Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus
Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and redu...
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| Published in | The Journal of infectious diseases Vol. 217; no. 6; pp. 887 - 896 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Oxford University Press
05.03.2018
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| Abstract | Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.
Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.
Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.
Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants. |
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| AbstractList | Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.
Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.
Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.
Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants. Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.BackgroundTreatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.MethodsHere, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.ResultsCombination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants.ConclusionsCollectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants. Immunocompromised mice were infected with an influenza virus and treated with viral neuraminidase or polymerase inhibitors, or combinations thereof. Combination therapy increased survival times but did not prevent the emergence of variants resistant to neuraminidase inhibitors. |
| Author | Yamashita, Makoto Lopes, Tiago J S Kawaoka, Yoshihiro Neumann, Gabriele Yamayoshi, Seiya Ito, Mutsumi Kiso, Maki Hasegawa, Hideki Nakajima, Noriko |
| AuthorAffiliation | 4 ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan 3 Department of Pathology, National Institute of Infectious Diseases, Tokyo 2 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison |
| AuthorAffiliation_xml | – name: 3 Department of Pathology, National Institute of Infectious Diseases, Tokyo – name: 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan – name: 2 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison – name: 4 ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan |
| Author_xml | – sequence: 1 givenname: Maki surname: Kiso fullname: Kiso, Maki organization: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan – sequence: 2 givenname: Tiago J S surname: Lopes fullname: Lopes, Tiago J S organization: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison – sequence: 3 givenname: Seiya surname: Yamayoshi fullname: Yamayoshi, Seiya organization: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan – sequence: 4 givenname: Mutsumi surname: Ito fullname: Ito, Mutsumi organization: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan – sequence: 5 givenname: Makoto surname: Yamashita fullname: Yamashita, Makoto organization: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan – sequence: 6 givenname: Noriko surname: Nakajima fullname: Nakajima, Noriko organization: Department of Pathology, National Institute of Infectious Diseases, Tokyo – sequence: 7 givenname: Hideki surname: Hasegawa fullname: Hasegawa, Hideki organization: Department of Pathology, National Institute of Infectious Diseases, Tokyo – sequence: 8 givenname: Gabriele surname: Neumann fullname: Neumann, Gabriele organization: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison – sequence: 9 givenname: Yoshihiro surname: Kawaoka fullname: Kawaoka, Yoshihiro organization: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin–Madison, ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29186472$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Amides - administration & dosage Amides - therapeutic use Animals Antiviral Agents - administration & dosage Antiviral Agents - therapeutic use Dose-Response Relationship, Drug Drug Therapy, Combination Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - therapeutic use Female Immunocompromised Host Influenza A Virus, H1N1 Subtype - drug effects Lung - pathology Lung - virology Major and Brief Reports Mice Mice, Inbred BALB C Mice, Nude Neuraminidase - antagonists & inhibitors Nucleic Acid Synthesis Inhibitors - administration & dosage Nucleic Acid Synthesis Inhibitors - therapeutic use Orthomyxoviridae Infections - drug therapy Orthomyxoviridae Infections - virology Oseltamivir - administration & dosage Oseltamivir - therapeutic use Pyrazines - administration & dosage Pyrazines - therapeutic use Zanamivir - administration & dosage Zanamivir - analogs & derivatives Zanamivir - therapeutic use |
| Title | Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus |
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