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

We must acknowledge several limitations to our study. First, this preliminary analysis was conducted on a partial set of data after enrolment of 541 patients instead of the 900 initially planned. However, it is highly unlikely that the lower response of the combination as compared to oseltamivir would have been reversed if all originally planned 900 patients had been enrolled. Second, as previous randomized clinical trials had shown the superiority of each monotherapy as compared to placebo in terms of time to symptom alleviation and viral shedding, it was decided, on the basis of ethical reasons, that the study would not comprise a double placebo arm. Third, the proportion of patients with unavailable viral swab on day 2 was higher in the combination arm. As the missing value equals failure, this may have biased the results in the combination arm towards reduced performance. Indeed, in the analysis of the 414 patients with available day 0 and day 2 nasal swabs, the same trends were observed. Fourth, the virological response was assessed only in one site (nose) and at one time (day 2), which prevents extrapolation of the results to the entire virological response over time and throughout the respiratory tract. However, clinical endpoints completed the picture, giving information on the overall response. Fifth, as mentioned above, day 2 sampling was chosen to show the virological effect. However, this is probably not the best moment to look for resistance emergence induced by drug selective pressure, as it has been shown to occur later in the course of treatment [18] [19] [20] . Nevertheless, we looked for neuraminidase inhibitor resistance using a standard fluorimetric test in the 65 patients with day 2 positive viral culture; none of them carried a resistant virus, except for one patient infected with an H1N1 virus resistant to oseltamivir but susceptible to zanamivir, as were all H1N1 viruses circulating during the study period. However, the absence of resistance at day 2 does not rule out any further (postday 2) resistance selection. Finally, this trial was conducted in adult outpatients, which prevents any extrapolation of the results to adults with severe presentation necessitating hospitalisation, and to children, who usually have more prolonged viral shedding. We chose the outpatient adult population because it seemed to be the most homogenous and the easiest in which to test our hypothesis.