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Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial.

Abstract

BACKGROUND

Neuraminidase inhibitors are thought to be efficacious in reducing the time to alleviation of symptoms in outpatients with seasonal influenza. The objective of this study was to compare the short-term virological efficacy of oseltamivir-zanamivir combination versus each monotherapy plus placebo.

METHODS AND FINDINGS

We conducted a randomized placebo-controlled trial with 145 general practitioners throughout France during the 2008-2009 seasonal influenza epidemic. Patients, general practitioners, and outcome assessors were all blinded to treatment assignment. Adult outpatients presenting influenza-like illness for less than 36 hours and a positive influenza A rapid test diagnosis were randomized to oseltamivir 75 mg orally twice daily plus zanamivir 10 mg by inhalation twice daily (OZ), oseltamivir plus inhaled placebo (O), or zanamivir plus oral placebo (Z). Treatment efficacy was assessed virologically according to the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/µl at day 2 (primary outcome), and clinically to the time to alleviation of symptoms until day 14. Overall 541 patients (of the 900 planned) were included (OZ,  =192; O, n=176; Z, n=173), 49% male, mean age 39 years. In the intention-to-treat analysis conducted in the 447 patients with RT-PCR-confirmed influenza A, 46%, 59%, and 34% in OZ (n=157), O (n=141), and Z (n=149) arms had RT-PCR<200 cgeq/µl (-13.0%, 95% confidence interval [CI] -23.1 to -2.9, p=0.025; +12.3%, 95% CI 2.39-22.2, p=0.028 for OZ/O and OZ/Z comparisons). Mean day 0 to day 2 viral load decrease was 2.14, 2.49, and 1.68 log(10) cgeq/µl (p=0.060, p=0.016 for OZ/O and OZ/Z). Median time to alleviation of symptoms was 4.0, 3.0, and 4.0 days (+1.0, 95% CI 0.0-4.0, p=0.018; +0.0, 95% CI -3.0 to 3.0, p=0.960 for OZ/O and OZ/Z). Four severe adverse events were observed. Nausea and/or vomiting tended to be more frequent in the combination arm (OZ, n=13; O, n=4; and Z, n=5 patients, respectively).

CONCLUSIONS

In adults with seasonal influenza A mainly H3N2 virus infection, the oseltamivir-zanamivir combination appeared less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy. Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice.

TRIAL REGISTRATION

www.ClinicalTrials.govNCT00799760.

Links

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  • Authors+Show Affiliations

    ,

    Inserm CIC 007, APHP, Hôpital Bichat, Paris, France.

    , , , , , , , , , , , , ,

    Source

    PLoS medicine 7:11 2010 Nov 02 pg e1000362

    MeSH

    Adult
    Antiviral Agents
    Double-Blind Method
    Drug Therapy, Combination
    Female
    Humans
    Influenza, Human
    Male
    Middle Aged
    Oseltamivir
    Treatment Outcome
    Zanamivir

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21072246

    Citation

    Duval, Xavier, et al. "Efficacy of Oseltamivir-zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: a Randomized Placebo-controlled Trial." PLoS Medicine, vol. 7, no. 11, 2010, pp. e1000362.
    Duval X, van der Werf S, Blanchon T, et al. Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS Med. 2010;7(11):e1000362.
    Duval, X., van der Werf, S., Blanchon, T., Mosnier, A., Bouscambert-Duchamp, M., Tibi, A., ... Leport, C. (2010). Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS Medicine, 7(11), pp. e1000362. doi:10.1371/journal.pmed.1000362.
    Duval X, et al. Efficacy of Oseltamivir-zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: a Randomized Placebo-controlled Trial. PLoS Med. 2010 Nov 2;7(11):e1000362. PubMed PMID: 21072246.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. AU - Duval,Xavier, AU - van der Werf,Sylvie, AU - Blanchon,Thierry, AU - Mosnier,Anne, AU - Bouscambert-Duchamp,Maude, AU - Tibi,Annick, AU - Enouf,Vincent, AU - Charlois-Ou,Cécile, AU - Vincent,Corine, AU - Andreoletti,Laurent, AU - Tubach,Florence, AU - Lina,Bruno, AU - Mentré,France, AU - Leport,Catherine, AU - ,, Y1 - 2010/11/02/ PY - 2010/04/29/received PY - 2010/09/22/accepted PY - 2010/11/13/entrez PY - 2010/11/13/pubmed PY - 2011/3/16/medline SP - e1000362 EP - e1000362 JF - PLoS medicine JO - PLoS Med. VL - 7 IS - 11 N2 - BACKGROUND: Neuraminidase inhibitors are thought to be efficacious in reducing the time to alleviation of symptoms in outpatients with seasonal influenza. The objective of this study was to compare the short-term virological efficacy of oseltamivir-zanamivir combination versus each monotherapy plus placebo. METHODS AND FINDINGS: We conducted a randomized placebo-controlled trial with 145 general practitioners throughout France during the 2008-2009 seasonal influenza epidemic. Patients, general practitioners, and outcome assessors were all blinded to treatment assignment. Adult outpatients presenting influenza-like illness for less than 36 hours and a positive influenza A rapid test diagnosis were randomized to oseltamivir 75 mg orally twice daily plus zanamivir 10 mg by inhalation twice daily (OZ), oseltamivir plus inhaled placebo (O), or zanamivir plus oral placebo (Z). Treatment efficacy was assessed virologically according to the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/µl at day 2 (primary outcome), and clinically to the time to alleviation of symptoms until day 14. Overall 541 patients (of the 900 planned) were included (OZ,  =192; O, n=176; Z, n=173), 49% male, mean age 39 years. In the intention-to-treat analysis conducted in the 447 patients with RT-PCR-confirmed influenza A, 46%, 59%, and 34% in OZ (n=157), O (n=141), and Z (n=149) arms had RT-PCR<200 cgeq/µl (-13.0%, 95% confidence interval [CI] -23.1 to -2.9, p=0.025; +12.3%, 95% CI 2.39-22.2, p=0.028 for OZ/O and OZ/Z comparisons). Mean day 0 to day 2 viral load decrease was 2.14, 2.49, and 1.68 log(10) cgeq/µl (p=0.060, p=0.016 for OZ/O and OZ/Z). Median time to alleviation of symptoms was 4.0, 3.0, and 4.0 days (+1.0, 95% CI 0.0-4.0, p=0.018; +0.0, 95% CI -3.0 to 3.0, p=0.960 for OZ/O and OZ/Z). Four severe adverse events were observed. Nausea and/or vomiting tended to be more frequent in the combination arm (OZ, n=13; O, n=4; and Z, n=5 patients, respectively). CONCLUSIONS: In adults with seasonal influenza A mainly H3N2 virus infection, the oseltamivir-zanamivir combination appeared less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy. Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice. TRIAL REGISTRATION: www.ClinicalTrials.govNCT00799760. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/21072246/Efficacy_of_oseltamivir_zanamivir_combination_compared_to_each_monotherapy_for_seasonal_influenza:_a_randomized_placebo_controlled_trial_ L2 - http://dx.plos.org/10.1371/journal.pmed.1000362 DB - PRIME DP - Unbound Medicine ER -