{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:39:25Z","timestamp":1790419165092,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2017,11,25]],"date-time":"2017-11-25T00:00:00Z","timestamp":1511568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan","doi-asserted-by":"crossref","award":["16H06429"],"award-info":[{"award-number":["16H06429"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan","doi-asserted-by":"crossref","award":["16K21723"],"award-info":[{"award-number":["16K21723"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan","doi-asserted-by":"crossref","award":["16H06434"],"award-info":[{"award-number":["16H06434"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Japan Initiative for Global Research Network on Infectious Diseases"},{"name":"JSPS KAKENHI","award":["25460562"],"award-info":[{"award-number":["25460562"]}]},{"name":"Center for Research on Influenza Pathogenesis"},{"name":"National Institute for Allergy and Infectious Diseases","award":["HHSN272201400008C"],"award-info":[{"award-number":["HHSN272201400008C"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Treatment of immunocompromised, influenza virus\u2013infected 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u2013resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor\u2013resistant variants.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jix606","type":"journal-article","created":{"date-parts":[[2017,11,23]],"date-time":"2017-11-23T23:11:46Z","timestamp":1511478706000},"page":"887-896","source":"Crossref","is-referenced-by-count":35,"title":["Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus"],"prefix":"10.1093","volume":"217","author":[{"given":"Maki","family":"Kiso","sequence":"first","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago J S","family":"Lopes","sequence":"additional","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan"},{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin\u2013Madison"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiya","family":"Yamayoshi","sequence":"additional","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutsumi","family":"Ito","sequence":"additional","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Institute of Infectious Diseases, Tokyo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Institute of Infectious Diseases, Tokyo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin\u2013Madison"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kawaoka","sequence":"additional","affiliation":[{"name":"Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan"},{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin\u2013Madison"},{"name":"ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,11,25]]},"reference":[{"key":"2026041420074347400_CIT0001","doi-asserted-by":"crossref","first-page":"4929","DOI":"10.3390\/v7092850","article-title":"Clinical implications of antiviral resistance in 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