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  • 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

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Infectious diseases
Research
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
  1. Remi Flicoteaux1,2,
  2. Camelia Protopopescu3,4,
  3. Annick Tibi5,
  4. Thierry Blanchon6,
  5. Sylvie Van Der Werf7,
  6. Xavier Duval1,
  7. Anne Mosnier8,
  8. Cécile Charlois-Ou1,
  9. Bruno Lina9,10,
  10. Catherine Leport1,
  11. Sylvie Chevret2
  1. 1 IAME (Infection, Antimicrobien, Modélisation, Evolution), UMR-1137, Inserm, Université Paris Diderot, Sorbonne Paris Cite, Paris, France
  2. 2 Service de Biostatistique et Information Médicale, ECSTRA Team, UMR-1153, Inserm, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Saint Louis, Paris, France
  3. 3 Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France., Marseille, France
  4. 4 ORS PACA, Observatoire régional de la santé Provence-Alpes-Côte d’Azur, Marseille, France., Marseille, France
  5. 5 Faculte de Pharmacie, Université Paris Descartes, Paris, France
  6. 6 Faculté de Médecine, Inserm Université Pierre et Marie Curie, U1136 - Institut Pierre Louis d’épidémiologie et de santé publique (IPLESP), Paris, France
  7. 7 Institut Pasteur, Centre National de Référence des virus influenzae (Région-Nord), Unité de Génétique Moléculaire des Virus à ARN, Paris, France
  8. 8 Réseau des Groupes Régionaux d’Observation de la Grippe (GROG), Coordination Nationale, Paris, France
  9. 9 Faculté de Médecine Lyon Est, VirPatH, EA 4610, Université Claude Bernard Lyon 1, Lyon, France
  10. 10 Laboratoire de Virologie & CNR des virus influenzae (site Lyon), Hospices Civils de Lyon, Lyon, France
  1. Correspondence to Remi Flicoteaux; remi.flicoteaux{at}aphp.fr

Abstract

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.

RCT registration number NCT00799760. This is a post-result analysis.

  • Medication Non-Adherence
  • Antiviral Agents
  • Human Influenza
  • Controlled Clinical Trials
  • Randomized

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjopen-2016-014546

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    Footnotes

    • Contributors ICMJE criteria for authorship read and met: CP, AT, TB SVDW, XD, AM, CCO, BL, CL and SC. Agree with the manuscript’s results and conclusions: RF, CP, AT, TB, SVDW, XD, AM, CCO, BL, CL and SC. Designed the experiments/the study: RF, XD, SVDW, CL and SC. Analysed the data: RF, CP, CL and SC. Collected data/did experiments for the study: RF, XD, SVDW, TB, CCO, AT and CL. Enrolled patients: CCO. Wrote the first draft of the paper: RF, CL and SC. Contributed to the writing of the paper: RF, TB, SVDW, BL, CL and SC. Enrolled investigators and took part in the epidemiological surveillance which gave the go-ahead to the study: AM. Responsible for data monitoring: RF. Obtained funding: AM,TB and CL.

    • Funding This work was supported by a research grant from the French Ministry of Health. The sponsor was Département à la Recherche Clinique et au Développement, Assistance Publique Hôpitaux de Paris (Programme hospitalier de recherche clinique, AOM 06060 and AOM 08209). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    • Competing interests XD has had a conference invitation from GSK and lecture fees from Roche and Gilead. SVDW has had a conference invitation from GSK, research grant from GSK on unrelated subject, joined patent from institution with GSK on unrelated subject, travel grants for meetings from GSK, contribution to clinical trial financed by Roche, member of the advisory committee on influenza of the French Ministry of Health, is a member of ESWI, is a member of the scientific committee of the GEIG and is vice-president of the GROG network. AM has membership in the ministry of health advisory board on influenza, involvement in some epidemiological studies partially or fully granted by Roche and GSK, and travel grants from Roche for participation in scientific meetings. AM received fees from Roche, preclinical pharmacokinetic department, for a course on MONOLIX in December 2008. BL has had paid consultancy and board membership (Roche, GSK, Novartis, BioCryst, MedImmune), has had research grants from Roche and Sanofi-Pasteur, and had received travel grants and honoraria for speaking or participation at meetings (Roche, Sanofi-Pasteur).

    • Patient consent Obtained.

    • Ethics approval Ethics Committee of Ile de France 1.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Technical appendix, statistical code and data set available on demand to the corresponding author.