Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial

Duval, Xavier; van der Werf, Sylvie; Blanchon, Thierry; Mosnier, Anne; Bouscambert-Duchamp, Maude; Tibi, Annick; Enouf, Vincent; Charlois-Ou, Cécile; Vincent, Corine; Andreoletti, Laurent; Tubach, Florence; Lina, Bruno; Mentré, France; Leport, Catherine

Neuraminidase inhibitors (oseltamivir [O] , zanamivir [Z] ) are thought to be efficacious as compared to placebo in outpatients with uncomplicated seasonal influenza [1] [2] [3] [4] [5] [6] , both clinically in terms of reduction in duration of symptoms, as well as in terms of a reduction in viral shedding. In 2008, they were considered an important strategy to limit the impact of an influenza pandemic both individually, by reducing morbidity and mortality, and collectively, by slowing spread of the virus to allow time for vaccine production, the cornerstone of influenza control [2] [3] [4] 7] . It was hypothesized that the widespread use of a single antiviral might result in the emergence of resistant strains whose subsequent spread could dramatically reduce the effectiveness of antiviral therapy. The combination of two antiviral agents, if well tolerated, and if producing at least additive antiviral activity, theoretically offers several advantages: reducing disease severity, viral shedding, and viral excretion period, thereby also lowering the attack rate and risk of selection of resistant viruses, specifically in individuals with prolonged viral shedding, such as immunocompromised patients [8, 9] . Indeed, mathematical modelling showed a reduction in risk of emergence of resistant strains during early phases of a pandemic, associated with use of two antivirals as compared to single antiviral therapy [9] . Finally, another theoretical advantage of combining two drugs would be to ensure optimal treatment of all circulating influenza virus types, subtypes, or variants, as susceptibility of influenza viruses has been shown to vary, and seasonal H1N1 viruses naturally resistant to oseltamivir, which remain susceptible to zanamivir, emerged in 2008 [10] . Among antivirals active against influenza virus, the combination of neuraminidase inhibitors is attractive, because both compounds are licensed for seasonal influenza, they are delivered to the respiratory tract by distinct means (directly through a diskhaler for zanamivir, after gastrointestinal absorption and hepatic metabolism for oseltamivir), and key mutations associated with resistance are different for each drug. However, negative interactions cannot not be ruled out owing to the possible competition between these two drugs, which target the same binding pocket in the neuraminidase.