Scepticism advice on anti flu drugs

This is our response posted on the BMJ to @deb_cohen  article on ‘GPs are told to treat with scepticism advice on anti-flu drugs from Public Health England’

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 [1] 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 [1] or the corresponding BMJ review. [2]

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).

Carl Heneghan, Professor of Evidence Based Medicine,
Tom Jefferson, Honorary Fellow, Centre for Evidence Based Medicine,
Igho Onakpoya, Research Fellow Evidence Based Practice and Pharmacovigilance, and Mark Jones, Senior Research Fellow.


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— 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.

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