Optimizing antiviral treatment in adult patients hospitalized for severe influenza - a randomized controlled, multi-center trial

BackgroundSince 2021 we are facing the largest ever epizootic of H5N1 avian influenza. Only a few cases in humans have been reported up to now, with no human-to-human transmission. However, the number of large transmission episodes to mammals is increasing and the appearance of adaptive mutations to the mammalian host as well as inter-mammalian transmission events have already been described.1 Such high circulation of a virus for which humans are immunologically naive makes influenza a major candidate for a future pandemic. Currently, therapeutic options against influenza are limited, while this rapidly mutating virus have already shown its potency to develop resistance. For example, H1N1 strains circulating before the 2009 pandemic were resistant to oseltamivir.2 Considering all the above, there is a crucial need to optimize antiviral treatment options as well as to refine the use of existing therapeutics in order to prevent the development of resistance by overuse. RationaleTwo drug families were shown to improve disease outcomes when administered early at the beginning of the disease: oseltamivir, a neuraminidase inhibitor, and baloxavir marboxil.2-8 Data supporting clinical benefit in patients with severe disease requiring hospitalization however are scarce and originate from non-randomized or retrospective studies. Evidence concerning oseltamivir use in hospitalized patients is controversial, especially when administered more than 48 hours after symptom onset. Concerning baloxavir, one retrospective study did not find significant difference compared to oseltamivir when assessing its impact on clinical outcomes such as 30 days all-cause mortality or the length of hospital stay.9 Finally, in one study combination treatment with baloxavir and oseltamivir did not show additional benefit compared to oseltamivir alone. 10Due to the lack of clear guidelines, antiviral prescription patterns in Switzerland are heterogenous: while in some hospitals oseltamivir is used in the majority of severe influenza cases regardless the time elapsed since symptom onset, hence regardless the probability of any clinical benefit, in others antiviral treatment is rarely prescribed.In conclusion, we lack solid data on treatment efficacy of antiviral treatments administered in hospitalized patients, especially late in the course of disease, as well as back up therapeutic options. During a pandemic in a context of limited resources, it would be crucial to identify the population which would benefit the most of antiviral treatment to spare treatment doses, limit unnecessary costs, decrease the risk of resistance and side effects. ObjectivesOur primary objective is to explore alternative treatment options during the early phase of severe influenza: assess the non-inferiority of the antiviral baloxavir compared to oseltamivir in patients hospitalized for severe influenza no later than 48 hours after symptom onset. Our secondary objective is to study the clinical benefits of late antiviral treatment: baloxavir or oseltamivir, compared to placebo in patients hospitalized for severe influenza later than 48 hours post symptom onset. MethodologyThis is a multicenter, double-blind, randomized-controlled trial. We will assess antiviral treatment benefits in two populations: 1) Patients with influenza symptoms evolving for less than 48 hours: two-arms design- baloxavir and oseltamivir; 2) Patients with influenza symptoms evolving for more than 48 hours: 3 arms design- baloxavir, oseltamivir, placebo. Only adults with a confirmed influenza illness by RT-PCR testing requiring hospitalization will be included after getting informed consent. Immunosuppression, severe disease requiring ICU care at admission, underweight (< 40 kg) and pregnancy will be exclusion criteria. The study will be conducted in 4 Swiss tertiary centers and aims to include participants over 2-3 influenza seasons.