Is combination antiviral therapy for influenza the optimal approach?

The recent study by Kumar and colleagues1Kumar D Ison MG Mira J-P et al.Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial.Lancet Infect Dis. 2022; (published online Jan 24.)https://doi.org/10.1016/S1473-3099(21)00469-2Summary Full Text Full Text PDF Scopus (25) Google Scholar showed that coadministration of antiviral agents with differing mechanisms of action against the influenza virus, baloxavir marboxil (a cap-dependent endonuclease inhibitor) plus standard of care (oseltamivir, zanamivir, and peramivir neuraminidase inhibitors; the baloxavir group), shortened the duration of shedding of culturable virus in individuals hospitalised with severe influenza compared with placebo plus standard of care (the control group) and was well tolerated. However, combination antiviral therapy did not result in improved clinical outcomes. Patients were enrolled up to 96 h after symptom onset, with only 39% of patients in the baloxavir group receiving baloxavir within 48 h of symptoms onset; therefore, possibly the timing of administration affected clinical outcomes. For neuraminidase inhibitors, the main current influenza treatment, it has previously been shown that the greatest clinical benefit is observed when antivirals are administered within 48 h of symptoms onset.2Muthuri SG Venkatesan S Myles PR et al.Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.Lancet Respir Med. 2014; 2: 395-404Summary Full Text Full Text PDF PubMed Scopus (517) Google Scholar In-vitro and murine studies of various antiviral agent combinations, including amantadine–oseltamivir–ribavirin (known as the triple combination antiviral drug [TCAD] regimen), MS-257 (an experimental zanamivir–oseltamivir hybrid inhibitor), and baloxavir–oseltamivir, have shown synergistic activity against sensitive and resistant influenza strains.3Lampejo T Influenza and antiviral resistance: an overview.Eur J Clin Microbiol Infect Dis. 2020; 39: 1201-1208Crossref PubMed Scopus (161) Google Scholar, 4Fukao K Noshi T Yamamoto A et al.Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection.J Antimicrob Chemother. 2019; 74: 654-662Crossref PubMed Scopus (65) Google Scholar However, these observations have not translated into improved clinical outcomes in human trials of the TCAD regimen, zanamivir–oseltamivir, or baloxavir plus standard of care in this recent study.1Kumar D Ison MG Mira J-P et al.Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial.Lancet Infect Dis. 2022; (published online Jan 24.)https://doi.org/10.1016/S1473-3099(21)00469-2Summary Full Text Full Text PDF Scopus (25) Google Scholar, 3Lampejo T Influenza and antiviral resistance: an overview.Eur J Clin Microbiol Infect Dis. 2020; 39: 1201-1208Crossref PubMed Scopus (161) Google Scholar Additionally, double dose of oseltamivir has shown no clear benefit in human studies.3Lampejo T Influenza and antiviral resistance: an overview.Eur J Clin Microbiol Infect Dis. 2020; 39: 1201-1208Crossref PubMed Scopus (161) Google Scholar Combination antiviral therapy aiming for more rapid and profound inhibition of viral replication might not be the most appropriate strategy, particularly in more advanced stages of an influenza illness, at reducing influenza-associated morbidity or mortality in the absence of major concerns regarding antiviral resistance. This observation is supported by the fact that although the duration of viral shedding in the study by Kumar and colleagues was longer in the control group, uncontrolled or prolonged heightened viral replication was not a frequent observation in either group; only two (1%) of 208 patients in the baloxavir group and one (1%) of 114 patients in the control group had a positive viral titre at day 10.1Kumar D Ison MG Mira J-P et al.Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial.Lancet Infect Dis. 2022; (published online Jan 24.)https://doi.org/10.1016/S1473-3099(21)00469-2Summary Full Text Full Text PDF Scopus (25) Google Scholar It has been widely recognised since the analysis of the devastating influenza A H1N1 pandemic in 1918, which infected 50% of the world's population and for which 95% of deaths were associated with bacterial coinfection, that secondary bacterial infection accounts for most influenza-associated morbidity and mortality.5Morris DE Cleary DW Clarke SC Secondary bacterial infections associated with influenza pandemics.Front Microbiol. 2017; 81041Crossref PubMed Scopus (308) Google Scholar Rather than combination antiviral strategies, future efforts against influenza should focus on early recognition and diagnosis with rapid initiation of antiviral therapy along with appropriately targeted antimicrobial use in patients with secondary bacterial infection. In view of the lessons from the COVID-19 pandemic, the use of immune agents that modulate the host response to influenza in conjunction with antiviral agents is a potential avenue for continued investigation with scarce data. We declare no competing interests. Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trialCombining baloxavir with NAIs did not result in superior clinical outcomes compared with NAIs alone. The combination of baloxavir plus NAI was well tolerated. The findings suggest that combination antivirals would not be routinely indicated in clinical practice for hospitalised patients with severe influenza. Full-Text PDF