GPs are told to treat with scepticism advice on anti-flu drugs from Public Health EnglandBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h258 (Published 15 January 2015) Cite this as: BMJ 2015;350:h258
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Professor Nick Phin's response on Neuraminidase Inhibitors (Nis) treatment presents only fragments of the evidence-base, and makes it difficult to present an evidence informed choice to clinicians.
Based upon this response there are three important questions that require clarification: 1) Do Nis reduce influenza? 2) Do the results of study WV15799, done in households, apply to a nursing home population? 3) Does NI treatment reduce pneumonia?
1. Do Nis reduce influenza?
Professor Phin and Dr Moll say that the Cochrane review  did find that the post exposure use of antivirals was associated with a significant reduction in the risk of lab-proven symptomatic influenza with a risk ratio of 0.45 (a 55% reduction in risk). However, what does that mean?
The definition for lab-proven symptomatic influenza is based on reported symptoms of nasal congestion, headache, chills/sweats, sore throat, cough, fatigue, myalgia and fever as well as results of culture testing and serology. Clinical influenza in the trials was based on temperature of at least 99 degrees Fahrenheit, at least one constitutional symptom, at least one respiratory symptom and positive culture test or 4-fold rise in influenza antibodies. Indeed, neuraminidase inhibitors reduce the risk of clinical influenza based on that definition. But, how does it do that?
Using data on symptoms that was only available in the module 3 of the clinical study reports we were able to determine this. We classified influenza-like-illness as any occasion when patients had 2 or more of the symptoms (listed above). Based on that definition we found oseltamivir did not reduce influenza-like illness (RR 0.95, 95% CI 0.86 to 1.06); however, we found fever is reduced (RR 0.62, 95% CI 0.42 to 0.93), proportion with laboratory confirmation is reduced (RR 0.59, 95% CI 0.41 to 0.85) but symptoms other than fever are not reduced (RR 0.96, 95% CI 0.86 to 1.07). Furthermore, it is clear from the treatment trials that oseltamivir reduces antibody response to influenza. Hence, it appears that infection is not prevented (as Roche have said) but rather oseltamivir suppresses fever, reduces antibody response and viral shedding but does not reduce the risk of symptomatic illness. Furthermore, to achieve this, risk of gastrointestinal symptoms, headaches, psychiatric syndromes and renal adverse effects are all increased.
In terms of presenting results it is important to include the absolute differences to aid understanding and interpretation.
In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (RR 0.45, 95% CI, 0.30 to 0.67). The corresponding absolute effect was 3.05% (1.83% to 3.88%). Therefore for every 100 persons treated prophylactically with oseltamivir there would be 3 people less with a diagnosis of influenza who reported symptoms. Importantly though, there was no significant effect on those with a diagnosis of influenza who reported being asymptomatic.
Also in prophylaxis trials we could not analyse effects on influenza-like illness because of a lack of definition in the clinical study reports. However, using our definition (see methods), oseltamivir did not reduce influenza-like illness in participants (risk ratio 0.95, 0.86 to 1.06).’
2. Do the results of study WV15799, done in households, apply to a nursing home population?
Professor Phin and Dr Moll say ‘The same review also states that when oseltamivir prophylaxis was used in cases of known exposure within a household, a situation akin to that in care homes, the risk reduction increased to 80%.’
We are unsure about where the statement ‘a situation akin to a nursing home” has arisen from? We did not make such a statement in the Cochrane review  or the corresponding BMJ review. 
WV 15799, was done in households with a minimum of 2 and a maximum of 8 contacts. 962 family contacts members of 377 index cases were randomised and given Tamiflu or placebo for 7 days (all index cases were left untreated apart from symptomatic relief).
Information available only from the clinical study report shows that index cases were aged 26-30; only 5 of these cases were elderly. Individuals were excluded if they had cancer, immunosuppression, chronic liver or renal disease, were taking steroids, or had unstable or uncontrolled renal, cardiac, pulmonary, vascular, neurologic or metabolic (diabetes, thyroid disorders, adrenal disease) disorders, hepatitis or cirrhosis. Subjects with known significant renal disease (defined as a creatinine clearance <30mL/min) were also excluded as were those with known cardiac failure resulting in limitation of physical activity.
Of the 962 contacts the mean age was 34 years and as result of the exclusion only 17 (1.8%) aged 65 or over were included.
Therefore, we would not consider this population ‘akin’ to a nursing home population and consider this study not applicable to a nursing home population, given the exclusion criteria and the small number of individuals over the age of 65 included.
3. Do neuraminidase inhibitors reduce pneumonia?
‘The other available antiviral, zanamivir, when used prophylactically was associated with a significant reduction in pneumonia (RR 0.30);’
In nine zanamivir trials pneumonia was only a self-reported measured, this outcome was not therefore verified by a clinician diagnosed and did not use X-ray confirmation. Overall, there was no significant effect of zanamivir in adult treatment trials, RR 0.90 (95% CI 0.58 to 1.4). [1, 3]
In prophylaxis trials, zanamivir reduced the risk of individuals, self-reported, unverified pneumonia in adults, RR 0.30 (95% CI 0.11 to 0.80). The risk difference, however was small (0.32%), meaning 311 people would need to be treated to prevent one person self-reporting they thought they had pneumonia (95% CI 244 to 1086).
Of note, in the two zanamivir adult trials, pneumonia reporting was based on an objective definition using X-ray confirmation and there was no significant treatment effect, RR 1.02 (95% CI 0.35 to 3.02).
We did not analyse the effect for oseltamivir because pneumonia was not a reported outcome in oseltamivir prophylaxis trials.
We did, however, analyse and present data in the Cochrane review on the adverse event as they were reported in the clinical study reports. This included the adverse event respiratory body system (analysis 2.40), which showed no significant effect, RR 1.04 (0.90 to 1.20). In the Cochrane review we also analysed cough on treatment (analysis 2.15) and off treatment (analysis 2.22) which both showed no effect, RR 0.96 (0.68 to 1.36) on treatment, and RR 0.72 (0.36 to 1.45).
Competing interests: TJ and CH were co-recipients of a UK National Institute for Health Research grant (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children—http://www.nets.nihr.ac.uk/projects/hta/108001). In addition: TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about Phase 1 or 2 pharmaceutical products. In 2011-2013, TJ acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in healthcare workers in Canada. In 1997-99 TJ acted as consultant for Roche, in 2001-2 for GSK, and in 2003 for Sanofi-Synthelabo for pleconaril (an anti-rhinoviral, which did not get approval from the Food and Drug Administration). TJ was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on the drug Tamiflu (oseltamivir, Roche). CH receives payment for running educational courses at the University of Oxford and University of Oxford ISIS consulting services for external teaching and training. He also receives royalties for books (Evidence Based Toolkit series by Blackwell BMJ Books). IO and MJ have no interests to disclose.
After this news item was published on the BMJ website, General Practitioners in the Thames Valley Area were sent a letter from their local NHS England Area Team. This was intended to encourage the prescribing of prophylactic oseltamivir along the guidelines from Public Health England (PHE).
Even the most ‘thick-skinned’ of GPs will have felt this letter to be threatening in its tone. We were told that the MDU had advised that "the public and the legal profession would expect that NICE guidance and PHE advice would be followed". We were reminded that “GPs have clinical responsibility for their patients". Even the GMC was invoked, with the suggestion of an expectation that GPs "would respond to an organisation advising on public health". This is a misquotation of paragraph 22e of 'Good Medical Practice' and is used out of context.
Jefferson and Heneghan have a very good understanding of the trials data. They are not convinced that the usefulness of oseltamivir in preventing influenza is clear cut, especially in care home residents. We are not convinced either. Indeed if the case were clear cut, would the debate be still ongoing, and would PHE need the support of the Area Team in producing a letter that was so defensively aggressive?
Rather than be antagonistic, our local Area Team should have engaged with doctors on an adult level. This would involve honestly balancing their understandable hopes for prophylactic treatment against the paucity of evidence that it leads to real life benefits as well as highlighting the difficulties that doctors might need to anticipate. These would include the difficulties in achieving informed consent which will include pointing out the definite side effects and potential benefits, if any, of this still contentious mode of treatment.
Personally we were irritated and were not convinced by the rhetoric delivered to us. This exercise has done little more than drive a divisive wedge between front-line GPs and PHE/NHS England. We will have to base decisions for individual patients on the evidence that is available from fully disclosed trial data, an understanding of our patients underlying comorbidities, the patient's wishes, and the ethical principle of ‘first, do not harm’.
Competing interests: No competing interests
Professor Phin and Dr Moll make a series of statements, which are at best unverifiable, as they lack any references to link them to evidence.
We note their declaration of absence of competing interests, but given the role of Public Health England in the promotion of antiviral use we ask that they explain to BMJ readers what their respective roles in decision-making have been and are.
Tom Jefferson, Honorary Fellow, Centre for Evidence Based Medicine,
Carl Heneghan, Professor of Evidence Based Medicine
Igho Onakpoya, Research Fellow Evidence Based Practice and Pharmacovigilance
Competing interests: Competing interests: TJ and CH were co-recipients of a UK National Institute for Health Research grant (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children—http://www.nets.nihr.ac.uk/projects/hta/108001). In addition: TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about Phase 1 or 2 pharmaceutical products. In 2011-2013, TJ acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in healthcare workers in Canada. In 1997-99 TJ acted as consultant for Roche, in 2001-2 for GSK, and in 2003 for Sanofi-Synthelabo for pleconaril (an anti-rhinoviral, which did not get approval from the Food and Drug Administration). TJ was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on the drug Tamiflu (oseltamivir, Roche). CH receives payment for running educational courses at the University of Oxford and University of Oxford ISIS consulting services for external teaching and training. He also receives royalties for books (Evidence Based Toolkit series by Blackwell BMJ Books). IO has no interests to disclose.
There can be no doubt that influenza can have a very serious impact on ill and vulnerable members of our society. It can spread rapidly within communities, the treatment of severe influenza can be challenging and the therapies available are limited. The public health emphasis is therefore on prevention and control.
Although the influenza vaccine offers individual protection, this may be sub-optimal for some groups, such as the elderly or those with underlying conditions (such as immunosuppression), who are at risk of severe outcomes following infection. Chemoprophylaxis may be offered to those in at risk groups with known exposure to influenza to reduce the risk of infection and such complications. In December 2014, following Public Health England (PHE) advice, the Chief Medical Officer issued guidance to all GPs on the use of antiviral drugs for the treatment and prophylaxis of influenza, as per NICE guidance for the use of antivirals once influenza is circulating in the community. However, we are aware that in one local area, the contractual arrangements for the prescription of antivirals in nursing homes have been disputed and as a consequence prophylaxis has been denied to this vulnerable group.
There is now convincing evidence and analysis to support the post exposure use of antiviral prophylaxis in certain circumstances. Although the often cited Cochrane review did not find any effect of antivirals on influenza-like symptoms, it did find that the post exposure use of antivirals was associated with a significant reduction in the risk of lab-proven symptomatic influenza with a risk ratio of 0.45 (a 55% reduction in risk). The same review also states that when oseltamivir prophylaxis was used in cases of known exposure within a household, a situation akin to that in care homes, the risk reduction increased to 80%. The other available antiviral, zanamivir, when used prophylactically was associated with a significant reduction in pneumonia (RR 0.30); the effect was not analysed for oseltamivir. It is therefore concerning that in the face of evidence from the Cochrane Review, NICE and PHE, family doctors are reluctant to prescribe therapies that may prevent their patients from becoming unwell or that could prevent significant morbidity and mortality due to influenza.
PHE continues to recommend the use of antivirals as prophylaxis to control influenza outbreaks in vulnerable patient populations such as nursing homes, in line with NICE Guidance (TA158). It also continues to recommend the early use of antivirals for treating patients with proven or suspected seasonal influenza who are in high risk groups or who are considerably unwell.
Competing interests: No competing interests
Re: GPs are told to treat with scepticism advice on anti-flu drugs from Public Health England
With the dismal performance of this season's influenza vaccine ("23% effective") the U.S. Center for Disease Control has also ratcheted up the pressure to use Tamiflu and other influenza antivirals (MMWR 1/16/15. CIDRAP News 1/15/15). It is ironic that our CDC has so many financial and bureaucratic ties to the manufacturers that they could not publish relevant guidelines in The BMJ, which is a good thing.
The facts about the vaccine are worse than the headlines: for adults over 50 vaccine effectiveness was only 14%, with a confidence interval including the possibiity that the vaccine Increased their influenza risk as much as 31%!! This is reinforced by news in central New York State that the last four 'influenza deaths' had all received the vaccine (Mulder, syracuse.com 1/13/15).
CDC classifies patients as 'vaccinated' only if they received the vaccine at least 2 weeks before onset of their illness; this biases their results in favor of vaccine effectiveness. In a study of the pandemic flu shot in Danes with chronic illness vaccine protection became evident only after 2 weeks; however, in the first week after the flu shot the risk of being hospitalized with a pH1N1 infection nearly quadrupled!! (Emborg, BMJ 344:d7901, 2012). How could this be?...Maybe some patients were getting sick when they went in for the shot....Maybe they caught influenza at the shot clinic...Maybe the vaccine itself transiently increased their susceptibiity to influenza; this phenomenon has been observed with other vaccines. Whatever the explanation, the CDC's methods sidestep this problem; therefore, "23%" may actually exaggerate this season's vaccine's effectiveness at preventing influenza, and says nothing about its potential for increasing susceptibility to other respiratory viruses.
Competing interests: No competing interests