OSELTAMIVIR TREATMENT FOR INFLUENZA IN ADULTS: A META-ANALYSIS OF RANDOMISED CONTROLLED TRIALS (Dobson et al., 2015)

I was interested to read about a new drug NICE have approved for HUS which by all accounts is massively expensive. All sorts of harrumphing followed in the press as well as the medical press about funding of expensive drugs and QALYs. Personally I think NICE have an important yet unforgiving job to do. I also do get a little cynical at yet another expensive breast cancer drug coming out which, accompanied by a powerful patient interest lobby, is guaranteed to net the drug company a good return. I remember reading the first papers on the initial Herceptin trials which were sponsored by big Pharma & thinking ‘this actually isn’t that great’. The study sample was small, the mortality pretty unchanged though admittedly the disease free interval was extended. I suppose if you have any cancer, these are small positives. My mother is currently in the terminal stages of bowel cancer and I know how awful it can be.

The other side is a drug which may benefit millions of us in the event of a pandemic. This brings us to Tamiflu, or oseltamivir. Not so long ago, a meta-analysis published in the BMJ reported that neuraminidase inhibitors at best had a modest effect (Jefferson et al., 2009). This was something I had always suspected. The patients I treated seemed to have more side effects than benefit in my admittedly small sample. I assumed powerful lobbying by Pharma alongside failure to disclose unpublished trial data had won the day.

It was the other day therefore whilst reading the Torygraph that this article piqued my interest. I won’t go into massive detail as one needs access to full text to assess it. Suffice to say it seems a well constructed systematic review with lots of blobograms (Forest plots) and actually is quite easy to read. The statistics seem sound too. When I see something that is too good to be true, it usually is. Not wanting to be unfair on the authors, there are one or two concerns. Firstly 2 of the 4 authors have been paid by Roche. Secondly, whilst they had no part in the analysis, Roche funded the study under the guise of the MUGAS foundation. The authors acknowledge this and make valid comment. The interesting thing about this study is that it used unpublished data. I don’t know which studies were unpublished but I could probably have a good guess. Of the 9 studies included, a sizeable minority have confidence intervals that cross the line of no effect. This includes the 2^nd largest. Clearly when doing a systematic review, one includes all the studies but it is interesting to see all the data.

Probably the biggest issue and the one that that relates to primary care in the UK is the different analyses that were carried out. The intention-to-treat-infected population showed far greater effectiveness than the intention-to-treat population. This is essentially saying that when the nasal swabs were analysed & the results broken down into those who had influenza & those who didn’t, the former group gained far more benefit from oseltamivir. Patients included in the studies presented with symptoms of influenza had their treatment started within 36hr of onset. In other words no time to obtain a lab result to confirm influenza. This means the only population relevant to us in primary care is the intention-to-treat population where the effect is much less. Indeed one of the headlines is reduction of hospital admissions which in the intention-to-treat group was not significant. What we really need is a rapid near test to enable a more accurate diagnosis so the drug is used more effectively.

There are several references to Jefferson’s earlier work and indeed for anyone interested, I would read both studies together. It is a good example of a systematic review and actually one of the easiest to read I have come across in a while. It also will give some justification to the Government for the millions of pounds spent on stockpiling drugs in the event of an influenza pandemic.

DOBSON, J., WHITLEY, R. J., POCOCK, S. & MONTO, A. S. 2015. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. The Lancet.

JEFFERSON, T., JONES, M., DOSHI, P. & DEL MAR, C. 2009. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. Bmj, 339.