Three weeks ago, The Tamiflu Controversy Continues we looked at the ongoing debate over the effectiveness of oseltamivir (Tamiflu ®) in the wake of the release of a new Cochrane group analysis that found insufficient evidence to show whether the drug reduces influenza complications and transmission.
Robert Roos of CIDRAP provided a good summation of that Cochrane group analysis in:
Robert Roos News Editor
Jan 19, 2012 (CIDRAP News) – A lengthy new analysis of unpublished clinical trial data is renewing questions about the effectiveness of the influenza drug oseltamivir (Tamiflu), saying that although the drug shortens flu symptoms by about a day, there is no evidence that it reduces hospital admissions.
While research purists may applaud their methods, the problem that I (and many others) have with this analysis is that the Cochrane group set the bar very high as to what studies they would consider, and effectively ignored any observational studies.
As few studies met their criteria, they were unable to determine one way or the other, the overall effectiveness of the drug.
Despite the fact that their analysis was inconclusive, some aspects of the media immediately latched onto this as `proof’ that Tamiflu was ineffective.
February 7, 2012 -- A recent review of randomized clinical trial data for the influenza neuraminidase inhibitor antiviral medications published by the Cochrane Collaboration, and two related commentaries [“Rethinking credible evidence synthesis” and “Questions Remain over safety and effectiveness of oseltamivir”] published in the British Medical Journal, raised questions about the value of antiviral medications for the prevention and treatment of influenza. After careful consideration of all available evidence, CDC guidance on the use of antiviral medications remains unchanged. The Centers for Disease Control and Prevention (CDC) continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct in the prevention and treatment of influenza.
The Cochrane review assessed unpublished and published data from randomized controlled trials (RCTs) of oral oseltamivir or inhaled zanamivir versus placebo for early treatment (within 48 hours after illness onset) or chemoprophylaxis of uncomplicated seasonal influenza in otherwise healthy adults and children. The review concluded that in adults and children with influenza-like illness, early oseltamivir treatment shortens the duration of symptoms by approximately 21 hours compared to placebo. This finding is similar to results in published RCTs which reported a reduction of approximately one day of laboratory-confirmed influenza illness by early oseltamivir treatment. One RCT in children aged 1 to 3 years with influenza found a reduction of 3.5 days when oseltamivir treatment was started within 24 hours after illness onset. The Cochrane review was unable to reach conclusions about the efficacy of oral oseltamivir or inhaled zanamivir treatment to reduce health complications, including those which might result in hospitalization. The review authors reported that they did not have full access to all unpublished data for oseltamivir RCTs as requested from the manufacturer.
A systematic review of RCTs should include unpublished and published data, and researchers should have full access to these data. However, such a review may not fully inform the question of whether antiviral treatment reduces severe influenza complications such as those resulting in hospitalization in generally healthy persons because enormous numbers of participants are needed. The burden of influenza disease is greatest among the elderly, persons with underlying medical conditions such as chronic obstructive pulmonary disease, asthma, congestive heart failure, diabetes, pregnant women, and young children. These groups are at highest risk for developing severe complications from influenza resulting in hospitalization or death, and generally have not been studied in RCTs.
The Cochrane review did not consider any data from uncontrolled observational studies of oseltamivir treatment. While such studies have inherent design limitations, they can inform clinical practice and public health, especially when data from RCTs are unavailable or have not been conducted among high-risk groups or hospitalized influenza patients, or because having a placebo group would be unethical since antiviral treatment is recommended for these groups. Indeed, many observational studies of antiviral treatment of seasonal influenza or influenza A (H1N1) pdm09 (2009 pandemic H1N1) have been conducted among hospitalized patients, including critically ill children and adults. These observational studies from many countries have consistently found that early oseltamivir treatment of influenza patients reduces the duration of hospitalization and risk of severe outcomes such as intensive care unit admission or death. These studies have reported that clinical benefit is greatest when oseltamivir treatment is started within 48 hours of illness onset; however clinical benefit has still been observed when oseltamivir treatment is started up to less than 5 days after illness onset.
While falling short of the `gold standard’ employed by the Cochrane group for inclusion into their analysis, we’ve a number of compelling observational studies to look at, including:
In 2010 we saw an observational study that appeared in JAMA (see Study: Antivirals Saved Lives Of Pregnant Women) that strongly suggested that Tamiflu was life saving for some patients with pandemic flu.
And again in 2010, in BMJ: Efficacy of Oseltamivir In Mild H1N1, we saw a study which suggested that the administration of oseltamivir may have significantly reduced the incidence of pneumonia among otherwise healthy pandemic H1N1 patients.
And lastly, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the outcomes of H5N1 patients who either received, or did not receive, antiviral treatment.
The research appears in the IDSA’s Journal of Infectious Diseases. The bottom line is essentially out of 308 cases studied, the overall survival rate was a dismal 43.5%.
But . . . of those who received at least one dose of Tamiflu . . . 60% survived . . . as opposed to only 24% who received no antivirals.
There are other concerns when it comes to use of oseltamivir, of course. Including the possibility inducing side effects and the possibility of generating resistant strains of the influenza virus.
But for now, it remains one of the few pharmacological options we have available to treat severe influenza.