Ribavirin monotherapy in patients with chronic hepatitis C: a retrospective study of 95 patients

Zoulim, Fabien; Haem, J.; Ahmed, Shahid; Chossegros, P.; Habersetzer, François; Chevallier, M.; Bailly, François; Trépo, Christian

doi:10.1046/j.1365-2893.1998.00099.x

Cited by 61 publications

(46 citation statements)

References 23 publications

(63 reference statements)

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“…However, ribavirin incorporation should occur at best only once/7000 nucleotides incorporated; that is, approximately once per genome. As a result, several cycles of replication may be necessary to cause a significant drop in production of infectious virus, consistent with the reduced efficacy of ribavirin monotherapy for treatment of HCV infection (15). We also observed a substantial block to elongation of nascent RNA when ribavirin was present in the template (Fig.…”

Section: Discussionsupporting

confidence: 80%

“…In this case, a single incorporation per genome may be more than sufficient to cause a substantial antiviral effect. If this is the case, then the reduced efficacy of ribavirin monotherapy may be a reflection of the use of reverse transcriptase-polymerase chain reaction as an indicator of viral load instead of a direct analysis of virus infectivity (15). HCV RNA may be stable for substantial periods of time in cells and defective RNA may be packaged if the appropriate signals remain intact.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis C Virus RNA-dependent RNA Polymerase (NS5B) as a Mediator of the Antiviral Activity of Ribavirin

Maag¹,

Castro²,

Hong³

et al. 2001

Journal of Biological Chemistry

267

201

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Ribavirin is administered in combination with interferon-␣ for treatment of hepatitis C virus (HCV) infection. Recently, we demonstrated that the antiviral activity of ribavirin can result from the ability of a viral RNA polymerase to utilize ribavirin triphosphate and to incorporate this nucleotide with reduced specificity, thereby mutagenizing the genome and decreasing the yield of infectious virus (Crotty, S., Maag, D., Arnold, J. J., Zhong, W., Lau, J. Y., Hong, Z., Andino, R., and Cameron, C. E. (2000) Nat. Med. 6, 1375-1379). In this study, we performed a quantitative analysis of a novel HCV RNA polymerase derivative that is capable of utilizing stably annealed primer-template substrates and exploited this derivative to evaluate whether lethal mutagenesis of the HCV genome is a possible mechanism for the anti-HCV activity of ribavirin. These studies demonstrate HCV RNA polymerase-catalyzed incorporation of ribavirin opposite cytidine and uridine. In addition, we demonstrate that templates containing ribavirin support CMP and UMP incorporation with equivalent efficiency. Surprisingly, templates containing ribavirin can also cause a significant block to RNA elongation. Together, these data suggest that ribavirin can exert a direct effect on HCV replication, which is mediated by the HCV RNA polymerase. We discuss the implications of this work on the development of nucleoside analogs for treatment of HCV infection. Hepatitis C virus (HCV)1 establishes a persistent infection of the liver, which leads to the development of cirrhosis and cancer (1). Currently, at least four million Americans are carriers of HCV. The available therapies are not very effective in clearing virus. The current therapeutic regimen includes a combination of interferon-␣ (IFN-␣) and ribavirin (2). IFN-␣ increases the nonadaptive antiviral response in cells (3). Ribavirin is a broad-spectrum antiviral nucleoside that is converted to the mono-, di-, and triphosphorylated forms inside of cells (4). Until this year, it was thought that the mechanism of action of ribavirin involved a decrease in cellular GTP pools resulting from inhibition of inosine monophosphate dehydrogenase by ribavirin monophosphate (5). The mechanism of action for ribavirin has been expanded to include lethal mutagenesis of the viral genome as a result of ribavirin triphosphate utilization by the viral RNA-dependent RNA polymerase and incorporation into viral RNA (6, 7). As shown in Fig. 1, the pseudo base of ribavirin can pair equivalently with both cytosine and uracil, thus providing a molecular basis for the mutagenic potential of ribavirin. Given the need for more effective strategies to control HCV infection, a precise understanding of the mechanism of action of existing antivirals should provide direction for the development of new anti-HCV therapeutics.Full-length HCV polymerase (NS5B) contains a very hydrophobic carboxyl terminus. To increase the solubility of this enzyme, the carboxyl-terminal 21 amino acids have been removed (8). This enzyme has been referred ...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus RNA-dependent RNA Polymerase (NS5B) as a Mediator of the Antiviral Activity of Ribavirin

Maag¹,

Castro²,

Hong³

et al. 2001

Journal of Biological Chemistry

267

201

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“…Recently, Cameron and colleagues (21,22) showed that ribavirin can be misincorporated into mRNA by viral RNA-dependent RNA polymerases because of its chemical similarity to guanosine, and this outcome leads to lethal mutagenesis of genomes of polio and HCV. Ribavirin triphosphate (RTP) binds the HCV polymerase with an observed dissociation constant (K d ) of 0.58 mM (23), which is consistent with micromolar concentrations necessary to achieve a therapeutic effect against HCV clinically (24). In addition to effects at millimolar concentrations, ribavirin is also active at micromolar concentrations.…”

mentioning

confidence: 72%

Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap

Kentsis

Topisirović

Čuljković

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

271

357

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The eukaryotic translation initiation factor eIF4E is deregulated in many human cancers, and its overexpression in cells leads to malignant transformation. Oncogenic properties of eIF4E are directly linked to its ability to bind 7-methyl guanosine of the 5 mRNA. Here, we observe that the antiviral guanosine analogue ribavirin binds to eIF4E with micromolar affinity at the functional site used by 7-methyl guanosine mRNA cap, competes with eIF4E:mRNA binding, and, at low micromolar concentrations, selectively disrupts eIF4E subcellular organization and transport and translation of mRNAs posttranscriptionally regulated by eIF4E, thereby reducing levels of oncogenes such as cyclin D1. Ribavirin potently suppresses eIF4E-mediated oncogenic transformation of murine cells in vitro, of tumor growth of a mouse model of eIF4E-dependent human squamous cell carcinoma in vivo, and of colony formation of eIF4E-dependent acute myelogenous leukemia cells derived from human patients. These findings describe a specific, potent, and unforeseen mechanism of action of ribavirin. Quantum mechanical and NMR structural studies offer directions for the development of derivatives with improved cytostatic and antiviral properties. In all, ribavirin's association with eIF4E may provide a pharmacologic means for the interruption of posttranscriptional networks of oncogenes that maintain and enhance neoplasia and malignancy in human cancer.cancer ͉ drug ͉ virus ͉ oncogenic network W hereas the precise causes of neoplasia and malignancy are known only for a few human cancers, deregulated tumor suppressors and oncogenes that maintain and enhance the malignant phenotype are becoming relatively well described (1, 2). Among these molecules are tumor suppressors like p53, Rb, and APC and oncogenes such as myc, cyclin D1, and eIF4E. Their interactions constitute a network of self-reinforcing feedback loops, whereby inactivation of principal elements can lead to reversal and at times even sustained loss of neoplastic phenotype (3, 4). eIF4E is overexpressed in a wide variety of malignant cell lines and primary human tumors such as carcinomas of the breast (5), colon (6), and head and neck (7), non-Hodgkin's lymphomas (8), and chronic and acute M4͞M5 myelogenous leukemias (9). Consistently, even moderate overexpression of eIF4E in rodent cells leads to deregulated proliferation and malignant transformation (10). eIF4E is essential for growth and survival of eukaryotes by acting at a critical step of cap-dependent translation and recruiting transcripts to the ribosome as a result of a specific interaction with the 5Ј 7-methyl guanosine (m 7 G) mRNA cap (11). It is important to stress that, although the interaction of eIF4E with the 5Ј mRNA cap is required for initiation of translation of cap-dependent mRNAs, up-regulation of eIF4E does not increase translation of all cap-dependent transcripts, but only of a specific subset of eIF4E-sensitive transcripts, as described below.As much as 70% of eIF4E is present in the nuclei of mammalian cells, where it i...

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“…A biochemical response was established. In 10% of the patients there was HCV RNA clearance (34). The data show only one study for the combination therapy with Inosine pranobex and Ribavirin (more than 20 years ago) in patients with HIV infection.…”

Section: Medinform 37mentioning

confidence: 93%

Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

Nikolova¹,

Antonov²,

Mateva³

et al. 2014

MedInform

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The management of patients with advanced chronic HCV liver disease is still a problem. There is insufficient data about the role of immunomodulatory agents. The aim of the present study was to evaluate the benefit of prolonged co-administration of Inosine pranobex (Isoprinosine) and Ribavirin in patients with HCV advanced liver disease and to assess the dynamics of the IP-10 serum levels and thus -changes in the immune status of patients. Methods: Five patients (2 males, 3 females; median age 63), with chronic HCV genotype 1 infection were studied (with failed standard bitherapy). All patients received Ribavirin and Isoprinosine. HCVRNA was measured at baseline and at day 40, month 3, 6 and 12 during treatment. IP-10 levels -at baseline and at day 10, 20, 40, 60, month 3, 6 and 12. Results: IP-10 levels were elevated in all patients at the baseline. An increase at day 10 or 20 was found in 4/5 patients and reduction at day 40 or 60 in same 4 patients. At month 12 the levels were significantly reduced (P=0.043). There was also an initially slight increase of ALT and subsequent reduction (P=0.043). The count of platelets increased in 4/5 patients. No effect on viral load was found. Conclusion: The therapeutic regime is well tolerated, no severe adverse events were documented. An improvement of the disease severity and liver inflammation were observed, with no effect on the viral load. We found reduction of IP-10 levels at month 12 -a sign of immune competence restoration.

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Ribavirin monotherapy in patients with chronic hepatitis C: a retrospective study of 95 patients

Cited by 61 publications

References 23 publications

Hepatitis C Virus RNA-dependent RNA Polymerase (NS5B) as a Mediator of the Antiviral Activity of Ribavirin

Hepatitis C Virus RNA-dependent RNA Polymerase (NS5B) as a Mediator of the Antiviral Activity of Ribavirin

Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap

Could Inosine pranobex and Ribavirin in combination restore immune competence in chronic HCV advanced liver disease?

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