Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus

• Published in: The Journal of infectious diseases Vol. 217; no. 6; pp. 887 - 896
• Main Authors: Kiso, Maki, Lopes, Tiago J S, Yamayoshi, Seiya, Ito, Mutsumi, Yamashita, Makoto, Nakajima, Noriko, Hasegawa, Hideki, Neumann, Gabriele, Kawaoka, Yoshihiro
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 05.03.2018
• Subjects: 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
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jix606

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.