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Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data.

Abstract

BACKGROUND

Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.

OBJECTIVES

To (1) describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu(®), Roche) treatment on mortality in patients with 2009A/H1N1 influenza.

METHODS

We searched trial registries, electronic databases and corresponded with regulators and sponsors to identify randomised trials of NIs. We requested full CSRs and accessed regulators' comments. We included only those trials for which we had CSRs. To examine the effects of oseltamivir on 2009A/H1N1 influenza mortality, we requested individual patient data (IPD) from corresponding authors of all included observational studies.

RESULTS

Effect of oseltamivir and zanamivir (Relenza®, GlaxoSmithKline) in the prevention and treatment of influenza: Oseltamivir reduced the time to first alleviation of symptoms in adults by 16.8 hours [95% confidence interval (CI) 8.4 to 25.1 hours]. Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days). Oseltamivir reduced unverified pneumonia in adult treatment [risk difference (RD) 1.00%, 95% CI 0.22% to 1.49%]; similar findings were observed with zanamivir prophylaxis in adults (RD 0.32%, 95% CI 0.09% to 0.41%). Oseltamivir treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90% to 7.39%) and vomiting (RD 4.56%, 95% CI 2.39% to 7.58%). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75% to 10.29%). Both oseltamivir and zanamivir prophylaxis reduced the risk of symptomatic influenza in individuals (oseltamivir RD 3.05%, 95% CI 1.83% to 3.88%; zanamivir RD 1.98%, 95% CI 0.98% to 2.54%) and in households (oseltamivir RD 13.6%, 95% CI 9.52% to 15.47%; zanamivir RD 14.84%, 95% CI 12.18% to 16.55%). Oseltamivir increased psychiatric adverse events in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07% to 2.76%) and the risk of headaches while on treatment (RD 3.15%, 95% CI 0.88% to 5.78%). Effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza: Analysis of summary data of 30 studies as well as IPD of four studies showed evidence of time-dependent bias. After adjusting for time-dependent bias and potential confounding variables, competing risks analysis of the IPD showed insufficient evidence that oseltamivir reduced the risk of mortality (hazard ratio 1.03, 95% CI 0.64 to 1.65).

CONCLUSIONS

Oseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults. The use of oseltamivir increases the risk of nausea, vomiting, psychiatric events in adults and vomiting in children. Oseltamivir has no protective effect on mortality among patients with 2009A/H1N1 influenza. Prophylaxis with either NI may reduce symptomatic influenza in individuals and in households. The balance between benefits and harms should be considered when making decisions about use of NIs for either prophylaxis or treatment of influenza.

STUDY REGISTRATION

This study is registered as PROSPERO CRD42012002245.

FUNDING

The National Institute for Health Research Health Technology Assessment programme.

Links

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  • Authors+Show Affiliations

    ,

    Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

    ,

    Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

    ,

    School of Population Health, The University of Queensland, Brisbane, QLD, Australia.

    ,

    Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, MD, USA.

    ,

    Centre for Research in Evidence-Based Practice (CREBP), Bond University, Robina, QLD, Australia.

    ,

    Japan Institute of Pharmacovigilance, Osaka, Japan.

    ,

    Department of Family Medicine, University of Washington, Seattle, WA, USA.

    ,

    Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

    ,

    Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

    ,

    Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

    ,

    Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

    The Cochrane Collaboration, Rome, Italy.

    Source

    MeSH

    Adult
    Antiviral Agents
    Asthma
    Child
    Dose-Response Relationship, Drug
    Humans
    Influenza A Virus, H1N1 Subtype
    Influenza, Human
    Neuraminidase
    Oseltamivir
    Randomized Controlled Trials as Topic
    Zanamivir

    Pub Type(s)

    Journal Article
    Meta-Analysis
    Review
    Systematic Review

    Language

    eng

    PubMed ID

    27246259

    Citation

    Heneghan, Carl J., et al. "Neuraminidase Inhibitors for Influenza: a Systematic Review and Meta-analysis of Regulatory and Mortality Data." Health Technology Assessment (Winchester, England), vol. 20, no. 42, 2016, pp. 1-242.
    Heneghan CJ, Onakpoya I, Jones MA, et al. Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. Health Technol Assess. 2016;20(42):1-242.
    Heneghan, C. J., Onakpoya, I., Jones, M. A., Doshi, P., Del Mar, C. B., Hama, R., ... Jefferson, T. (2016). Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. Health Technology Assessment (Winchester, England), 20(42), pp. 1-242. doi:10.3310/hta20420.
    Heneghan CJ, et al. Neuraminidase Inhibitors for Influenza: a Systematic Review and Meta-analysis of Regulatory and Mortality Data. Health Technol Assess. 2016;20(42):1-242. PubMed PMID: 27246259.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. AU - Heneghan,Carl J, AU - Onakpoya,Igho, AU - Jones,Mark A, AU - Doshi,Peter, AU - Del Mar,Chris B, AU - Hama,Rokuro, AU - Thompson,Matthew J, AU - Spencer,Elizabeth A, AU - Mahtani,Kamal R, AU - Nunan,David, AU - Howick,Jeremy, AU - Jefferson,Tom, PY - 2016/6/2/entrez PY - 2016/6/2/pubmed PY - 2018/2/13/medline SP - 1 EP - 242 JF - Health technology assessment (Winchester, England) JO - Health Technol Assess VL - 20 IS - 42 N2 - BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVES: To (1) describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu(®), Roche) treatment on mortality in patients with 2009A/H1N1 influenza. METHODS: We searched trial registries, electronic databases and corresponded with regulators and sponsors to identify randomised trials of NIs. We requested full CSRs and accessed regulators' comments. We included only those trials for which we had CSRs. To examine the effects of oseltamivir on 2009A/H1N1 influenza mortality, we requested individual patient data (IPD) from corresponding authors of all included observational studies. RESULTS: Effect of oseltamivir and zanamivir (Relenza®, GlaxoSmithKline) in the prevention and treatment of influenza: Oseltamivir reduced the time to first alleviation of symptoms in adults by 16.8 hours [95% confidence interval (CI) 8.4 to 25.1 hours]. Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days). Oseltamivir reduced unverified pneumonia in adult treatment [risk difference (RD) 1.00%, 95% CI 0.22% to 1.49%]; similar findings were observed with zanamivir prophylaxis in adults (RD 0.32%, 95% CI 0.09% to 0.41%). Oseltamivir treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90% to 7.39%) and vomiting (RD 4.56%, 95% CI 2.39% to 7.58%). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75% to 10.29%). Both oseltamivir and zanamivir prophylaxis reduced the risk of symptomatic influenza in individuals (oseltamivir RD 3.05%, 95% CI 1.83% to 3.88%; zanamivir RD 1.98%, 95% CI 0.98% to 2.54%) and in households (oseltamivir RD 13.6%, 95% CI 9.52% to 15.47%; zanamivir RD 14.84%, 95% CI 12.18% to 16.55%). Oseltamivir increased psychiatric adverse events in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07% to 2.76%) and the risk of headaches while on treatment (RD 3.15%, 95% CI 0.88% to 5.78%). Effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza: Analysis of summary data of 30 studies as well as IPD of four studies showed evidence of time-dependent bias. After adjusting for time-dependent bias and potential confounding variables, competing risks analysis of the IPD showed insufficient evidence that oseltamivir reduced the risk of mortality (hazard ratio 1.03, 95% CI 0.64 to 1.65). CONCLUSIONS: Oseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults. The use of oseltamivir increases the risk of nausea, vomiting, psychiatric events in adults and vomiting in children. Oseltamivir has no protective effect on mortality among patients with 2009A/H1N1 influenza. Prophylaxis with either NI may reduce symptomatic influenza in individuals and in households. The balance between benefits and harms should be considered when making decisions about use of NIs for either prophylaxis or treatment of influenza. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002245. FUNDING: The National Institute for Health Research Health Technology Assessment programme. SN - 2046-4924 UR - https://www.unboundmedicine.com/medline/citation/27246259/Neuraminidase_inhibitors_for_influenza:_a_systematic_review_and_meta_analysis_of_regulatory_and_mortality_data_ L2 - https://doi.org/10.3310/hta20420 DB - PRIME DP - Unbound Medicine ER -