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

Heneghan, Carl J., Onakpoya, Igho, Jones, Mark A., Doshi, Peter, Del Mar, Chris B., Hama, Rokuro, Thompson, Matthew J., Spencer, Elizabeth A., Mahtani, Kamal R., Nunan, David, Howick, Jeremy and Jefferson, Tom (2016) Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. Health Technology Assessment, 20 42: 1-242. doi:10.3310/hta20420

Author Heneghan, Carl J.
Onakpoya, Igho
Jones, Mark A.
Doshi, Peter
Del Mar, Chris B.
Hama, Rokuro
Thompson, Matthew J.
Spencer, Elizabeth A.
Mahtani, Kamal R.
Nunan, David
Howick, Jeremy
Jefferson, Tom
Title Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data
Journal name Health Technology Assessment   Check publisher's open access policy
ISSN 2046-4924
Publication date 2016-05-01
Year available 2016
Sub-type Critical review of research, literature review, critical commentary
DOI 10.3310/hta20420
Open Access Status Not Open Access
Volume 20
Issue 42
Start page 1
End page 242
Total pages 242
Place of publication Southampton, United Kingdom
Publisher National Coordinating Centre for Health Technology Assessment
Collection year 2017
Language eng
Formatted 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.

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and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu®, Roche) treatment on mortality in patients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.
Keyword Neuraminidase inhibitors (NIs)
Public health agencies
Clinical study reports (CSRs)
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: HERDC Pre-Audit
School of Public Health Publications
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