Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C

Asahina, Yasuhiro; Izumi, Namiki; Enomoto, Nobuyuki; Uchihara, Masakatsu; Kurosaki, Masayuki; Onuki, Yuko; Nishimura, Yuki; Ueda, Ken; Tsuchiya, Kaoru; Nakanishi, Hiroyuki; Kitamura, Takatoshi; Miyake, Shozo

doi:10.1016/j.jhep.2005.05.032

Cited by 108 publications

(93 citation statements)

References 25 publications

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“…Among the three populations of clones from NR patients, we did not find any aa substitutions between M3 and M6 treatment points, as recently described in NS5A during ribavirin monotherapy [38] . No other specific aa substitutions were found in the NS5A protein.…”

Section: Possible Mutagenic Effect Of Ribavirin During Combination Thsupporting

confidence: 81%

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Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Veillon

Payan²,

Guillou‐Guillemette³

et al. 2007

WJG

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AIM:To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNAdependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear.METHODS: HCV quasispecies were studied by cloning and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-α2b for 3 mo followed by IFN-α2b alone or combined IFN-R therapy for 9 additional months. Patients were categorized intro two groups based on their response to the treatments: 7 with sustained virological response (SVR) (quasispecies = 150) and 3 non-responders (NR) to IFN-R (quasispecies = 106). RESULTS:Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispecies during therapy. Analysis of amino acids substitutions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate the two groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION:These results suggest that detailed molecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.

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Section: Possible Mutagenic Effect Of Ribavirin During Combination Thsupporting

confidence: 81%

“…Asahina et al [38] studied the possible mutagenic effect of ribavirin during a period of 28 days of ribavirin monotherapy before combined IFN-R therapy. During the first phase of ribavirin monotherapy, they observed an accumulation of non-synonymous substitutions located in NS5A.…”

Section: Applicationsmentioning

confidence: 99%

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Veillon

Payan²,

Guillou‐Guillemette³

et al. 2007

WJG

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“…61 When infectivity was used as a functional readout for mutagenesis, diminished infectivity was found with ribavirin treatment of HCV cultures.58 , 60 The concentrations of ribavirin needed to achieve mutagenic effects were high (up to 400 uM) and may exceed those achieved in vivo. These concentration differences may help to explain the discordance observed between cell culture and human studies 54,55,[62][63][64][65][66][67] (Table 3). The studies done on human samples were often limited by the circumscribed nature of the viral genomic regions sampled and the lack of a functional assay for the sequences identified.…”

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confidence: 99%

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

et al. 2007

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The current recommended therapy for chronic hepatitis C is the combination of peginterferon and ribavirin, which results in a sustained clearance of hepatitis C virus (HCV) in at least half of patients. However, the mechanisms by which interferon alpha (IFN-α) and ribavirin act against HCV are not well defined. The importance of understanding the biological pathways, cellular effects, and antiviral activities of these agents is underscored by clinical observations that nonresponders frequently have little or no decrease in HCV RNA levels during treatment, suggesting intrinsic resistance to IFN-α. Cell culture and animal models of HCV have shown that the infection itself may block IFN-α induction and action. Still other findings suggest that individual innate and adaptive immune responses, host genetic factors, viral genetic diversity, and clinical comorbidities account for part of nonresponse to therapy. To provide an overview of the current knowledge of the mechanisms of action of IFN-α and ribavirin against HCV and offer guidance for future research, the American Association for the Study of Liver Diseases held a single topic conference entitled "Interferon and Ribavirin in Hepatitis C Virus Infection: Mechanisms of Response and Non-Response" on March [1][2][3] 2007. This article summarizes that conference. Interferons (IFNs): An OverviewThe IFNs (Dr. Howard Young, National Cancer Institute, National Institutes of Health)The type 1 IFNs [interferon alpha and beta (IFN-α/β)] comprise a family of distinct proteins1 that are produced by a wide variety of cells, including fibroblasts, epithelial cells, and hepatocytes, 2 although plasmacytoid dendritic cells (DCs) are probably the major source in most viral infections. In contrast, type II IFN [interferon gamma (IFN-γ)] is a single gene cytokine unrelated in structure to IFN-α/β that is produced largely by macrophages, natural Copyright © 2007 by the American Association for the Study of Liver Diseases.Address reprint requests to: Raymond T. Chung, M.D., Gastrointestinal Unit, GRJ724, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. rtchung@partners.org; fax: 617-643-0446.. Potential conflict of interest: Dr. Lemon is a consultant for Novartis, GlaxoSmithKline, Hoffman-LaRoche, Genelabs Technology, Abbott, Pharmasett. He also received grants from Schering-Plough and Tibotec. Dr. Chung received grants from Roche and ScheringPlough. NIH Public Access Author ManuscriptHepatology. Author manuscript; available in PMC 2009 December 29. Published in final edited form as:Hepatology. 2008 January ; 47(1): 306-320. doi:10.1002/hep.22070. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript killer (NK) cells, and T lymphocytes. Both types of IFNs interact with cells via distinct cellular receptors. The details of the signaling mechanisms by which IFN-α/β and IFN-γ induce the transcription of interferon-stimulated genes (ISGs) and depress the transcription of others are still being defined. 3 However, it is increasingly clear that the c...

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“…17,[40][41][42][43][44][45] To understand how ribavirin can increase response rate, Dixit et al 25 developed a viral dynamic model in which they assumed that in a dose-dependent manner ribavirin (alone or in combination with interferon) causes a fraction of newly produced virions to be non-infectious, presumably through mutagenic action. 41,[43][44][45] Because the concentration of ribavirin increases during the first month of therapy, they also assumed that increases with time on therapy, reaching saturation at 28 days. Analysis of the model then showed that when ⑀ is high, ribavirin has negligible influence on viral load, whereas when ⑀ is low, ribavirin is predicted to enhance viral load decay.…”

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confidence: 99%

“…Which interpretation is correct remains to be seen, although a recent report provides the first direct evidence of increased in vivo HCV mutagenesis during ribavirin monotherapy. 45 In spite of recent advances in the therapy of chronic HCV infection, sustained virological response rates to current treatments with PEG IFN in combination with ribavirin are still unsatisfying in patients infected with HCV-genotypes 1 or 4 or co-infected with HIV. The analysis of new therapies is thus a further challenge of HCV RNA kinetic studies.…”

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confidence: 99%

New kinetic models for the hepatitis C virus

et al. 2005

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K inetic models of hepatitis C virus (HCV) RNA decay induced by interferon (IFN) therapy have been developed by us and others. [1][2][3][4][5][6] The models, inspired by previous work on HIV and hepatitis B virus kinetics, 7-9 stimulated the collection of frequent viral loads and alanine aminotransferase (ALT) measurements after the initiation of therapy that revealed previously unknown kinetic patterns of HCV RNA change. The models have successfully summarized much of these new kinetic data and have given insights into features of HCV biology in vivo, such as the rate of virion clearance and the daily rate of virion production. More importantly from a clinical perspective, the models have allowed quantification of the antiviral effects of therapy and thus have made comparison of the antiviral effectiveness of different drug regimens possible using data collected over short intervals.

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Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C

Cited by 108 publications

References 25 publications

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

New kinetic models for the hepatitis C virus

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