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Cited by 383Influenza Virus Research StudiesRespiratory viral infections researchBacterial Infections and Vaccines

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Neuraminidase inhibitors for preventing and treating influenza in adults and children

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Jefferson, Tom, Jones, Mark A, Doshi, Peter, Del Mar, Chris B, Hama, Rokuro, Thompson, Matthew J, Spencer, Elizabeth A, Onakpoya, Igho J, Mahtani, Kamal R, Nunan, David, Howick, Jeremy, Heneghan, Carl J·2014·Cochrane Database of Systematic Reviews
DOI 10.1002/14651858.cd008965.pub4PMC PMC6464969
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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 describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. SEARCH METHODS: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. SELECTION CRITERIA: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. DATA COLLECTION AND ANALYSIS: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported. Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children. Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self

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Research works printed but not linked: 5

  1. Cass, 1999, Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers, Clinical Pharmacokinetics, 36, 1, 10.2165/00003088-199936001-00001 · DOI
  2. Ghersi D Clarke MJ Reveiz L Do Cochrane reviews search databases of ongoing trials, and how well do they report these searches? Oral presentation at the Joint Cochrane and Campbell Collaboration http://www.cochrane.org/sites/default/files/uploads/abstract_book_keystone_2010.pdf 2010 45 6 10.1002/14651858 · DOI
  3. Hama R Jones M Hayashi K Yanagi K Sakaguchi K Oseltamivir: a systematic review and meta-analysis of adverse effects in prospective cohort studies Presentation at the 16th Japanese Society for Pharmaco-epidemiology (JSPE) and 5th Activities and Co-operation for Drug Safety in Asia (ACPE) Joint Meeting Tokyo 2010
  4. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) M4: the common technical document http://www.ich.org/products/ctd.html
  5. Jefferson, 2010, Neuraminidase inhibitors for preventing and treating influenza in healthy adults, Cochrane Database of Systematic Reviews, 10.1002/14651858.CD001265.pub2 · DOI

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Authors
Jefferson, T., Jones, M. A., Doshi, P., Del Mar, C. B., Hama, R., Thompson, M. J., Spencer, E. A., Onakpoya, I. J., Mahtani, K. R., Nunan, D., Howick, J., & Heneghan, C. J.
Affiliations
  • University of Oxford (GB)
  • The University of Queensland (AU)
  • University of Maryland, Baltimore (US)
  • Bond University; Centre for Research in Evidence-Based Practice (CREBP); University Drive Gold Coast Queensland Australia 4229
  • Japan Institute of Pharmacovigilance; 902 Ueshio 3-2-17 Osaka Japan 543-0002
  • University of Washington (US)
ORCID
Venue
Cochrane Database of Systematic Reviews
Publisher
Wiley
Published
2014-04-10
Volume
2018
Issue
1
Pages
CD008965-CD008965
ISSN
  • 1361-6137 (ISSN-L)
  • 1465-1858
DOI
10.1002/14651858.cd008965.pub4
PMC
PMC6464969
OpenAlex
W2411777732
Cited by
382
References
104
Citations by year
2026: 15 · 2025: 26 · 2024: 36 · 2023: 34 · 2022: 29 · 2021: 32 · 2020: 44 · 2019: 23 · 2018: 19 · 2017: 30 · 2016: 32 · 2015: 36 · 2014: 24
FWCI
5.43
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Cochrane Database of Systematic Reviews (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • Bond University Research Portal (Bond University) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
Funders
National Institute for Health and Care Research (CL-2011-13-006, 10/80/01)
Topics
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
neuraminidase inhibitors, oseltamivir, zanamivir, influenza, antiviral prophylaxis, antiviral therapy, clinical study reports, risk of bias, selective reporting, attrition bias, performance bias, selection bias, influenza complications, hospitalization, adverse events, children, adults, regulatory comments, pandemic influenza preparedness
MeSH terms
Adult, Antiviral Agents, Child, Drug Evaluation, Enzyme Inhibitors, Europe, United Kingdom, Health Status, Humans, Influenza, Human, Japan, Legislation, Drug, Neuraminidase, Pneumonia, United States, Randomized Controlled Trials as Topic, Publication Bias, Oseltamivir, Zanamivir

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