Antivirals and swine flu

Several newspapers have reported today on a review of the effectiveness of antivirals for treating and preventing flu. The Daily Express said that "Tamiflu does not work on healthy patients who get swine flu".

While there is little evidence that antivirals prevent the transmission of flu, or cut the risk of complications, it is wrong to state that “Tamiflu does not work”. This well-conducted review found that antivirals have a significant effect in reducing the duration of flu symptoms by about one day.

The review does have some weaknesses, one of which was the limited number of quality studies that were suitable for inclusion. An issue identified here is that there is a lack of evidence, rather than there is no evidence. As the researchers state, more published trials in this area are needed.

Overall, for healthy people with seasonal flu, antivirals will probably only give minimal relief of symptoms and the researchers’ view that these drugs should be considered optional for this group seems appropriate.

It is important to make clear that this is not a review of the effectiveness of antivirals for swine flu as it looked at trials on seasonal flu. Also, the subjects were healthy adults so the results do not apply to children or people with underlying health conditions. People in at-risk groups, such as pregnant women or those with compromised immune systems, are advised to start taking antivirals as soon as possible if they contract flu.

Where did the story come from?

This research was carried out by Tom Jefferson and colleagues from the Cochrane Collaboration. The study was funded by the Australian National Health and Medical Research Council and the UK NHS Research and Development fund. It was published in the British Medical Journal.

In general, the findings of this well-conducted review have been oversimplified in the media reports.

The researchers did not actually find that Tamiflu and other anti-flu drugs do not work, but that the benefit may not be as extensive as hoped. They also found that there is a lack of robust data on the effectiveness of antivirals at preventing flu complications, as well as the incidence of serious adverse effects of treatment, and whether treatment prevents the risk of an infected person passing flu to others.

What kind of research was this?

This is a systematic review and meta-analysis. The researchers searched for all trials in which oseltamivir (Tamiflu) or zanamivir (Relenza) were used to treat the symptoms of flu, or to reduce the risk of complications and transmission. The results of the individual trials were then combined in a meta-analysis to give an overall result.

This type of study provides the best evidence of the overall effectiveness of a treatment. However, when combining the results of studies that are likely to have used slightly different methods, there are limitations that have to be considered.

What did the research involve?

This research is an update of a Cochrane systematic review published in 2006. The researchers looked in several medical databases for relevant clinical trials, post-marketing drug safety surveillance data, and cohort studies looking for adverse effects in people who have taken the drugs. Included trials were of previously healthy 14 to 60 year olds who had developed flu.

The main outcomes examined were duration and incidence of flu symptoms, incidence of lower respiratory tract infections e.g. pneumonia or bronchitis, and adverse effects (safety) issues. The researchers considered the quality of the trials and combined the data from the selected studies using statistical methods that took into account the differences in trial sizes, methods and results. They then calculated the chance of the drugs being effective and the risk of adverse effects.

This is a well-conducted review and analysis in which the researchers had clear inclusion criteria. They considered the quality and differences in the included studies and clearly defined the outcomes that they were examining.

What were the basic results?

Twenty placebo-controlled trials met the inclusion criteria: 12 on the effectiveness and safety of the drugs, four on the prevention of flu in healthy people, and four on the prevention of flu in people who had definitely been exposed to flu, for example from living with an affected person.

Overall, oseltamivir and zanamivir (any dose) had no effect in preventing flu symptoms when taken by healthy people as prophylaxis (a preventative measure). However, at the 75mg daily dose, oseltamivir did decrease the risk of having laboratory-confirmed influenza by 61% (risk ratio 0.39, 95% confidence interval [CI] 0.18 to 0.85), and by 73% at 150mg daily (0.27, 0.11 to 0.67).

Inhaled zanamivir, 10mg daily, was similarly effective in reducing the risk of having laboratory-confirmed flu (62% risk reduction; risk ratio 0.38, 95% CI 0.17 to 0.85). In four trials of flu prevention in exposed households, oseltamivir and zanamivir were similarly effective in reducing the risk of having flu.

The researchers found 13 trials in people with flu (five used oseltamivir and eight used zanamivir). Overall, antiviral treatment significantly reduced the time to alleviation of influenza-like symptoms if it was started within 48 hours of the symptoms showing (20% chance of a shortened illness with oseltamivir and 24% chance with zanamivir. Overall 22% reduced risk). There was limited evidence of their effectiveness in reducing complications, including a non-significant effect on the risk of lower respiratory tract complications.

Oseltamivir was found to significantly increase risk of nausea by 79% (odds ratio 1.79, 95% confidence interval 1.10 to 2.93). The researchers say they were not able to make conclusions on the risk of rare or serious adverse effects of treatment as post-marketing drug surveillance data was of poor quality. It is also likely to be incomplete due to under-reporting of adverse effects.

How did the researchers interpret the results?

The researchers conclude that oseltamivir and zanamivir have modest effectiveness against the symptoms of influenza in otherwise healthy adults. However, overall they are not effective for preventing flu symptoms when taken as prophylaxis by people who have been exposed to flu.

They say that the drugs may be regarded as optional for reducing the symptoms of seasonal influenza, but that there is limited evidence that they reduce the risk of complications.

Conclusion

This well-conducted review found that oseltamivir and zanamivir have a significant effect in reducing the duration of flu symptoms by about one day. However, they appear to have little benefit when taken as prophylaxis against flu. It also remains unclear whether or not antivirals reduce the risk of people with flu developing complications.

Although this is a good-quality review, meta-analyses are limited by the variable methods and quality of the studies they include. The researchers say that many of these trials were at risk of bias and had poor descriptions of their study methods (including no information on blinding or on how many subjects were followed up). The researchers say they tried to contact the study authors to clarify some of these issues but were unsuccessful.
It is possible that systematic reviews can fail to find all relevant studies or can exclude studies that could alter the results if they were included. These reviewers excluded a 2003 meta-analysis of 10 studies as it did not give enough information about population groups that were included in these studies. Attempts were made to contact the authors but without success. If the data from these 10 studies had been included, it is possible their conclusions would have been different.
This review calculated overall hazard ratio risks. However, many of the individual studies had not actually calculated hazard ratios, and the researchers estimated what these figures might have been by comparing the duration of flu symptoms in the treatment and placebo groups. Therefore, these estimated hazard ratios are not as accurate as if the individual studies had been designed to calculate these risk figures themselves.
It is unclear if all of the cases involved in the studies had laboratory-confirmed influenza. Some of those treated with flu drugs may have had other illnesses.
As the researchers say, there is limited evidence that antivirals reduce complications from flu. Eight unpublished studies that could have provided results had to be excluded. Further research is needed into this issue.
The review cannot demonstrate the effectiveness of the drugs in limiting viral shedding and reducing the risk of an infected person transmitting flu to others.

As the researchers say, the effectiveness of antivirals in preventing transmission and complications of influenza in a pandemic needs further research. Further data collection on any serious adverse effects of the drugs is also needed.

However, it is important to make clear that this is not a review of the effectiveness of antivirals for swine flu as it looked at trials on seasonal flu. In addition, the subjects were healthy adults and so the results do not apply to children or people with underlying health conditions. People in at-risk groups, such as pregnant women or those with compromised immune systems, are advised to start taking antivirals as soon as possible if they contract flu.