Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C

Rotman, Yaron; Noureddin, Mazen; Feld, Jordan J.; Guedj, Jérémie; Witthaus, Michael; Han, Hwalih; Park, Yoon J.; Park, Su–Hyung; Heller, Theo; Ghany, Marc G.; Doo, Edward; Koh, Christopher; Abdalla, Ahmed; Gara, Naveen; Sarkar, Souvik; Thomas, Emmanuel; Ahlenstiel, Golo; Edlich, Birgit; Titerence, Rachel; Hogdal, Leah J.; Rehermann, Barbara; Dahari, Harel; Perelson, Alan S.; Hoofnagle, Jay H.; Liang, T. Jake

doi:10.1136/gutjnl-2012-303852

Cited by 54 publications

(89 citation statements)

References 26 publications

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“…It is conceivable that the clinical effect of ribavirin may be at least partially mediated by resetting the IFN responsiveness in the liver (14). In conclusion, this explorative study analyzed ribavirin-induced mutations with high sensitivity and demonstrated that ribavirin induces nucleotide transitions during monotherapy.…”

Section: Discussionmentioning

confidence: 97%

“…It was recently shown that ribavirin in conjunction with IFN-␣/PEG-IFN-␣ induces the expression of specific interferon-stimulated genes (ISGs) in vitro and in vivo, thereby potentiating the anti-HCV effect of interferon (12)(13)(14). Other possible mechanisms of ribavirin action include the following models: strengthening of the adaptive antiviral immune response, impairment of the cellular enzyme IMP dehydrogenase (IMPDH), direct inhibition of the HCV nonstructural 5B (NS5B) RNA-dependent RNA polymerase, and exertion of a mutagenic effect on RNA viruses and the resulting error catastrophe (15,16).…”

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confidence: 99%

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Deep Sequencing Reveals Mutagenic Effects of Ribavirin during Monotherapy of Hepatitis C Virus Genotype 1-Infected Patients

Dietz

Schelhorn

Fitting

et al. 2013

J Virol

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The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the hepatitis C virus (HCV) genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nucleotides [nt] 330 to 9351) of patients treated with 6-week ribavirin monotherapy (n ‫؍‬ 6) in comparison to placebo (n ‫؍‬ 6). Baseline HCV RNA levels maximally declined on average by ؊0.8 or ؊0.1 log 10 IU/ml in ribavirin-versus placebo-treated patients. No general increase in rates of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week 6 in ribavirin-treated patients in comparison to placebo-treated patients (rate of 0.0041 transitions per base pair versus rate of 0.0022 transitions per base pair; P ‫؍‬ 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients than in placebo-treated patients (rate of 0.0331 transitions versus rate of 0.0186 transitions per G/C-containing position at baseline; P ‫؍‬ 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group (P ‫؍‬ 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Deep Sequencing Reveals Mutagenic Effects of Ribavirin during Monotherapy of Hepatitis C Virus Genotype 1-Infected Patients

Dietz

Schelhorn

Fitting

et al. 2013

J Virol

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“…Control liver biopsies were obtained from 5 nondiabetic patients (mean age, 47 years; n = 3 female patients) who had a past history of chronic hepatitis C and were successfully treated with viral eradication at least 6 months prior to the biopsy (64). Histological evaluation of these samples revealed no signs of steatosis or hepatic inflammation or injury.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Gi signaling regulates whole-body glucose homeostasis

Rossi¹,

Zhu²,

McMillin³

et al. 2018

Journal of Clinical Investigation

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“…According to Rotman et al Ribavirin monotherapy decreases IP-10 serum levels, but it has no effect on ISG expression in PBMC (Peripheral blood mononuclear cell) (19). The available data on the effect on viremia and sustained response of 4-6 weeks pretreatment with Ribavirin before the standard bi-therapy with Peg-interferon are controversial (19,20,21,22,23,24,25,26,27).…”

Section: Introductionmentioning

confidence: 99%

“…The available data on the effect on viremia and sustained response of 4-6 weeks pretreatment with Ribavirin before the standard bi-therapy with Peg-interferon are controversial (19,20,21,22,23,24,25,26,27). Administration of the drug within 6 months after a standard bi-therapy does not improve response (28).…”

Section: Introductionmentioning

confidence: 99%

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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Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C

Cited by 54 publications

References 26 publications

Deep Sequencing Reveals Mutagenic Effects of Ribavirin during Monotherapy of Hepatitis C Virus Genotype 1-Infected Patients

Deep Sequencing Reveals Mutagenic Effects of Ribavirin during Monotherapy of Hepatitis C Virus Genotype 1-Infected Patients

Hepatic Gi signaling regulates whole-body glucose homeostasis

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

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