Maki Kiso1, Tiago J S Lopes1,2, Seiya Yamayoshi1, Mutsumi Ito1, Makoto Yamashita1, Noriko Nakajima3, Hideki Hasegawa3, Gabriele Neumann2, Yoshihiro Kawaoka1,2,4. 1. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan. 2. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison. 3. Department of Pathology, National Institute of Infectious Diseases, Tokyo. 4. ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants.
Background: Treatment of immunocompromised, influenza virus-infectedpatients 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. Methods: 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. Results: 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. Conclusions: 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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