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Adeboyejo K, Grosche VR, José DP, Ferreira GM, Shimizu JF, King BJ, Tarr AW, Soares MMCN, Ball JK, McClure CP, Jardim ACG. Simultaneous determination of HCV genotype and NS5B resistance associated substitutions using dried serum spots from São Paulo state, Brazil. Access Microbiol 2022; 4:000326. [PMID: 35693474 PMCID: PMC9175972 DOI: 10.1099/acmi.0.000326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 12/30/2021] [Indexed: 11/26/2022] Open
Abstract
Hepatitis C virus (HCV) is responsible for more than 180 million infections worldwide, and about 80 % of infections are reported in Low and Middle-income countries (LMICs). Therapy is based on the administration of interferon (INF), ribavirin (RBV) or more recently Direct-Acting Antivirals (DAAs). However, amino acid substitutions associated with resistance (RAS) have been extensively described and can contribute to treatment failure, and diagnosis of RAS requires considerable infrastructure, not always locally available. Dried serum spots (DSS) sampling is an alternative specimen collection method, which embeds drops of serum onto filter paper to be transported by posting to a centralized laboratory. Here, we assessed feasibility of genotypic analysis of HCV from DSS in a cohort of 80 patients from São Paulo state Brazil. HCV RNA was detected on DSS specimens in 83 % of samples of HCV infected patients. HCV genotypes 1a, 1b, 2a, 2c and 3a were determined using the sequence of the palm domain of NS5B region, and RAS C316N/Y, Q309R and V321I were identified in HCV 1b samples. Concerning therapy outcome, 75 % of the patients who used INF +RBV as a previous protocol of treatment did not respond to DAAs, and 25 % were end-of-treatment responders. It suggests that therapy with INF plus RBV may contribute for non-response to a second therapeutic protocol with DAAs. One patient that presented RAS (V321I) was classified as non-responder, and combination of RAS C316N and Q309R does not necessarily imply in resistance to treatment in this cohort of patients. Data presented herein highlights the relevance of studying circulating variants for a better understanding of HCV variability and resistance to the therapy. Furthermore, the feasibility of carrying out genotyping and RAS phenotyping analysis by using DSS card for the potential of informing future treatment interventions could be relevant to overcome the limitations of processing samples in several location worldwide, especially in LMICs.
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Affiliation(s)
- Kazeem Adeboyejo
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Victória Riquena Grosche
- Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.,Institute of Bioscience, Language and Exact Sciences, São Paulo State University, São José do Rio Preto, São Paulo, Brazil
| | | | - Giulia Magalhães Ferreira
- Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
| | - Jacqueline Farinha Shimizu
- Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.,Institute of Bioscience, Language and Exact Sciences, São Paulo State University, São José do Rio Preto, São Paulo, Brazil
| | - Barnabas J King
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,School of Life Sciences, University of Nottingham, Nottingham, UK.,MRC/EPSRC Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK
| | - Alexander W Tarr
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,School of Life Sciences, University of Nottingham, Nottingham, UK.,MRC/EPSRC Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK
| | | | - Jonathan K Ball
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,School of Life Sciences, University of Nottingham, Nottingham, UK.,MRC/EPSRC Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK
| | - C Patrick McClure
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,School of Life Sciences, University of Nottingham, Nottingham, UK.,MRC/EPSRC Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK
| | - Ana Carolina Gomes Jardim
- Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.,Institute of Bioscience, Language and Exact Sciences, São Paulo State University, São José do Rio Preto, São Paulo, Brazil
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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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Duncan JD, Urbanowicz RA, Tarr AW, Ball JK. Hepatitis C Virus Vaccine: Challenges and Prospects. Vaccines (Basel) 2020; 8:vaccines8010090. [PMID: 32079254 PMCID: PMC7157504 DOI: 10.3390/vaccines8010090] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/25/2020] [Accepted: 02/04/2020] [Indexed: 02/07/2023] Open
Abstract
The hepatitis C virus (HCV) causes both acute and chronic infection and continues to be a global problem despite advances in antiviral therapeutics. Current treatments fail to prevent reinfection and remain expensive, limiting their use to developed countries, and the asymptomatic nature of acute infection can result in individuals not receiving treatment and unknowingly spreading HCV. A prophylactic vaccine is therefore needed to control this virus. Thirty years since the discovery of HCV, there have been major gains in understanding the molecular biology and elucidating the immunological mechanisms that underpin spontaneous viral clearance, aiding rational vaccine design. This review discusses the challenges facing HCV vaccine design and the most recent and promising candidates being investigated.
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Affiliation(s)
- Joshua D. Duncan
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
- Correspondence:
| | - Richard A. Urbanowicz
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Alexander W. Tarr
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Jonathan K. Ball
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
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Wu R, Geng D, Chi X, Wang X, Gao X, Xu H, Shi Y, Guan Y, Wang Y, Jin J, Ding Y, Niu J. Computational analysis of naturally occurring resistance-associated substitutions in genes NS3, NS5A, and NS5B among 86 subtypes of hepatitis C virus worldwide. Infect Drug Resist 2019; 12:2987-3015. [PMID: 31571951 PMCID: PMC6756830 DOI: 10.2147/idr.s218584] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/22/2019] [Indexed: 12/14/2022] Open
Abstract
Background and objective Direct-acting antivirals (DAA) facing resistance continue to be used in some areas worldwide. Thus, identifying hepatitis C virus (HCV) genotypes/subtypes and loci with certain prevalent resistance-associated substitutions (RASs) deserves attention. We investigated the global and regional frequencies of naturally occurring RASs among all confirmed HCV subtypes (n=86) and explored co-occurring and mutually exclusive RAS pairs within and between genes NS3, NS5A, and NS5B. Methods A total of 213,908 HCV sequences available as of July 10, 2019 were retrieved from the NCBI nucleotide database. After curation, 17,312 NS3, 8,478 NS5A, and 25,991 NS5B sequence fragments from DAA-naïve patients were screened for RASs. MEGA 6.0 was used to translate aligned nucleotide sequences into amino acid sequences, and RAS pairs were identified by hypergeometric analysis. Results RAS prevalence varied significantly among HCV subtypes. For example, D168E, highly resistanct to all protease inhibitors except voxilaprevir, was nearly absent in all subtypes except in 43.48% of GT5a sequences. RASs in NS3 exhibiting significantly different global distribution included Q80K in GT1a with the highest frequency in North America (54.49%), followed by in Europe (22.66%), Asia (6.98%), Oceania (6.62%), and South America (1.03%). The prevalence of NS3 S122G in GT1b was highest in Asia (26.6%) and lowest in Europe (2.64%). NS5A L28M, R30Q, and Y93H in GT1b, L31M in GT2b, and NS5B C316N in GT1b was most prevalent in Asia. A150V in GT3a, associated with sofosbuvir treatment failure, was most prevalent in Asia (44.09%), followed by Europe (31.19%), Oceania (24.29%), and North America (19.05%). Multiple mutually exclusive or co-occurring RAS pairs were identified, including Q80K+R155K and R155K+D168G in GT1a and L159F+C316N and R30Q (NS5A)+C316N (NS5B) in GT1b. Conclusion Our data may be of special relevance for those countries where highly effective antivirals might not be available. Considering the specific RASs prevalence will help the clinicians to make optimal treatment choices. The RASs pairs would benefit anti-HCV drug development.
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Affiliation(s)
- Ruihong Wu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Dongfeng Geng
- Centre for Reproductive Medicine, Centre for Prenatal Diagnosis, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xiumei Chi
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xiaomei Wang
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xiuzhu Gao
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Hongqin Xu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Ying Shi
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Yazhe Guan
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Yang Wang
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Jinglan Jin
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Yanhua Ding
- Phase I Clinical Research Center, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
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El-Shabrawi M, Hassanin F. Paediatric hepatitis C virus infection and its treatment: Present, past, and future. Arab J Gastroenterol 2019; 20:163-174. [PMID: 31585703 DOI: 10.1016/j.ajg.2019.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/01/2019] [Accepted: 09/15/2019] [Indexed: 01/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease in the world. It is a challenging medico-social problem in the paediatric population. High HCV infection rates are reported in low and middle incomes countries. From the health economic point of view treatment of hepatitis C virus (HCV) with subsequent virus eradication is very effective as it eliminates the long-term sequelae of untreated or maltreated HCV. In this review we summarize the updates and highlight the historical approach of treatment of chronic HCV infection in children in the new era of directly acting antiviral (DAA) agents.
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Masternak J, Gilewska A, Kazimierczuk K, Khavryuchenko OV, Wietrzyk J, Trynda J, Barszcz B. Synthesis, physicochemical and theoretical studies on new rhodium and ruthenium dimers. Relationship between structure and cytotoxic activity. Polyhedron 2018. [DOI: 10.1016/j.poly.2018.07.054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Development of robust genotype 1a hepatitis C replicons harboring adaptive mutations for facilitating the antiviral drug discovery and study of virus replication. J Virol Methods 2018; 259:10-17. [PMID: 29782889 DOI: 10.1016/j.jviromet.2018.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 05/15/2018] [Accepted: 05/17/2018] [Indexed: 11/20/2022]
Abstract
The hepatitis C virus (HCV) subgenomic replicon is a valuable tool for studying virus replication and HCV drug development. Despite the fact that HCV genotype 1a (HCV1a) is the most prevalent genotype in the United States, few HCV1a reporter replicon constructs have been reported, and their replication capacities are not as efficient as those of HCV1b or 2a, especially in transient expression. In this study, we selected efficient HCV1a replicons and characterized the novel adaptive mutations derived from stable HCV1a (strain H77) replicon cells after G418 selection. These novel adaptive mutations were scored in NS3 (A1065V, C1073S, N1227D, D1431Y, and E1556G), NS4A (I1694T and E1709V), and NS4B (G1871C). The D1431Y mutation alone or combinations of other adaptive mutations introduced into the parental HCV1a replicon construct was observed to differentially enhance either transient or stable expression of replicon. In particular, two replicon mutants VDYG (A1065V, N1227D, D1431Y, and E1556G within NS3) and VDYGRG, VDYG with two additional adaptive mutations (NS4A-K1691R and NS4B-E1726G), displayed robust replication and exhibited no impairment in the susceptibility of replicon activity to various known HCV inhibitors.
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8
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Raj VS, Hundie GB, Schürch AC, Smits SL, Pas SD, Le Pogam S, Janssen HLA, de Knegt RJ, Osterhaus ADME, Najera I, Boucher CA, Haagmans BL. Identification of HCV Resistant Variants against Direct Acting Antivirals in Plasma and Liver of Treatment Naïve Patients. Sci Rep 2017; 7:4688. [PMID: 28680115 PMCID: PMC5498547 DOI: 10.1038/s41598-017-04931-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 05/22/2017] [Indexed: 02/06/2023] Open
Abstract
Current standard-of-care treatment of chronically infected hepatitis C virus (HCV) patients involves direct-acting antivirals (DAA). However, concerns exist regarding the emergence of drug -resistant variants and subsequent treatment failure. In this study, we investigate potential natural drug-resistance mutations in the NS5B gene of HCV genotype 1b from treatment-naïve patients. Population-based sequencing and 454 deep sequencing of NS5B gene were performed on plasma and liver samples obtained from 18 treatment- naïve patients. The quasispecies distribution in plasma and liver samples showed a remarkable overlap in each patient. Although unique sequences in plasma or liver were observed, in the majority of cases the most dominant sequences were shown to be identical in both compartments. Neither in plasma nor in the liver codon changes were detected at position 282 that cause resistance to nucleos(t)ide analogues. However, in 10 patients the V321I change conferring resistance to nucleos(t)ide NS5B polymerase inhibitors and in 16 patients the C316N/Y/H non-nucleoside inhibitors were found mainly in liver samples. In conclusion, 454-deep sequencing of liver and plasma compartments in treatment naïve patients provides insight into viral quasispecies and the pre-existence of some drug-resistant variants in the liver, which are not necessarily present in plasma.
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Affiliation(s)
- V Stalin Raj
- Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Anita C Schürch
- Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Saskia L Smits
- Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands.,Viroclinics Biosciences BV, Rotterdam, The Netherlands
| | - Suzan D Pas
- Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Sophie Le Pogam
- Virology Discovery, Pharma Research Early Development Hoffmann La Roche, Nutley, NJ, USA
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.,Division of Gastroenterology, University Health Network, Toronto, Canada
| | - Rob J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Albert D M E Osterhaus
- Artemis One health, Utrecht, The Netherlands.,Center for Infection Medicine and Zoonoses Research, University of Veterinary Medicine, Hannover, Germany
| | - Isabel Najera
- Virology Discovery, Pharma Research Early Development Hoffmann La Roche, Nutley, NJ, USA
| | - Charles A Boucher
- Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Bart L Haagmans
- Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands.
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Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase. Viruses 2017. [PMID: 28621755 PMCID: PMC5490826 DOI: 10.3390/v9060151] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.
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10
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Tao W, Gan T, Lu J, Zhong J. A profiling study of a newly developed HCVcc strain PR63cc's sensitivity to direct-acting antivirals. Antiviral Res 2016; 139:18-24. [PMID: 28025084 DOI: 10.1016/j.antiviral.2016.12.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Accepted: 12/15/2016] [Indexed: 02/08/2023]
Abstract
The development of direct-acting antivirals (DAAs) has significantly improved hepatitis C virus (HCV) treatment. However, drug resistance remains a potential concern in the real-world DAA-based therapies. We previously developed a novel full-length genotype 2a HCVcc clone PR63cc directly from clinical isolates. Here in this study, we compared the sensitivity of PR63cc and JFH1 to 12 different DAAs most of which are either already in clinical use or in the late clinical development phase. For NS5B inhibitors, PR63cc and JFH1 displayed comparable sensitivity to nucleoside/nucleotide analogues sofosbuvir and 2'-C-methyladenosine, while PR63cc was 4-fold more sensitive than JFH1 to nesbuvir, a non-nucleoside inhibitor. Interestingly, PR63cc and JFH1 were both completely resistant to dasabuvir which efficiently inhibited the replication of genotype 1b HCV replicon. For NS5A inhibitors, while PR63cc was as sensitive as JFH1 to ombitasvir and velpatasvir, it was much more resistant than JFH1 to daclatasvir and ledipasvir, which was mainly due to methionine at amino acid residue 31 of NS5A. For NS3 inhibitors, PR63cc was generally less sensitive than JFH1 to simeprevir, grazoprevir, asunaprevir and paritaprevir. Serine at residue 67 of NS3 was identified to be a resistance-associated variant (RAV) for asunaprevir. Finally, we showed that PR63cc was more resistant than JFH1 to the asunaprevir/daclatasvir combination treatment. In summary, our study systemically analyzed the DAA sensitivity of a new HCVcc strain and identified critical RAVs. These results are not only important for monitoring the emergence of drug-resistant mutations of current DAA therapies, but also valuable for developing next-generation DAAs.
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Affiliation(s)
- Wanyin Tao
- Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China
| | - Tianyu Gan
- Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Jie Lu
- Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China
| | - Jin Zhong
- Unit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China.
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Kao JH, Tung SY, Lee Y, Thongsawat S, Tanwandee T, Sheen IS, Wu JJ, Li H, Brennan BJ, Zhou J, Le Pogam S, Najera I, Thommes JA, Hill G. Ritonavir-boosted danoprevir plus peginterferon alfa-2a and ribavirin in Asian chronic hepatitis C patients with or without cirrhosis. J Gastroenterol Hepatol 2016; 31:1757-1765. [PMID: 26992248 DOI: 10.1111/jgh.13374] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 03/04/2016] [Accepted: 03/07/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed-dose ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-naive Asian patients with chronic hepatitis C virus (HCV) genotype (G)1 infection. METHODS Treatment-naive G1 patients in Taiwan, Thailand, and Korea with serum HCV-RNA level ≥ 105 IU/mL received ritonavir-boosted danoprevir 125/100 mg twice daily plus peginterferon alfa-2a/ribavirin for either 12 (noncirrhotic patients: Arm A, n = 34) or 24 weeks (cirrhotic patients: Arm B, n = 27) in this phase II open-label study. Sustained virologic response was defined as HCV-RNA < 25 IU/mL 12 weeks after end of treatment (SVR12). RESULTS Similar SVR12 rates were achieved in Arms A (88.2%; 95% confidence interval, 73.4-95.3%) and B (88.9%; 71.9-96.2%). Most patients had G1b infection, among whom SVR12 rates in Arms A and B were 96.7% and 91.7%, respectively. The overall SVR12 rate was 94.0% in noncirrhotic Taiwanese patients (100% in the subset of G1b patients). No patients withdrew for safety reasons. Three (11%) cirrhotic patients (Arm B) experienced serious adverse events, none of which was considered to be related to treatment. No Grade 3/4 alanine aminotransferase elevations were reported. The pharmacokinetic properties of danoprevir were broadly overlapping in noncirrhotic and cirrhotic patients both on Days 1 and 14. CONCLUSIONS Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin produced sustained virologic response rates > 90% after 12 weeks' treatment in noncirrhotic and 24 weeks' treatment in cirrhotic Asian patients with G1b infection and was well tolerated. These regimens are well suited to countries where G1b predominates.
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Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University and Hospital, Taipei, Taiwan.
| | - Shui-Yi Tung
- Department of Gastroenterology, Chang Gung Memorial Hospital, Chia Yi, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Younjae Lee
- Pusan Paik Hospital, Inje University, Pusan, Korea
| | | | | | - I-Shyan Sheen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | | | - Hui Li
- Roche Product Development, Shanghai, China
| | - Barbara J Brennan
- Roche Translational and Clinical Research Center, New York, New York, USA
| | | | | | - Isabel Najera
- Roche Pharma and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - George Hill
- Genentech, South San Francisco, California, USA
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12
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Jiménez-Pérez M, González-Grande R, España Contreras P, Pinazo Martínez I, de la Cruz Lombardo J, Olmedo Martín R. Treatment of chronic hepatitis C with direct-acting antivirals: The role of resistance. World J Gastroenterol 2016; 22:6573-6581. [PMID: 27547001 PMCID: PMC4970473 DOI: 10.3748/wjg.v22.i29.6573] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
The use of direct-acting antivirals (DAAs) to treat chronic hepatitis C has resulted in a significant increase in rates of sustained viral response (around 90%-95%) as compared with the standard treatment of peginterferon/ribavirin. Despite this, however, the rates of therapeutic failure in daily clinical practice range from 10%-15%. Most of these cases are due to the presence of resistant viral variants, resulting from mutations produced by substitutions of amino acids in the viral target protein that reduce viral sensitivity to DAAs, thus limiting the efficacy of these drugs. The high genetic diversity of hepatitis C virus has resulted in the existence of resistance-associated variants (RAVs), sometimes even before starting treatment with DAAs, though generally at low levels. These pre-existing RAVs do not appear to impact on the sustained viral response, whereas those that appear after DAA therapy could well be determinant in virological failure with future treatments. As well as the presence of RAVs, virological failure to treatment with DAAs is generally associated with other factors related with a poor response, such as the degree of fibrosis, the response to previous therapy, the viral load or the viral genotype. Nonetheless, viral breakthrough and relapse can still occur in the absence of detectable RAVs and after the use of highly effective DAAs, so that the true clinical impact of the presence of RAVs in therapeutic failure remains to be determined.
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13
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Kartashev V, Döring M, Nieto L, Coletta E, Kaiser R, Sierra S, Guerrero A, Stoiber H, Paar C, Vandamme A, Nevens F, Ranst MV, Cuypers L, Braun P, Ehret R, Obermeier M, Schneeweiss S, Scholten S, Römer K, Isernhagen K, Qurashi N, Heger E, Knops E, Neumann-Fraune M, Timm J, Walker A, Lübke N, Wedemeyer H, Wiesch JSZ, Lütgehetmann M, Polywka S, Däumer M, Hoffmann D, Protzer U, Marascio N, Foca A, Liberto M, Barreca G, Galati L, Torti C, Pisani V, Perno C, Ceccherini-Silberstein F, Cento V, Ciotti M, Zazzi M, Rossetti B, Luca A, Caudai C, Mor O, Devaux C, Staub T, Araujo F, Gomes P, Cabanas J, Markin N, Khomenko I, Govorukhina M, Lugovskaya G, Dontsov D, Mas A, Martró E, Saludes V, Rodríguez-Frías F, García F, Casas P, Iglesia ADL, Alados J, Pena-López M, Rodríguez M, Galán J, Suárez A, Cardeñoso L, Guerrero M, Vegas-Dominguez C, Blas-Espada J, García R, García-Bujalance S, Benítez-Gutiérrez L, Mendoza CD, Montiel N, Santos J, Viciana I, Delgado A, Martínez-Sanchez P, Fernández-Alonso M, Reina G, Trigo M, Echeverría M, Aguilera A, Navarro D, Bernal S, Lozano M, Fernández-Cuenca F, Orduña A, Eiros J, Lejarazu ROD, Martínez-Sapiña A, García-Díaz A, Haque T. New findings in HCV genotype distribution in selected West European, Russian and Israeli regions. J Clin Virol 2016; 81:82-9. [DOI: 10.1016/j.jcv.2016.05.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 05/17/2016] [Accepted: 05/19/2016] [Indexed: 02/06/2023]
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Geno2pheno[HCV] - A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents. PLoS One 2016; 11:e0155869. [PMID: 27196673 PMCID: PMC4873220 DOI: 10.1371/journal.pone.0155869] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 05/05/2016] [Indexed: 12/18/2022] Open
Abstract
The face of hepatitis C virus (HCV) therapy is changing dramatically. Direct-acting antiviral agents (DAAs) specifically targeting HCV proteins have been developed and entered clinical practice in 2011. However, despite high sustained viral response (SVR) rates of more than 90%, a fraction of patients do not eliminate the virus and in these cases treatment failure has been associated with the selection of drug resistance mutations (RAMs). RAMs may be prevalent prior to the start of treatment, or can be selected under therapy, and furthermore they can persist after cessation of treatment. Additionally, certain DAAs have been approved only for distinct HCV genotypes and may even have subtype specificity. Thus, sequence analysis before start of therapy is instrumental for managing DAA-based treatment strategies. We have created the interpretation system geno2pheno[HCV] (g2p[HCV]) to analyse HCV sequence data with respect to viral subtype and to predict drug resistance. Extensive reviewing and weighting of literature related to HCV drug resistance was performed to create a comprehensive list of drug resistance rules for inhibitors of the HCV protease in non-structural protein 3 (NS3-protease: Boceprevir, Paritaprevir, Simeprevir, Asunaprevir, Grazoprevir and Telaprevir), the NS5A replicase factor (Daclatasvir, Ledipasvir, Elbasvir and Ombitasvir), and the NS5B RNA-dependent RNA polymerase (Dasabuvir and Sofosbuvir). Upon submission of up to eight sequences, g2p[HCV] aligns the input sequences, identifies the genomic region(s), predicts the HCV geno- and subtypes, and generates for each DAA a drug resistance prediction report. g2p[HCV] offers easy-to-use and fast subtype and resistance analysis of HCV sequences, is continuously updated and freely accessible under http://hcv.geno2pheno.org/index.php. The system was partially validated with respect to the NS3-protease inhibitors Boceprevir, Telaprevir and Simeprevir by using data generated with recombinant, phenotypic cell culture assays obtained from patients’ virus variants.
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15
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Resistance to direct-acting antiviral agents: clinical utility and significance. Curr Opin HIV AIDS 2016; 10:381-9. [PMID: 26248125 DOI: 10.1097/coh.0000000000000177] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW This article examines the dynamics and factors underlying hepatitis C virus (HCV) resistance, along with their impact on daily clinical management of HCV-infected patients. RECENT FINDINGS Across available treatment-regimens, GT-3 is the most difficult-to-cure genotype, but also genotype-1a may show lower success-rates compared with genotype-1b. Natural resistance to NS3, NS5A and NS5B inhibitors may contribute to treatment failures. The Q80K NS3-protease mutation affects sensibility to simeprevir + peg-interferon/ribavirin combinations. It reaches up to 48% prevalence in genotype-1a in some studies (but it is lower in other). Resistant variants (particularly in NS5A) developed at failure can persist, in a substantial proportion of patients, even 3 years after treatment-discontinuation, potentially affecting readministration of the same direct-acting antiviral agent (DAA)-class. This will become an issue for those patients failing all-oral regimens with multiple-resistant viruses. SUMMARY Recent data support the importance of an accurate genotype and genotype-1 subtype (1a/1b) assignment prior therapy. Resistance testing at baseline has no clear indication so far in clinical practice for all-DAA regimens selection, while it remains a valuable option at the retreatment of patients who failed DAA-containing regimens, provided that data are generated to inform treatment decisions based on the results of resistance testing. In this context, long-term RAVs persistence after failure should be taken into account.
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16
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Gane EJ, Rouzier R, Hassanein T, Stedman CA, Mazur W, Kupcova V, Le Pogam S, Eng S, Voulgari A, Morcos PN, Brennan BJ, Scalori A, Thommes J. Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis. Hepatol Int 2016; 10:478-87. [PMID: 26886127 DOI: 10.1007/s12072-015-9699-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 12/16/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis. METHODS An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18-35 kg/m(2). Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24). RESULTS In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred. CONCLUSIONS Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.
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Affiliation(s)
- Edward J Gane
- Auckland Clinical Studies, Grafton, New Zealand. .,Auckland City Hospital, Auckland, 1442, New Zealand.
| | - Régine Rouzier
- Centre Cap, Centre Médical Odysséum, Montpellier, France
| | | | - Catherine A Stedman
- Christchurch Clinical Studies and University of Otago, Christchurch, New Zealand
| | - Wlodzimierz Mazur
- Department of Infectious Diseases, Medical University of Silesia, Katowice, Poland
| | - Viera Kupcova
- Medical Faculty of Comenius University, Dérer's Hospital, Bratislava, Slovakia
| | | | - Simon Eng
- Genentech, South San Francisco, CA, USA
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17
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Bagaglio S, Uberti-Foppa C, Messina E, Merli M, Hasson H, Andolina A, Galli A, Lazzarin A, Morsica G. Distribution of natural resistance to NS3 protease inhibitors in hepatitis C genotype 1a separated into clades 1 and 2 and in genotype 1b of HIV-infected patients. Clin Microbiol Infect 2015; 22:386.e1-386.e3. [PMID: 26706617 DOI: 10.1016/j.cmi.2015.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 10/15/2015] [Accepted: 12/05/2015] [Indexed: 10/22/2022]
Abstract
Naturally occurring resistance-associated variants (RAVs) within the protease domain of hepatitis C virus (HCV) genotype (G) 1a separated into clades 1 and 2, and G1b were investigated in 59 HIV/HCV coinfected patients. RAVs were detected in 10/23 G1a/clade 1 and 1/19 G1b (p 0.0059). A similar frequency of RAVs was found when comparing G1a/clade 2 and G1b (p 0.1672). A cross-resistance to the macrocyclic compounds simeprevir and paritaprevir was detected in two G1a/clade 2 and 1 G1b sequences and none of G1a/clade 1 sequences. The simultaneous characterization of subtype and natural RAVs by population analysis of the NS3 domain by may add important information for anti-HCV treatment strategies including protease inhibitors.
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Affiliation(s)
- S Bagaglio
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy; Vita-Salute University, Milan, Italy.
| | - C Uberti-Foppa
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy
| | - E Messina
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy
| | - M Merli
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy
| | - H Hasson
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy
| | - A Andolina
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy
| | - A Galli
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy
| | - A Lazzarin
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy; Vita-Salute University, Milan, Italy
| | - G Morsica
- Department of Infectious Diseases, Scientific Institute Ospedale San Raffaele, Italy
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18
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Perales C, Quer J, Gregori J, Esteban JI, Domingo E. Resistance of Hepatitis C Virus to Inhibitors: Complexity and Clinical Implications. Viruses 2015; 7:5746-66. [PMID: 26561827 PMCID: PMC4664975 DOI: 10.3390/v7112902] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 10/23/2015] [Accepted: 10/26/2015] [Indexed: 12/20/2022] Open
Abstract
Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic. We put the experimental observations in the context of quasi-species dynamics, in particular what the genetic and phenotypic barriers to resistance mean in terms of exploration of sequence space while HCV replicates in the liver of infected patients or in cell culture. Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined.
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Affiliation(s)
- Celia Perales
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Biologia Molecular "Severo Ochoa" (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
| | - Josep Quer
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
- Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
| | - Josep Gregori
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
- Roche Diagnostics SL, 08174 Sant Cugat del Vallès, Spain.
| | - Juan Ignacio Esteban
- Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
- Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
| | - Esteban Domingo
- Centro de Biologia Molecular "Severo Ochoa" (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08035 Barcelona, Spain.
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Shepherd SJ, Abdelrahman T, MacLean AR, Thomson EC, Aitken C, Gunson RN. Prevalence of HCV NS3 pre-treatment resistance associated amino acid variants within a Scottish cohort. J Clin Virol 2015; 65:50-3. [PMID: 25766988 PMCID: PMC4728298 DOI: 10.1016/j.jcv.2015.02.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 02/04/2015] [Accepted: 02/06/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND Protease inhibitors (PI) including boceprevir, telaprevir and simeprevir have revolutionised HCV genotype 1 treatment since their introduction. A number of pre-treatment resistance associated amino acid variants (RAVs) and polymorphisms have been associated with reduced response to treatment. OBJECTIVES We measured the prevalence of RAVs/polymorphisms in a PI treatment-naïve HCV genotype 1 Scottish cohort using Sanger sequencing. STUDY DESIGN Chronically infected, treatment-naïve, HCV genotype 1 patients (n = 146) attending NHS Greater Glasgow and Clyde clinics were investigated for RAVs/polymorphisms to the PIs boceprevir, telaprevir and simeprevir. The NS3/4A region was amplified by nested polymerase chain reaction. The 1.4 kb amplified product was sequenced using an ABI 3710XL DNA sequencer. Sequence analysis was performed using web-based ReCall (beta 2.10). Amino acid positions 36, 41, 43, 54, 55, 80, 109, 122, 155, 156, 168 and 170 were analysed for RAVs/polymorphisms. RESULTS Overall, 23.29% (34/146) of patients had an RAV or polymorphism detected. Overall, 13.69% (20/146) of patients had HCV virus that contained the Q8 K polymorphism. Other RAVs detected were: V36 M 0.70% (1/146), V36L 0.70% (1/146), T54S 6.85% (10/146), V55A 3.42% (5/146) and V/I170A 0.68% (1/146). Four patients had dual combinations of mutations (T54S+V36L; T54S+V55A and 2 patients with T54S+Q80K). CONCLUSIONS Q80K was the most prevalent baseline polymorphism detected in the Scottish cohort. Simeprevir treatment is not recommended in patients infected with the Q80K genotype 1a variant. This highlights the need for baseline sequencing prior to administration of this drug in this population.
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Affiliation(s)
- Samantha J Shepherd
- West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom.
| | - Tamer Abdelrahman
- MRC-University of Glasgow Centre for Virus Research, Stoker Building, 464 Bearsden Road, Glasgow G61 1QH, United Kingdom
| | - Alasdair R MacLean
- West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom
| | - Emma C Thomson
- MRC-University of Glasgow Centre for Virus Research, Stoker Building, 464 Bearsden Road, Glasgow G61 1QH, United Kingdom
| | - Celia Aitken
- West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom
| | - Rory N Gunson
- West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom
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Andriulli A, Morisco F, Ippolito AM, Di Marco V, Valvano MR, Angelico M, Fattovich G, Granata R, Smedile A, Milella M, Felder M, Gaeta GB, Gatti P, Fasano M, Mazzella G, Santantonio T. HCV genotype 1 subtypes (1a and 1b): similarities and differences in clinical features and therapeutic outcome. Hepatol Int 2015; 9:52-7. [PMID: 25788379 DOI: 10.1007/s12072-014-9556-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 06/21/2014] [Indexed: 01/06/2023]
Abstract
AIM To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA). PATIENTS AND METHODS A total of 1,233 naïve patients with HCV genotype-1 infection, 159 (13%) with subtype 1a and 1,074 (87%) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma-glutamiltranspeptidase (γGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype. RESULTS At multivariate analysis, baseline characteristics differentiating patients with HCV-1a versus HCV-1b were young age, male gender, no F4 fibrosis, and no diabetes. SVR was achieved by 37% of patients with subtype 1b and 45% of those with subtype 1a, a nonsignificant difference of 8% (p = 0.069). In patients with subtype 1a, predictors of SVR were IL28B CC (OR 5.78, CI 1.98-16.83), RVR (OR 4.18, CI 1.66-10.55), female gender (OR 2.83, CI 1.83-6.78), and HCVRNA (OR 0.55, CI 0.32-0.96). In patients with subtype 1b, the ranking of predictors was levels RVR (OR 6.49, CI 4.32-9.73), IL28B CC (OR 3.32, CI 2.15-4.58), γGT (OR 1.59, CI 0.14-2.22), HCVRNA (OR 0.61, CI 0.47-0.79), and age (OR 0.01, CI 0.02-0.42). CONCLUSION In Italy HCV-1 subtype 1a prevails in young male patients with less advanced liver damage, findings that imply a more recent spreading of the infection with this viral strain. The two HCV-1 subtypes appear equally responsive to Peg-IFN/RIBA, with IL28B genotyping and monitoring of RVR mostly influencing the therapeutic response.
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Affiliation(s)
- A Andriulli
- Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy,
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21
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Preciado MV, Valva P, Escobar-Gutierrez A, Rahal P, Ruiz-Tovar K, Yamasaki L, Vazquez-Chacon C, Martinez-Guarneros A, Carpio-Pedroza JC, Fonseca-Coronado S, Cruz-Rivera M. Hepatitis C virus molecular evolution: Transmission, disease progression and antiviral therapy. World J Gastroenterol 2014; 20:15992-16013. [PMID: 25473152 PMCID: PMC4239486 DOI: 10.3748/wjg.v20.i43.15992] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 06/22/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents an important public health problem worldwide. Reduction of HCV morbidity and mortality is a current challenge owned to several viral and host factors. Virus molecular evolution plays an important role in HCV transmission, disease progression and therapy outcome. The high degree of genetic heterogeneity characteristic of HCV is a key element for the rapid adaptation of the intrahost viral population to different selection pressures (e.g., host immune responses and antiviral therapy). HCV molecular evolution is shaped by different mechanisms including a high mutation rate, genetic bottlenecks, genetic drift, recombination, temporal variations and compartmentalization. These evolutionary processes constantly rearrange the composition of the HCV intrahost population in a staging manner. Remarkable advances in the understanding of the molecular mechanism controlling HCV replication have facilitated the development of a plethora of direct-acting antiviral agents against HCV. As a result, superior sustained viral responses have been attained. The rapidly evolving field of anti-HCV therapy is expected to broad its landscape even further with newer, more potent antivirals, bringing us one step closer to the interferon-free era.
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22
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Svarovskaia ES, Dvory-Sobol H, Parkin N, Hebner C, Gontcharova V, Martin R, Ouyang W, Han B, Xu S, Ku K, Chiu S, Gane E, Jacobson IM, Nelson DR, Lawitz E, Wyles DL, Bekele N, Brainard D, Symonds WT, McHutchison JG, Miller MD, Mo H. Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis 2014; 59:1666-74. [PMID: 25266287 DOI: 10.1093/cid/ciu697] [Citation(s) in RCA: 173] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Sofosbuvir is a chain-terminating nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with HCV genotype 1-6 infection. Sofosbuvir resistance is primarily conferred by the S282T substitution in NS5B. METHODS NS5B sequencing and susceptibility testing of HCV from subjects infected with genotypes 1-6 who participated in phase 2 and 3 sofosbuvir clinical trials was performed. RESULTS No NS5B variants present at baseline among 1645 sofosbuvir-treated subjects were associated with treatment failure; sofosbuvir susceptibility was within 2-fold of reference. Among 282 subjects who did not achieve sustained virologic response, no novel sofosbuvir resistance-associated variants were identified, and the NS5B changes observed did not confer significant reductions in sofosbuvir susceptibility. In 1 subject with S282T observed at relapse 4 weeks after sofosbuvir monotherapy, the resistant variant (13.5-fold reduced sofosbuvir susceptibility, replication capacity <2% of control) became undetectable by deep sequencing 12 weeks after treatment. L159F and V321A were identified as treatment-emergent variants but did not confer resistance to sofosbuvir in the replicon system. CONCLUSIONS These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.
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Affiliation(s)
| | | | - Neil Parkin
- Data First Consulting Inc, Belmont, California
| | | | | | | | | | - Bin Han
- Gilead Sciences, Foster City
| | | | | | | | - Edward Gane
- University of Auckland, Auckland City Hospital, New Zealand
| | | | | | | | - David L Wyles
- Division of Infectious Diseases, University of California, San Diego
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23
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Chen YC, Bernaards C, Kulkarni R, Moreira S, Zhu Y, Chan A, Badman E, Ackrill A, Thommes J, Smith PF. Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP-C and PROPEL studies. Br J Clin Pharmacol 2014; 78:533-42. [PMID: 24602156 PMCID: PMC4243904 DOI: 10.1111/bcp.12369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/21/2014] [Indexed: 01/22/2023] Open
Abstract
AIMS The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C). METHODS We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin. RESULTS Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1). CONCLUSIONS Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.
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Affiliation(s)
| | | | | | | | | | - Anna Chan
- Hoffmann-La Roche Inc.Nutley, NJ, USA
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24
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Li Y, Peng Z, Gao L, Song D. Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents. Acta Pharm Sin B 2014; 4:307-12. [PMID: 26579400 PMCID: PMC4629077 DOI: 10.1016/j.apsb.2014.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 06/04/2014] [Accepted: 06/12/2014] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection has become a major public health burden worldwide. Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro. The structure-activity analysis revealed that (i) sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold; (ii) the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonyl Δ (βγ) sophocarpinic acids was beneficial for the antiviral activity against HCV. Among them, compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9, respectively. Therefore, both were selected as antiviral candidates for further investigation.
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25
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de Carvalho IMVG, Alves R, de Souza PAVM, da Silva EF, Mazo D, Carrilho FJ, Queiroz ATL, Pessoa MG. Protease inhibitor resistance mutations in untreated Brazilian patients infected with HCV: novel insights about targeted genotyping approaches. J Med Virol 2014; 86:1714-21. [PMID: 25042789 DOI: 10.1002/jmv.24015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2014] [Indexed: 12/11/2022]
Abstract
Several new direct-acting antiviral (DAA) drugs are being developed or are already approved for the treatment of chronic hepatitis C virus (HCV) infection. HCV variants presenting drug-resistant phenotypes were observed both in vitro and during clinical trials. The aim of this study was to characterize amino acid changes at positions previously associated with resistance in the NS3 protease in untreated Brazilian patients infected with HCV genotypes 1a and 1b. Plasma samples from 171 untreated Brazilian patients infected with HCV were obtained from the Department of Gastroenterology of Clinics Hospital (HCFMUSP) in São Paulo, Brazil. Nested PCR and Sanger sequencing were used to obtain genetic information on the NS3 protein. Bioinformatics was used to confirm subtype information and analyze frequencies of resistance mutations. The results from the genotype analysis using non-NS3 targeted methods were at variance with those obtained from the NS3 protease phylogenetic analyses. It was found that 7.4% of patients infected with HCV genotype 1a showed the resistance-associated mutations V36L, T54S, Q80K, and R155K, while 5.1% of patients infected with HCV genotype 1b had the resistance-associated mutations V36L, Q41R, T54S, and D168S. Notably, codons at positions 80 and 155 differed between samples from Brazilian patient used in this study and global isolates. The present study demonstrates that genotyping methods targeting the NS3 protein showed a difference of results when compared to mainstream methodologies (INNO-LiPA and polymerase sequencing). The resistance mutations present in untreated patients infected with HCV and codon composition bias by geographical location warrant closer examination.
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Affiliation(s)
- Isabel M V G de Carvalho
- Viral Imunology, Butantan Institute, Avenida Doutor Vital Brasil, São Paulo, Brazil; Applied Molecular Hepatology Laboratory (LHeMA), Hepatitis Sector, Gastroenterology Division, São Paulo Federal University, São Paulo, Brazil
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26
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Abstract
An all-oral therapy for treating hepatitis C (HCV) is now available for the most common genotypes although interferon-based therapy is still recommended for interferon-eligible patients with HCV genotype 1. For most patients, a prior history of treatment or presence of cirrhosis does not appear to significantly impact eradication rates with direct acting antivirals (DAA). The promising results from the numerous clinical trials of DAA's for HCV together with their tolerability represent a tremendous advance in our management of this disease, particularly as treatment is often well-tolerated, associated with few side effects and significantly shortened in duration. We will review several of the peer-reviewed landmark studies of DAA's for the treatment HCV and conclude with an expert commentary and five year view.
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Affiliation(s)
- Manogna Nookathota
- Creighton University Medical Center, 601 North 30th Street, Omaha, NE 68131, USA
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27
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Ali M, Rehman IU, Idrees M. Emergence of genetically variant Hepatitis C virus population in response to increased antiviral drug pressure, Pakistan. Virus Genes 2014; 48:543-9. [PMID: 24532035 DOI: 10.1007/s11262-014-1047-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 01/30/2014] [Indexed: 01/06/2023]
Abstract
Mutations in NS5B gene of Hepatitis C virus (HCV) have been reported in patients undergoing antiviral therapy. In the present study, we report emerging clade of HCV-3a in patients administered with IFN plus ribavirin therapy for 24 weeks and having low viral loads (<250 IU/mL). Mutations D/N244E, K304R, N/K307G, Q/T329V, and A338V were found associated with these emerging strains. This distinct HCV could be associated with the increased antiviral drug pressure.
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Affiliation(s)
- Muhammad Ali
- Division of Molecular Virology, National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal bank Road, Thokar Niaz baig, Lahore, 53700, Pakistan,
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28
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Rose L, Bias TE, Mathias CB, Trooskin SB, Fong JJ. Sofosbuvir: A Nucleotide NS5B Inhibitor for the Treatment of Chronic Hepatitis C Infection. Ann Pharmacother 2014; 48:1019-1029. [PMID: 24811396 DOI: 10.1177/1060028014534194] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To review the use of sofosbuvir for the treatment of chronic hepatitis C virus (HCV). DATA SOURCES Review and nonreview articles were identified through MEDLINE (1996-April 2014), citations of articles, and meeting abstracts using keywords, including NS5B polymerase inhibitor, GS-7977, sofosbuvir, direct-acting antiviral (DAA), and others. STUDY SELECTION AND DATA EXTRACTION Phase 1, 2, and 3 studies describing dose-ranging potential, pharmacokinetics, efficacy, safety, and tolerability of sofosbuvir were identified. DATA SYNTHESIS Sofosbuvir is an NS5B polymerase inhibitor that was approved for use by the Food and Drug Administration in December 2013 for the treatment of chronic HCV in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for genotype 1. Additionally, it has been evaluated with other oral DAAs, such as simeprevir and others in the pipeline. It is not recommended as monotherapy because of lower sustained virological response (SVR) rates in clinical studies. Most of the treatment regimens are 12 weeks in duration; however, certain populations require a longer duration. Sofosbuvir has activity against all 6 genotypes, although most clinical trials evaluated genotypes 1 to 3. Sofosbuvir has a favorable safety and tolerability profile, making it a recommended first-line agent for chronic HCV infection. CONCLUSION In clinical trials, 12 weeks of sofosbuvir with concomitant peg-IFN and RBV therapy in treatment-naïve and experienced HCV genotype 1 patients resulted in SVR rates of >90%. An all-oral regimen of sofosbuvir and RBV is highly effective for genotype 2 and 3 patients. Sofosbuvir was found to be tolerable with minimal adverse effects (AEs), and no treatment discontinuations occurred secondary to drug related AEs..
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Affiliation(s)
- Lucia Rose
- Western New England University, Springfield, MA, USA
| | | | | | | | - Jeffrey J Fong
- MCPHS University-Worcester/Manchester, Worcester, MA, USA
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29
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Saludes V, González V, Planas R, Matas L, Ausina V, Martró E. Tools for the diagnosis of hepatitis C virus infection and hepatic fibrosis staging. World J Gastroenterol 2014; 20:3431-3442. [PMID: 24707126 PMCID: PMC3974510 DOI: 10.3748/wjg.v20.i13.3431] [Citation(s) in RCA: 20] [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: 09/27/2013] [Revised: 12/05/2013] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents a major public health issue. Hepatitis C can be cured by therapy, but many infected individuals are unaware of their status. Effective HCV screening, fast diagnosis and characterization, and hepatic fibrosis staging are highly relevant for controlling transmission, treating infected patients and, consequently, avoiding end-stage liver disease. Exposure to HCV can be determined with high sensitivity and specificity with currently available third generation serology assays. Additionally, the use of point-of-care tests can increase HCV screening opportunities. However, active HCV infection must be confirmed by direct diagnosis methods. Additionally, HCV genotyping is required prior to starting any treatment. Increasingly, high-volume clinical laboratories use different types of automated platforms, which have simplified sample processing, reduced hands-on-time, minimized contamination risks and human error and ensured full traceability of results. Significant advances have also been made in the field of fibrosis stage assessment with the development of non-invasive methods, such as imaging techniques and serum-based tests. However, no single test is currently available that is able to completely replace liver biopsy. This review focuses on approved commercial tools used to diagnose HCV infection and the recommended hepatic fibrosis staging tests.
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30
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Ivanisenko NV, Mishchenko EL, Akberdin IR, Demenkov PS, Likhoshvai VA, Kozlov KN, Todorov DI, Gursky VV, Samsonova MG, Samsonov AM, Clausznitzer D, Kaderali L, Kolchanov NA, Ivanisenko VA. A new stochastic model for subgenomic hepatitis C virus replication considers drug resistant mutants. PLoS One 2014; 9:e91502. [PMID: 24643004 PMCID: PMC3958367 DOI: 10.1371/journal.pone.0091502] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 02/12/2014] [Indexed: 12/17/2022] Open
Abstract
As an RNA virus, hepatitis C virus (HCV) is able to rapidly acquire drug resistance, and for this reason the design of effective anti-HCV drugs is a real challenge. The HCV subgenomic replicon-containing cells are widely used for experimental studies of the HCV genome replication mechanisms, for drug testing in vitro and in studies of HCV drug resistance. The NS3/4A protease is essential for virus replication and, therefore, it is one of the most attractive targets for developing specific antiviral agents against HCV. We have developed a stochastic model of subgenomic HCV replicon replication, in which the emergence and selection of drug resistant mutant viral RNAs in replicon cells is taken into account. Incorporation into the model of key NS3 protease mutations leading to resistance to BILN-2061 (A156T, D168V, R155Q), VX-950 (A156S, A156T, T54A) and SCH 503034 (A156T, A156S, T54A) inhibitors allows us to describe the long term dynamics of the viral RNA suppression for various inhibitor concentrations. We theoretically showed that the observable difference between the viral RNA kinetics for different inhibitor concentrations can be explained by differences in the replication rate and inhibitor sensitivity of the mutant RNAs. The pre-existing mutants of the NS3 protease contribute more significantly to appearance of new resistant mutants during treatment with inhibitors than wild-type replicon. The model can be used to interpret the results of anti-HCV drug testing on replicon systems, as well as to estimate the efficacy of potential drugs and predict optimal schemes of their usage.
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Affiliation(s)
- Nikita V. Ivanisenko
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Elena L. Mishchenko
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Ilya R. Akberdin
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Pavel S. Demenkov
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Vitaly A. Likhoshvai
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Konstantin N. Kozlov
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
| | - Dmitry I. Todorov
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
- Chebyshev Laboratory, St. Petersburg State University, St. Petersburg, Russia
| | - Vitaly V. Gursky
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
- Theoretical Department, Ioffe Physical-Technical Institute of the Russian Academy of Sciences, St.Petersburg, Russia
| | - Maria G. Samsonova
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
| | - Alexander M. Samsonov
- Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia
- Theoretical Department, Ioffe Physical-Technical Institute of the Russian Academy of Sciences, St.Petersburg, Russia
| | - Diana Clausznitzer
- Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany
| | - Lars Kaderali
- Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany
| | - Nikolay A. Kolchanov
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Vladimir A. Ivanisenko
- Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
- PB-soft Llc, Novosibirsk, Russia
- * E-mail:
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31
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Schneider MD, Sarrazin C. Antiviral therapy of hepatitis C in 2014: do we need resistance testing? Antiviral Res 2014; 105:64-71. [PMID: 24583028 DOI: 10.1016/j.antiviral.2014.02.011] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 02/10/2014] [Accepted: 02/13/2014] [Indexed: 12/15/2022]
Abstract
The treatment of chronic hepatitis C has fundamentally changed since the approval of the first direct-acting antivirals (DAA) in 2011. In addition to telaprevir and boceprevir, in 2014 two new NS3 protease inhibitors (simeprevir and faldaprevir), one non-nucleoside polymerase inhibitor (sofosbuvir) and one NS5a replication complex inhibitor (daclatasvir) have expanded the treatment options for chronic hepatitis C. Resistance-associated variants (RAV) are naturally produced during the HCV life cycle. The frequency of RAVs within HCV quasispecies mainly depends on their replicational fitness. Variants conferring resistance to nucleos(t)ide analogues have not been detected, and the majority of NS3 protease-resistant variants are present at low frequencies (0.1-3%) before initiation of DAA-based therapies. However, the Q80K variant conferring resistance to simeprevir has been observed in 9-48% of untreated HCV genotype 1a-infected patients, leading to reduced SVR rates. Resistant variants are detectable in the majority of patients with treatment failure to NS3 protease inhibitor- or NS5a inhibitor-based antiviral therapy. Long-term follow-up studies by population-based sequence analysis have shown the disappearance of resistant variants in the majority of patients, with median times to loss of mutations of 4-64weeks. For the nucleotide analogue sofosbuvir, the emergence of the S282T resistant variant has been observed only in single patients, with reversion to wild-type within several weeks. Data are sparse on retreatment of patients with the same DAA or the same class of DAAs. However, retreatment with a different class of DAAs after failure of NS3 protease inhibitor-based therapy has been successful in small studies. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Maximilian David Schneider
- J. W. Goethe University Hospital, Department of Internal Medicine I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Christoph Sarrazin
- J. W. Goethe University Hospital, Department of Internal Medicine I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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32
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Schinazi R, Halfon P, Marcellin P, Asselah T. HCV direct-acting antiviral agents: the best interferon-free combinations. Liver Int 2014; 34 Suppl 1:69-78. [PMID: 24373081 PMCID: PMC7737539 DOI: 10.1111/liv.12423] [Citation(s) in RCA: 192] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
For HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct-acting antivirals (DAA) showing high potency, favourable tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan-genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN-based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross-resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN.
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Affiliation(s)
- Raymond Schinazi
- Center for AIDS Research, Emory University School of Medicine and Veterans Affairs Medical Center, Decatur, GA, USA
| | - Philippe Halfon
- Internal Medicine and Infectious Diseases Department, Hôpital Europeen and Laboratoire Alphabio Marseille, Marseille, France
| | - Patrick Marcellin
- Hepatology Department, AP-HP, University Paris Diderot 7 and INSERM U773, CRB3, Beaujon Hospital, Clichy, France
| | - Tarik Asselah
- Hepatology Department, AP-HP, University Paris Diderot 7 and INSERM U773, CRB3, Beaujon Hospital, Clichy, France
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33
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Gryadunov D, Dementieva E, Mikhailovich V, Nasedkina T, Rubina A, Savvateeva E, Fesenko E, Chudinov A, Zimenkov D, Kolchinsky A, Zasedatelev A. Gel-based microarrays in clinical diagnostics in Russia. Expert Rev Mol Diagn 2014; 11:839-53. [DOI: 10.1586/erm.11.73] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Dmitry Gryadunov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Ekaterina Dementieva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Vladimir Mikhailovich
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Tatiana Nasedkina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Alla Rubina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Elena Savvateeva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Eugeny Fesenko
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Alexander Chudinov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | - Danila Zimenkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
| | | | - Alexander Zasedatelev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia
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34
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Lange CM, Jacobson IM, Rice CM, Zeuzem S. Emerging therapies for the treatment of hepatitis C. EMBO Mol Med 2014; 6:4-15. [PMID: 24106239 PMCID: PMC3936496 DOI: 10.1002/emmm.201303131] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 08/12/2013] [Accepted: 08/14/2013] [Indexed: 12/24/2022] Open
Abstract
Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon‐α monotherapy in 1992 to the approval of telaprevir‐ and boceprevir‐based triple therapies with pegylated interferon‐α and ribavirin in 2011, the chances of curing patients infected with HCV genotype 1 have improved from <10% to approximately 70%. Significant further improvements are on the horizon, which may well cure virtually all hepatitis C patients with an all‐oral, interferon‐free regimen in the very near future. These exciting developments are reviewed in the present article.
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Affiliation(s)
- Christian M Lange
- Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M.Frankfurt a.M, Germany
| | | | - Charles M Rice
- Laboratory of Virology and Infectious Diseases, Center for the Study of Hepatitis C, The Rockefeller UniversityNew York, NY, USA
| | - Stefan Zeuzem
- Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M.Frankfurt a.M, Germany
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35
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Abstract
Advances in our understanding of the HCV lifecycle and refinement of in vitro methods to select candidate compounds with anti-HCV activity have led to development of DAA agents and other novel antiviral therapies capable of increasing the curative SVR rates in patients with CHC. The use of the liner protease inhibitors telaprevir and boceprevir, in combination with Peg-IFN-a and ribavirin has become the new SOC for treatment of CHC genotype 1. Rapid development of new protease inhibitors, NI and NNI NS5B polymerase inhibitors, NS5A inhibitors, Peg-IFN-l, cyclophilin inhibitors, caspase inhibitors, and therapeutic vaccines promises to provide even safer and more effective therapy. Combination therapies with 2 or more oral agents may permit elimination of Peg-IFN-a in the near future. Introduction of DAA therapies will confront physicians and patients with regimens of increased complexity, a greater need for compliance, and the necessity of monitoring for virological resistance. Patients with CHC should continue to consider participation in clinical trials of new therapies to accelerate progress.
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Affiliation(s)
- Jawad A Ilyas
- Liver Center, St Luke's Episcopal Hospital, Baylor College of Medicine, 1709 Dryden, Suite 1500, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, 1709 Dryden Street, Suite 500, Houston, TX 77030, USA; Department of Surgery, Baylor College of Medicine, 1709 Dryden Street, Suite 1500, Houston, TX 77030, USA
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González V, Gomes-Fernandes M, Bascuñana E, Casanovas S, Saludes V, Jordana-Lluch E, Matas L, Ausina V, Martró E. Accuracy of a commercially available assay for HCV genotyping and subtyping in the clinical practice. J Clin Virol 2013. [DOI: 10.1016/j.jcv.2013.09.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Resistance to HCV nucleoside analogue inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Curr Opin Virol 2013; 3:508-13. [DOI: 10.1016/j.coviro.2013.08.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Revised: 08/12/2013] [Accepted: 08/20/2013] [Indexed: 11/20/2022]
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Antiviral effect, safety, and pharmacokinetics of five-day oral administration of Deleobuvir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C. Antimicrob Agents Chemother 2013; 57:4727-35. [PMID: 23856779 DOI: 10.1128/aac.00565-13] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.
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González V, Gomes-Fernandes M, Bascuñana E, Casanovas S, Saludes V, Jordana-Lluch E, Matas L, Ausina V, Martró E. Accuracy of a commercially available assay for HCV genotyping and subtyping in the clinical practice. J Clin Virol 2013; 58:249-53. [PMID: 23731847 DOI: 10.1016/j.jcv.2013.05.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 05/02/2013] [Accepted: 05/03/2013] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) genotyping is mandatory for tailoring dose and duration of pegylated interferon-α plus ribavirin treatment and for deciding on triple therapy eligibility. Additionally, subtyping may play a role in helping to select future treatment regimens that include directly-acting antivirals. However, commercial assays for HCV genotyping fail to identify the genotype/subtype in some cases. OBJECTIVE Our aims were (i) to determine the success rate of the commercial genotyping assay Abbott RealTime HCV Genotype II at identifying the genotype and the HCV-1 subtype; and (ii) to phylogenetically characterise the obtained indeterminate results. STUDY DESIGN HCV genotyping results obtained between 2009 and 2012 in a Spanish reference hospital were reviewed. A total of 896 people were genotyped with the Abbott RealTime HCV Genotype II assay. Specimens with an indeterminate result were retrospectively genotyped using the reference method based on the phylogenetic analysis of HCV NS5B sequences. RESULTS Using the commercially available assay, an indeterminate HCV genotype result was obtained in 20 of 896 patients (2.2%); these corresponded to genotypes 3a, 3k and 4d. Importantly, 8.6% of all cases where genotype 3 was detected were indeterminate. In addition, the HCV-1 subtype was not assigned in 29 of 533 cases (5.4%). CONCLUSIONS The implementation in the clinical microbiology laboratory of the reference method for HCV genotyping allows indeterminate genotype/subtype results to be interpreted and may lead to the identification of previously uncharacterised subtypes.
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Affiliation(s)
- Victoria González
- Microbiology Service, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
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42
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Maynard A, Crosby RM, Ellis B, Hamatake R, Hong Z, Johns BA, Kahler KM, Koble C, Leivers A, Leivers MR, Mathis A, Peat AJ, Pouliot JJ, Roberts CD, Samano V, Schmidt RM, Smith GK, Spaltenstein A, Stewart EL, Thommes P, Turner EM, Voitenleitner C, Walker JT, Waitt G, Weatherhead J, Weaver K, Williams S, Wright L, Xiong ZZ, Haigh D, Shotwell JB. Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase. J Med Chem 2013; 57:1902-13. [DOI: 10.1021/jm400317w] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Andrew Maynard
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Renae M. Crosby
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Byron Ellis
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Robert Hamatake
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Zhi Hong
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Brian A. Johns
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Kirsten M. Kahler
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Cecilia Koble
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Anna Leivers
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Martin R. Leivers
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Amanda Mathis
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Andrew J. Peat
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Jeffrey J. Pouliot
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Christopher D. Roberts
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Vicente Samano
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Rachel M. Schmidt
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Gary K. Smith
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Andrew Spaltenstein
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Eugene L. Stewart
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Pia Thommes
- GlaxoSmithKline, Infectious Diseases Centre
for Excellence for Drug Discovery, Gunnels Wood Road, Stevenage, Hertfordshire
SG1 1NY, U.K
| | - Elizabeth M. Turner
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Christian Voitenleitner
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Jill T. Walker
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Greg Waitt
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Jason Weatherhead
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - Kurt Weaver
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Shawn Williams
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Lois Wright
- GlaxoSmithKline,
Platform Technology and Science, 5 Moore Drive, Research Triangle
Park, North Carolina 27709-3398, United States
| | - Zhiping Z. Xiong
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
| | - David Haigh
- GlaxoSmithKline, Infectious Diseases Centre
for Excellence for Drug Discovery, Gunnels Wood Road, Stevenage, Hertfordshire
SG1 1NY, U.K
| | - J. Brad Shotwell
- GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5
Moore Drive, Research Triangle Park, North Carolina 27709-3398, United
States
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Sequencing assays for failed genotyping with the versant hepatitis C virus genotype assay (LiPA), version 2.0. J Clin Microbiol 2013; 51:2815-21. [PMID: 23616453 DOI: 10.1128/jcm.00586-13] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
For optimal antiviral therapy, the hepatitis C virus (HCV) genotype needs to be determined, as it remains a strong predictor of sustained viral response. In this study, we assessed the number of HCV genotyping results that could not be determined using the commercially available line probe assay (LiPA) (Versant hepatitis C virus genotype 2.0 assay) in a large international panel of samples from 9,874 HCV-positive patients. In-house sequencing assays targeting the 5' untranslated region (UTR), core region, NS3 region, and NS5B region of the HCV genome and phylogenetic analyses were used to resolve these LiPA failures. Among all cases, the genotypes of 51 samples (0.52%) could not be determined with the LiPA. These undetermined results were observed more frequently among samples from non-European regions (mainly the Arabian Peninsula). The use of sequencing assays coupled with phylogenetic analysis provided reliable genotype results for 86% of the LiPA failures, which exhibited higher rates of genotypes 4, 5, and 6 than did LiPA-resolved genotypes. As expected, the 5' UTR was not sufficiently variable for clear discrimination between genotypes 1 and 6, but it also resulted in errors in classification of some genotype 3 and 4 cases using well-known Web-based BLAST programs. This study demonstrates the low frequency of genotyping failures with the Versant hepatitis C virus genotype 2.0 assay (LiPA) and also underlines the need for a complex combination of sequences and phylogenetic analyses in order to genotype these particular HCV strains correctly.
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Lange CM, Zeuzem S. Perspectives and challenges of interferon-free therapy for chronic hepatitis C. J Hepatol 2013; 58:583-92. [PMID: 23104162 DOI: 10.1016/j.jhep.2012.10.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 09/28/2012] [Accepted: 10/13/2012] [Indexed: 12/13/2022]
Abstract
Recent data have clearly shown that a sustained virologic response can be achieved in different HCV infected patient populations with various interferon-free treatment regimens. Despite the successful implementation of telaprevir- and boceprevir-based triple therapies, all-oral regimens will certainly become a first choice for a number of HCV-infected patients in the very near future, as triple therapy approaches are burdened with significant side-effects and limited success in patients with advanced liver fibrosis and prior null-response to pegylated interferon-α (pegIFN-α)/ribavirin therapy. However, available data from phase I and II clinical trials evaluating interferon-free regimens have not yet revealed a clearly outstanding all-oral combination, and numerous challenges remain to be addressed by intensive ongoing and future research. In particular, thus far evaluated all-oral regimens did not cure a satisfactory percentage of patients with unfavorable baseline characteristics, namely patients infected with HCV genotype 1a, previous null-response to pegIFN-α/ribavirin, or liver cirrhosis. In this review, we summarize available data of interferon-free regimens for the treatment of chronic hepatitis C and assess implications for perspectives and challenges in the further development of all-oral therapies.
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Affiliation(s)
- Christian M Lange
- Klinikum der J W Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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Herbst DA, Reddy KR. Sofosbuvir, a nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus infection. Expert Opin Investig Drugs 2013; 22:527-36. [PMID: 23448131 DOI: 10.1517/13543784.2013.775246] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) infection is ubiquitous, affecting approximately 180 million individuals worldwide and around 3.2 million in the United States. While peginterferon and ribavirin alone continue to be used, the treatment landscape for patients with genotype 1 has recently changed to include one of two protease inhibitors: boceprevir and telaprevir. Despite this, effective therapies for chronic HCV for all genotypes represent a largely unmet need. AREAS COVERED Sofosbuvir , formally labeled GS-7977, is an HCV NS5B nucleotide polymerase inhibitor that has entered multiple Phase III trials. Phase II trials demonstrated that treatments including sofosbuvir have higher sustained virologic response rates for genotypes 1, 2, 3, 4 and 6 in comparison with treatments that include only peginterferon and ribavirin. In addition, the side-effect profile of sofosbuvir and ribavirin dual treatment has an improved tolerability in comparison with treatment regimes that include interferon-based options. EXPERT OPINION The hope and expectation is that interferon is eliminated from the armamentarium of HCV therapy and that all-oral therapies prove effective although interferon in combination with multiple drugs may still be required to treat select patients. In addition, there is a need to develop effective therapies for all HCV genotypes with simple and well-tolerated regimes.
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Affiliation(s)
- David Alan Herbst
- University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
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Abstract
The current treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct-acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG-IFN) plus ribavirin (RBV) regimen. Major progress has been made in the past few years: numerous ongoing trials with different compounds, increasing sustained virological response (SVR) rates with oral regimens and shortened treatment duration. Combinations of antivirals with additive potency that lack cross-resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN.
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Affiliation(s)
- Tarik Asselah
- Hepatology Department, AP-HP, University Paris Diderot 7 and INSERM U773, CRB3, Beaujon Hospital, Clichy, France.
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Kong Y, Wang X, Shang Y, Schroder PM, Liang W, Ling X, Guo Z, He X. Efficacy and tolerability of telaprevir for chronic hepatitis virus C genotype 1 infection: a meta-analysis. PLoS One 2012; 7:e52158. [PMID: 23284915 PMCID: PMC3527389 DOI: 10.1371/journal.pone.0052158] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Accepted: 11/15/2012] [Indexed: 01/22/2023] Open
Abstract
Background Chronic hepatitis C virus (HCV) infection is one of the leading causes of hepatic cirrhosis and hepatocellular carcinoma, and HCV genotype 1 is the most prevalent genotype and is resistant to current standard therapy. We performed this meta-analysis to evaluate the efficacy and safety of telaprevir-based therapy for chronic HCV genotype 1 infection. Methods We included randomized controlled trials with no year or language restriction. All data were analyzed using a random-effects model by Review Manager v5.0. The primary outcome was the proportion of patients achieving sustained virologic response (SVR), and the secondary outcomes were HCV relapse rate, incidence of severe adverse events (SAEs), and discontinuation due to adverse events. Results The proportion of achieving SVR was significantly higher in the telaprevir group (odds ratio [OR] = 3.40 [1.92, 6.00], P<0.0001; I2 = 87%) regardless of a patients’ previous treatment status. It was also significantly higher in the 24-week and 48-week treatment groups (OR = 4.52 [2.08, 9.81], P<0.001; I2 = 85%, and OR = 4.05 [1.56, 10.56], P = 0.004; I2 = 92%, respectively), while it was comparable in the 12-week treatment group (OR = 1.32 [0.63, 2.75], P = 0.46; I2 = 35%). In addition, the HCV relapse rate was significantly reduced in the telaprevir group (OR = 0.28 [0.16, 0.49], P<0.001; I2 = 76%). However, the incidence of SAE (OR = 1.56 [1.15, 2.10], P = 0.004; I2 = 0%) and study discontinuation due to adverse events (OR = 2.24 [1.43, 3.50], P<0.001; I2 = 37%) were significantly higher in the telaprevir group. Conclusion Despite its higher incidence of SAEs and discontinuation due to adverse events, telaprevir-based therapy can increase the proportion of achieving SVR in both previously treated and untreated chronic HCV-1 infected patients.
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Affiliation(s)
- Yuan Kong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yushu Shang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Paul M. Schroder
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America
| | - Wenhua Liang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoting Ling
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- * E-mail: (ZG); (XH)
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- * E-mail: (ZG); (XH)
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Telaprevir and boceprevir in African Americans with genotype 1 chronic hepatitis C: implications for patients and providers. South Med J 2012; 105:431-6. [PMID: 22864102 DOI: 10.1097/smj.0b013e31825f033e] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Telaprevir and boceprevir have received US Food and Drug Administration approval for use as triple therapy with pegylated interferon and ribavirin in genotype 1 chronic hepatitis C virus (HCV) infection. Clinical trials of these agents included few African Americans, despite the overwhelming need for improved therapies in this racial group. Although African Americans are predicted to have improved response rates with this new treatment paradigm, clinical trials illustrate lower rates of sustained virologic response for this racial group versus whites. African Americans with genotype 1 HCV infection appear to require longer durations of therapy than do whites to achieve a sustained virologic response. Further investigation is required to adequately counsel African Americans with genotype 1 chronic HCV infection on the efficacy of telaprevir and boceprevir in their racial group. Increased participation of this racial group in HCV clinical trials is needed to improve therapies in this difficult-to-treat population.
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Castilho MCB, Martins AN, Horbach IS, Perez RDM, Figueiredo FAF, Pinto PDTA, Nabuco LC, Lima DBD, Tanuri A, Porto LC, Ferreira Júnior ODC. Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients. Mem Inst Oswaldo Cruz 2012; 106:968-75. [PMID: 22241118 DOI: 10.1590/s0074-02762011000800011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Accepted: 09/08/2011] [Indexed: 01/06/2023] Open
Abstract
Mutations located in the 109-amino acid fragment of NS5B are typically associated with resistance to interferon (IFN) and ribavirin (RIB) and to new antiviral drugs. The prevalence of these mutations was examined in 69 drug-naïve individuals with hepatitis C virus (HCV) infections in Rio de Janeiro, Brazil. Mutations related to non-response to IFN/RIB were observed in all subtypes studied (1a, 1b, 2b, 3a and 4). The most common mutation was Q309R, present in all subtypes, except subtype 2b with frequency above 20%. D244N was detected only in subtype 3a and A333E was detected only in subtype 2b. We did not detect the S282T, S326G or T329I mutations in any of the samples analysed. Of note, the C316N mutation, previously related to a new non-nucleoside compound (HCV796 and AG-021541), was observed in only eight of 33 (24%) samples from subtype 1b. Site 316 was under positive selection in this HCV variant. Our data highlight the presence of previously described resistance mutations in HCV genotypes from drug-naïve patients.
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Affiliation(s)
- Magda Cristina Bernardino Castilho
- Laboratório de Histocompatibilidade e Criopreservação, Policlínica Piquet Carneiro, Departamento de Histologia e Embriologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
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Hepatitis C genotype 1a replicon improved through introduction of fitness mutations. Biotechniques 2012; 52:273-5. [PMID: 22482443 DOI: 10.2144/000113841] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Accepted: 02/08/2012] [Indexed: 11/23/2022] Open
Abstract
The use of subgenomic replicon systems has long been a valuable screening tool for the discovery of small molecule antivirals against Hepatitis C virus. While genotype 1a replicon systems have been widely used in stable systems, use in transient assays has been hampered by low signal. Here we describe the generation of a more robust genotype 1a (H77) replicon through the introduction of two fitness mutations, NS4A-K1691R and NS4B-E1726G, for use in transient transfections. While these mutations significantly improved the signal to noise ratio, leading to more robust data, they have no effect on the potency of tool compounds against various targets of HCV, thereby making this new system a powerful tool for screening of compounds against the genotype 1a replicon.
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