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

Carl J. Heneghan, Igho Onakpoya, Mark A. Jones, Peter Doshi, Chris B. Del Mar, Rokuro Hama, Matthew J. Thompson, Elizabeth A. Spencer, Kamal R. Mahtani, David Nunan, Jeremy Howick, Tom Jefferson

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and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu®, Roche) treatment on mortality in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

Original languageEnglish
Pages (from-to)1-242
Number of pages242
JournalHealth Technology Assessment
Volume20
Issue number42
DOIs
Publication statusPublished - 1 May 2016

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Oseltamivir
Meta-Analysis
Zanamivir
Human Influenza
Mortality
Confidence Intervals
Neuraminidase
Vomiting
influenza A virus NA protein
Therapeutics
Nausea
Psychiatry
Confounding Factors (Epidemiology)

Cite this

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. / Neuraminidase inhibitors for influenza : A systematic review and meta-analysis of regulatory and mortality data. In: Health Technology Assessment. 2016 ; Vol. 20, No. 42. pp. 1-242.
@article{7a1c851e4f52490a9aadb6ae1c9e77c4,
title = "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{\circledR}, 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{\circledR}, 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.",
author = "Heneghan, {Carl J.} and Igho Onakpoya and Jones, {Mark A.} and Peter Doshi and {Del Mar}, {Chris B.} and Rokuro Hama and Thompson, {Matthew J.} and Spencer, {Elizabeth A.} and Mahtani, {Kamal R.} and David Nunan and Jeremy Howick and Tom Jefferson",
year = "2016",
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doi = "10.3310/hta20420",
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journal = "Health Technology Assessment",
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Heneghan, CJ, Onakpoya, I, Jones, MA, Doshi, P, Del Mar, CB, Hama, R, Thompson, MJ, Spencer, EA, Mahtani, KR, Nunan, D, Howick, J & Jefferson, T 2016, 'Neuraminidase inhibitors for influenza: A systematic review and meta-analysis of regulatory and mortality data' Health Technology Assessment, vol. 20, no. 42, pp. 1-242. https://doi.org/10.3310/hta20420

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; Jefferson, Tom.

In: Health Technology Assessment, Vol. 20, No. 42, 01.05.2016, p. 1-242.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Neuraminidase inhibitors for influenza

T2 - 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 - 2016/5/1

Y1 - 2016/5/1

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.

AB - 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.

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DO - 10.3310/hta20420

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