Synergistic Combinations of Favipiravir and Oseltamivir Against Wild-Type Pandemic and Oseltamivir-Resistant Influenza A Virus Infections in Mice

Smee, Donald F.; Tarbet, E. Bart; Furuta, Yoshihiko; Morrey, John D.; Barnard, Dale L.

doi:10.2217/fvl.13.98

Cited by 40 publications

(38 citation statements)

References 36 publications

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“…vir against new and emerging strains of influenza is frequently tested in mice and other animal species and is used as a predictor for efficacy in humans (12)(13)(14)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)), but we demonstrate here that evaluation of antiviral efficacy in in vitro assays as well as in vivo analyses in other animal species should be assessed collectively to ensure that an accurate understanding of antiviral efficacy for humans will be predicted.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

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During the first wave of the 2009 pandemic, caused by a H1N1 influenza virus (pH1N1) of swine origin, antivirals were the only form of therapeutic available to control the proliferation of disease until the conventional strain-matched vaccine was produced. Oseltamivir is an antiviral that inhibits the sialidase activity of the viral neuraminidase (NA) protein and was shown to be effective against pH1N1 viruses in ferrets. Furthermore, it was used in humans to treat infections during the pandemic and is still used for current infections without reported complication or exacerbation of illness. However, in an evaluation of the effectiveness of oseltamivir against pH1N1 infection, we unexpectedly observed an exacerbation of disease in virus-infected mice treated with oseltamivir, transforming an otherwise mild illness into one with high morbidity and mortality. In contrast, an identical treatment regime alleviated all signs of illness in mice infected with the pathogenic mouse-adapted virus A/WSN/33 (H1N1). The worsened clinical outcome with pH1N1 viruses occurred over a range of oseltamivir doses and treatment schedules and was directly linked to a reduction in NA enzymatic activity. Our results suggest that the suppression of NA activity with antivirals may exacerbate disease in a host-dependent manner by increasing replicative fitness in viruses that are not optimally adapted for replication in that host. IMPORTANCEHere, we report that treatment of pH1N1-infected mice with oseltamivir enhanced disease progression, transforming a mild illness into a lethal infection. This raises a potential pitfall of using the mouse model for evaluation of the therapeutic efficacy of neuraminidase inhibitors. We show that antiviral efficacy determined in a single animal species may not represent treatment in humans and that caution should be used when interpreting the outcome. Furthermore, increased virulence due to oseltamivir treatment was the effect of a shift in the hemagglutinin (HA) and neuraminidase (NA) activity balance. This is the first study that has demonstrated that altering the HA/NA activity balance by reduction in NA activity can result in an increase in virulence in any animal model from nonpathogenic to lethal and the first to demonstrate a situation in which treatment with a NA activity inhibitor has an effect opposite to the intended therapeutic effect of ameliorating the infection.

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Section: Discussionmentioning

confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

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“…Adamantanes are active against influenza A virus only, but are now rarely used because of resistance (Cheng et al, 2012). Favipiravir, a novel viral RNA polymerase inhibitor with broad-spectrum antiviral activity including anti-influenza activity, has been approved in Japan, but is still undergoing phase 3 clinical trials in the United States (Cao et al, 2014;ClinicalTrials.gov identifier: NCT02008344;Daikoku et al, 2014;Smee et al, 2013). Arbidol, which inhibits several steps of the influenza virus life cycle, has been approved for clinical use in Russia and China (Blaising et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

Mok

Chan

et al. 2016

Journal of General Virology

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“…These two drug clas-72 ses differ not only in their mechanisms of action, but also in their 73 pharmacokinetics, tolerance profiles, and resistance patterns (De 74 Clercq, 2006 (Deyde et al, 2007;Mossad, 2009), as are the majority of H3N2 79 viruses (Bright et al, 2005;Hata et al, 2007) and the most highly 80 pathogenic H5N1 avian viruses (Hurt et al, 2007;Govorkova 81 et al, 2013). Additionally, the unexpected dominance ($98%) of 82 oseltamivir-resistant H1N1 strains between 2007 and 2009 demon-83 strated that NA inhibitor resistance can emerge rapidly and spread 84 worldwide (Hurt et al, 2009;Lackenby et al, 2008) Smee et al, 2013;Tarbet et al, 2012). 99 Type I interferons (e.g., IFN-a/b) and the more recently discov-100 ered type III interferons are key mediators of 101 the innate immune response against influenza virus infection 102 (Durbin et al, 2000;Hsu et al, 2012;Sheppard et al, 2003; 103 Kotenko et al, 2003).…”

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confidence: 99%

In vitro anti-influenza A activity of interferon (IFN)-λ1 combined with IFN-β or oseltamivir carboxylate

Ilyushina

Donnelly

2014

Antiviral Research

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Influenza viruses, which can cross species barriers and adapt to new hosts, pose a constant potential threat to human health. The influenza pandemic of 2009 highlighted the rapidity with which an influenza virus can spread worldwide. Currently available antivirals have a number of limitations against influenza, and novel antiviral strategies, including novel drugs and drug combinations, are urgently needed. Here, we evaluated the in vitro effects of interferon (IFN)-β, IFN-λ1, oseltamivir carboxylate (a neuraminidase (NA) inhibitor), and combinations of these agents against two seasonal (i.e., H1N1 and H3N2) influenza A viruses. We observed that A/California/04/09 (H1N1) and A/Panama/2007/99 (H3N2) isolates were equally sensitive to the antiviral activity of IFN-β and oseltamivir carboxylate in A549 and Calu-3 cells. In contrast, IFN-λ1 exhibited substantially lower protective potential against the H1N1 strain (64-1030-fold ↓, P<0.05), and was ineffective against H3N2 virus in both cell lines. Three dimensional analysis of drug-drug interactions revealed that IFN-λ1 interacted with IFN-β and oseltamivir carboxylate in an additive or synergistic manner, respectively, to inhibit influenza A virus replication in human airway epithelial cells. Overall, the present study demonstrated that anti-influenza agents with different mechanisms of action (e.g., a NA inhibitor combined with IFN-λ1) exerted a significantly greater (P<0.05) synergistic effect compared to co-treatment with drugs that target the same signaling pathway (i.e., IFN-β plus IFN-λ1) in vitro. Our findings provide support for the combined use of interferon plus oseltamivir as a potential means for treating influenza infections.

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Synergistic Combinations of Favipiravir and Oseltamivir Against Wild-Type Pandemic and Oseltamivir-Resistant Influenza A Virus Infections in Mice

Cited by 40 publications

References 36 publications

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

In vitro anti-influenza A activity of interferon (IFN)-λ1 combined with IFN-β or oseltamivir carboxylate

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