#Combination #Therapy with #Oseltamivir and #Favipiravir Delays #Mortality but Does Not Prevent Oseltamivir #Resistance in Immunodeficient Mice Infected with #H1N1pdm09 Influenza Virus (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2018 Nov 3;10(11). pii: E610. doi: 10.3390/v10110610.

Combination Therapy with Oseltamivir and Favipiravir Delays Mortality but Does Not Prevent Oseltamivir Resistance in Immunodeficient Mice Infected with Pandemic A(H1N1) Influenza Virus.

Baz M1, Carbonneau J2, Rhéaume C3, Cavanagh MH4, Boivin G5.

Author information: 1 Research Center in Infectious Diseases of the CHU of Québec and Laval University, 2705, Boul. Laurier (RC-709), Québec City, QC G1V 4G2, Canada. mariana.baz@crchudequebec.ulaval.ca. 2 Research Center in Infectious Diseases of the CHU of Québec and Laval University, 2705, Boul. Laurier (RC-709), Québec City, QC G1V 4G2, Canada. julie.carbonneau@crchudequebec.ulaval.ca. 3 Research Center in Infectious Diseases of the CHU of Québec and Laval University, 2705, Boul. Laurier (RC-709), Québec City, QC G1V 4G2, Canada. rheaumec@hotmail.com. 4 Research Center in Infectious Diseases of the CHU of Québec and Laval University, 2705, Boul. Laurier (RC-709), Québec City, QC G1V 4G2, Canada. Marieelene.Cavanagh@crchudequebec.ulaval.ca.  5 Research Center in Infectious Diseases of the CHU of Québec and Laval University, 2705, Boul. Laurier (RC-709), Québec City, QC G1V 4G2, Canada. Guy.Boivin@crchul.ulaval.ca.

 

Abstract

Immunosuppressed individuals can shed influenza virus for prolonged periods of time, leading to the frequent emergence of antiviral resistance. We evaluated the benefits of oseltamivir and favipiravir combination therapy compared to single antiviral agents and monitored the emergence of drug-resistant variants in a pharmacologically immunosuppressed mouse model infected with the A(H1N1) pandemic influenza virus. C57BL/6 mice were immunosuppressed with cyclophosphamide and infected with a lethal dose of pandemic influenza A(H1N1) virus. Forty-eight hours post-infection, mice were treated with oseltamivir (20 mg/kg), favipiravir (20 or 50 mg/kg) or both agents BID for 5 or 10 days. Body weight losses, survival rates, lung viral titers, cytokine levels and emergence of resistant viruses were evaluated. Treatment of immunosuppressed mice with high (50 mg/kg) but not low (20 mg/kg) doses of favipiravir in combination with oseltamivir (20 mg/kg) significantly delayed mortality and reduced lung viral titers compared to treatment with a single drug regimen with oseltamivir but did not prevent the emergence of oseltamivir-resistant H275Y neuraminidase variants. Combination therapy with oseltamivir and favipiravir should be considered for evaluation in clinical trials.

KEYWORDS: combination therapy; favipiravir; immunosuppression; mice; oseltamivir; pandemic influenza virus; resistance

PMID: 30400276 DOI: 10.3390/v10110610

Keywords: Influenza A; H1N1pdm09; Antivirals; Drugs Resistance; Oseltamivir; Favipiravir; Animal models.

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#Favipiravir inhibits in vitro #Usutu virus replication and delays disease progression in an #infection model in mice (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res. 2018 Oct 29. pii: S0166-3542(18)30467-4. doi: 10.1016/j.antiviral.2018.10.026. [Epub ahead of print]

Favipiravir inhibits in vitro Usutu virus replication and delays disease progression in an infection model in mice.

Segura Guerrero NA1, Sharma S2, Neyts J3, Kaptein SJF2.

Author information: 1 KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium; Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia. 2 KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium. 3 KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium. Electronic address: johan.neyts@kuleuven.be.

 

Abstract

Usutu virus (USUV) is an emerging flavivirus that causes Usutu disease mainly in birds, but infection of mammals such as rodents, bats and horses has also been demonstrated. In addition, human cases (both in immunocompromised and -competent individuals) were also reported. Large outbreaks with other flaviviruses, such as West Nile virus and Zika virus, indicate that one should be vigilant for yet other outbreaks. To allow the identification of inhibitors of USUV replication, we established in vitro antiviral assays, which were validated using a small selection of known flavivirus inhibitors, including the broad-spectrum viral RNA polymerase inhibitor favipiravir (T-705). Next, an USUV infection model in AG129 (IFN-α/β and IFN-γ receptor knockout) mice was established. AG129 mice proved highly susceptible to USUV; an inoculum as low as 102 PFU (1.3 × 105 TCID50) resulted in the development of symptoms as early as 3 days post infection with viral RNA being detectable in various tissues. Treatment of mice with favipiravir (150 mg/kg/dose, BID, oral gavage) significantly reduced viral load in blood and tissues and significantly delayed virus-induced disease. This USUV mouse model is thus amenable for assessing the potential in vivo efficacy of (novel) USUV/flavivirus inhibitors.

KEYWORDS: AG129 mice; Antivirals; Emerging flavivirus; Mouse model; Usutu virus

PMID: 30385306 DOI: 10.1016/j.antiviral.2018.10.026

Keywords: Flavivirus; Usutu virus; Antivirals; Favipiravir; Animal models.

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Determining the #Mutation Bias of #Favipiravir in #Influenza Using Next-generation #Sequencing (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Determining the Mutation Bias of Favipiravir in Influenza Using Next-generation Sequencing

Daniel H. Goldhill, Pinky Langat, Hongyao Xie, Monica Galiano, Shahjahan Miah, Paul Kellam, Maria Zambon, Angie Lackenby, Wendy Barclay

DOI: 10.1128/JVI.01217-18

 

ABSTRACT

Favipiravir is a broad-spectrum antiviral drug that may be used to treat influenza. Previous research has identified that favipiravir likely acts as a mutagen but the precise mutation bias that favipiravir induces in influenza virus RNAs has not been described. Here, we use next-generation sequencing (NGS) with barcoding of individual RNA molecules to accurately and quantitatively detect favipiravir-induced mutations and to sample orders of magnitude more mutations than would be possible through Sanger sequencing. We demonstrate that favipiravir causes mutations and show that favipiravir primarily acts as a guanine analogue and secondarily as an adenine analogue resulting in the accumulation of transition mutations. We also use a standard NGS pipeline to show that the mutagenic effect of favipiravir can be measured by whole genome sequencing of virus.

 

IMPORTANCE

New antiviral drugs are needed as a first line of defence in the event of a novel influenza pandemic. Favipiravir is a broad-spectrum antiviral which is effective against influenza. The exact mechanism of how favipiravir works to inhibit influenza is still unclear. We used next-generation sequencing (NGS) to demonstrate that favipiravir causes mutations in influenza RNA. The greater depth of NGS sequence information over traditional sequencing methods allowed us to precisely determine the bias of particular mutations caused by favipiravir. NGS can also be used in a standard diagnostic pipeline to show that favipiravir is acting on the virus by revealing the mutation bias pattern typical to the drug. Our work will aid in testing whether viruses are resistant to favipiravir and may help demonstrate the effect of favipiravir on viruses in a clinical setting. This will be important if favipiravir is used during a future influenza pandemic.

Copyright © 2018 Goldhill et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Influenza A; Antivirals; Drugs Resistance; Favipiravir.

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Therapeutic effects of #favipiravir against #SFTS virus #infection in a lethal mouse model: Dose-efficacy studies upon oral administration (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]

PLoS One. 2018 Oct 26;13(10):e0206416. doi: 10.1371/journal.pone.0206416. eCollection 2018.

Therapeutic effects of favipiravir against severe fever with thrombocytopenia syndrome virus infection in a lethal mouse model: Dose-efficacy studies upon oral administration.

Tani H1,2, Komeno T3, Fukuma A1, Fukushi S1, Taniguchi S1, Shimojima M1, Uda A4, Morikawa S4, Nakajima N3, Furuta Y3, Saijo M1.

Author information: 1 Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan. 2 Department of Virology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. 3 Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan. 4 Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan.

 

Abstract

Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), is a viral hemorrhagic fever with a high case fatality rate. Favipiravir was reported to be effective in the treatment of SFTSV infection in vivo in type I interferon receptor knockout (IFNAR-/-) mice at treatment dosages of both 60 mg/kg/day and 300 mg/kg/day for a duration of 5 days. In this study, the efficacy of favipiravir at dosages of 120 mg/kg/day and 200 mg/kg/day against SFTSV infection in an IFNAR-/- mouse infection model was investigated. IFNAR-/- mice were subcutaneously infected with SFTSV at a 1.0 × 106 50% tissue culture infectious dose followed by twice daily administration of favipiravir, comprising a total dose of either 120 mg/kg/day or 200 mg/kg/day. The treatment was initiated either immediately post infection or at predesignated time points post infection. Neutralizing antibodies in the convalescent-phase mouse sera was examined by the pseudotyped VSV system. All mice treated with favipiravir at dosages of 120 mg/kg/day or 200 mg/kg/day survived when the treatment was initiated at no later than 4 days post infection. A decrease in body weight of mice was observed when the treatment was initiated at 3-4 days post infection. Furthermore, all control mice died. The body weight of mice did not decrease when treatment with favipiravir was initiated immediately post infection at dosages of 120 mg/kg/day and 200 mg/kg/day. Neutralizing antibodies were detected in the convalescent-phase mouse sera. Similar to the literature-reported peritoneal administration of favipiravir at 300 mg/kg/day, the oral administration of favipiravir at dosages of 120 mg/kg/day and 200 mg/kg/day to IFNAR-/- mice infected with SFTSV was effective.

PMID: 30365543 DOI: 10.1371/journal.pone.0206416

Keywords: SFTS; Antivirals; Favipiravir; Animal Models.

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The effectiveness of #antiviral agents with broad-spectrum activity against #chikungunya virus varies between host cell lines (Antivir Chem Chemother., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antivir Chem Chemother. 2018 Jan-Dec;26:2040206618807580. doi: 10.1177/2040206618807580.

The effectiveness of antiviral agents with broad-spectrum activity against chikungunya virus varies between host cell lines.

Franco EJ1,2, Rodriquez JL1, Pomeroy JJ1, Hanrahan KC1, Brown AN1.

Author information: 1 Department of Medicine, Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, FL, USA. 2 Department of Pharmaceutics, University of Florida College of Pharmacy, Orlando, FL, USA.

 

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne virus that has recently emerged in the Western Hemisphere. Approved antiviral therapies or vaccines for the treatment or prevention of CHIKV infections are not available. This study aims to evaluate the antiviral activity of commercially available broad-spectrum antivirals against CHIKV. Due to host cell-specific variability in uptake and intracellular processing of drug, we evaluated the antiviral effects of each agent in three cell lines. Antiviral activities of ribavirin (RBV), interferon-alfa (IFN-α) and favipiravir (FAV) were assessed in CHIKV-infected Vero, HUH-7, and A549 cells. CHIKV-infected cells were treated with increasing concentrations of each agent for three days and viral burden was quantified by plaque assay on Vero cells. Cytotoxic effects of RBV, FAV and IFN-α were also evaluated. Antiviral activity differed depending on the cell line used for evaluation. RBV had the greatest antiviral effect in HUH-7 cells (EC50 = 2.575 µg/mL); IFN-α was most effective in A549 cells (EC50 = 4.235 IU/mL); and FAV in HUH-7 cells (EC50 = 20.00 μg/mL). The results of our study show FAV and IFN-α are the most promising candidates, as their use led to substantial reductions in viral burden at clinically achievable concentrations in two human-derived cell lines. FAV is an especially attractive candidate for further investigation due to its oral bioavailability. These findings also highlight the importance of cell line selection for preclinical drug trials.

KEYWORDS: Chikungunya virus; antiviral agents; drug repurposing; favipiravir; interferon-alpha; ribavirin

PMID: 30354193 DOI: 10.1177/2040206618807580

Keywords: Chikungunya fever; Antivirals; Interferons; Favipiravir; Ribavirin.

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The #mechanism of #resistance to #favipiravir in #influenza (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

The mechanism of resistance to favipiravir in influenza

Daniel H. Goldhill, Aartjan J. W. te Velthuis, Robert A. Fletcher, Pinky Langat, Maria Zambon, Angie Lackenby, and Wendy S. Barclay

PNAS published ahead of print October 23, 2018 / DOI: https://doi.org/10.1073/pnas.1811345115

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved October 2, 2018 (received for review July 2, 2018)

 

Significance

Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections, in particular due to the apparent lack of emergence of resistance mutations against the drug in cell culture or animal studies. We demonstrate here that a mutation in a conserved region of the viral RNA polymerase confers resistance to favipiravir in vitro and in cell culture. The resistance mutation has a cost to viral fitness, but this can be restored by a compensatory mutation in the polymerase. Our findings support the development of favipiravir-resistance diagnostic and surveillance testing strategies and reinforce the importance of considering combinations of therapies to treat influenza infections.

 

Abstract

Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.

antiviral – resistance – polymerase – influenza – virus

Keywords: Influenza A; Antivirals; Drugs resistance; Favipiravir; H1N1pdm09.

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#Ebola viral #dynamics in nonhuman #primates provides insights into virus immuno-pathogenesis and #antiviral strategies (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 01 October 2018

Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies

Vincent Madelain, Sylvain Baize, Frédéric Jacquot, Stéphanie Reynard, Alexandra Fizet, Stephane Barron, Caroline Solas, Bruno Lacarelle, Caroline Carbonnelle, France Mentré, Hervé Raoul, Xavier de Lamballerie & Jérémie Guedj

Nature Communications, volume 9, Article number: 4013 (2018)

 

Abstract

Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks.

Keywords: Ebola; Antivirals; Favipiravir; Remdesivir; Animal Models.

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