title: Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data.
abstract: 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and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu(®), Roche) treatment on mortality in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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  This study is registered as PROSPERO CRD42012002245.
  
  
  
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Heneghan
authors.affiliation: Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: Igho
authors.initials: I
authors.lastname: Onakpoya
authors.affiliation: School of Population Health, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jones
authors.affiliation: Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, MD, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Doshi
authors.affiliation: Centre for Research in Evidence-Based Practice (CREBP), Bond University, Robina, QLD, Australia.
authors.forename: Chris B
authors.initials: CB
authors.lastname: Del Mar
authors.affiliation: Japan Institute of Pharmacovigilance, Osaka, Japan.
authors.forename: Rokuro
authors.initials: R
authors.lastname: Hama
authors.affiliation: Department of Family Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Thompson
authors.affiliation: Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Spencer
authors.affiliation: Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: Kamal R
authors.initials: KR
authors.lastname: Mahtani
authors.affiliation: Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Nunan
authors.affiliation: Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Howick
authors.affiliation: The Cochrane Collaboration, Rome, Italy.
authors.forename: Tom
authors.initials: T
authors.lastname: Jefferson
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000453:epidemiology; D002648:Child; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000188:drug therapy* / Q000453:epidemiology / Q000401:mortality* / Q000517:prevention & control; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D053243:Zanamivir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir