NPC Archive Item: Observational data in swine influenza pandemic indicate benefit of early antivirals; new Cochrane review finds oseltamivir▼’s ability to prevent complications of seasonal influenza in otherwise healthy adults not proven.

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22 December 2009

Health professionals’ responses to the swine influenza pandemic should not be affected by the controversy regarding oseltamivir▼’s ability to prevent complications of seasonal influenza in otherwise healthy adults. A growing body of observational data from the current swine influenza epidemic supports early antiviral treatment. The Chief Medical Officer (CMO) has confirmed that formal UK clinical management guidelines are unchanged, and early and systematic treatment of all symptomatic patients will continue to characterise the National Pandemic Flu Service response in England.

Data from new meta-analyses suggest that the effectiveness of oseltamivir in preventing complications in otherwise healthy adults with seasonal influenza is currently “not proven”. Users of our patient decision aid (PDA) should note this caveat. The conclusions about oseltamivir’s effects on alleviation of symptoms in otherwise healthy adults with influenza-like symptoms, and its effectiveness regarding this or other outcomes in other patient groups, are not affected by the conclusions of the 2009 Cochrane review. We are keeping all our influenza PDAs under review as new data emerges and if changes are needed we will of course make them.

Emerging data supports use of oseltamivir and zanamivir▼ in swine flu
The CMO is quoted in an email to RCGP members as saying that early and systematic treatment of all symptomatic patients will continue to characterise the National Pandemic Flu Service response to swine flu in England. The CMO notes that a growing body of international observational evidence supports early antiviral treatment in swine flu, and this view still underpins formal UK clinical management guidelines. This evidence has been summarised in a recent editorial from the US Centers for Disease Control, published in the New England Journal of Medicine.

Questions regarding oseltamivir in seasonal flu
In contrast to the emerging data about antivirals in pandemic flu, the Cochrane review of randomised controlled trials (RCTs) of neuraminidase inhibitors in seasonal flu in otherwise healthy adults has recently been updated (8th December 2009) and has raised certain questions. The issues around the review have been covered in depth in a BMJ feature by Cohen, a member of BMJ staff, a BMJ article by Doshi, one of the Cochrane authors and an editorial by Godlee.

Effect on symptoms
Like the previous, 2006 Cochrane review, the 2009 review concluded that oseltamivir is effective in alleviating symptoms in otherwise healthy adults with flu-like illness if taken within 48 hours of the onset of symptoms. A Health Technology Assessment (HTA) of antiviral drugs in influenza has recently been published (December 2009). This concluded that oseltamivir reduces the median time to alleviation of symptoms in this population by 13 hours (95% confidence interval [CI] 3 to 25 hours). The HTA review also examined the effectiveness of oseltamivir and zanamivir in other populations. It concluded that “for the at-risk subgroups, effect sizes for differences in symptom duration were generally larger, and potentially more clinically significant, than those seen in healthy adults. However, there was greater uncertainty around these results, with estimates often failing to reach statistical significance. For the overall at-risk population, treatment reduced the median duration of symptoms by approximately 1–2 days with zanamivir, and by 0.50–0.75 days with oseltamivir. A similar pattern was seen in the time taken to return to normal activity, with the median reduction being between 1 and 2 days with zanamivir and 0.75 and 2.50 (data for at-risk adults only) days with oseltamivir.”

Effect on complications
The 2009 Cochrane review concluded that no statistically significant benefit from oseltamivir on the risk of complications in otherwise healthy adults has been shown. This is different from the conclusion of the 2006 Cochrane review and arose because the authors decided not to include some of the data from a 2003 paper by Kaiser et al in its 2009 update, which had been included in 2006. The Kaiser et al paper was itself a summary of data from ten RCTs of which only two were fully published and available for review. The Cochrane group was not able to obtain sufficient data regarding the other eight studies in time to complete its review.

Roche has commented that it has already posted study summaries, including data tables, for all the component studies online: it promises that “full reports for these studies will also shortly be available by password protected access for all bona fide scientific investigation.” In both Cochrane reviews, the point estimate indicated a benefit, but in 2009 (presumably because there were fewer people with fewer complications in fewer studies in the 2009 review) the 95%CI includes 1. Including more data when this becomes available will help improve the precision of this result, and confirm or refute the conclusion from 2006.

The recent HTA of antiviral drugs in influenza did not use the Kaiser et al paper per se, but did include some data from RCTs of oseltamivir not published in full. Like the 2009 Cochrane review the HTA also found that on data judged appropriate for inclusion in the analysis a statistically significant reduction in complications in otherwise healthy adults was absent. However, oseltamivir did reduce the use of antibiotics both in otherwise healthy adults with flu-like illness (odds ratio [OR] 0.37, 95%CI 0.29 to 0.48, P<0.0001) and otherwise healthy adults with confirmed flu infection (OR 0.52, 95%CI 0.27 to 1.00, P=0.05).

So what?
This is a developing story and it is likely we will return to it as data emerges. Roche has undertaken to make data available and the Cochrane group has undertaken to analyse it. In the meantime, health professionals treating people with suspected swine flu should continue to follow advice from the CMO and the Department of Health.

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