Effects of ribavirin monotherapy on the viral population in patients with chronic hepatitis C genotype 1: Direct sequencing and pyrosequencing of the HCV regions

Quiles-Pérez, Rosa; Muñoz-de-Rueda, Paloma; Maldonado, Alicia Martín Lagos; Martín-Álvarez, A.; Quer, Josep; Salmerón, Javier

doi:10.1002/jmv.24035

Cited by 6 publications

(10 citation statements)

References 58 publications

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“…Whether the mutagenic effect of these agents on influenza virus also plays in the clinical context is at this stage speculative; recent in vivo data obtained in a mouse influenza model (28) suggest that this may be possible for T-705. Quasispecies formation of hepatitis C virus following exposure to ribavirin has been observed in cell culture-based studies but not during long-term treatment of patients (56). In the case of influenza virus, T-705-or ribavirin-induced noninfectious or mutant viruses may be even less likely to appear, considering that influenza treatment is much shorter and that nonviable virus particles are probably cleared by the patient's immune response.…”

Section: Discussionmentioning

confidence: 99%

Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis

Vanderlinden

Vrancken

Houdt

et al. 2016

Antimicrob Agents Chemother

100

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c T-705 (favipiravir) is a new antiviral agent in advanced clinical development for influenza therapy. It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an established and broad antiviral drug that shares structural similarity with T-705. We here performed a comparative analysis of the effects of T-705 and ribavirin on influenza virus and host cell functions. Influenza virusinfected cell cultures were exposed to T-705 or ribavirin during single or serial virus passaging. The effects on viral RNA synthesis and infectious virus yield were determined and mutations appearing in the viral genome were detected by whole-genome virus sequencing. In addition, the cellular nucleotide pools as well as direct inhibition of the viral polymerase enzyme were quantified. We demonstrate that the anti-influenza virus effect of ribavirin is based on IMP dehydrogenase inhibition, which results in fast and profound GTP depletion and an imbalance in the nucleotide pools. In contrast, T-705 acts as a potent and GTP-competitive inhibitor of the viral polymerase. In infected cells, viral RNA synthesis is completely inhibited by T-705 or ribavirin at >50 M, whereas exposure to lower drug concentrations induces formation of noninfectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is 2-fold higher for T-705 than for ribavirin. Hence, T-705 and ribavirin both act as purine pseudobases but profoundly differ with regard to the mechanism behind their antiviral and mutagenic effects on influenza virus.

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Section: Discussionmentioning

confidence: 99%

Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis

Vanderlinden

Vrancken

Houdt

et al. 2016

Antimicrob Agents Chemother

100

View full text Add to dashboard Cite

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“…Lethal mutagenesis is well known as a potential antiviral therapy with reduced probability of selection of escape mutants in RNA viruses . RBV monotherapy was shown to induce HCV genome mutations in genotype 1a or 1b HCV‐infected patients …”

Section: Introductionmentioning

confidence: 99%

“…14,15 RBV monotherapy was shown to induce HCV genome mutations in genotype 1a or 1b HCV-infected patients. [16][17][18][19][20][21][22] Although the proportion of RAVs emerging in patients with DCV/ ASV treatment failures gradually declines over time, it is unknown whether or not RBV treatment induces HCV genome mutation in patients with DCV/ASV treatment failure.…”

Section: Introductionmentioning

confidence: 99%

“…RBV has several modes of action on HCV, and this reduction in infectious virus may be one of the reasons that RBV treatment induces the effect of anti-HCV therapy.In chronic hepatitis patients, studies about the effect of RBV on HCV genome mutation are contradictory. RBV monotherapy was reported to induce genome mutations in the NS5A and NS5B regions in genotype 1a or 1b HCV-infected patients, based on clonal sequence analysis [16][17][18][19][20][21][22]. In contrast, Chevaliez et al28 reported that genome mutation rates had increased neither in the HCV NS3 nor the NS5A region after RBV therapy in genotype 1b patients with chronic hepatitis.…”

mentioning

confidence: 99%

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Ribavirin induces hepatitis C virus genome mutations in chronic hepatitis patients who failed to respond to prior daclatasvir plus asunaprevir therapy

Saito

Imamura

Uchida

et al. 2019

Journal of Medical Virology

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Ribavirin (RBV) induces nucleotide (nt) substitutions in hepatitis C virus (HCV) genome nonstructural (NS) regions. Although emergence of drug resistance‐associated variants is associated with direct‐acting antiviral treatment failure, the effect of RBV on genome substitutions in such patients is unknown. Genotype 1b HCV subgenomic replicon cells were treated with RBV for 120 hours. Six patients with chronic genotype 1b with HCV‐infected patients who failed to respond to prior daclatasvir plus asunaprevir (DCV/ASV) therapy were treated with 12 weeks of sofosbuvir and ledipasvir plus RBV after 4 weeks of RBV monotherapy. RBV‐induced genome mutations in the HCV NS region (nt3493‐9301) in replicon cells and in patients during 4 weeks of RBV monotherapy were analyzed by deep sequencing. RBV‐associated G‐to‐A and C‐to‐U transitions increased in a dose‐dependent manner in HCV replicon cells after the RBV treatment. In patients with prior DCV/ASV treatment failures, the median serum HCV RNA level was 6.25 ± 0.31 log IU/mL at the start of RBV therapy and decreased significantly to 5.95 ± 0.4 log IU/mL (P = .03) after 4 weeks of RBV monotherapy. Although predominant HCV genome substitutions rates were similar between nontreatment and RBV‐treatment periods (0.042 and 0.031 per base pair, respectively; P = .248), the frequencies of G‐to‐A and C‐to‐U transitions significantly increased after RBV monotherapy. These transitions were enriched, particularly within the HCV NS3 region in all patients. RBV treatment induces G‐to‐A and C‐to‐U transitions in the HCV genome even in chronic patients with hepatitis C with prior DCV/ASV treatment failures.

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“…However, the use of high dose treatment is hampered by enhanced side effects, most importantly a dose dependent hemolytic anemia, possibly secondary to oxidative stress caused by posterior depletion of ATP in erythrocytes [ 34 , 35 ]. Recently some studies have evaluated the effect of using a lead-in phase of ribavirin mono-therapy prior to the addition of interferon, with the goal of achieving steady state concentrations early in combination-treatment without causing severe anemia; however, thus far this strategy has not been reported to impact on outcome [ 27 , 36 – 38 ].…”

Section: Introductionmentioning

confidence: 99%

Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

et al. 2016

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In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naïve patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-α (pegIFN-α), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-α, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-α. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log10 IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log10 IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-α and thus shortened treatment duration (P<0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P<0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an anti-viral effect differently regulated across IL28B genotypes.Trial RegistrationClinicalTrials.gov NCT01226771

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Effects of ribavirin monotherapy on the viral population in patients with chronic hepatitis C genotype 1: Direct sequencing and pyrosequencing of the HCV regions

Cited by 6 publications

References 58 publications

Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis

Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis

Ribavirin induces hepatitis C virus genome mutations in chronic hepatitis patients who failed to respond to prior daclatasvir plus asunaprevir therapy

Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

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