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

Abstract

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and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu®, Roche) treatment on mortality in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

Immortal time bias in observational studies of time-to-event outcomes

“…Please note that we have included additional patients compared to the original study hence data are not directly comparable. For more information on the dataset used for the analysis, see Chapter 3 of Heneghan et al [9]. Of 578 patients with a survival time, 540 received oseltamivir, an antiviral treatment for influenza.…”

Evidence synthesis and decision modelling to support complex decisions: stockpiling neuraminidase inhibitors for pandemic influenza usage

“…Only adults were considered on the grounds that NAI effectiveness 4,6 is less certain in children and to determine if the decision to stockpile could be justified on the basis of any benefit among adults alone.…”

“…Early administration of the medication is associated with better clinical outcomes [4][5][6] , although the temporal relationship between changes in influenza viral shedding and clinical outcomes have not been well-established Randomised controlled trials, while under-powered for outcomes such as death and hospitalisation, show reduction in the duration of illness for treatment and reduction in symptomatic influenza for prophylaxis 4,5 .…”

“…Clinical trials show that NAIs have beneficial effects on a number of outcomes as described above [4][5][6] . The treatment has a plausible rationale and it works in vitro and in animal models for this zoonosis 10 .…”

“…A caveat of these studies, which were required for licensure of drug in healthy adults, is that they were not powered to determine low frequency but critical end points such as mortality in a largely healthy adult population. A further metaanalysis of observational data from pandemic influenza did find evidence of a reduction in the risk of mortality when NAIs were given to patients hospitalised with influenza 6 . Some authors have criticised it for being subject to a large degree of bias and rejected it as a suitable form of evidence with which to formulate policy decisions 7,8 , though others argue that this evidence strongly supports the use of NAI treatment for influenza in hospitalised patients 9 .…”