Impact of Neuraminidase Inhibitor Treatment on Outcomes of Public Health Importance During the 2009-2010 Influenza A(H1N1) Pandemic: A Systematic Review and Meta-Analysis in Hospitalized Patients

Muthuri, Stella G.; Myles, Puja R.; Venkatesan, Sudhir; Leonardi‐Bee, Jo; Nguyen-Van-Tam, Jonathan S.

doi:10.1093/infdis/jis726

Cited by 176 publications

(120 citation statements)

References 23 publications

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“…To our knowledge, there have been five deaths in comparative Phase II/III RCTs of oseltamivir; 167,168 however, none of the deaths was in a patient with confirmed influenza. Reviews of observational studies of influenza 2009A/H1N1 have shown protective effects of NIs on mortality [169][170][171][172][173] and oseltamivir is now listed as an essential medicine, 174 although there is insufficient evidence based on randomised studies to show that oseltamivir reduces complications of influenza 106 and case series have suggested increased mortality. 15,141 The objective of this systematic review was to determine the effect of oseltamivir treatment on mortality in patients with 2009A/H1N1 influenza.…”

Section: Introductionmentioning

confidence: 99%

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

Heneghan

Onakpoya

Jones

et al. 2016

Health Technol Assess

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BackgroundNeuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.ObjectivesTo (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and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu®, Roche) treatment on mortality in patients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.MethodsWe 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.ResultsEffect 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).ConclusionsOseltamivir 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 registrationThis study is registered as PROSPERO CRD42012002245.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Section: Introductionmentioning

confidence: 99%

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

Heneghan

Onakpoya

Jones

et al. 2016

Health Technol Assess

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“…There are also a number of published observational studies providing data that support the efficacy of NIs (oral oseltamivir, inhaled zanamivir) for uncomplicated influenza, reducing fever and illness duration by approximately one day [51,52]. NIs have also been found to be effective in reducing mortality in patients hospitalized with pH1N1 virus infection including, but not limited to, pregnant women [50,53].…”

Section: Treatmentmentioning

confidence: 99%

Influenza in the US Military: An Overview

Sánchez¹,

Cooper²

2016

J Infec Dis Treat

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“…Sudden death is another concern [5-7]. A causal association between oseltamivir use and abnormal behaviours or sudden death has not been established and it is considered negative [1,2] based on retrospective observational studies [8-12], systematic reviews of retrospective observational studies [13,14] and a systematic review and meta-analysis of randomized controlled trials of oseltamivir treatment for influenza of adults [15]. …”

Section: Introductionmentioning

confidence: 99%

The mechanisms of sudden-onset type adverse reactions to oseltamivir

Hama¹,

Bennett

2016

Acta Neurol Scand

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Oseltamivir is contraindicated for people aged 10 to 19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden-onset type reactions to oseltamivir. First the importance of animal models and the concept of human equivalent dose (HED) is summarised. Second, the specific condition for oseltamivir use: influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described. Finally, coherence of toxicokinetic and molecular-level of evidence (channels, receptors, and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death. Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase-A (MAO-A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABAA, GABAB, and NMDA and their related receptors/channels including Na+ and Ca2+ channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic) respectively.

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Impact of Neuraminidase Inhibitor Treatment on Outcomes of Public Health Importance During the 2009-2010 Influenza A(H1N1) Pandemic: A Systematic Review and Meta-Analysis in Hospitalized Patients

Cited by 176 publications

References 23 publications

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

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

Influenza in the US Military: An Overview

The mechanisms of sudden-onset type adverse reactions to oseltamivir

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