Combinations of Oseltamivir and T-705 Extend the Treatment Window for Highly Pathogenic Influenza A(H5N1) Virus Infection in Mice

Marathe, Bindumadhav M.; Wong, Sook‐San; Vogel, Peter; García-Alcalde, Fernando; Webster, Robert G.; Webby, Richard J.; Nájera, Isabel; Govorkova, Elena A.

doi:10.1038/srep26742

Cited by 51 publications

(67 citation statements)

References 58 publications

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“…Second, the presence of a natural ribose implies that in theory, chain elongation is possible in the case that T-705-RTP or RBV-TP is used as an alternative substrate by the influenza virus polymerase. These two factors could explain recent observations that cell culture passaging of influenza virus in the presence of T-705 (25) or ribavirin (26,27) leads to virus mutagenesis; this mutagenic effect was also seen in influenza virus-infected mice receiving T-705 therapy (28). Enzymatic studies showed that influenza virus polymerase recognizes T-705-RTP as an alternative substrate versus GTP and ATP (29,30).…”

mentioning

confidence: 84%

“…Whereas T-705 functions at the level of the viral polymerase, ribavirin acts by GTP depletion via IMPDH inhibition; this explains why the therapeutic index of T-705 by far exceeds that of ribavirin. 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).…”

Section: Discussionmentioning

confidence: 99%

“…For ribavirin, the cellular IMPDH enzyme was presented as the indirect and predominant target for antiviral activity (34,50), although inhibition of the influenza virus polymerase was also reported (23,(31)(32)(33). Since both T-705 (25,28) and ribavirin (26,27) were recently reported as influenza virus mutagens, the aim of our study was to make a side-by-side comparison between these two molecules, using cell-based virus infection methods combined with biochemical assays to verify and, particularly, link all possible mechanisms of action. A schematic summary of our findings is presented in Fig.…”

Section: Discussionmentioning

confidence: 99%

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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

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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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confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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

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“…A robust immune response is crucial for resolving viral infections, but immune-mediated pathology can exacerbate disease [5][6][7][8][9]. High viral loads also play a role in disease progression [10], but these do not always correlate with the strength of the host response or with disease severity [11][12][13][14]. An understanding of how viral loads, host immune responses, and disease progression are related is critical to identify disease-specific markers that may help predict hospitalization or other complications.…”

Section: Author Summarymentioning

confidence: 99%

Dynamically Linking Influenza Virus Infection Kinetics, Lung Injury, Inflammation, and Disease Severity

Myers

Smith

Lane

et al. 2019

Preprint

Self Cite

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Influenza A viruses cause a significant amount of morbidity and mortality. Understanding how the infection is controlled by host immune responses and how different factors influence severity are critical to combat the infection. During infection, viral loads increase exponentially, peak, then decline until resolution. The viral decline is often biphasic, which we previously determined is a consequence of density-dependent infected cell clearance. The second, rapid clearance phase corresponds with the infiltration of CD8 + T cells, but how the rate changes with infected cell density and T cell density is unclear. Further, the kinetics of virus, infected cells, and CD8 + T cells all contribute to disease severity but do not seem to be directly correlated. Thus, we investigated the relations between viral loads, infected cells, CD8 + T cells, lung pathology, and disease severity/symptoms by infecting mice with influenza A/PR8, simultaneously measuring virus and CD8 + T cells, and developing and calibrating a kinetic model. The model predicted that infection resolution is sensitive to CD8 + T cell expansion, that there is a critical T cell magnitude below which the infection is significantly prolonged, and that the efficiency of T cell-mediated clearance is dependent on infected cell density. To further examine the latter finding and validate the model's predicted dynamics, we quantified infected cell kinetics using lung histomorphometry. These data showed that the area of lung infected matches the predicted cumulative infected cell dynamics, and that the area of resolved infection parallels the relative CD8 + T cell magnitude. Our analysis further revealed a nonlinear relationship between disease severity (i.e., weight loss) and the percent of the lung damaged. Establishing the predictive capabilities of the model and the critical connections that map the kinetics of virus, infected cells, CD8 + T cells, lung pathology, and disease severity during influenza virus infection aids our ability to forecast the course of infection, disease progression, and potential complications, thereby providing insight for clinical decisions.

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“…A recent study of combined treatment of oseltamivir (20 mg/kg/day) and T705 (50 mg/kg/day) resulted in 100% survival in mice infected with H5N1 and extended the treatment window to 48, 72 and 96 hours post-infection. This combination therapy was more effective compared to treatment with oseltamivir alone (40% survival at 72 and 96 hours post-infection) or T705 alone (90% and 40% survival at 72 and 96 hours post-infection), respectively 52. Overall, these studies indicate that a single dose of T705 per day can protect against mortality in mice, and that when delivered as monotherapy or in combination with oseltamivir, T705 greatly extended the treatment window to achieve survival of mice infected with H5N1.T705 has received a limited licensure in Japan, where it has been approved for use only in patients infected with novel or re-emerging influenza viruses (ie in the event of a pandemic), and only when that virus is resistant to other influenza antivirals.…”

mentioning

confidence: 90%

Influenza antivirals currently in late‐phase clinical trial

Koszalka

Tilmanis

Hurt

2017

Influenza Resp Viruses

121

102

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Influenza antiviral drugs are important for the control of influenza, most specifically for the treatment of influenza patients with severe disease following infection with a seasonal influenza virus, a newly emerging influenza strain, or in the event of a pandemic. Many influenza antivirals that are currently under investigation in late‐stage clinical trials differ in their mechanism of action compared to drugs currently licensed for the treatment of influenza. Nitazoxanide and DAS181 target components of the host cell and alter the ability of the virus to replicate efficiently, while small molecule drugs such as T705, JNJ63623872 and S‐033188 bind to the viral polymerase complex and restrict viral replication. Monoclonal antibodies that are currently in clinical trial for the treatment of influenza most commonly are targeted to the stem region of the haemagglutinin molecule. Early findings from animal models and in vitro studies suggest that many of the new antiviral drugs when tested in combination with oseltamivir have improved effectiveness over monotherapy. Clinical trials assessing both monotherapy and combination therapy are currently under investigation. It is hoped that as new antivirals are licensed, they will improve the standard of care and outcomes for influenza patients with severe disease.

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Combinations of Oseltamivir and T-705 Extend the Treatment Window for Highly Pathogenic Influenza A(H5N1) Virus Infection in Mice

Cited by 51 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

Dynamically Linking Influenza Virus Infection Kinetics, Lung Injury, Inflammation, and Disease Severity

Influenza antivirals currently in late‐phase clinical trial

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