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A systematic review of studies of the efficacy of antiviral drugs used to treat influenza has found only modest benefits in their use, raising questions over public health policy regarding their use in the current flu pandemic.
Prof Peter Openshaw, Director, Centre for Respiratory Infection, National Heart & Lung Institute, Imperial College London, said:
“It’s very useful that detailed overviews like this are being done, but important to realise the limitations.
“First, the BMJ review is only about studies of previously healthy adults with normal seasonal influenza, not about swine flu. The patients that get bad swine flu are very different from those who typically suffer from seasonal flu.
“Second, the evidence that they reviewed is not sufficient to draw a conclusion about whether oseltamivir reduces complications or not: on average, lung complications were almost halved if oseltamivir was used, but this was not significant because the studies were too small. As the authors say, you need better studies to answer this question. There are many studies now being done and reported that will help to improve planning for the next outbreak, and new information about the side effects needs to be taken into account as well.
“We have always known that treatment has to be given early to have much effect and in the studies reviewed by Jefferson et al treatment was usually started too late to have great benefit. In hospital, we see the bad cases and often regret that antivirals were not given back at the start. By the time the patients get to us, antivirals really do have limited use and it’s difficult to know who is going to progress to severe disease. We have a good stockpile in the UK.
“It’s also important to remember that the stockpiling of oseltamivir and zanamivir was decided at a time when we were all quite rightly worried about an outbreak of mutated H5N1 bird flu: that still has about a 60% death rate but fortunately has not yet adapted to spread from person to person. If we were faced with an outbreak like that and had not laid down good antiviral stocks, the public would have every reason to accuse the government of a failure to plan properly.
“There are many strands to the control and treatment of flu and antivirals are but a part of it. I am not at all starry-eyed about the benefits of antivirals but think it’s too early to change the policy on swine flu the basis of this review.”
Dr Matthew Thompson, Clinical Lecturer & Co-Director of Oxford Centre for Monitoring & Diagnosis in Primary Care (MaDOx), Department of Primary Health Care, University of Oxford, said:
“This latest investigation into the value of antiviral drugs Tamiflu and Relenza suggest to me that it is imperative to urgently review the current UK Department of Health policy on the use of these drugs for otherwise healthy adults and children with flu like symptoms. Practicing GPs like me know that it is virtually impossible to tell which patient has pandemic influenza from those with normal coughs and colds. Most of the antiviral drugs are therefore being given to patients who in all likelihood do not have pandemic flu. Not only this, we now can be even less sure about how effective these drugs really are. What most patients and parents want to know is not only whether the drug will help them get better quicker, but more importantly if it might prevent a serious complication such as pneumonia or being hospitalised.
“This latest information suggests that we cannot give parents or patients such reassurance. What is also concerning as a GP and researcher is the apparent lack of scrutiny that there appears to be in spending vast sums of NHS money on drugs which seem to have little evidence for being particularly useful. We pride ourselves in the UK of having a system to spend NHS money on medications wisely; we now need an urgent investigation into why this did not seem to happen, and to review the widespread use of these antivirals for otherwise healthy individuals.”
Carl Heneghan: Clinical Lecturer & Deputy Director of Centre of Evidence-Based Medicine, Dept of Primary Health Care, University of Oxford, said:
“This is the second major systematic review to appear in the BMJ investigating the evidence underpinning neuraminidase inhibitors for preventing and treating influenza in healthy a
Jefferson and his colleagues should be commended for systematically searching for the truth, and asking, what are the exact benefits and harms of Neuraminidase inhibitors? These drugs are being used liberally in the current H1N1 pandemic and it is important that these types of studies – systematic reviews – are undertaken and independently funded by national bodies to ensure impartiality.
“These results are not surprising, in that the benefits of neuraminidase inhibitors are modest, which is what most clinicians probably already knew, yet amongst policy makers and the wider public this message seems not to be getting through. Significantly, this paper differs from previous published in that the investigators attempted to systematically investigate the potential harms of the drugs. What is disturbing is that only one study explicitly examined drug safety. This is an important omission given the widespread use of oseltamivir.
“Moreover, we now know that the evidence-base for a reduction of serious complications such as pneumonia is uncertain. Simply this means the benefits drug may be outweighed by the complications, and so it is not implausible that Neuraminidase inhibitors could cause more cases of pneumonia than prevent form what we now know.
“What happened next in this study proves pretty shocking. To get key access to the data the BMJ and Channel 4 News undertook their own investigation. Problems with which Roche investigators saw which date was difficult to pin down, and it was unclear who authored the papers. One major author named on the abstract of one of the most influential studies had told the BMJ he not even been involved in the study. Yet, we continue to be bombarded with news stories of apparent benefits of antivirals; whilst now knowing that major data are being withheld and manipulated to propagate the unwarranted use of these drugs.
“The BMJ commissioned Freemantle to pass judgement on the observational studies. Freemantle rightly states that randomised trials rarely include people with co-morbidities, as adverse events in these groups may be significantly worse and undermine attempts to establish the safety of the new drug. To be able to generalize results to the wider population what we require is observational data of the safety profile in routine practice. That is real life patients who are excluded from the trials for the reasons outlined above.
“Jefferson has come under a lot of fire for his call for better evidence for influenza treatment, his persistence and refusal to sign a confidentiality agreement should be admired and the publication of these results should be a benefit to us all. Policy makers and national governments have got it wrong on the policy. There is a pressing need to understand the benefits and potential adverse effects of these drugs as the current evidence base supporting their use is now so uncertain. In Individuals with mild symptoms there use should be discontinued with immediate effect. Using antivirals liberally runs the risk of generating resistance. We have known this for many years. More worryingly in those at high risk the benefits remain and uncertain and there use has to be considered by clinicians on a case by case basis. Experts and those that generate policy should look at these documents carefully and stick to the evidence.
“Overall the benefits of these drugs are fairly limited. In children Neuraminidase inhibitors provide only a small benefit by shortening the duration of illness in children with influenza and have little effect on asthma exacerbations or the use of antibiotics. Their effects on the incidence of serious complications and on the current A/H1N1 influenza strain in both adults and children are unknown.
So what should change? Fiona Godlee is right to call for clarity and freedom of data. Free access to such data would substantially improve the ability to make informed choices. However, such analyses are not cheap and require funding infrastructure to be responsiveness to the demands of current policy needs. A simple interim solution is to demand full access to data for drugs we are willing to pay for. A call for independent review of this data is wise, and essential, if we are to make evidence-based decisions about important health care issues in the future.”
Dr Tarit Mukhopadhyay, Lecturer, Vaccine Bioprocess Development, University College London, said:
“Healthcare is much like national defence. It is very expensive, but should cost nothing for the individual. My concern is not how much it has cost but the role of Roche, NICE, and MHRA. Have the regulators been misled, intentionally or otherwise? Was any evidence-based review initiated by the regulators? How is it possible that Roche can claim 60% reduction in complications, but both the EMEA and FDA are unable to substantiate such claims? I think it is perhaps inaccurate in Deborah Cohen’s report to say that the EMEA and FDA have reached two different conclusions. The EMEA state the numbers and say there is a 4.1% (12.7%-8.6%) reduction in complications when Tamiflu is used. Only the FDA draws conclusions.
“Having been presented with a 4.1% reduction of complications in healthy people, did the Dept of Health/NICE or any other body undergo a risk-benefit analysis? What was the conclusion of this analysis and was it decided that even a marginal benefit was worth administering Tamiflu to healthy people?
“Furthermore, nothing is mentioned about those with pre-existing conditions and the report itself is inconclusive. Clearly more studies will have to be conducted to get all the answers, but this should serve as a reminder for vigilance, especially when it comes to the next pandemic.”