{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:14:19Z","timestamp":1791951259196,"version":"4.3.4"},"reference-count":100,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003921","name":"Department of Health, Australian Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003921","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Antiviral drugs are an important measure of control for influenza in the population, particularly for those that are severely ill or hospitalised. The neuraminidase inhibitor (NAI) class of drugs, including oseltamivir, have been the standard of care (SOC) for severe influenza illness for many years. The approval of drugs with novel mechanisms of action, such as baloxavir marboxil, is important and broadens potential treatment options for combination therapy. The use of antiviral treatments in combination for influenza is of interest; one potential benefit of this treatment strategy is that the combination of drugs with different mechanisms of action may lower the selection of resistance due to treatment. In addition, combination therapy may become an important treatment option to improve patient outcomes in those with severe illness due to influenza or those that are immunocompromised. Clinical trials increasingly evaluate drug combinations in a range of patient cohorts. Here, we summarise preclinical and clinical advances in combination therapy for the treatment of influenza with reference to immunocompromised animal models and clinical data in hospitalised patient cohorts where available. There is a wide array of drug categories in development that have also been tested in combination. Therefore, in this review, we have included polymerase inhibitors, monoclonal antibodies (mAbs), host-targeted therapies, and adjunctive therapies. Combination treatment regimens should be carefully evaluated to determine whether they provide an added benefit relative to effectiveness of monotherapy and in a variety of patient cohorts, particularly, if there is a greater chance of an adverse outcome. Safe and effective treatment of influenza is important not only for seasonal influenza infection, but also if a pandemic strain was to emerge.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010481","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T17:25:46Z","timestamp":1652376346000},"page":"e1010481","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":46,"title":["Preclinical and clinical developments for combination treatment of influenza"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8346-1624","authenticated-orcid":true,"given":"Paulina","family":"Koszalka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanta","family":"Subbarao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1230-0735","authenticated-orcid":true,"given":"Mariana","family":"Baz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"issue":"11","key":"ppat.1010481.ref001","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1038\/s41564-019-0513-7","article-title":"The structure of the influenza A virus genome","volume":"4","author":"B Dadonaite","year":"2019","journal-title":"Nat 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Goodwin","year":"2006","journal-title":"Vaccine"},{"issue":"6","key":"ppat.1010481.ref005","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1080\/21645515.2018.1445446","article-title":"Seasonal influenza vaccine in immunocompromised persons","volume":"14","author":"M Bosaeed","year":"2018","journal-title":"Hum Vaccin Immunother"},{"issue":"3","key":"ppat.1010481.ref006","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/clpt.2009.142","article-title":"Stockpiling antiviral drugs for the next influenza pandemic","volume":"86","author":"A Patel","year":"2009","journal-title":"Clinical Pharmacology & Therapeutics"},{"issue":"3620","key":"ppat.1010481.ref007","first-page":"862","article-title":"Antiviral activity of 1-adamantanamine (amantadine).","volume":"144","author":"W Davies","year":"1964"},{"issue":"4","key":"ppat.1010481.ref008","first-page":"141","volume":"10","author":"CU Kim","year":"1999","journal-title":"Neuraminidase inhibitors as anti-influenza virus 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trial.","volume":"20","author":"MG Ison","year":"2020"},{"key":"ppat.1010481.ref013","article-title":"S-033447\/S-033188, a novel small molecule inhibitor of cap-dependent endonuclease of influenza A and B virus: in vitro antiviral activity against clinical strains.","author":"T Noshi","year":"2016","journal-title":"Poster presentation at OPTIONS IX."},{"issue":"1","key":"ppat.1010481.ref014","first-page":"1","article-title":"A two-year survey of the oseltamivir-resistant influenza A (H1N1) virus in Yamagata.","volume":"7","author":"Y Matsuzaki","year":"2010","journal-title":"Japan and the clinical effectiveness of oseltamivir and zanamivir."},{"issue":"3","key":"ppat.1010481.ref015","first-page":"346","article-title":"Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: impact on clinical and virologic outcomes in uncomplicated influenza.","volume":"221","author":"T 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Lee","year":"2009"},{"issue":"5","key":"ppat.1010481.ref024","first-page":"e1003343","article-title":"Prolonged influenza virus shedding and emergence of antiviral resistance in immunocompromised patients and ferrets.","volume":"9","author":"E van der Vries","year":"2013"},{"issue":"2","key":"ppat.1010481.ref025","first-page":"214","article-title":"The natural history of influenza infection in the severely immunocompromised vs nonimmunocompromised hosts.","volume":"58","author":"MJ Memoli","year":"2014"},{"issue":"6","key":"ppat.1010481.ref026","first-page":"760","article-title":"Recovery of drug-resistant influenza virus from immunocompromised patients: a case series.","volume":"193","author":"MG Ison","year":"2006"},{"issue":"9","key":"ppat.1010481.ref027","first-page":"867","article-title":"Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient.","volume":"348","author":"DM 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infection.","volume":"50","author":"KK To","year":"2010"},{"issue":"4","key":"ppat.1010481.ref036","first-page":"507","article-title":"Benefit of early initiation of influenza antiviral treatment to pregnant women hospitalized with laboratory-confirmed influenza.","volume":"214","author":"IK Oboho","year":"2016"},{"issue":"7","key":"ppat.1010481.ref037","first-page":"735","article-title":"Antiviral treatment of influenza in children: a retrospective cohort study.","volume":"31","author":"L Shi","year":"2014"},{"key":"ppat.1010481.ref038","article-title":"A Phase 2 Study of Pimodivir (JNJ-63623872) in Combination With Oseltamivir in Elderly and Nonelderly Adults Hospitalized With Influenza A Infection: OPAL Study.","author":"B O\u2019Neil","year":"2020","journal-title":"J Infect Dis"},{"issue":"10","key":"ppat.1010481.ref039","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1093\/infdis\/jiz656","article-title":"Comparative effectiveness of combined favipiravir and oseltamivir 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Newer influenza antivirals, biotherapeutics and combinations.","volume":"7","author":"FGJI Hayden","year":"2013"},{"key":"ppat.1010481.ref048","article-title":"Inhibitory effect of S-033188, a novel inhibitor of influenza virus Cap-dependent endonuclease, against avian influenza A\/H7N9 virus in vitro and in vivo.","author":"K Taniguchi","year":"2017"},{"issue":"7","key":"ppat.1010481.ref049","first-page":"3741","article-title":"T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro.","volume":"87","author":"T Baranovich","year":"2013"},{"key":"ppat.1010481.ref050","doi-asserted-by":"crossref","first-page":"105035","DOI":"10.1016\/j.antiviral.2021.105035","article-title":"Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir","volume":"188","author":"MC Patel","year":"2021","journal-title":"Antiviral Res"},{"issue":"2","key":"ppat.1010481.ref051","first-page":"782","article-title":"T-705 (favipiravir) inhibition of arenavirus replication in cell culture.","volume":"55","author":"M Mendenhall","year":"2011"},{"issue":"7","key":"ppat.1010481.ref052","first-page":"449","article-title":"Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase.","volume":"93","author":"Y Furuta","year":"2017"},{"key":"ppat.1010481.ref053","first-page":"153","article-title":"Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model.","volume":"104","author":"SJ Smither","year":"2014"},{"issue":"5","key":"ppat.1010481.ref054","first-page":"a038687","article-title":"Influenza polymerase inhibitors: mechanisms of action and resistance.","volume":"11","author":"EJCSHpim Takashita","year":"2021"},{"issue":"4","key":"ppat.1010481.ref055","doi-asserted-by":"crossref","DOI":"10.3851\/IMP3212","article-title":"Pimodivir treatment in adult volunteers experimentally inoculated with live influenza virus: a Phase IIa, randomized, double-blind, placebo-controlled study, 335\u01e644.","volume":"23","author":"JM Trevejo","year":"2018","journal-title":"Antivir Ther."},{"issue":"7","key":"ppat.1010481.ref056","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1093\/infdis\/jiy547","article-title":"Phase 2b study of pimodivir (JNJ-63623872) as monotherapy or in combination with oseltamivir for treatment of acute uncomplicated seasonal influenza A: TOPAZ trial.","volume":"219","author":"RW Finberg","year":"2019","journal-title":"J Infect Dis"},{"issue":"10","key":"ppat.1010481.ref057","first-page":"1139","article-title":"In Vitro combinations of baloxavir acid and other inhibitors against seasonal influenza a viruses.","volume":"12","author":"L Checkmahomed","year":"2020"},{"issue":"3","key":"ppat.1010481.ref058","first-page":"654","article-title":"Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection.","volume":"74","author":"K Fukao","year":"2019"},{"issue":"12","key":"ppat.1010481.ref059","first-page":"1968","article-title":"Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A\/H3N2.","volume":"8","author":"Z Mhamdi","year":"2020","journal-title":"Virus"},{"key":"ppat.1010481.ref060","first-page":"105126","article-title":"Baloxavir-oseltamivir combination therapy inhibits the emergence of resistant substitutions in influenza A virus PA gene in a mouse model.","author":"J-H Park","year":"2021"},{"issue":"11","key":"ppat.1010481.ref061","first-page":"1053","article-title":"Evaluation of drug\u2013drug interaction potential between baloxavir marboxil and oseltamivir in healthy subjects.","volume":"38","author":"N Kawaguchi","year":"2018"},{"issue":"9","key":"ppat.1010481.ref062","first-page":"1637","article-title":"Early combination treatment with baloxavir and peramivir for hospitalized adults with influenza A in Yokohama.","volume":"39","author":"Y Yoshimura","year":"2020","journal-title":"Japan"},{"issue":"6","key":"ppat.1010481.ref063","first-page":"1279","article-title":"In vitro activity of favipiravir and neuraminidase inhibitor combinations against oseltamivir-sensitive and oseltamivir-resistant pandemic influenza A (H1N1) virus.","volume":"159","author":"EB Tarbet","year":"2014"},{"issue":"1","key":"ppat.1010481.ref064","first-page":"126","article-title":"Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice.","volume":"54","author":"DF Smee","year":"2010"},{"issue":"1","key":"ppat.1010481.ref065","first-page":"103","article-title":"Combinations of favipiravir and peramivir for the treatment of pandemic influenza A\/California\/04\/2009 (H1N1) virus infections in mice.","volume":"94","author":"EB Tarbet","year":"2012"},{"issue":"7","key":"ppat.1010481.ref066","first-page":"e101325","article-title":"Combination effects of peramivir and favipiravir against oseltamivir-resistant 2009 pandemic influenza A (H1N1) infection in mice.","volume":"9","author":"S Park","year":"2014"},{"issue":"1","key":"ppat.1010481.ref067","first-page":"1","article-title":"Combinations of oseltamivir and T-705 extend the treatment window for highly pathogenic influenza A (H5N1) virus infection in mice.","volume":"6","author":"BM Marathe","year":"2016"},{"issue":"11","key":"ppat.1010481.ref068","first-page":"610","article-title":"Combination therapy with oseltamivir and favipiravir delays mortality but does not prevent oseltamivir resistance in immunodeficient mice infected with pandemic A (H1N1) influenza virus.","volume":"10","author":"M Baz","year":"2018"},{"key":"ppat.1010481.ref069","first-page":"103125","article-title":"Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza.","volume":"62","author":"Y Wang","year":"2020"},{"issue":"7","key":"ppat.1010481.ref070","first-page":"e191","article-title":"Favipiravir and zanamivir cleared infection with influenza B in a severely immunocompromised child.","volume":"71","author":"CK Lumby","year":"2020"},{"key":"ppat.1010481.ref071","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.antiviral.2016.10.009","article-title":"Activities of JNJ63623872 and oseltamivir against influenza A H1N1pdm and H3N2 virus infections in mice","volume":"136","author":"DF Smee","year":"2016","journal-title":"Antiviral Res"},{"issue":"3","key":"ppat.1010481.ref072","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1128\/AAC.04623-14","article-title":"Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit","volume":"59","author":"RA Byrn","year":"2015","journal-title":"Antimicrob Agents 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delivery of anti-influenza monoclonal antibodies results in enhanced antiviral activities and enables broad-coverage combination therapies.","volume":"94","author":"A Vigil","year":"2020"},{"issue":"1","key":"ppat.1010481.ref080","first-page":"1","article-title":"Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice.","volume":"3","author":"M Kiso","year":"2020"},{"issue":"9","key":"ppat.1010481.ref081","first-page":"e00284","article-title":"Monoclonal antibody therapy protects pharmacologically immunosuppressed mice from lethal infection with influenza B virus.","volume":"64","author":"BM Marathe","year":"2020"},{"issue":"1","key":"ppat.1010481.ref082","first-page":"1","article-title":"A potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus.","volume":"6","author":"Y Wu","year":"2015"},{"issue":"7","key":"ppat.1010481.ref083","doi-asserted-by":"crossref","first-page":"e0236172","DOI":"10.1371\/journal.pone.0236172","article-title":"Broader neutralization of CT-P27 against influenza A subtypes by combining two human monoclonal antibodies.","volume":"15","author":"KS Yi","year":"2020","journal-title":"PLoS ONE."},{"issue":"3","key":"ppat.1010481.ref084","first-page":"356","article-title":"The hemagglutinin A stem antibody MEDI8852 prevents and controls disease and limits transmission of pandemic influenza viruses.","volume":"216","author":"CI Paules","year":"2017"},{"issue":"11","key":"ppat.1010481.ref085","first-page":"e00694","article-title":"Evaluation of MEDI8852, an anti-influenza a monoclonal antibody, in treating acute uncomplicated influenza.","volume":"62","author":"SO Ali","year":"2018"},{"issue":"2","key":"ppat.1010481.ref086","first-page":"1061","article-title":"Santoro MGJAa, chemotherapy, Synergistic effect of nitazoxanide with 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