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

Health Technology Assessment, No. 20.42

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Author Information
Southampton (UK): NIHR Journals Library; .

Headline

The study found that the neuraminidase inhibitors oseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults. Oseltamivir increases the risk of nausea, vomiting, psychiatric events in adults and vomiting in children and has no protective effect on mortality among patients with 2009A/H1N1 influenza.

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and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu®, Roche) treatment on mortality in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

Contents

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 10/80/01. The contractual start date was in February 2011. The draft report began editorial review in June 2014 and was accepted for publication in October 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

All review authors have applied for and received competitive research grants. Carl J Heneghan reports grants from the UK National Institute for Health Research (NIHR), the NIHR School of Primary Care, Wellcome Trust and the World Health Organization (WHO) during the conduct of the study, and has received expenses and payments for media work. In addition, he is an expert witness in an ongoing medical device legal case. He receives expenses for teaching evidence-based medicine and is paid for NHS general practitioner work in the out of hours service in Oxford. Tom Jefferson receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. Tom Jefferson is occasionally interviewed by market research companies for anonymous interviews about Phase I or II pharmaceutical products. In 2011–13, Tom Jefferson acted as an expert witness in a labour case on influenza vaccines in health-care workers in Canada. In 1997–9, Tom Jefferson acted as a consultant for Roche, in 2001–2 for GlaxoSmithKline, and in 2003 for Sanofi-Synthelabo for pleconaril, which did not get approval from the US Food and Drug Administration (FDA). Tom Jefferson was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on the drug Tamiflu (oseltamivir, Roche). In 2014–15, Tom Jefferson was a member of two advisory boards for Boerhinger and is in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. Tom Jefferson has a potential financial conflict of interest in the investigation of the drug oseltamivir. Tom Jefferson is acting as an expert witness in a medicolegal negligence case involving the drug oseltamivir (Roche). Peter Doshi received €1500 (£1241; US$2052) from the European Respiratory Society in support of his travel to the society’s September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. Peter Doshi is an associate editor of the British Medical Journal (BMJ). Peter Doshi gratefully acknowledges the American Association of Colleges of Pharmacy for its funding support ($10,000) for a study to analyse written medical information regarding the possible harms of statins. Peter Doshi is also an unpaid member of the IMEDS steering committee at the Reagan–Udall Foundation for the FDA, which focuses on drug safety research. CDelM is the Co-ordinating Editor of the Acute Respiratory Infections Group of the Cochrane Collaboration. CDelM reports personal fees from Key Pharmaceuticals during the conduct of the study; grants from the National Health and Medical Research Council (Australia), grants from NIHR (UK), personal fees from Elsevier and BMJ Books, from conference organisers for International Viral Infections Conference, personal fees from GlaxoSmithKline Pharmaceuticals, personal fees from Key Pharmaceutical, outside the submitted work. Rokuro Hama provided scientific opinions and expert testimony on 11 adverse reaction cases related to oseltamivir for the applications by their families for adverse reaction relief by the Pharmaceuticals and Medical Devices Agency (PMDA) and in the lawsuits for revocation of the PMDA’s decision concerning with these reactions. Most of the cases were reported in the International Journal of Research Studies in Management (2008:20:5–36). Rokuro Hama was an expert witness in the lawsuit on the adverse reaction of (death from) gefitinib against AstraZeneca and Japanese Minister of Health Labour and Welfare, and provided scientific opinions and expert testimony. He argued that gefitinib’s fatal toxicity was known before approval in Japan, as shown in ‘Gefitinib story’ (http://npojip.org/english/The-gefitinib-story.pdf) and in other articles (http://npojip.org/). Plaintiffs finally lost the case on 12 April 2013 at the Supreme Court of Japan. Rokuro Hama has received royalties from a published book.

Copyright © Queen’s Printer and Controller of HMSO 2016. This work was produced by Heneghan et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK363109DOI: 10.3310/hta20420

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