02/07/2023]
Abstract
To determine the genotypic distribution of HCV, frequency of risk factors involved in its transmission, and correlation of genotype with viral load in Mardan population which is the second largest city of Khyber Pakhtunkhwa (KPK), Pakistan. Blood samples of 1140 were collected from different regions of Mardan and major proportion of recruited patients were internally displaced people (IDPs), refugees, and slum dwellers. Complete patient's history was analyzed to assess the possible risks involved in HCV transmission. Viral genotype was determined by PCR (polymerase chain reaction) whereas, HCV RNA was measured by qRT-PCR. Data was analyzed using SPSS statistical software. Our results indicate 3a as the most abundant subtype in Mardan population followed by 3b, 2a, 2b, 4a, untypeable, mixed, 1a, and 1b. In contrast to previous findings, genotype 1 was the least prevalent genotype and the overall prevalence of HCV in Mardan population was significantly higher in females (n = 687, 60.2%) than males (n = 453, 39.7%). Significant difference between-genotypes and gender was observed in genotype 1 (p < .034) and genotype 3 (p < .004). The mean age was 44 (SD ± 9.51). The most frequently found mixed genotype was 3a + 1b and mixed genotype was more prevalent in males. The proportion of middle-aged people (41-49 years) was higher whereas, older and younger people were least infected with HCV. This is the first study that showed substantial correlation of genotype 3 with low and intermediate viral load in Mardan population. Moreover, high and extremely high viral load was associated with other genotypes. Our findings showed that most of the patients who experienced high and extremely high viremia in their blood were males and belonged to Takhat Bhai and Mardaan regions. There were significant difference in the prevalence of HCV genotype 3a (p = .001) and genotype 3b (p = .005) in different regions of Mardan. Pre-treatment viral load is significantly high (p 0.001) in tehsil Mardan patients infected with HCV genotype 3 as compared to other genotypes. Unsafe medical practices such as medical and dental surgeries, intravenous drug use, and blood transfusions were the main risk factors for HCV transmission in Mardan, KPK Pakistan. This study gives clear insights into the epidemiological status of HCV in Mardan population. Genotype 3 is correlated with low and intermediate viral load whereas high viral loads were revealed among patients infected with genotypes other than genotype 3. In the absence of better data and robust epidemiological information, this detailed analysis of HCV genotypes with special reference to risk factors, pretreatment viral load, gender, and age will provide the baseline data for development of optimal HCV eradication and preventive strategies.
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Affiliation(s)
- Braira Wahid
- Department of Life Sciences, School of Science, University of Management and Technology, Lahore, Pakistan.
| | - Muhammad Waqar
- Genome Centre for Molecular Based Diagnostics and Research, Cl-25 Block B Al-Sudais Plaza, Abdalian Cooperative Society, Lahore, Pakistan
| | - Nouman Rasool
- Department of Life Sciences, School of Science, University of Management and Technology, Lahore, Pakistan
| | - Zobaria Rehman
- Genome Centre for Molecular Based Diagnostics and Research, Cl-25 Block B Al-Sudais Plaza, Abdalian Cooperative Society, Lahore, Pakistan
| | - Jamaluddin Saeed
- Department of Medicine, Khyber Teaching Hospital, Peshawar, KPK, Pakistan
| | - Muhammad Wasim
- Department of Medicine, Khyber Teaching Hospital, Peshawar, KPK, Pakistan
| | - Muhammad Arif Khan
- Departments of Medicine, District Head Quarter Hospital, Mardan, Khyber Paktunkhwa, Pakistan
| | - Amjad Ali
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road, Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Shazia Rafique
- Division of Molecular Virology and Diagnostics, Center of Excellence in Molecular Biology (CEMB), 87-West Canal Bank Road, Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Sajjad
- Genome Centre for Molecular Based Diagnostics and Research, Cl-25 Block B Al-Sudais Plaza, Abdalian Cooperative Society, Lahore, Pakistan
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10
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Starace M, Minichini C, De Pascalis S, Macera M, Occhiello L, Messina V, Sangiovanni V, Adinolfi LE, Claar E, Precone D, Stornaiuolo G, Stanzione M, Ascione T, Caroprese M, Zampino R, Parrilli G, Gentile I, Brancaccio G, Iovinella V, Martini S, Masarone M, Fontanella L, Masiello A, Sagnelli E, Punzi R, Salomone Megna A, Santoro R, Gaeta GB, Coppola N. Virological patterns of HCV patients with failure to interferon-free regimens. J Med Virol 2018; 90:942-950. [PMID: 29315640 DOI: 10.1002/jmv.25022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 12/29/2017] [Indexed: 01/02/2023]
Abstract
The study characterized the virological patterns and the resistance-associated substitutions (RASs) in patients with failure to IFN-free regimens enrolled in the real-life setting. All 87 consecutive HCV patients with failed IFN-free regimens, observed at the laboratory of the University of Campania, were enrolled. All patients had been treated with DAA regimens according to the HCV genotype, international guidelines, and local availability. Sanger sequencing of NS3, NS5A, and NS5B regions was performed at failure by home-made protocols. Of the 87 patients enrolled, 13 (14.9%) showed a misclassified HCV genotype, probably causing DAA failure, 16 had been treated with a sub-optimal DAA regimen, 19 with a simeprevir-based regimen and 39 with an optimal DAA regimen. A major RAS was identified more frequently in the simeprevir regimen group (68.4%) and in the optimal regimen group (74.4%) than in the sub-optimal regimen group (56.3%). The prevalence of RASs in NS3 was similar in the three groups (30.8-57.9%), that in NS5A higher in the optimal regimen group (71.8%) than in the sub-optimal regimen group (12.5%, P < 0.0001) and in the simeprevir regimen group (31.6%, P < 0.0005), and that in NS5B low in all groups (0-25%). RASs in two or more HCV regions were more frequently identified in the optimal regimen group (46.6%) than in the simeprevir-based regimen group (31.6%) and sub-optimal regimen group (18.7%). In our real-life population the prevalence of RASs was high, especially in NS3 and NS5A and in those treated with suitable DAA regimens.
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Affiliation(s)
- Mario Starace
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Carmine Minichini
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Stefania De Pascalis
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Margherita Macera
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Laura Occhiello
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | | | | | - Ernesto Claar
- Internal Medicine Unit, Evangelical Hospital Villa Betania, Naples, Italy
| | | | - Gianfranca Stornaiuolo
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Maria Stanzione
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Tiziana Ascione
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, Naples, Italy
| | - Mara Caroprese
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, University of Campania L. Vanvitelli, and Infectious and Transplant Medicine, AORN Ospedali dei Colli-Monaldi Hospital, Naples, Italy
| | - Gianpaolo Parrilli
- Gastroenterology Unit, AOU San Giovanni di Dio Ruggi d'Aragona, Salerno, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Giuseppina Brancaccio
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | | | - Mario Masarone
- Internal Medicine and Hepatology Unit, University of Salerno, Naples, Italy
| | - Luca Fontanella
- Internal Medicine Unit, AO Madonna del Buon Consiglio FATEBENEFRATELLI, Naples, Italy
| | | | - Evangelista Sagnelli
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Rodolfo Punzi
- Infectious Diseases Unit, AORN dei Colli, Naples, Italy
| | | | - Renato Santoro
- Infectious Diseases Unit, AOU San Giovanni di Dio Ruggi d'Aragona, Salerno, Italy
| | - Giovanni B Gaeta
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Nicola Coppola
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy.,Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
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11
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Pinto EF, Andrade C. Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem. Curr Neuropharmacol 2017; 14:743-8. [PMID: 26733280 PMCID: PMC5050402 DOI: 10.2174/1570159x14666160106155129] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Revised: 11/27/2015] [Accepted: 11/28/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Depression is among the commonest of psychiatric disorders, and inflammatory mechanisms have been suggested to play a role in its pathophysiology. Interferons are a superfamily of proinflammatory cytokines that play a role in host defence mechanisms. Interferons are used in the treatment of a variety of autoimmune (e.g. multiple sclerosis), viral (e.g. chronic hepatitis B and C), and malignant (e.g. malignant melanoma, hairy cell leukemia) disorders; depression, however, is a notable and clinically troublesome adverse effect. OBJECTIVE This article seeks to present a simple explanation and update for the reader about what interferons are, how interferons are classified, the clinical conditions in which interferons are used, the occurrence of depression as a clinical adverse effect of interferon therapy, possible mechanisms that explain interferon-related depression, the treatment of interferon-related depression, and the prevention of interferon-related depression. METHODS A qualitative literature review is presented. RESULTS AND CONCLUSIONS Irrespective of the indication for IFN therapy, IFNs are associated with a 30- 70% risk of treatment-emergent depression. This risk could be due to the IFN, or to an interaction between the IFN and the indication for which it was prescribed. Various neurohormonal, neurochemical, neurohistological, and other mechanisms have been put forth to explain IFN-related depression. Prophylactic treatment with antidepressants reduces the risk of IFN-related depression; antidepressants also effectively treat the condition. Recent alternatives to IFNs have shown to decrease the risk of treatment-emergent depression.
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Affiliation(s)
| | - Chittaranjan Andrade
- Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
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Lee SS, Jeong SH, Jang ES, Kim YS, Lee YJ, Jung EU, Kim IH, Bae SH, Lee HC. Treatment rate and factors related to interferon-based treatment initiation for chronic hepatitis C in South Korea. J Med Virol 2016; 88:275-281. [PMID: 26211752 DOI: 10.1002/jmv.24335] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2015] [Indexed: 12/12/2022]
Abstract
Under-recognition and under-treatment of chronic hepatitis C virus (HCV) infection is an important determinant of the disease outcome. The aim of this study was to investigate the treatment rate and factor of initiation of interferon-based antiviral treatment for chronic hepatitis C patients in a prospective, multicenter Korean HCV cohort. Treatment-naïve 759 patients with chronic HCV infection were prospectively followed from January 2007-2013 at six university hospitals during a median (interquartile range) follow-up of 769 (76-1,427) days. The subjects consisted of patients with chronic hepatitis C (n = 553, 72.9%), liver cirrhosis (n = 127, 16.7%), and hepatocellular carcinoma (n = 79, 10.4%), and were treated usually using pegylated interferon alpha and ribavirin. Treatment initiation rate and its related factors were analysed. The initiation rate of antiviral treatment was 37.3% (n = 273), and the cumulative probability of treatment initiation over 5 years was 39.4%. Multivariate analysis showed that age <58 years (hazard ratio [HR] = 1.588, 95% CI = 1.151-2.193), job employment (HR = 1.737, 95% CI = 1.279-2.363), absence of HCC (chronic hepatitis, HR = 2.534, 95% CI = 1.003-6.400; liver cirrhosis, HR = 2.873, 95% CI = 1.101-7.494), alanine transaminase (ALT) >40 IU/L (HR = 1.682, 95% CI = 1.228-2.303), and genotype 2 (HR = 1.364, 95% CI = 1.034-1.798) were independent factors related to treatment initiation. Interferon-based antiviral treatment was initiated in more than one third of chronic HCV infected patients visiting university hospitals, who were young, employed, HCV genotype 2, and with abnormal ALT without HCC, in Korea.
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Affiliation(s)
- Sang Soo Lee
- Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Eun Sun Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
| | - Youn Jae Lee
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Eun Uk Jung
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Hopital, Chonbuk National University College of Medicine, Chonju, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, The Catholic University of Korea Seoul Saint Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Tamori A, Enomoto M, Kawada N. Recent Advances in Antiviral Therapy for Chronic Hepatitis C. Mediators Inflamm 2016; 2016:6841628. [PMID: 27022210 PMCID: PMC4752984 DOI: 10.1155/2016/6841628] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 01/06/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major worldwide health problem. Chronic infection induces continuous inflammation in the liver, progression of hepatic fibrosis, eventual cirrhosis, and possible hepatocellular carcinoma. Eradication of the virus is one of the most important treatment aims. A number of promising new direct-acting antivirals (DAAs) have been developed over the past 10 years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs have been approved for patients with HCV, including those with cirrhosis. This review introduces the characteristics and results of recent clinical trials of several DAAs: NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. DAA treatment failure and prognosis after DAA therapy are also discussed.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
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14
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Coppola N, Pisaturo M, Zampino R, Macera M, Sagnelli C, Sagnelli E. Hepatitis C virus markers in infection by hepatitis C virus: In the era of directly acting antivirals. World J Gastroenterol 2015; 21:10749-10759. [PMID: 26478667 PMCID: PMC4600577 DOI: 10.3748/wjg.v21.i38.10749] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 07/04/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
About 130-170 million people are infected with the hepatitis C virus (HCV) worldwide and more than 350000 people die each year of HCV-related liver diseases. The combination of pegylated interferon (Peg-IFN) and ribavirin (RBV) was recommended as the treatment of choice for chronic hepatitis C for nearly a decade. In 2011 the directly acting antivirals (DAA) HCV NS3/4A protease inhibitors, telaprevir and boceprevir, were approved to treat HCV-genotype-1 infection, each in triple combination with Peg-IFN and RBV. These treatments allowed higher rates of SVR than the double Peg-IFN + RBV, but the low tolerability and high pill burden of these triple regimes were responsible for reduced adherence and early treatment discontinuation. The second and third wave DAAs introduced in 2013-2014 enhanced the efficacy and tolerability of anti-HCV treatment. Consequently, the traditional indicators for disease management and predictors of treatment response should be revised in light of these new therapeutic options. This review article will focus on the use of the markers of HCV infection and replication, of laboratory and instrumental data to define the stage of the disease and of predictors, if any, of response to therapy in the DAA era. The article is addressed particularly to physicians who have patients with hepatitis C in care in their everyday clinical practice.
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Quigley JM, Bryden PA, Scott DA, Kuwabara H, Cerri K. Relative efficacy and safety of simeprevir and telaprevir in treatment-naïve hepatitis C-infected patients in a Japanese population: A Bayesian network meta-analysis. Hepatol Res 2015; 45:E89-98. [PMID: 25559771 DOI: 10.1111/hepr.12467] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 11/07/2014] [Accepted: 12/20/2014] [Indexed: 02/07/2023]
Abstract
AIM Simeprevir (SMV) is an oral, once-daily protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In phase II/III randomized controlled trials (RCT) conducted in Japan, SMV, in combination with peginterferon-α and ribavirin (PEG IFN/RBV), demonstrated potent efficacy in HCV genotype 1-infected patients relative to PEG IFN/RBV and was generally well tolerated. Telaprevir (TVR) in combination with PEG IFN/RBV is licensed for the treatment of HCV in Japan. In the absence of head-to-head comparisons of TVR and SMV in a Japanese population, we undertook a network meta-analysis (NMA) to examine the relative efficacy and safety of SMV and TVR in combination with PEG IFN/RBV. METHODS A systematic review identified SMV and TVR RCT in Japanese treatment-naïve patients. Bayesian NMA was performed assuming fixed study effects. RESULTS Three studies met our inclusion criteria: two SMV and one TVR. SMV showed a higher mean odds ratio (OR) of achieving SVR versus TVR (OR, 1.68 (95% credible interval 0.66-4.26)). SMV showed a lower mean OR of discontinuation: overall, 0.35 (0.12-1.00); and due to AE, 0.87 (0.23-3.34) versus TVR. SMV showed a lower mean OR of experiencing anemia 0.20 (0.07-0.56) and rash 0.41 (0.17-0.99) but a higher mean OR of experiencing pruritus 1.26 (0.46-3.47) versus TVR. CONCLUSION In this indirect treatment comparison, SMV, in combination with PEG IFN/RBV, showed a favorable risk-benefit profile compared with TVR with PEG IFN/RBV in Japanese treatment-naïve HCV patients.
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Affiliation(s)
| | - Peter A Bryden
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | | | | | - Karin Cerri
- London School of Economics and Political Sciences, London, UK.,Janssen Pharmaceutica, Beerse, Belgium
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Coppola N, Pisaturo M, Sagnelli C, Onorato L, Sagnelli E. Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases 2015; 3:807-822. [PMID: 26380828 PMCID: PMC4568530 DOI: 10.12998/wjcc.v3.i9.807] [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: 07/27/2014] [Revised: 12/09/2014] [Accepted: 06/08/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C (CHC).
METHODS: We conducted an electronic search on the PubMed and MEDLINE (2000-2014) databases and Cochrane library (2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.
RESULTS: Several studies associated polymorphisms in the interleukin 28B gene on chromosome 19 (19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon (Peg-IFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation.
CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
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Signorovitch JE, Betts KA, Song Y, Sorg RA, Li J, Behl AS, Kalsekar A. Comparative efficacy and safety of daclatasvir/asunaprevir versus IFN-based regimens in genotype 1b hepatitis C virus infection. J Comp Eff Res 2015; 4:593-605. [PMID: 26159375 DOI: 10.2217/cer.15.33] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM Efficacy and safety comparison of daclatasvir/asunaprevir (DCV + ASV) versus peginterferon-α/ribavirin (A/R) alone or combined with telaprevir, boceprevir, simeprevir or sofosbuvir in chronic genotype 1b hepatitis C virus infection. METHODS Network meta-analysis (NMA) and matching-adjusted indirect comparisons (MAICs). RESULTS Among treatment-naive patients, DCV + ASV demonstrated higher sustained virologic response (SVR) rates than telaprevir + A/R, boceprevir + A/R and A/R in NMA and MAICs and simeprevir + A/R in NMA. DCV + ASV among treatment-experienced patients had higher SVR rates than telaprevir + A/R, boceprevir + A/R, simeprevir + A/R and A/R in MAICs. DCV + ASV had lower adverse events rates than comparators. CONCLUSION DCV + ASV demonstrated superior efficacy and safety compared with A/R-based regimens.
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Affiliation(s)
| | | | - Yan Song
- Analysis Group, Inc., Boston, MA 02199, USA
| | | | - Junlong Li
- Analysis Group, Inc., Boston, MA 02199, USA
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Ashtari S, Pourhoseingholi MA, Sharifian A, Zali MR. Hepatocellular carcinoma in Asia: Prevention strategy and planning. World J Hepatol 2015; 7:1708-1717. [PMID: 26140091 PMCID: PMC4483553 DOI: 10.4254/wjh.v7.i12.1708] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/31/2014] [Accepted: 05/26/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To review all of epidemiological and etiological aspects of hepatocellular carcinoma (HCC) and examined the prevention of this disease in Asia. METHODS We conducted a systematic review according to the PRISMA guidelines. We were chosen articles that published previously, from PubMed (MEDLINE), the Cochrane database and Scopus. The key words used in this research were as follows: HCC in Asia and the way of prevention of this disease, with no language limitations. We selected those papers published before 2014 that we considered to be most important and appropriate. All relevant articles were accessed in full text and all relevant materials was evaluated and reviewed. RESULTS More than 70% of all new cases of liver cancer were diagnosed in Asia, a region that 75% of all those chronically infected with hepatitis B virus (HBV) in the world. Chronic HBV infection is the main cause of HCC in Asia, where the virus is endemic and vertical transmission is common. Japan, Saudi Arabia, Egypt and Pakistan are exception because of high prevalence of HCV infection in these regions. The prevalence of this cancer is high in Eastern and South-Eastern Asia, But Middle Eastern countries are characterized as moderate prevalence rate of HCC region and Central Asia and some part of Middle Eastern countries are known as low prevalence rate of HCC. In addition of HBV and HCV the other factors such as aflatoxin, alcohol, obesity, diabetes and non-alcoholic fatty liver disease (NAFLD) might be responsible for a low prevalence of HCC in Asian countries. Currently available HCC therapies, chemotherapy, surgical are inefficient, mainly due to usually late diagnosis and high recurrence rates after surgical resection, and usually end with treatment failure. Liver transplantation also remains as a difficult strategy in patients with HCC. Thus prevention of HCC by treating and prevention HBV and HCV infection, the major causative agents of HCC, and the other risk factors such as aflatoxin, alcohol, obesity, diabetes and NAFLD is of a great medical importance. CONCLUSION The main challenge which still present in Asia, is the high prevalence of chronic hepatitis. So, prevention of HBV and HCV is the key strategy to reduce the incidence of HCC in Asia.
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Affiliation(s)
- Sara Ashtari
- Sara Ashtari, Mohamad Amin Pourhoseingholi, Afsaneh Sharifian, Mohamad Reza Zali, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Mohamad Amin Pourhoseingholi
- Sara Ashtari, Mohamad Amin Pourhoseingholi, Afsaneh Sharifian, Mohamad Reza Zali, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Afsaneh Sharifian
- Sara Ashtari, Mohamad Amin Pourhoseingholi, Afsaneh Sharifian, Mohamad Reza Zali, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Mohamad Reza Zali
- Sara Ashtari, Mohamad Amin Pourhoseingholi, Afsaneh Sharifian, Mohamad Reza Zali, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
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Coppola N, Martini S, Pisaturo M, Sagnelli C, Filippini P, Sagnelli E. Treatment of chronic hepatitis C in patients with HIV/HCV coinfection. World J Virol 2015; 4:1-12. [PMID: 25674512 PMCID: PMC4308522 DOI: 10.5501/wjv.v4.i1.1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/30/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection is one of the most frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCV-genotype 1, both for the HCV-monoinfected and HIV/HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.
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Tamori A, Kioka K, Sakaguchi H, Enomoto M, Hai H, Kawamura E, Hagihara A, Fujii H, Uchida-Kobayashi S, Iwai S, Morikawa H, Murakami Y, Kawasaki Y, Tsuruta D, Kawada N. Effects on anemia of drug adjustment in patients with chronic hepatitis C during telaprevir-combined therapy. Ann Hepatol 2015; 14:28-35. [PMID: 25536639 DOI: 10.1016/s1665-2681(19)30798-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
AIM Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy. MATERIAL AND METHODS This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups. RESULTS No differences in the proportion of patients who became HCV RNA-negative were detected between the TVR-standard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant). CONCLUSIONS TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kiyohide Kioka
- Department of Hepatology Osaka City General Hospital, Osaka Japan
| | | | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Shuji Iwai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuko Kawasaki
- Department of Hepatology Osaka City General Hospital, Osaka Japan
| | - Daisuke Tsuruta
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Abstract
Hepatocellular carcinoma (HCC) is a development of severe liver disease frequently due to HBV and/or HCV infection. The aim of this retrospective study was to evaluate the development of HCC in patients with HBV-HCV chronic infection compared with patients with single HBV or HCV infection and the viral and host factors correlated to HCC in co-infected patients. We studied 268 patients with histology proven chronic hepatitis: 56 had HBV-HCV co-infection (HBV-HCV group), 46 had HBV infection (HBV group) and 166 had HCV infection (HCV group). Patients were followed up for at least 3 years. Viral and host factors were studied. HCC was more frequent in HBV-HCV group (14%) compared with HBV (2%, p = 0.006) and HCV monoinfected (4%, p = 0.006). The Mantel-Haenszel test used to investigate the relationship between HBV-HCV co-infection and development of HCC indicated an association between development of HCC and HBV-HCV co-infection (p < 0.001). In the HBV-HCV group, patients with HCC were significantly older (p = 0.000), had longer disease duration (p = 0.001), higher blood glucose levels (p = 0.001), lower levels of steatosis (p = 0.02), higher levels of fibrosis (p = 0.000), higher HCV RNA (p = 0.01) than those without HCC. ALT, lipid profile, PNPLA3 variant distribution and HBV viral load did not differ among co-infected patients with or without HCC. In conclusion HCC was more frequent in our patients with HBV-HCV co-infection, than in those with HBV or HCV mono-infection; possible associated risk factors for HCC development seem a long duration of disease, high levels of fibrosis and carbohydrate intolerance.
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Hajiaghamohammadi A, Samimi R, Miroliaee A, Kazemifar AM, Nazem M. Treatment outcome in chronic hepatitis C infection: a four years survey among Iranian patients. Glob J Health Sci 2014; 7:75-81. [PMID: 25948447 PMCID: PMC4802067 DOI: 10.5539/gjhs.v7n3p75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 11/01/2014] [Accepted: 10/08/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is universal. Side effects of its treatment are observed in many patients. The present study was designed to evaluate treatment outcome and side effects of the treatment in chronic HCV infection. MATERIALS & METHODS The current study was conducted prospectively on patients with hepatitis C infection. They had been treated with the standard drug regimen, if indicated. They were followed for treatment response, side effects of therapy, and its related factors. FINDINGS From ninety one patients, eighty four persons finished their treatment course. They comprised 71 (84.5%) males and 13 (15.5%) females. Their mean age was 41.5 ± 11.90 years (20-69 years). Genotype 3 was the most common virus genotype (51.2%). Sustained virologic response (SVR) was 84.5% for genotype 3 and 47.5% for genotype 1. Decrease in hemoglobin (43%), weakness and fatigue (26%), neutropenia (13%), and thrombocytopenia (13%) were the most common side effects of the treatment. Seven patients can not finish their treatment course, because of the side effects. CONCLUSION Genotype 3, viral load less than 600000, and more than 3- fold rise in AST are associated with higher SVR. Early administration of the added drugs such as erythropoietin and G-CSF to not reduce the drug doses were also influential.
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Gentile I, Buonomo AR, Zappulo E, Borgia G. Discontinued drugs in 2012 – 2013: hepatitis C virus infection. Expert Opin Investig Drugs 2014; 24:239-51. [DOI: 10.1517/13543784.2015.982274] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Ivan Gentile
- University of Naples ‘Federico II’, Department of Clinical Medicine and Surgery (Ed. 18), via S. Pansini 5,I-80131, Naples, Italy ;
| | - Antonio Riccardo Buonomo
- University of Naples ‘Federico II’, Department of Clinical Medicine and Surgery (Ed. 18), via S. Pansini 5,I-80131, Naples, Italy ;
| | - Emanuela Zappulo
- University of Naples ‘Federico II’, Department of Clinical Medicine and Surgery (Ed. 18), via S. Pansini 5,I-80131, Naples, Italy ;
| | - Guglielmo Borgia
- University of Naples ‘Federico II’, Department of Clinical Medicine and Surgery (Ed. 18), via S. Pansini 5,I-80131, Naples, Italy ;
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Petruzziello A, Coppola N, Loquercio G, Marigliano S, Giordano M, Azzaro R, Diodato AM, Iervolino V, Di Costanzo G, Di Macchia CA, Di Meo T, Paradiso L, Ferro R, Giuliano P, Russo F, Pasquale G, Cacciapuoti C. Distribution pattern of hepatitis C virus genotypes and correlation with viral load and risk factors in chronic positive patients. Intervirology 2014; 57:311-8. [PMID: 25170801 DOI: 10.1159/000363386] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 05/02/2014] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Hepatitis C virus (HCV) has emerged as a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. The purpose of this study was to describe the distribution pattern of HCV genotypes in chronic hepatitis patients in the Campania region of southern Italy and estimate their association with risk factors and viral load. MATERIALS AND METHODS 404 consecutive HCV ribonucleic acid-positive patients were included in the study. HCV genotyping was carried out by the HCV line probe assay test and viral load estimation by the TaqMan real-time PCR system. RESULTS The predominant genotype was 1 (63.6%), followed by genotype 2 (29.4%), 3 (6.2%) and 4 (0.8%). Subtype 1b was more frequent in females than in males. Conversely, genotype 3 was more frequent in males. No significant difference was observed in age distribution of HCV genotypes. Surgery and dental therapy were the most frequent risk factors for genotype 1 and intravenous drug abuse and tattooing for genotype 3. Patients with genotype 1 more frequently showed high HCV viral load when compared to those with genotypes 2 and 3. CONCLUSION The present study revealed that HCV genotypes 1 and 2 accounted for over 95% of all HCV infections in the Campania region, and genotype 1 was more frequently associated with a higher viral load when compared to genotypes 2 and 3.
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Affiliation(s)
- Arnolfo Petruzziello
- Laboratory of Virology and Molecular Biology 'V. Tridente', Transfusion Service, Department of Haemathology, Istituto Nazionale Tumori - Fondazione 'G. Pascale', IRCCS Italia, Naples, Italy
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Gentile I, Buonomo AR, Borgia G. Ombitasvir: a potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther 2014; 12:1033-43. [PMID: 25074011 DOI: 10.1586/14787210.2014.940898] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) chronically infects about 150,000,000 people worldwide and is a relevant cause of liver cirrhosis, hepatocellular carcinoma and death. Antiviral treatment is rapidly moving from interferon (IFN)-based therapy to IFN-free approaches. This review focuses on the mechanism of action, pharmacokinetics, efficacy, tolerability, safety and resistance of ombitasvir, which is an inhibitor of the HCV nonstructural protein 5A. The pharmacokinetics of ombitasvir enables its once daily administration. In vivo, in combinations with other oral direct acting antivirals, ombitasvir achieves very high rates of sustained virological response (about 95%) in patients with HCV genotype 1 infection with a good tolerability. Resistance profiling revealed a low barrier to resistance when given as monotherapy. However, coadministration of ombitasvir and other antivirals enhances its barrier to resistance. In conclusion, ombitasvir is a good drug to be used in IFN-free combinations for the treatment of chronic hepatitis C.
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Affiliation(s)
- Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", via S. Pansini 5, I-80131 Naples, Italy
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27
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Gentile I, Buonomo AR, Zappulo E, Minei G, Morisco F, Borrelli F, Coppola N, Borgia G. Asunaprevir, a protease inhibitor for the treatment of hepatitis C infection. Ther Clin Risk Manag 2014; 10:493-504. [PMID: 25061308 PMCID: PMC4079632 DOI: 10.2147/tcrm.s66731] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
According to the World Health Organization, approximately 150 million people worldwide are chronic carriers of hepatitis C virus (HCV). HCV infection can evolve into cirrhosis of the liver and its complications, which are ultimately responsible for more than 350,000 deaths every year. Antiviral therapy, when successful, is able to decrease the rate of progression and increase survival. Two types of therapies are currently available, ie, interferon-based therapies and interferon-free ones. The latter have several advantages in terms of safety and tolerability, and could be used even in the most advanced stages of the disease. However, their use is restricted to some viral genotypes (genotype 2 and 3) and they are expensive. Several molecules are in an advanced phase of development. This review deals with the pharmacokinetics, pharmacodynamics, tolerability, and safety of asunaprevir, an inhibitor of HCV nonstructural 3 protease. Asunaprevir exerts optimal in vitro activity particularly against HCV genotypes 1 and 4, and its pharmacokinetic profile enables twice daily administration. The drawback of asunaprevir, and of all protease inhibitors, is its low barrier to resistance. Consequently, it is used in association with other drugs to prevent resistance. Specifically, when combined with daclatasvir, an NS5A inhibitor, asunaprevir results in a very high rate of viral eradication in both treatment-naïve and treatment-experienced patients, with a sustained virological response rate of 80%-90%. Tolerability is fair; in fact, asunaprevir is associated with a transient increase in aminotransferase levels, which is mild in most cases. In conclusion, asunaprevir is a good candidate component of interferon-free combinations and may revolutionize the treatment of chronic HCV infection in the near future.
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Affiliation(s)
- Ivan Gentile
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonio Riccardo Buonomo
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Emanuela Zappulo
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giuseppina Minei
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Filomena Morisco
- Section of Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Francesco Borrelli
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Nicola Coppola
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Guglielmo Borgia
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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28
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Sagnelli E, Sagnelli C, Pisaturo M, Coppola N. Hepatic flares in chronic hepatitis C: spontaneous exacerbation vs hepatotropic viruses superinfection. World J Gastroenterol 2014; 20:6707-6715. [PMID: 24944463 PMCID: PMC4051912 DOI: 10.3748/wjg.v20.i22.6707] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 01/13/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) causes an acute infection that is frequently asymptomatic, but a spontaneous eradication of HCV infection occurs only in one-third of patients. The remaining two-thirds develop a chronic infection that, in most cases, shows an indolent course and a slow progression to the more advanced stages of the illness. Nearly a quarter of cases with chronic hepatitis C (CHC) develop liver cirrhosis with or without hepatocellular carcinoma. The indolent course of the illness may be troubled by the occurrence of a hepatic flare, i.e., a spontaneous acute exacerbation of CHC due to changes in the immune response, immunosuppression and subsequent restoration, and is characterized by an increase in serum aminotransferase values, a frequent deterioration in liver fibrosis and necroinflammation but also a high frequency of sustained viral response to pegylated interferon plus ribavirin treatment. A substantial increase in serum aminotransferase values during the clinical course of CHC may also be a consequence of a superinfection by other hepatotropic viruses, namely hepatitis B virus (HBV), HBV plus hepatitis D virus, hepatitis E virus, cytomegalovirus, particularly in geographical areas with high endemicity levels. The etiology of a hepatic flare in patients with CHC should always be defined to optimize follow-up procedures and clinical and therapeutic decisions.
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Gentile I, Coppola N, Buonomo AR, Zappulo E, Borgia G. Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus. Expert Opin Investig Drugs 2014; 23:1211-23. [PMID: 24848437 DOI: 10.1517/13543784.2014.921680] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION About 150 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV). Successful antiviral treatment can stop the progression of the disease toward liver cirrhosis, hepatocellular carcinoma and death. IFN has been the drug of choice and the backbone of all combinations in the past two decades. However, an IFN-free combination (sofosbuvir and ribavirin) has been recently approved for genotypes 2 and 3 patients with many other drugs in preclinical and clinical development. AREAS COVERED This review focuses on investigational nucleoside or nucleotide inhibitors of viral polymerase that are potential treatments of HCV. The article reviews drugs that are currently under investigational status. EXPERT OPINION Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time. Other promising molecules are LG-7501, ACH-3422 and EP-NI266, although no clinical studies have been performed thus far, so this must be rectified. Another drug of promise GS-6620 has displayed a high degree of pharmacokinetic and pharmacodynamic variability, which makes further development unlikely.
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Affiliation(s)
- Ivan Gentile
- University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples , Italy +39 0 81 7463083 ; +39 0 81 7463190 ;
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Coppola N, Pisaturo M, Sagnelli C, Sagnelli E, Angelillo IF. Peg-interferon plus ribavirin with or without boceprevir or telaprevir for HCV genotype 1: a meta-analysis on the role of response predictors. PLoS One 2014; 9:e94542. [PMID: 24728219 PMCID: PMC3984165 DOI: 10.1371/journal.pone.0094542] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 03/18/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND & AIM To compare the efficacy of pegylated-interferon (Peg-IFN) α-2a or α-2b and ribavirin given as dual therapy versus triple therapy (Peg-IFN and ribavirin plus boceprevir or telaprevir) in patients with HCV-1 chronic hepatitis naïve for anti-HCV therapy or relapsers to dual therapy in relation to the presence of constitutional, clinical and virological predictors of treatment response. METHODS Included in the meta-analysis were studies meeting these criteria: original data from randomized trials on the efficacy of dual versus triple therapy in therapy-naïve patients or relapsers; at least one primary outcome clearly defined: sustained virological response in patients with or without rapid virological response (RVR), with genotype 1a or 1b, low or high HCV load, IL28-B CC or non-CC genotype, mild or severe fibrosis; odds ratio estimates of relative risk (RR) and 95% confidence intervals; English language; and published up to the end of June 2013. RESULTS Seven original studies met the inclusion criteria, allowing a meta-analysis on 3,652 patients. Triple therapy was more effective than dual, regardless of IL-28B genotype, HCV sub-genotype, liver fibrosis, and baseline HCV load. In 1,045 patients who achieved RVR, SVR was more frequently achieved with dual therapy (RR = 1.11; p = 0.002) than triple. The same results were achieved when only the therapy-naïve patients were considered. CONCLUSIONS Triple therapy provides a significantly higher SVR rate than dual therapy, but dual therapy obtains a significantly higher SVR rate in patients with RVR. The data stress the clinical importance of a 4-week lead-in phase in direct-acting antiviral-based treatment.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Caterina Sagnelli
- Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara”, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Italo F. Angelillo
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
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Coppola N, Marrone A, Pisaturo M, Starace M, Signoriello G, Gentile I, Adinolfi LE, Sagnelli E, Zampino R. Role of interleukin 28-B in the spontaneous and treatment-related clearance of HCV infection in patients with chronic HBV/HCV dual infection. Eur J Clin Microbiol Infect Dis 2014; 33:559-67. [PMID: 24081499 DOI: 10.1007/s10096-013-1985-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 09/11/2013] [Indexed: 12/27/2022]
Abstract
The purpose of this investigation was to evaluate the role of IL28-B polymorphism in the clearance of hepatitis C virus (HCV) in chronic hepatitis B virus (HBV)/HCV coinfection during a long-term follow-up. Thirty-four consecutive patients with HBV surface antigen (HBsAg)-positive/anti-HCV-positive chronic hepatitis were retrospectively enrolled at their first liver biopsy (LB). For all patients, a documented clinical, serological and virological follow-up of at least 3 years (range 3-16 years) after LB and a sample of whole blood for genetic evaluation were available. Of the 24 patients with detectable serum HBV-DNA and HCV-RNA at their first observation, three cleared both HBV-DNA and HCV-RNA, 12 HCV-RNA and five HBV-DNA. Of the seven HBV DNA-positive/HCV RNA-negative patients at enrolment, three cleared HBV-DNA and one remained HBV DNA-positive and became HCV RNA-positive. All three HBV DNA-negative/HCV RNA-positive patients remained unchanged. Compared with the 12 patients with HCV persistence, the 15 patients who cleared HCV were younger, had lower serum alanine aminotransferase (ALT), HCV load, and histological activity index (HAI) and fibrosis score, more frequently had IL28-B CC variant, had been receiving an interferon-based treatment and less frequently cleared serum HBV-DNA. To investigate the relationship between the IL28-B variants and clearance of HCV, excluding the confounding effect of interferon-based treatment, the Mantel-Haenszel test was used, which indicated an association between HCV clearance and IL28-B variants (p = 0.009). In chronic HBV/HCV coinfection, a long-term follow-up showed a frequent spontaneous or treatment-related clearance of active replication of one or both viruses and identified the IL28-B CC genotype as an independent predictor of HCV clearance.
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Affiliation(s)
- N Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Via L. Armanni 5, 80133, Naples, Italy,
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Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G. MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection. Expert Opin Investig Drugs 2014; 23:719-28. [PMID: 24666106 DOI: 10.1517/13543784.2014.902049] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Approximately 170 million people worldwide are chronic carriers of the hepatitis C virus (HCV). Twenty-five percent of them develop liver cirrhosis and hepatocellular carcinoma during their life. Successful antiviral treatment dramatically reduces the risk of disease progression. HCV infection is treated with pegylated interferon and ribavirin; the addition of a protease inhibitor (boceprevir or telaprevir) can also be considered for patients with genotype 1. AREAS COVERED This review summarizes the data about the pharmacokinetics, pharmacodynamics, efficacy and safety of MK-5172 , a second-generation inhibitor of HCV NS3/4A protease. EXPERT OPINION The pharmacokinetic profile allows for once-a-day administration. Combined with pegylated interferon and ribavirin, MK-5172 results in a high rate of HCV eradication (in about 90% of cases) and a better outcome than boceprevir-based triple therapy. Also in interferon-free combinations, MK-5172-associated eradication rates are very high (89 - 100%). MK-5172 has a higher barrier to resistance than first-generation protease inhibitors and is active against most variants associated with resistance to first-generation protease inhibitors. Tolerability and safety profile are good. Although data are limited, MK-5172 appears to overcome most of the drawbacks of the first-generation protease inhibitors and is thus a very promising agent to be used in combination with other antivirals to eradicate HCV infection.
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Affiliation(s)
- Ivan Gentile
- University of Naples "Federico II", Department of Clinical Medicine and Surgery (Ed. 18) , via S. Pansini 5, I-80131 Naples , Italy +39 0 81 7463178 ; +39 0 81 7463190 ;
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Gentile I, Buonomo AR, Borgia F, Castaldo G, Borgia G. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opin Investig Drugs 2014; 23:561-71. [DOI: 10.1517/13543784.2014.892581] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Messori A, Fadda V, Maratea D, Trippoli S, Marinai C. Pegylated interferon-α2a versus pegylated interferon-α2b in hepatitis C: reappraisal of effectiveness on the basis of trial sequential analysis. Eur J Gastroenterol Hepatol 2014; 26:246-8. [PMID: 24366456 DOI: 10.1097/meg.0b013e3283657e20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- Andrea Messori
- aHTA Unit bDrug Committee, Regional Center for Pharmaceutical and Technical Services, 'Toscana Centro' Jurisdiction, Regional Health Service, Firenze, Italy
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Dogan UB, Akin MS, Yalaki S. Alanine aminotransferase normalization at week 8 predicts viral response during hepatitis C treatment. World J Gastroenterol 2013; 19:8678-8686. [PMID: 24379586 PMCID: PMC3870514 DOI: 10.3748/wjg.v19.i46.8678] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 09/21/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate alanine aminotransferase (ALT) and sustained virological response (SVR) in chronic hepatitis C (CHC) during peginterferon-ribavirin treatment.
METHODS: One hundred and fifty-one genotype 1 CHC patients underwent treatment for 48 wk with peginterferon and ribavirin, and were retrospectively divided into two groups as having a rapid virological response (RVR) (Group 1, n = 52) and not having an RVR (Group 2, n = 99). We also subdivided each group into two according to the initial ALT level being high (Group 1h and Group 2h) or normal (Group 1n and Group 2n). HCV RNA and ALT levels were measured at baseline; at 4, 12, 24 and 48 wk during the treatment period; and at 24 wk follow-up. ALT levels were also obtained at 8 wk. According to the results of ALT, patients were enrolled in either the follow-up abnormal or follow-up normalized ALT groups at each interval. Patients with high and normal ALT levels were compared for each interval in terms of SVR.
RESULTS: The SVR rates were 83% vs 40% (P = 0.000), 82% vs 84% (P = 0.830), and 37% vs 44% (P = 0.466) when comparing Group 1 with 2, 1h with 1n, and 2h with 2n, respectively. In Group 2h, the SVR rates were 34% vs 40% (P = 0.701), 11% vs 52% (P = 0.004), 12% vs 50% (P = 0.007), 7% vs 50% (P = 0.003), 6% vs 53% (P = 0.001), and 0% vs 64% (P = 0.000) when comparing patients with high and normalized ALT levels at week 4, 8, 12, 24, 48 and 72, respectively. The multiple logistic regression analysis revealed that RVR (OR = 7.05; 95%CI: 3.1-16.05, P = 0.000), complete early virological response (cEVR) (OR = 17.55; 95%CI: 6.32-48.76, P = 0.000), normalization of ALT at 8 wk (OR = 3.04; 95%CI: 1.31-7.06, P = 0.008), and at 12 wk (OR = 4.21; 95%CI: 1.65-10.76, P = 0.002) were identified as independent significant predictive factors for SVR.
CONCLUSION: Normalization of ALT at 8 wk may predict viral response during peginterferon-ribavirin treatment in genotype-1 CHC patients especially without RVR.
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Sustained virological response based on the week 4 response in hepatitis C virus genotype 1 patients treated with peginterferons α-2a and α-2b, plus ribavirin. Eur J Gastroenterol Hepatol 2013; 25:1317-20. [PMID: 23680912 DOI: 10.1097/meg.0b013e328362797b] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND It is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of peginterferon-ribavirin treatment influences the probability of achieving a sustained virological response (SVR) in patients without a rapid virological response (RVR). METHODS Data of 151 genotype 1 chronic hepatitis C patients treated with 48 weeks of peginterferon α-2a (group 1, n=86) and peginterferon α-2b (group 2, n=65), plus ribavirin, were evaluated retrospectively. Patients of each group were further divided into those who had RVR and those who did not. Patients without an RVR were then subdivided into four discrete categories on the basis of the magnitude of decrease in HCV RNA from baseline to week 4: those with a ≥3 log10 drop, those with a ≥2 log10 but <3 log10 drop, those with a ≥1 log10 but <2 log10 drop, and those with a <1 log10 drop. The proportion of SVR was calculated for each category. RESULTS Overall, 80 and 88.2% of RVR patients and 41.2 and 39.6% of non-RVR patients achieved an SVR in group 1 and group 2, respectively. Among non-RVR patients, the SVR rates were 75, 50, 16.7, and 11.1% in group 1 (trend test P=0.001) and 63.6, 42.9, 30, and 23.1% in group 2 (trend test P=0.038) in those with a drop in HCV RNA level of ≥3 log10, ≥2 log10, ≥1 log10, and <1 log10 at week 4, respectively. CONCLUSION Patients with a ≥3 log10 drop in HCV RNA at week 4 have a high probability of achieving an SVR when treated with either peginterferon α-2a-ribavirin or peginterferon α-2b-ribavirin.
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The comparison of the efficacy of pegylated interferon α-2a and α-2b in chronic hepatitis C patients with genotype 1. Eur J Gastroenterol Hepatol 2013; 25:1082-5. [PMID: 23524524 DOI: 10.1097/meg.0b013e32836076d1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND/AIM The aim of this study was to assess the efficacy of treatment with pegylated interferon α-2a (Peg-INFα-2a) versus Peg-INFα-2b, plus ribavirin, in inducing rapid virological response (RVR), early virological response (EVR), end of treatment response (ETR), and sustained virological response (SVR) in chronic hepatitis C. METHODS We reviewed 78 chronic hepatitis C patients with genotype 1 treated with 48 weeks of Peg-INFα-2a (n=35) and Peg-INFα-2b (n=43), plus ribavirin, between 2008 and 2011. The ETR and SVR of the patients were ascertained by assessing hepatitis C virus (HCV)-RNA levels at the end of the treatment and after 24 weeks of follow-up after the cessation of treatment. RESULTS The RVR (31 vs. 26%), EVR (83 vs. 81%), ETR (74 vs. 63%), and SVR (46 vs. 51%) rates were similar for Peg-INFα-2a and Peg-INFα-2b groups. The overall SVR rate for these standard therapies was 48.7%. Multivariate analysis showed that HCV viral load was significantly associated with RVR, EVR, ETR, and SVR inversely (r=-0.25, P<0.05, and r=-0.34, r=-0.53, r=-0.42, P<0.01, respectively). CONCLUSION In patients infected with HCV genotype 1, the rates of SVR did not differ significantly between the two available Peg-INF-ribavirin regimens, and HCV viral load was important in RVR, EVR, ETR, and SVR.
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Ashtari S, Vahedi M, Pourhoseingholi MA, Karkhane M, Kimiia Z, Pourhoseingholi A, Safaee A, Moghimi-Dehkordi B, Zali MR, Alavian SM. Direct medical care costs associated with patients diagnosed with chronic HCV. HEPATITIS MONTHLY 2013; 13:e8415. [PMID: 23930132 PMCID: PMC3736623 DOI: 10.5812/hepatmon.8415] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Revised: 12/26/2012] [Accepted: 02/18/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND HCV virus (HCV) is a significant global problem with wide-ranging socio-economic impacts. Because of the high morbidity and mortality associated with end-stage liver disease, cirrhosis, and hepatocellular carcinoma (HCC), the economic burden of HCV infection is substantial. OBJECTIVES This study aimed to estimate the direct medical care costs of chronic HCV infection. PATIENTS AND METHODS For this cross-sectional study, 365 courses of HCV treatment were extracted from medical records of 284 patients being referred to Tehran HCV clinic, a clinical clinic of Baqiyatallah Research Center for Gastroenterology and Liver diseases, from 2005 to 2010. All the patients had been diagnosed with HCV. Direct medical care costs for each course of HCV treatment have been calculated based on Purchasing Power Parity Dollar (PPP$). RESULTS Average direct medical costs for the courses treated with conventional interferon plus ribavirin (INF-RBV) were 4,403 PPP$, and 20,010 PPP$ for peg-interferon plus ribavirin (PEG-RBV) courses. There was an increase of the direct costs in both courses of treatment to achieve Sustain Viral Response (SVR). The costs amounted to 10,072 PPP$ in (INF-RBV) treatment and 34,035 PPP$ in (PEG-RBV). The significant difference between the costs of these two courses of treatment is attributable to high cost of Peg-interferon. This indicates that the medication costs are the dominant costs. CONCLUSIONS According to the results, total direct medical costs for HCV patients in Iran exceeded 12 billion PPP$ in (INF-RBV) treatment and 55 billion PPP$ in (PEG-RBV).
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Affiliation(s)
- Sara Ashtari
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Science, Tehran, IR Iran
| | - Mohsen Vahedi
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Karkhane
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Science, Tehran, IR Iran
| | - Zahra Kimiia
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Science, Tehran, IR Iran
| | - Asma Pourhoseingholi
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Science, Tehran, IR Iran
| | - Azadeh Safaee
- Department of Disease Control and Prevention, Deputy of Health, Shahid Beheshti University of Medical Science, Tehran, IR Iran
| | - Bijan Moghimi-Dehkordi
- Department of Disease Control and Prevention, Deputy of Health, Shahid Beheshti University of Medical Science, Tehran, IR Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Science, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
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