Factors associated with non-persistence to oral and inhaled antiviral therapies for seasonal influenza: a secondary analysis of a double-blind, multicentre, randomised clinical trial

Rémi Flicoteaux (1, 2) , Camelia Protopopescu (3, 4) , Annick Tibi (5) , Thierry Blanchon (6) , Sylvie van Der Werf (7, 8) , Xavier Marie Duval (1) , Anne Mosnier (9) , Cécile Charlois-Ou (1) , Bruno Lina (10, 11) , Catherine Leport (1) , Sylvie Chevret (12, 2)

1 IAME (UMR_S_1137 / U1137) - Infection, Anti-microbiens, Modélisation, Evolution
2 SBIM - Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA)
3 SESSTIM - U912 INSERM - Aix Marseille Univ - IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale
4 ORS PACA - Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille]
5 UPD5 Pharmacie - Faculté de Pharmacie de Paris - Université Paris Descartes
6 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique
7 Centre National de Référence de la Grippe (France Nord) - Centre Collaborateur de l'OMS Grippe et autres virus respiratoires (CNR - CCOMS)
8 GMV-ARN (UMR_3569 / U-Pasteur_2) - Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses
9 GROG - Réseau des Groupes Régionaux d'Observation de la Grippe
10 Virpath - Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control
11 CNR - laboratoire associé - Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon]
12 Service de biostatistiques et information médicale [Saint-Louis]

OBJECTIVES: We aimed to evaluate and compare non-adherence to oral and inhaled antiviral therapies prescribed of a randomised clinical trial in outpatients with influenza A infection. DESIGN: A parallel, three-arm, double-blinded trial randomly allocated antiviral therapies twice daily for 5 days: (1) oral oseltamivir plus inhaled zanamivir (arm OZ); (2) oseltamivir plus inhaled placebo (arm Opz); or (3) oral placebo plus inhaled zanamivir (arm poZ). Analysis of non-adherence was a secondary objective of the trial. SETTINGS: Outpatients were enrolled by 145 general practitioners throughout France during the 2008-2009 seasonal influenza epidemics. PARTICIPANTS: A total of 541 adults presenting with influenza-like illness for less than 36 hours. PRIMARY OUTCOMES: Non-persistence, the time between inclusion and the last dose treated as a failure time, was used as the primary endpoint. RESULTS: The proportions of patients who persisted on treatment until the end of prescription were estimated at 85.73% (±3.28%) for the oral route and 82.73% (±3.44%) for the inhaled route. Based on multivariable models, non-persistence was associated with a PCR confirmation of influenza for both the oral (HR=0.54, p=0.010) and inhaled (HR=0.59, p=0.018) drugs and antibiotic coprescriptions (HR=2.07, p=0.007; and HR=1.88, p=0.017, respectively) and active combination treatment (HR=1.71, p=0.035; and HR=1.58, p=0.035, respectively). The hazard of non-persistence of the inhaled therapy was increased compared with that of the oral therapy (HR=1.23, p=0.043). CONCLUSION: In addition to the clinical and virological profiles of influenza infection, non-persistence may have been influenced by an active combination and the route of administration.

Mots clés: Controlled Clinical Trials; Medication Non-Adherence; Randomized; Antiviral Agents; Human Influenza

Domaines: Maladies infectieuses; Santé publique et épidémiologie

Rémi Flicoteaux, Camelia Protopopescu, Annick Tibi, Thierry Blanchon, Sylvie van Der Werf, et al.. Factors associated with non-persistence to oral and inhaled antiviral therapies for seasonal influenza: a secondary analysis of a double-blind, multicentre, randomised clinical trial. BMJ Open, 2017, 7 (7), pp.e014546. ⟨10.1136/bmjopen-2016-014546⟩. ⟨inserm-01980846⟩