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Systematic review
Neuraminidase inhibitors produce a small reduction in duration of seasonal influenza in children and reduce transmission in affected households, but effects on serious complications unclear
  1. Tom Jefferson
  1. Tom Jefferson
    Cochrane Acute Respiratory Infections Group; jefferson.tom{at}gmail.com

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Commentary on: OpenUrlAbstract/FREE Full Text

During the so-called influenza pandemic, the publication of an update of a Cochrane review on the effects of neuramini dase inhibitors in children aged ≤12 years is a timely addition to our knowledge. Antivirals (and more specifically neuraminidase inhibitors and the bestselling oseltamivir) have long been touted as an important part of the armoury against seasonal and pandemic influenza and have been stockpiled in huge quantities. A 2005 World Health Organization document went so far as to state that “wide scale use of antivirals and vaccines during a pandemic will depend on familiarity with their effective application during the interpandemic period. The increasing use of these modalities will expand capacity and mitigate the morbidity and mortality of annual influenza epidemics. Studies conducted during the interpandemic period can refine the strategies for use during a pandemic”.1 No more so than in UK, where oseltamivir can be obtained from a government website without consulting a medical practitioner.

The review followed a standard Cochrane pattern, with objectives, inclusion criteria and searches defined a priori and evaluation and synthesis conducted in the most unbiased manner possible. The only slight change from standard practice was the inclusion only of trials “that we considered sufficiently free from bias”. The authors found four treatment trials and three post-exposure prophylaxis trials. In the former, participant children with influenza-like illness symptoms were given antivirals to shorten duration of illness or a placebo. In the post-exposure prophylaxis trials, antiviral performance in child contacts of patients with influenza-like illnesses was compared with placebo or donothing. Study quality was variable, but the conclusions are very close to those of our Cochrane review on neuraminidase inhibitors in healthy adults. Neuraminidase inhibitors offer some shortening of the duration of illness and are pretty toxic (especially oseltamivir on the gastrointestinal tract). They also appear to interrupt viral transmission but have no apparent effect on the risk of complications. Not surprisingly, their effects are confined to influenza cases, not influenza-like illness. In other words, they are efficacious against symptoms but ineffective. In addition they do not prevent infection causing an antibody response.

My take on the authors’ work and their conclusions is biased by the vicissitudes faced by my group in trying to update our own review, failing to verify independently a Roche-sponsored review of the evidence of effects on influenza complications and finding that even the pharmacovigilance databases are unable to answer questions on the toxicity of oseltamivir as they are underreported and lack detail.2,,4 With hindsight, I think we should have joined forces and conducted a thorough update of the whole children and adults dataset. As things stand, our knowledge of the effects of oseltamivir is inadequate, and some 60% of the randomised dataset has never been published, although Roche has recently given us access to the reports of eight unpublished treatment trials in adults.

The questions that the two Cochrane reviews raise are such that had I been recommending and prescribing the drugs, I would be seriously worried. If I had authorised their web-based distribution, I would probably be contemplating suicide.

We are not sure how neuraminidase inhibitors work, or indeed whether they are less toxic than (say) paracetamol or ibuprofen. They are certainly more expensive, and their sponsors are powerful. We should urgently fund independent large randomised head-to-head trials. We should test neuraminidase inhibitors against proven public health measures such as barriers and personal hygiene to interrupt transmission and we should test them against nonsteroidal anti-inflammatory drugs for symptom relief.

Because of their cost and unknown toxicity and the lack of evidence of an effect on influenza complications, the use of neuraminidase inhibitors should be confined to serious and compassionate cases until the whole randomised dataset is available for public scrutiny and independent trials have been carried out.

References

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Footnotes

  • Competing interests TJ is the first author of the companion Cochrane review on neuraminidase inhibitors in healthy adults