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expert reaction to report on use of neuraminidase inhibitor antiviral drugs (Tamiflu and Relenza) during seasonal and pandemic flu

The Academy of Medical Sciences and the Wellcome Trust have published a report into the effectiveness of neuraminidase inhibitor antiviral drugs for the treatment and prevention of influenza. These comments accompanied a briefing.

 

Prof. Wendy Barclay, Chair in Influenza Virology, Imperial College London, said:

“This new report does a wonderful job of assimilating current knowledge about using antivirals against influenza, and highlights real difficulties in developing and using such antiviral drugs. Influenza is a virus that can vary widely in the severity of disease it causes, depending on the strain of virus and the person infected. Researchers and pharmaceutical companies alike who are aiming towards developing new antivirals for influenza should bear these difficulties in mind for the future.

“The report concludes that, although the neuraminidase inhibitor drugs like Tamiflu and Relenza are effective, using them to treat people with mild influenza did not bring a huge benefit and sometimes caused vomiting as a side effect. However the report importantly emphasises that the drugs are much more important for treating severe influenza, and that early during an outbreak, before the severity is known, using them is prudent. In addition the report stresses that clinical judgement should guide treatments on an individual patient basis.

“Perhaps one of the key issues the public and government want this report to address is whether an antiviral stockpile was or is justified. The report makes it very clear that influenza severity is difficult to predict ahead of time. Although the 2009 pandemic was thankfully mild, future influenza outbreaks may be more severe and in that case one would expect more people to benefit from using these drugs both in terms of lives saved and getting the country back to work. Whether in the end this is ‘cost effective’ can be modelled to some extent, but it is difficult to put a value on the panic that can ensue in the early weeks of a new outbreak of a virus that has the potential to cause severe disease.

“One of the primary outputs of the report is the call by the report’s authors for more trials using these drugs in hospital settings for severe cases.  Whilst such trials are an important part of evidence-based medicine,  the report itself does emphasise that retrospective analysis can also be used to inform medical practice and acknowledges the persuasive data obtained from hospitalised patients in 2009 showing that using NAIs saved lives.  On the other hand the report laments the fact that we don’t have evidence from random controlled trials conducted on severe flu cases and strongly recommends conducting such trials during future outbreaks. It will be important going forward to be clear about how such trials will be conducted, for example, how does one allocate a placebo group in this situation? If a pregnant woman comes to hospital with flu, can we justify using her to test the effect of not giving Tamiflu, bearing in mind the retrospective analysis from 2009? These difficult situations are not that dissimilar from those faced recently in West Africa thinking about how to properly conduct trials with agents against Ebola, another deadly viral disease. Whilst new styles of clinical trial are being designed to address these concerns, it is important that patients at high risk are not denied this licensed drug.

 

Prof. Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This report is excellent and provides a dispassionate view of these drugs and their benefits which have limitations. It makes clear that in some circumstances, such as when a potentially significant fraction of key workers may be ill and not able to work, even temporarily, that a small benefit may firstly reduce the time off work but most importantly, reduce the height of a peak in the numbers absent from work on any particular day. This latter point is not made clearly in the report though it is alluded to. It can have a major economic benefit in possibly preventing a cascade of problems (beyond a “tipping point’) when a major epidemic or pandemic occurs.

“The downside is that strains of flu may become rapidly resistant to it, and this seems to have happened already.

“The benefits of the drugs in the most severely ill or vulnerable are uncertain and the proposal to have good randomised trials in such groups is to be welcomed.

“The wise course may be to reserve such drugs for key workers and, if the randomised trials proposed by the report show benefits in the high risk groups, given to those at high risk and not those at low risk.

“Media-induced panics that led to widespread use of the drugs in the previous pandemic are harmful; perhaps we will have learnt a lesson. This report is absolutely rigorous in its evaluation of our current knowledge.”

 

Prof. Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said:

“We know that the virus can become resistant to these antivirals so it is really important that they are only used where there is clear evidence of their value; otherwise we jeopardise rendering them useless for those circumstances where they could do some good. Also these drugs aren’t cheap so government could end up generating profit for drugs companies when there is no clear evidence that it is money well spent.

“Widespread use and stockpiling of antivirals during the swine flu pandemic caused much heated debate, so it is important that we have an evidence base to know when and where to use these antivirals. A key take home message from this report is that the evidence-base isn’t as strong as it should be. We risk misusing these drugs until this important knowledge gap is filled.”

 

Prof. Peter Openshaw, Director of the Centre for Respiratory Infection, Imperial College London, said:

“This balanced and well-considered report is timely and welcome, bringing together the views of opposing groups about the use of antivirals for influenza. It supports using antivirals in patients with severe influenza and emphasises the vital importance of early treatment; antivirals have to be used as soon as possible if significant benefits are to be obtained.

“Importantly, it calls for additional research to understand where to focus the use of antivirals and identifies situations in which antivirals should be used more widely (e.g. with new outbreaks of influenza that are of unknown severity). It also makes the point that observational data should be taken into account in judging the effectiveness of antivirals and accepts that, with proper safeguards, data from studies funded by manufacturers represent an important and valuable source of information.

“In sum, this is a helpful and wise summary that clarifies the current situation with respect to antivirals and identifies future directions for research. It will make a significant contribution to evaluation of new drugs and to future policy, and is to be applauded.”

 

Prof. Carl Heneghan, Professor of Evidence-Based Medicine, University of Oxford, said:

“The Academy of Medical Sciences & Wellcome Trust report emphasises the need to conduct trials into the effectiveness of antivirals in pandemic situations. The implications of this report should not be underestimated; the misinterpretation of the evidence to date has wasted scarce resources and led to widespread confusion.

“Use of antivirals in a pandemic would not be based on the best available evidence, but principally on poor quality evidence and opinion. This is primarily due to the failure to undertake trials in the last outbreak.

“Current policy, therefore, has not kept abreast with the evidence and should change to reflect the academy’s interpretation of the trial results to date: antivirals, as the report clarifies, are not beneficial in seasonal flu.

“There is an urgent need to know whether antivirals work in hospitalised patients. To ensure we best serve patients, and to reduce any further uncertainties, trials in hospitalised patients should be done independently and ensure results are published in full.”

 

Dr Andrew Freedman, Reader & Consultant in Infectious Diseases, Cardiff University, said:

“This is a timely and valuable report which evaluates the current evidence base for the use of these drugs in both seasonal and pandemic flu situations. It highlights areas where uncertainty persists, such as their cost effectiveness when used in primary care for both treatment and prevention. It stresses the importance of carrying out randomised controlled trials in the future, while acknowledging the very real challenges in conducting such trials.”

 

Prof. Anne Cooke, Chair of British Society for Immunology Policy Forum, and Professor of Immunobiology, University of Cambridge, said:

“Influenza pandemics have the potential to cause huge loss of human life, illness and social and economic disruption, so it’s critical that we know more about the treatments, and that we learn from future outbreaks. From this timely report, it’s clear that we currently don’t have the knowledge we need to understand how we can make best use of antiviral drugs in flu pandemic situations. It is key that health professionals have access to data from properly controlled clinical trials which are the cornerstone of all evidence-based medicine. We support the report’s recommendation that the UK must be prepared to conduct the clinical trials into the effectiveness of antiviral drugs when the next influenza pandemic arises. Ensuring our infrastructure is ready to carry out such research during a pandemic means that we need to start planning now for the appropriate networks to be in place, which would allow scientists and clinicians to act quickly and decisively when the need arises. As a global leader in infectious disease research, the UK is well placed to take on this role, which could lead huge health benefits regarding our knowledge of effective treatments and also boost our national resilience to future health emergencies.”

 

‘Use of neuraminidase inhibitors in influenza’ will be published by the Academy of Medical Sciences and the Wellcome Trust at 00:01 UK time on Thursday 8 October 2015, which is also when the embargo will lift. 

 

Declared interests

Prof. Wendy Barclay: “I have no conflicts at present. I once supervised a PhD student who also worked with GSK, manufacturer of Relenza.”

Prof. Peter Openshaw’s research is funded by the Wellcome Trust, the MRC, BBSRC and the European Union. He has received honoraria or consultancy fees from GSK, Janssen, and Mucosis BV.

Prof. Carl Heneghan is a co-founder of the AllTrials initiative and has an active interest in all studies being reported and published in full. CH has also been a co-recipient of a WHO grant on barriers to effective publication in public health emergencies and received a UK NIHR research grant for the update and amalgamation of two Cochrane reviews using unpublished data. He has received expenses and payments for his media work and for his teaching.

Prof. Stephen Evans, Dr Andrew Freedman and Prof. Anne Cooke declare no conflicts of interest.

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