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Echeverría N, Gámbaro F, Beaucourt S, Soñora M, Hernández N, Cristina J, Moratorio G, Moreno P. Mixed Infections Unravel Novel HCV Inter-Genotypic Recombinant Forms within the Conserved IRES Region. Viruses 2024; 16:560. [PMID: 38675902 PMCID: PMC11053413 DOI: 10.3390/v16040560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/12/2024] [Accepted: 03/16/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge, affecting millions of people worldwide, with chronic infection a persistent threat. Despite the advent of direct-acting antivirals (DAAs), challenges in diagnosis and treatment remain, compounded by the lack of an effective vaccine. The HCV genome, characterized by high genetic variability, consists of eight distinct genotypes and over ninety subtypes, underscoring the complex dynamics of the virus within infected individuals. This study delves into the intriguing realm of HCV genetic diversity, specifically exploring the phenomenon of mixed infections and the subsequent detection of recombinant forms within the conserved internal ribosome entry site (IRES) region. Previous studies have identified recombination as a rare event in HCV. However, our findings challenge this notion by providing the first evidence of 1a/3a (and vice versa) inter-genotypic recombination within the conserved IRES region. Utilizing advanced sequencing methods, such as deep sequencing and molecular cloning, our study reveals mixed infections involving genotypes 1a and 3a. This comprehensive approach not only confirmed the presence of mixed infections, but also identified the existence of recombinant forms not previously seen in the IRES region. The recombinant sequences, although present as low-frequency variants, open new avenues for understanding HCV evolution and adaptation.
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Affiliation(s)
- Natalia Echeverría
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Evolución Experimental de Virus, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Fabiana Gámbaro
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
| | - Stéphanie Beaucourt
- Viral Populations and Pathogenesis Laboratory, Institut Pasteur, 75015 Paris, France;
| | - Martín Soñora
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Simulaciones Biomoleculares, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Nelia Hernández
- Clínica de Gastroenterología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay;
| | - Juan Cristina
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
| | - Gonzalo Moratorio
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Evolución Experimental de Virus, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Pilar Moreno
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; (N.E.); (F.G.); (M.S.); (J.C.); (G.M.)
- Laboratorio de Evolución Experimental de Virus, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
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Rezaei O, Ghiasvand H, Higgs P, Noroozi A, Noroozi M, Rezaei F, Armoon B, Bayani A. Factors associated with injecting-related risk behaviors among people who inject drugs: a systematic review and meta-analysis study. J Addict Dis 2020; 38:420-437. [DOI: 10.1080/10550887.2020.1781346] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Omid Rezaei
- Fellowship of Psychosomatic, Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Hesam Ghiasvand
- Health Management and Economics Research Center, Iran University of Medical Sciences, Tehran, Iran
- Health Economics Group, Medical School, Saint Luke’s Campus, University of Exeter, Exeter, UK
| | - Peter Higgs
- Department of Public Health, La Trobe University, Melbourne, Australia
| | - Alireza Noroozi
- Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Noroozi
- Social Determinants of Health Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Fatemeh Rezaei
- Department of Epidemiology and Biostatics, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Bahram Armoon
- Social Determinants of Health Research Center, Saveh University of Medical Sciences, Saveh, Iran
| | - Azadeh Bayani
- Student Research Committee, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Ferrari C, Barili V, Varchetta S, Mondelli MU. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2020:821-850. [DOI: 10.1002/9781119436812.ch63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Fernández-Caso B, Fernández-Caballero JÁ, Chueca N, Rojo E, de Salazar A, García Buey L, Cardeñoso L, García F. Infection with multiple hepatitis C virus genotypes detected using commercial tests should be confirmed using next generation sequencing. Sci Rep 2019; 9:9264. [PMID: 31239457 PMCID: PMC6592891 DOI: 10.1038/s41598-019-42605-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/01/2019] [Indexed: 12/21/2022] Open
Abstract
Current HCV genotyping methods may have some limitations in detecting mixed infections. We aimed to determine the accuracy of genotyping and the detection of mixed-genotype infections using the Abbott-RealTime HCV Genotype II assay (Abbott-RT-PCR) in comparison with a Roche-Next Generation Sequencing assay (Roche-NGS). Plasma samples collected from 139 HCV-infected patients tested with Abbott-RT-PCR, 114 with single genotype (GT) and 25 with mixed GTs were genotyped using Roche-NGS. Roche-NGS confirmed all single GTs obtained with Abbott-RT-PCR. One case of Abbott GT 4 was found as GT 1a using Roche-NGS. Genotype 5 was confirmed using Roche-NGS in 75% cases (3 out of 4 cases). Twenty-five patients were identified as having mixed HCVinfections using Abbott-RT-PCR. The concordance between Abbott-RT-PCR and Roche-NGS was 76% (19 out of 25 cases). Three mixed-GT infections identified with the Abbott assay (two (1b + 4); one (1a + 3)) were reported as pure 1b using Roche-NGS. Very divergent results were found for the other three samples. When compared to Roche-NGS, Abbott-RT-PCR has performed excellently for the determination of patients infected with single GTs. For patients that are categorized as having a mixed infection using Abbott-RT-PCR, we recommend an NGS assay as a confirmation test.
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Affiliation(s)
- Belén Fernández-Caso
- Servicio de Microbiologia, Hospital Universitario de La Princesa; Instituto de Investigacion Sanitaria La Princesa, Madrid, Spain
| | - Jose Ángel Fernández-Caballero
- Unidad de Gestión Clinica de Microbiologia, Hospital Universitario San Cecilio; Instituto de Investigación Biosanitaria ibs.Granada; Red de Investigación en SIDA, RD16/0025/0040, Granada, Spain
| | - Natalia Chueca
- Unidad de Gestión Clinica de Microbiologia, Hospital Universitario San Cecilio; Instituto de Investigación Biosanitaria ibs.Granada; Red de Investigación en SIDA, RD16/0025/0040, Granada, Spain
| | - Eukene Rojo
- Servicio de Aparato Digestivo - Unidad de Hepatologia, Hospital Universitario de La Princesa; Instituto de Investigacion Sanitaria La Princesa, Madrid, Spain
| | - Adolfo de Salazar
- Unidad de Gestión Clinica de Microbiologia, Hospital Universitario San Cecilio; Instituto de Investigación Biosanitaria ibs.Granada; Red de Investigación en SIDA, RD16/0025/0040, Granada, Spain
| | - Luisa García Buey
- Servicio de Aparato Digestivo - Unidad de Hepatologia, Hospital Universitario de La Princesa; Instituto de Investigacion Sanitaria La Princesa, Madrid, Spain
| | - Laura Cardeñoso
- Servicio de Microbiologia, Hospital Universitario de La Princesa; Instituto de Investigacion Sanitaria La Princesa, Madrid, Spain
| | - Federico García
- Unidad de Gestión Clinica de Microbiologia, Hospital Universitario San Cecilio; Instituto de Investigación Biosanitaria ibs.Granada; Red de Investigación en SIDA, RD16/0025/0040, Granada, Spain.
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Manee N, Thongbaiphet N, Pasomsub E, Chantratita W. Clinical evaluation of a newly developed automated massively parallel sequencing assay for hepatitis C virus genotyping and detection of resistance-association variants. Comparison with a line probe assay. J Virol Methods 2017; 249:31-37. [PMID: 28851606 DOI: 10.1016/j.jviromet.2017.08.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 07/13/2017] [Accepted: 08/21/2017] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Recently, HCV was classified into 6 major genotypes (GTs) and 67 subtypes (STs). Efficient genotyping has become an essential tool for prognosis and indicating suitable treatment, prior to starting therapy in all HCV-infected individuals. The widely used genotyping assays have limitation with regard to genotype accuracy. This study was a comparative evaluation of exact HCV genotyping in a newly developed automated-massively parallel sequencing (MPS) system, versus the established Line probe assay 2.0 (LiPA), substantiated by Sanger sequencing, using 120 previously identified-HCV RNA positive specimens. LiPA gave identical genotypes in the majority of samples tested with MPS. However, as much as 25% of LiPA did not identify subtypes, whereas MPS did, and 0.83% of results were incompatible. Interestingly, only MPS could identify mixed infections in the remaining cases (1.67%). In addition, MPS could detect Resistance-Associated Variants (RAVs) simultaneously in GT1 in 56.82% of the specimens, which were known to affect drug resistance in the HCV NS3/NS4A and NS5A genomic regions. MPS can thus be deemed beneficial for guiding decisions on HCV therapy and saving costs in the long term when compared to traditional methods.
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Affiliation(s)
- Narathon Manee
- Department of Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Nipa Thongbaiphet
- Virology Laboratory and Center for Medical Genomics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Ekawat Pasomsub
- Department of Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Virology Laboratory and Center for Medical Genomics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Wasun Chantratita
- Department of Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; Virology Laboratory and Center for Medical Genomics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
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6
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Diagnostic and Therapeutic Implications in a Case of Mixed Hepatitis C Virus (HCV) Infection. HEPATITIS MONTHLY 2017. [DOI: 10.5812/hepatmon.44774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Midgard H, Weir A, Palmateer N, Lo Re V, Pineda JA, Macías J, Dalgard O. HCV epidemiology in high-risk groups and the risk of reinfection. J Hepatol 2016; 65:S33-S45. [PMID: 27641987 DOI: 10.1016/j.jhep.2016.07.012] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 07/08/2016] [Accepted: 07/12/2016] [Indexed: 12/18/2022]
Abstract
Injecting risk behaviours among people who inject drugs (PWID) and high-risk sexual practices among men who have sex with men (MSM) are important routes of hepatitis C virus (HCV) transmission. Current direct-acting antiviral treatment offers unique opportunities for reductions in HCV-related liver disease burden and epidemic control in high-risk groups, but these prospects could be counteracted by HCV reinfection due to on-going risk behaviours after successful treatment. Based on existing data from small and heterogeneous studies of interferon-based treatment, the incidence of reinfection after sustained virological response range from 2-6/100 person years among PWID to 10-15/100 person years among human immunodeficiency virus-infected MSM. These differences mainly reflect heterogeneity in study populations with regards to risk behaviours, but also reflect variations in study designs and applied virological methods. Increasing levels of reinfection are to be expected as we enter the interferon-free treatment era. Individual- and population-level efforts to address and prevent reinfection should therefore be undertaken when providing HCV care for people with on-going risk behaviour. Constructive strategies include acknowledgement, education and counselling, harm reduction optimization, scaled-up treatment including treatment of injecting networks, post-treatment screening, and rapid retreatment of reinfections.
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Affiliation(s)
- Håvard Midgard
- Department of Infectious Diseases, Akershus University Hospital, Lørenskog, Norway; Institute for Clinical Medicine, University of Oslo, Norway; Department of Gastroenterology, Oslo University Hospital, Norway.
| | - Amanda Weir
- School of Health and Life Sciences, Glasgow Caledonian University, United Kingdom; NHS National Services Scotland, Health Protection Scotland, Glasgow, United Kingdom
| | - Norah Palmateer
- School of Health and Life Sciences, Glasgow Caledonian University, United Kingdom; NHS National Services Scotland, Health Protection Scotland, Glasgow, United Kingdom
| | - Vincent Lo Re
- Division of Infectious Diseases, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, United States
| | - Juan A Pineda
- Unidad de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain
| | - Juan Macías
- Unidad de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain
| | - Olav Dalgard
- Department of Infectious Diseases, Akershus University Hospital, Lørenskog, Norway; Institute for Clinical Medicine, University of Oslo, Norway
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Abstract
The majority of new and existing cases of HCV infection in high-income countries occur among people who inject drugs (PWID). Ongoing high-risk behaviours can lead to HCV re-exposure, resulting in mixed HCV infection and reinfection. Assays used to screen for mixed infection vary widely in sensitivity, particularly with respect to their capacity for detecting minor variants (<20% of the viral population). The prevalence of mixed infection among PWID ranges from 14% to 39% when sensitive assays are used. Mixed infection compromises HCV treatment outcomes with interferon-based regimens. HCV reinfection can also occur after successful interferon-based treatment among PWID, but the rate of reinfection is low (0-5 cases per 100 person-years). A revolution in HCV therapeutic development has occurred in the past few years, with the advent of interferon-free, but still genotype-specific regiments based on direct acting antiviral agents. However, little is known about whether mixed infection and reinfection has an effect on HCV treatment outcomes in the setting of new direct-acting antiviral agents. This Review characterizes the epidemiology and natural history of mixed infection and reinfection among PWID, methodologies for detection, the potential implications for HCV treatment and considerations for the design of future studies.
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Next-Generation Sequencing of 5' Untranslated Region of Hepatitis C Virus in Search of Minor Viral Variant in a Patient Who Revealed New Genotype While on Antiviral Treatment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 885:11-23. [PMID: 26747069 DOI: 10.1007/5584_2015_186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The role of mixed infections with different hepatitis C virus (HCV) genotypes in viral persistence, treatment effects, and tissue tropism is unclear. Next-generation sequencing (NGS), which is suitable for analysis of large, genetically diverse populations offers unparalleled advantages for the study of mixed infections. The aim of the study was to determine, using two different deep sequencing strategies (pyrosequencing - 454 Life Sciences/Roche and reversible terminator sequencing-by-synthesis by Illumina), the origin of a novel HCV genotype transiently detectable during antiviral therapy (pre-existing minor population vs. de novo superinfection). Secondly, we compared 5' untranslated region (5'-UTR) variants obtained by the two NGS approaches. 5' UTR amplification products from 9 samples collected from genotype 1b infected patient before, during, and after treatment (4 serum and 5 peripheral blood mononuclear cell - PBMC - samples) were subjected to the next-generation sequencing. The sequencing revealed the presence of two (454/Roche) and one (Illumina) genotype 4 variants in PBMC at Week 16. None of these variants were present either in the preceding or following samples as revealed by both platforms. 454/Roche sequencing detected 24 different 5'-UTR variants: 8 were present in serum and PBMC, 4 only in serum and 12 only in PBMC. Illumina sequencing detected 11 different 5'-UTR variants: 5 in serum and PBMC, 4 only in serum and 2 only in PBMC. Six variants were identical for both sequencing platforms. The difference in variants number was primarily due to variability in two 5'-UTR homopolymeric regions. In conclusion, longitudinal analysis of HCV variants, employing two independent deep sequencing methods, suggests that the transient presence of a different genotype strain in PBMC was a result of superinfection and not a selection of pre-existing minor variant.
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Yang YC, Wang DY, Cheng HF, Chuang EY, Tsai MH. A reliable multiplex genotyping assay for HCV using a suspension bead array. Microb Biotechnol 2014; 8:93-102. [PMID: 25042084 PMCID: PMC4321376 DOI: 10.1111/1751-7915.12140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 05/27/2014] [Accepted: 05/27/2014] [Indexed: 01/25/2023] Open
Abstract
The genotyping of the hepatitis C virus (HCV) plays an important role in the treatment of HCV because genotype determination has recently been incorporated into the treatment guidelines for HCV infections. Most current genotyping methods are unable to detect mixed genotypes from two or more HCV infections. We therefore developed a multiplex genotyping assay to determine HCV genotypes using a bead array. Synthetic plasmids, genotype panels and standards were used to verify the target-specific primer (TSP) design in the assay, and the results indicated that discrimination efforts using 10 TSPs in a single reaction were extremely successful. Thirty-five specimens were then tested to evaluate the assay performance, and the results were highly consistent with those of direct sequencing, supporting the reliability of the assay. Moreover, the results from samples with mixed HCV genotypes revealed that the method is capable of detecting two different genotypes within a sample. Furthermore, the specificity evaluation results suggested that the assay could correctly identify HCV in HCV/human immunodeficiency virus (HIV) co-infected patients. This genotyping platform enables the simultaneous detection and identification of more than one genotype in a same sample and is able to test 96 samples simultaneously. It could therefore provide a rapid, efficient and reliable method of determining HCV genotypes in the future.
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Affiliation(s)
- Yi-Chen Yang
- Food and Drug Administration, Ministry of Health and Welfare, Taipei, Taiwan; Institute of Biotechnology, National Taiwan University, Taipei, Taiwan
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Min JA, Yoon Y, Lee HJ, Choi J, Kwon M, Kim K, Lee CU, Kim DJ, Yun H. Prevalence and associated clinical characteristics of hepatitis B, C, and HIV infections among injecting drug users in Korea. J Med Virol 2013; 85:575-82. [PMID: 23364858 DOI: 10.1002/jmv.23523] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2012] [Indexed: 12/13/2022]
Abstract
Injecting drug use is associated with an increased risk of blood-borne viral infections, such as hepatitis B and C viruses (HBV and HCV, respectively) and human immunodeficiency virus (HIV). However, their prevalence, virological characteristics, and associated factors are not clear among the injecting drug users in Korea. The aim of this study was to determine the prevalence of HBV, HCV, and HIV infection, as well as their virological and clinical characteristics of injecting drug users in South Korea. Between 2007 and 2010, 318 injecting drug users (89.3% male; mean ± age 41.9 ± 8.15 years) were participated. While HIV infection was not found, the seroprevalence of anti-HCV and HBV surface antigen (HBsAg) was 48.4% (n = 154) and 6.6% (n = 21), respectively. HBV/HCV co-infection was found in 4.1% (n = 13). Occult HBV infection was suggested in 5.0% (n = 16). Among the HCV genotypes, 1b (37.7%) and 2a/2c (35.7%) were mostly often detected. HCV RNA was detected in 98.1% (n = 151/154) and high-level viremia (HCV RNA level, ≥400,000 IU/ml) were observed in 59.6% (n = 90/151). In multiple logistic regression analysis, old age (OR 1.18 per year, 95% CI = 1.09-1.27) and ever-sharing injecting equipment (OR 4.17, 95% CI = 1.39-12.45) independently predicted HCV mono-infection. The prevalence of HBV and HCV infection were high but largely undiagnosed in the present sample of Korean injecting drug users. Strategic prevention, screening, and treatment are needed to reduce further transmission and morbidity.
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Affiliation(s)
- Jung-Ah Min
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Republic of Korea
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Raghwani J, Thomas XV, Koekkoek SM, Schinkel J, Molenkamp R, van de Laar TJ, Takebe Y, Tanaka Y, Mizokami M, Rambaut A, Pybus OG. Origin and evolution of the unique hepatitis C virus circulating recombinant form 2k/1b. J Virol 2012; 86:2212-2220. [PMID: 22114341 PMCID: PMC3302385 DOI: 10.1128/jvi.06184-11] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 11/14/2011] [Indexed: 02/06/2023] Open
Abstract
Since its initial identification in St. Petersburg, Russia, the recombinant hepatitis C virus (HCV) 2k/1b has been isolated from several countries throughout Eurasia. The 2k/1b strain is the only recombinant HCV to have spread widely, raising questions about the epidemiological background in which it first appeared. In order to further understand the circumstances by which HCV recombinants might be formed and spread, we estimated the date of the recombination event that generated the 2k/1b strain using a Bayesian phylogenetic approach. Our study incorporates newly isolated 2k/1b strains from Amsterdam, The Netherlands, and has employed a hierarchical Bayesian framework to combine information from different genomic regions. We estimate that 2k/1b originated sometime between 1923 and 1956, substantially before the first detection of the strain in 1999. The timescale and the geographic spread of 2k/1b suggest that it originated in the former Soviet Union at about the time that the world's first centralized national blood transfusion and storage service was being established. We also reconstructed the epidemic history of 2k/1b using coalescent theory-based methods, matching patterns previously reported for other epidemic HCV subtypes. This study demonstrates the practicality of jointly estimating dates of recombination from flanking regions of the breakpoint and further illustrates that rare genetic-exchange events can be particularly informative about the underlying epidemiological processes.
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Affiliation(s)
- Jayna Raghwani
- Institute of Evolutionary Biology, University of Edinburgh, Ashworth Laboratories, Edinburgh, United Kingdom
| | - Xiomara V. Thomas
- Academic Medical Center, Department of Medical Microbiology, Section of Clinical Virology, Amsterdam, The Netherlands
| | - Sylvie M. Koekkoek
- Academic Medical Center, Department of Medical Microbiology, Section of Clinical Virology, Amsterdam, The Netherlands
| | - Janke Schinkel
- Academic Medical Center, Department of Medical Microbiology, Section of Clinical Virology, Amsterdam, The Netherlands
| | - Richard Molenkamp
- Academic Medical Center, Department of Medical Microbiology, Section of Clinical Virology, Amsterdam, The Netherlands
| | - Thijs J. van de Laar
- VU University Medical Centre, Department of Medical Microbiology and Infection Control, Amsterdam, The Netherlands
| | - Yutaka Takebe
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Andrew Rambaut
- Institute of Evolutionary Biology, University of Edinburgh, Ashworth Laboratories, Edinburgh, United Kingdom
- Fogarty International Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Oliver G. Pybus
- Department of Zoology, University of Oxford, Oxford, United Kingdom
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Abstract
SUMMARYOver the last 40 years, the dynamics of hepatitis C virus (HCV) infection in drug users has been affected by the illicit drug market, the health environment including the devastating impact of the HIV/AIDS epidemic which erupted in the 1980s, and the diffusion of substitution treatment beginning in 1995. The purpose of this literature review is to present the dynamics of HCV infection in drug users in France over the last 40 years. Two prevalence studies of HCV infection in the general population were conducted by the French Institute for Public Health Surveillance in 1994 and 2004 and were the touchstone data sources for this analysis. Hypotheses constructed from the findings of these two studies were examined in light of results reported by multicentre prevalence and incidence studies in drug-user populations. The incidence of HCV infection in drug users in France reached a peak in the late 1980s or early 1990s after a lengthy period of epidemic expansion. Implementation of a risk reduction policy enabled a very significant reduction in the incidence of HCV infection in drug users over the last 20 years, leading to incidence figures which are now 10–15% of the 1990 estimate.
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Morel V, Fournier C, François C, Brochot E, Helle F, Duverlie G, Castelain S. Genetic recombination of the hepatitis C virus: clinical implications. J Viral Hepat 2011; 18:77-83. [PMID: 21235686 DOI: 10.1111/j.1365-2893.2010.01367.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genetic recombination is a well-known feature of RNA viruses that plays a significant role in their evolution. Although recombination is well documented for Flaviviridae family viruses, the first natural recombinant strain of hepatitis C virus (HCV) was identified as recently as 2002. Since then, a few other natural inter-genotypic, intra-genotypic and intra-subtype recombinant HCV strains have been described. However, the frequency of recombination may have been underestimated because not all known HCV recombinants are screened for in routine practice. Furthermore, the choice of treatment regimen and its predictive outcome remain problematic as the therapeutic strategy for HCV infection is genotype dependent. HCV recombination also raises many questions concerning its mechanisms and effects on the epidemiological and physiopathological features of the virus. This review provides an update on recombinant HCV strains, the process that gives rise to recombinants and clinical implications of recombination.
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Affiliation(s)
- V Morel
- Virology Department, Amiens University Hospital Center, South Hospital, Amiens, France
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Smith J, Aberle JH, Fleming VM, Ferenci P, Thomson EC, Karayiannis P, McLean AR, Holzmann H, Klenerman P. Dynamic coinfection with multiple viral subtypes in acute hepatitis C. J Infect Dis 2010; 202:1770-9. [PMID: 21067369 PMCID: PMC3107554 DOI: 10.1086/657317] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Accepted: 07/19/2010] [Indexed: 01/28/2023] Open
Abstract
INTRODUCTION Acute hepatitis C virus (HCV) infection is rarely studied, but virus sequence evolution and host-virus dynamics during this early stage may influence the outcome of infection. Hypervariable region 1 (HVR1) is genetically diverse and under selective pressure from the host immune response. We analyzed HVR1 evolution by frequent sampling of an acutely infected HCV cohort. METHODS Three or more pretreatment samples were obtained from each of 10 acutely infected subjects. Polymerase chain reaction amplification was performed with multiple primer combinations to identify the full range of sequences present. Positive samples were cloned and sequenced. Phylogenetic analyses were used to assess viral diversity. RESULTS Eight of the 10 subjects were coinfected with at least 2 HCV subtypes. Multiple subtypes were detected in individual samples, and their relative proportions changed through acute infection. The subjects with the most complex subtype structure also had a dynamic viral load; however, changes in viral load were not directly linked to changes in subtype. CONCLUSIONS This well-sampled cohort with acute HCV infection was characterized by dynamic coinfection with multiple viral subtypes, representing a highly complex virologic landscape extremely early in infection.
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Affiliation(s)
- Jennifer Smith
- Institute for Emerging Infections, University of Oxford, Oxford
| | - Judith H. Aberle
- Institute of Virology, Medical University of Vienna, Vienna, Austria
| | - Vicki M. Fleming
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford
| | - Peter Ferenci
- Department of Internal Medicine, Gastroenterology, and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Emma C. Thomson
- Department of Hepatology, Imperial College, London, United Kingdom
| | | | | | | | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford
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Tanimoto T, Cuong NH, Ishizaki A, Chung PTT, Huyen HTT, Trung NV, Kageyama S, Oka S, Thuc PV, Ichimura H. Multiple routes of hepatitis C virus transmission among injection drug users in Hai Phong, Northern Vietnam. J Med Virol 2010; 82:1355-63. [DOI: 10.1002/jmv.21787] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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17
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Morel V, Descamps V, François C, Fournier C, Brochot E, Capron D, Duverlie G, Castelain S. Emergence of a genomic variant of the recombinant 2k/1b strain during a mixed Hepatitis C infection: a case report. J Clin Virol 2010; 47:382-6. [PMID: 20153975 DOI: 10.1016/j.jcv.2010.01.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Revised: 01/18/2010] [Accepted: 01/22/2010] [Indexed: 12/22/2022]
Abstract
To date, few natural intergenotypic recombinant hepatitis C virus (HCV) strains have been characterized. A recombinant strain 2k/1b was detected for one HCV RNA-positive individual who had just completed therapy for HCV 3a genotype infection. In the present report, five serum samples collected over the pre- and post-treatment periods were used to investigate all the present HCV strains and the change over time of the infection pattern. Interestingly, the 2k/1b strain was already present during the genotype 3a infection and persisted during treatment. In the specimen collected three months post-treatment, two distinct strains, 2k/1b and type 1, were found and then one 2k/1b strain in the subsequent ones. A genomic variant of the HCV RF1_2k/1b strain was identified. It was part of a mixed HCV infection and persisted and re-emerge after eradication of the dominant subtype 3a. This case indicates that HCV co-infection screening after relapse should be an alternative to explain the lack of response to treatment and the necessity to carefully study the epidemic spreading of this recombinant strain.
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Affiliation(s)
- Virginie Morel
- Virology Department, Amiens University Hospital Center, South Hospital, EA4294-Jules Verne University of Picardy, F-80054 Amiens Cedex 1, France
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18
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Ferrari C, Mondelli M. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2009:835-857. [DOI: 10.1002/9780470747919.ch51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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19
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Giugliano S, Oezkan F, Bedrejowski M, Kudla M, Reiser M, Viazov S, Scherbaum N, Roggendorf M, Timm J. Degree of cross-genotype reactivity of hepatitis C virus-specific CD8+ T cells directed against NS3. Hepatology 2009; 50:707-16. [PMID: 19637188 DOI: 10.1002/hep.23096] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED The inherent sequence diversity of the hepatitis C virus (HCV) with the existence of multiple genotypes that differ up to 20% at the amino acid level represents one of the major obstacles for immune control. Accordingly, immune control of a heterologous virus challenge, particularly across genotypes, is difficult to achieve; however, the overall role of genotype-specific sequence differences has not yet been defined at the epitope level. The aim of this study was to determine the role of genotype-specific sequence differences for the CD8+ T cell response against HCV. We analyzed a cohort of anti-HCV-positive injection drug users infected with HCV genotype 1 (n = 17) or genotype 3 (n = 22) or undetectable HCV-RNA (n = 14) with overlapping peptides covering consensus sequences of NS3 from both genotypes. Importantly, the majority of HCV-specific CD8 T cells were specific for one genotype only indicating that sequence differences between genotypes are relevant at the epitope level. Interestingly, T cells active against both genotypes were significantly more frequent in HCV-RNA-negative subjects. Of note, we identified five subjects with undetectable viremia and coexistence of two T cell populations-one for each genotype-suggesting immune control of two different genotypes. CONCLUSION We systematically analyzed the degree of cross-genotype reactivity of HCV-specific T cells and have shown that CD8 responses targeting different HCV genotypes can be primed in the same individual and that such responses potentially characterize a subgroup among injection drug users being protected from chronic HCV infection.
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20
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Sereno S, Perinelli P, Laghi V. Changes in the prevalence of hepatitis C virus genotype among Italian injection drug users-relation to period of injection started. J Clin Virol 2009; 45:354-7. [PMID: 19497783 DOI: 10.1016/j.jcv.2009.04.022] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2008] [Revised: 04/20/2009] [Accepted: 04/28/2009] [Indexed: 12/23/2022]
Abstract
BACKGROUND Chronic hepatitis C is a worldwide health problem. Intravenous drug users are the main risk group. OBJECTIVES To determine the prevalence of HCV genotypes in Italian injecting drug users and the distribution of genotypes in relation to the period when the infection was acquired. STUDY DESIGN Two hundred sera from patients with chronic hepatitis C and a history of intravenous drug use were assayed for HCV-RNA and genotyped by a commercial line probe assay. RESULTS Genotypes 1 (45.5%) and 3 (35%) were the most common genotypes, followed by genotypes 4 (15%) and 2 (3%). One genotype 5 (0.5%) was found. Two mixed infections (1%) were detected. Subtype could be determined in 160 cases (80%): subtype 3a was the most prevalent (41.3%), followed by subtypes 1a (23.1%) and 1b (20.6%). A significant change in the distribution of prevalent genotypes occurred since 1965 (p=0.020). Genotype 3 infections declined from 48/116 (41.4%) in 1965-1985 to 22/84 (26.2%) in 1986-2006. The prevalence of genotype 4 was significantly higher in patients infected after 1985 compared to patients infected before this year (11/116 [9.5%] vs. 19/84 [22.6%], respectively; p=0.018). CONCLUSIONS Since 1965 the common HCV genotype 3 has become less common in Italy. Genotype 4, an imported genotype, has become more common.
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Affiliation(s)
- Silvia Sereno
- Department of Infectious and Tropical Diseases, University La Sapienza, Viale del Policlinico, 00161 Rome, Italy.
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21
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Cox J, Morissette C, De P, Tremblay C, Allard R, Graves L, Stephenson R, Roy E. Access to sterile injecting equipment is more important than awareness of HCV status for injection risk behaviors among drug users. Subst Use Misuse 2009; 44:548-68. [PMID: 19242863 PMCID: PMC2929254 DOI: 10.1080/10826080802544349] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Awareness of hepatitis C virus (HCV) infection status is expected to influence risk behaviors. In 2004-2005, injection drug users (IDUs) recruited from syringe exchange programs (SEPs) and methadone clinics in Montreal, Canada, were interviewed on drug use behaviors (past 6 months) and HCV testing. Subjects (n = 230) were classified as low/intermediate risk (20.4% borrowed drug preparation equipment only) and high risk (19.6% borrowed syringes), and 54.5% reported being HCV positive. Logistic regression modeling showed that compared to no risk (60% borrowed nothing), low/intermediate risk was associated with fewer noninjecting social network members, poor physical health, and problems obtaining sterile injecting equipment. High risk was associated with all of these factors except social networks. HCV status was not associated with any level of risk. Improved access to sterile injecting equipment may be more important than knowledge of HCV status in reducing injection risks among this IDU population. The study limitations are noted and recommendations discussed.
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Affiliation(s)
- Joseph Cox
- Direction de Santé publique, Agence de la Santé et des services Sociaux de Montreal, Montreal, Canada.
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22
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Yun H, Kim D, Kim S, Kang S, Jeong S, Cheon Y, Joe K, Gwon DH, Cho SN, Jee Y. High prevalence of HBV and HCV infection among intravenous drug users in Korea. J Med Virol 2008; 80:1570-5. [DOI: 10.1002/jmv.21255] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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23
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PARODI C, CULASSO A, ALOISI N, GARCA G, BASTN M, CORTI M, BIANCO RP, CAMPOS R, ARES BR, BAR P. Evidence of occult HCV genotypes in haemophilic individuals with unapparent HCV mixed infections. Haemophilia 2008; 14:816-22. [DOI: 10.1111/j.1365-2516.2008.01773.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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24
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Micalessi MI, Gérard C, Ameye L, Plasschaert S, Brochier B, Vranckx R. Distribution of hepatitis C virus genotypes among injecting drug users in contact with treatment centers in Belgium, 2004-2005. J Med Virol 2008; 80:640-5. [PMID: 18297717 DOI: 10.1002/jmv.21145] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The aim of this study was to determine the current prevalence of HCV genotypes in injecting drug users recruited at treatment centers all over Belgium, and to analyze if the distribution of genotypes was correlated with demographic characteristics, at-risk behaviors, and co-infection with other viruses. Therefore 147 anti-HCV-positive serum samples were selected for subsequent HCV RNA detection and genotyping. HCV RNA could be detected in 98 (67%) of the 147 serum samples. Genotype 1 (38%) and 3 (49%) were the most common genotypes followed by genotype 4 (9%) and genotype 2 (2%). One mixed infection (1%) was detected. The subtype could be determined in 80 cases: genotype 3a was the most prevalent (49%), followed by genotype 1a (16%) and genotype 1b (15%). No significant difference was found between the distribution of genotypes and the location of treatment centers, at-risk behaviors and co-infection with other viruses. Nevertheless, a slight variation over time could be identified (P = 0.06): one in two genotype 3 drug users started with their injecting drug use in the last 10 years (33% in the period 1995-1999 and 21% in the period > or =2000) compared to only one in four genotype 1 drug users (20% in the period 1995-1999 and 9% in the period > or =2000).
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Affiliation(s)
- M I Micalessi
- Scientific Institute of Public Health, Virology Section, Department of Microbiology, Juliette Wytsmanstraat 14, Brussels, Belgium.
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25
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Winter R, Nguyen O, Higgs P, Armstrong S, Duong D, Thach ML, Aitken C, Hellard M. Integrating enhanced hepatitis C testing and counselling in research. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2008; 19:66-70. [DOI: 10.1016/j.drugpo.2007.04.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2006] [Revised: 02/26/2007] [Accepted: 04/16/2007] [Indexed: 10/23/2022]
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26
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Trapero-Marugan M, Moreno-Monteagudo JA, Garcia-Buey L, Borque MJ, Medina J, Garcia-Sanchez A, Moreno-Otero R. Clinical and pathological characteristics and response to combination therapy of genotype 4 chronic hepatitis C patients: experience from a spanish center. J Chemother 2007; 19:423-7. [PMID: 17855187 DOI: 10.1179/joc.2007.19.4.423] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
This observational study evaluated the characteristics of genotype 4 chronic hepatitis C (CHC) patients and their response to combination therapy in Spain. 383 patients with CHC, 44 with genotype 4-HCV infection, were investigated. Nineteen genotype 4-HCV infected patients received IFNalpha-2b (3 MU three times weekly) plus ribavirin (1-1.2 g/day) and ten received Peg-IFNalpha-2b (1.5 microg/kg/week) plus ribavirin (1-1.2 g/day) for 12 months. A sustained virological response (SVR) was evaluated. Genotype 4-HCV was detected in 11.5% of patients, and was significantly associated with a higher proportion of infection through intravenous drug use (46% vs 11%; p<0.001), a higher alcohol intake (35% vs. 7%; p<0.001), higher proportion of anti-HBc positivity (41% vs. 22%; p<0.05), lower ALT (87+/-50 vs. 139+/-142 IU/L; p<0.001) and AST (53+/-30 vs. 85+/-126 IU/L; p<0.001) levels, lower viremia (4.1 +/- 7.7 (x 10(5)) vs . 7.3 +/- 9.8 IU(x 10(5) )/mL) p<0.05) and less fibrosis (stage 3-4 in 21% vs. 32%; p<0.06). Sixteen (55%) out of the 29 patients treated with combination therapy achieved a sustained virological response (SVR) while 10 (36%) were non-responders and 3 (9% relapsed. In conclusion, the lower stage of fibrosis, lower viremia and higher SVR rate than genotype 1 suggest a less aggressive pattern of diseased caused by this genotype.
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Affiliation(s)
- M Trapero-Marugan
- Gastroenterology and Hepatology Department, Hospital Universitario de La Princesa, Autonomous University of Madrid, Spain.
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27
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Batey RG. Controversies in and challenges to our understanding of hepatitis C. World J Gastroenterol 2007; 13:4168-76. [PMID: 17696244 PMCID: PMC4250614 DOI: 10.3748/wjg.v13.i31.4168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Discovered in 1989, the hepatitis C virus (HCV) continues to cause significant morbidity and mortality world-wide despite a huge research commitment to defining and understanding the virus and the disease it causes. This paper discusses a number of areas where progress in the management of the HCV have not kept pace with the scientific understanding of the HCV. It is suggested that in the fields of HCV prevention and providing access to treatment, practice falls short of what could be achieved. The role of alcohol in the pathogenesis of HCV liver injury is discussed. Discrimination against those with HCV infection and particularly those in prison settings fails to match good clinical practice. The complicated processes of sharing information between specialty groups is also discussed in an attempt to optimise knowledge dissemination in this field.
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Affiliation(s)
- Robert G Batey
- Drug and Alcohol Clinical Services, Hunter New England Area Health Services, Newcastle, New South Wales, Australia.
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28
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Walsh N, Higgs P, Crofts N. Recognition of Hepatitis C Virus Coinfection in HIV-Positive Injecting Drug Users in Asia. J Acquir Immune Defic Syndr 2007; 45:363-5. [PMID: 17592339 DOI: 10.1097/qai.0b013e318050d8d8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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29
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Nainan OV, Lu L, Gao FX, Meeks E, Robertson BH, Margolis HS. Selective transmission of hepatitis C virus genotypes and quasispecies in humans and experimentally infected chimpanzees. J Gen Virol 2006; 87:83-91. [PMID: 16361420 DOI: 10.1099/vir.0.81268-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
This study determined whether selective transmission of hepatitis C virus (HCV) species occurred among human and chimpanzee recipients of contaminated blood products or plasma containing multiple genotypes, subgenotypes and quasispecies. Commercially prepared factor VIII concentrate (lot DO56), produced prior to HCV testing and inactivation, was subsequently found by direct cloning to contain the following subgenotypes: 1a and 1b (73 % of clones), 2a (13 % of clones), 2b (11 % of clones) and 3a (4 % of clones). A patient transfused with factor VIII concentrate DO56 was diagnosed with clinical non-A, non-B hepatitis and subsequently found to be infected with HCV subgenotype 1b. Among five chimpanzees inoculated experimentally with the same factor VIII concentrate, two were infected only with HCV subgenotype 1a and three were infected with approximately equivalent clonal proportions of subgenotypes 1a and 1b. HCV hypervariable region 1 (HVR1) quasispecies analysis of the DO56 factor VIII concentrate and a serum specimen from the single chimpanzee that developed a chronic HCV infection following inoculation with DO56 showed 0-56 % nucleotide variation. However, specimens from chimpanzees infected in the second to fourth passages of the DO56 inoculum had 0-8 % HVR1 quasispecies nucleotide variation. The high HVR1 quasispecies variation in the factor VIII concentrate and its first passage in chimpanzees indicates the presence of multiple HCV isolates, whereas the low variation in the second to fourth chimpanzee passages suggests transmission of a single HCV isolate. These findings strongly suggest selective transmission of HCV isolates during experimental chimpanzee infection and among humans exposed to multiple HCV species.
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Affiliation(s)
- Omana V Nainan
- Division of Viral Hepatitis, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), 1600 Clifton Road NE, MS A33, Atlanta, GA 30333, USA
| | - Ling Lu
- Division of Viral Hepatitis, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), 1600 Clifton Road NE, MS A33, Atlanta, GA 30333, USA
| | - Feng-Xiang Gao
- Division of Viral Hepatitis, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), 1600 Clifton Road NE, MS A33, Atlanta, GA 30333, USA
| | - Emory Meeks
- Division of Viral Hepatitis, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), 1600 Clifton Road NE, MS A33, Atlanta, GA 30333, USA
| | - Betty H Robertson
- Division of Viral Hepatitis, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), 1600 Clifton Road NE, MS A33, Atlanta, GA 30333, USA
| | - Harold S Margolis
- Division of Viral Hepatitis, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), 1600 Clifton Road NE, MS A33, Atlanta, GA 30333, USA
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