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Gold standard review casts further doubt on benefit of antivirals for flu

The most comprehensive gold standard analysis of antiviral flu treatments to date has revealed that neither olseltamivir nor zanamivir reduced hospital admissions or serious complications of influenza, bringing Government advice to use the antivirals under even closer scrutiny.

The research team called on the Department of Health (DH) and NICE to review their advice to use olseltamivir – better known as Tamiflu – and zanamivir – known as Relenza – to avoid complications of flu, although both drugs were found to clear up the symptoms of flu quicker than a placebo, by about half a day.

The researchers also found olseltamivir was associated with increased risk of nausea in adults and vomiting in both adults and children.

And although both drugs cut the chance of succumbing to flu in prevention trials, there was no evidence they reduced transmission of the virus – while olseltamivir was additionally linked to an increased risk of headaches, psychiatric disturbances and renal events in these studies.

However, some experts said further research was needed, in particular into the effects in at-risk groups of patients who are most vulnerable to complications.

The latest evidence comes after research questioning the claimed benefits of antivirals on complications started to emerge – and follows a long-running ‘tug-of-war’ between the Cochrane reviewers and the manufacturers of olseltamivir (Roche) and zanamivir (Glaxo-Smith Kline) over unpublished clinical data and related documents.

The new, updated Cochrane review – also published in the BMJ – includes that previously unreported information, after both companies relented to requests and handed over the information last year (see box).

According to the study authors it reveals not only that the benefits of the drugs are much smaller than previously reported, but also that the harms may be greater than previously recognised, including the new concern over psychiatric disturbances.

The investigators, led by Dr Tom Jefferson from The Cochrane Collaboration, called for a change in how evidence is used for approving drugs.

They wrote: ‘Drug approval and use cannot be based on biased or missing information any longer. We risk too much in our population’s health and economy.’

‘This updated Cochrane review is the first time a Cochrane systematic review has been based only on clinical study reports and regulators’ comments. It is the first example of open science in medicine using full clinical study reports available without conditions. And therefore the conclusions are that much richer.’

They also said it raised questions about whether stockpiling of the antivirals carried out by the Department of Health in preparation for a potential flu pandemic was justifiable when the risks and benefits remained uncertain. The Department of Health has spent almost £424 million to stockpile around 40 million doses of Tamiflu, according to Government documents.

However, Professor Wendy Barclay, chair in influenza virology at Imperial College London, said the review could still be missing out on evidence that would support the use of the antivirals – in particular because there is not enough research in people at risk of complications and during outbreaks of severe flu.

Professor Barclay said: ‘Most of the trials on the neuraminidase inhibitors drugs that have been re-analysed by Cochrane were conducted on previously healthy adults, infected with a seasonal influenza virus. Influenza viruses vary considerably in their severity year on year.

‘The rates of influenza-like illness reported by GPs were low through the period (1990s and 2000s) when most of the drug trials were happening, and so the trials might only pick up “moderate” effects of drug treatment, particularly when patients begin treatment several days into the infection and after virus replication has peaked.’ 

GPs are currently advised by the Department of Health they can prescribe olseltamivir and zanamivir to at-risk groups when circulating levels of flu are high, while NICE recommends the drugs to treat people at high risk of complications.

But Dr Andrew Green, chair of the GPC’s prescribing subcommittee, said many GPs were doubtful about the usefulness of antivirals for flu and the new evidence should inform future policy on approving drugs.

Dr Green said: ‘This is a landmark review whose importance extends far beyond the purchase and use of drugs which most GPs have used very rarely, having remained unconvinced of their benefits. Never again should important policy decisions about drugs be made without full access to the raw trial data, and its provision should be made compulsory not only for new drugs, but also for those already in use.’

A DH spokesperson said: ‘The UK is recognised by the World Health Organization as being one of the best prepared countries in the world for a potential flu pandemic. Our stockpile of antivirals is a key part of this.’

‘Tamiflu is licensed around the world for the treatment of seasonal flu and is a licensed product with a proven record of safety, quality and efficacy. We regularly review all published data and will consider the Cochrane review closely.’

NICE said it would review its guidance on using of oseltamivir in light of the new Cochrane findings, and would be publishing new arrangements on the sharing of information in agreement with the UK and European drugs regulators soon.

A NICE spokesperson said: ‘NICE’s guidance recommending oseltamivir (Tamiflu) for the treatment of influenza was published in February 2009 [and] based on the best available evidence at the time.’

‘All of NICE’s guidance is developed in an open and transparent way and we agree with the committee’s call for greater transparency in clinical trials and the publication of resulting data.’

Roche’s UK medical director Dr Daniel Thurley said: ‘We disagree with the overall conclusions of this report. Roche stands behind the wealth of data for Tamiflu and the decisions of public health agencies worldwide, including the US and European Centres for Disease Control & Prevention and the World Health Organization.

‘The report’s methodology is often unclear and inappropriate, and their conclusions could potentially have serious public health implications. Neuraminidase inhibitors are a vital treatment option for patients with influenza.’


Cochrane Review of Neurominidase Inhibitors – Summary


What did the study look at?

Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza

Covered 107 clinical study reports from the European Medicines Agency, GlaxoSmithKline and Roche, plus comments by US Food and Drug Administration and Japanese drugs regulator.

Total of 20 trials of oseltamivir (9,623 participants) and 26 trials of zanamivir  (14,628 participants) included in formal analysis after initial judgement of design of the studies.


What were the main findings?


Duration of symptoms and hospitalisations/complications

Oseltamivir reduced the time to first alleviation of symptoms from 7.0 to 6.8 days in adults, and by 29 hours in healthy children, but had no effect in children with asthma.

Zanamivir reduced the time to first alleviation of symptoms from 6.6 to 6.0 days in adults, but had no effect in children.

Oseltamivir had no significant effect on hospitalisations compared with placebo, with a risk difference of 0.15%. There were no zanamivir hospitalisation data.

Neither drug had any impact on serious complications of influenza leading to study withdrawal, where tested.

Oseltamivir cut self-reported, investigator-mediated, unverified pneumonia by 1.0% but had no effect in five trials that used a more detailed diagnostic form of pneumonia, while zanamivir had no effect on either self-reported or radiologically confirmed pneumonia.

Zanamivir reduced bronchitis risk by 1.80% in adults, but oseltamivir had no effect on this. Neither drug reduced the risk of otitis media or sinusitis in children or adults.

Side effects

Oseltamivir increased nausea (by 3.7%; number needed to harm [NNTH] of 28) and vomiting (4.7%; NNTH of 22) in adults and vomiting (5.3%; NNTH of 19) in children, but cut risk of diarrhoea (2.3%) and cardiac events (0.68%) in adults.

Oseltamivir also had dose-response effect on psychiatric events in two ‘pivotal’ trials.

Flu prevention

The risk of developing symptomatic influenza was reduced by 3% by oseltamivir (number needed to benefit [NNTB] of 33) and 2% by zanamivir (NNTB of 51) in individuals but there was no reduction in asymptomatic influenza with either drug.

Side effects

Oseltamivir increased psychiatric events (1.1%, NNTH of 94), headaches (3.2%, NNTH of 32), renal events (0.7%, NNTH of 150) and nausea (4.2%, NNTH of 25).

The Cochrane Collaboration 2014; available online 10 April