Over the past several years the value of oseltamivir (Roche’s Tamiflu ®) has been questioned by Cochrane meta-studies, medical journals, conspiracy theorists, pundits, and the press.
Roche Pharmaceuticals has been widely criticized for their refusal to release all of the testing data on their best selling antiviral drug, which has led to critical editorials in the BMJ, and excoriation in the British press.
“And yet for all we know, Tamiflu might be no better than paracetamol: because Roche, the company making it, still withholds vital information on the risks and benefits from researchers, doctors and patients.”
These claims, while hyperbolic, are not dissimilar to concerns voiced in a Cochrane group analysis, released in January of 2012, that found insufficient evidence to prove that the drug reduces flu complications and transmission.
From CIDRAP News, we saw this balanced overview:
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Jan 19, 2012 (CIDRAP News) – A lengthy new analysis of unpublished clinical trial data is renewing questions about the effectiveness of the influenza drug oseltamivir (Tamiflu), saying that although the drug shortens flu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.
With all of this negative press (which let’s face it, sells newspapers & drives web traffic), it would be easy to assume that Tamiflu is next to worthless, a waste of money, and not worth risking the (usually mild) side effects.
Yet amid all of this furor and handwringing - last Friday, in a media briefing on this year’s influenza season, Dr. Thomas Frieden, Director of the CDC – had this to say about the value of antivirals, including Tamiflu.
So when people have symptoms of flu for those who are older or for young children or people with underlying health problem, very important to get seen by a health provider promptly and what we're seeing is not as many people as we would like who are in those categories are getting treated with Tamiflu.
That's important because Tamiflu can reduce the likelihood of hospitalization, severe illness or death.
Why, you might ask, would the CDC express confidence in a drug that been so disparaged online and in the media?
Well, despite the critics, there are studies that show that Tamiflu can significantly reduce morbidity and mortality associated with influenza.
Ideally what researchers want to see are a series of well mounted Randomized controlled trials (RCTs) – long considered the `gold standard’ for drug research. But these types of studies are expensive, and difficult to conduct ethically when trying to evaluate a potentially life saving drug.
So what we are often left with are observational studies, which the Cochrane group often discards as being unreliable. With few studies that can meet their requirements, there is – in their opinion - insufficient evidence to show whether the drug reduces influenza complications and transmission.
But observational studies are not without value, and often they are the only evidence available. 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.
Quite recently, in December of 2012, in Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic we looked at a meta-analysis of 90 observational studies that appeared in the Journal of Infectious Diseases that spanned nearly 35,000 patients, 85% of whom has laboratory confirmed H1N1.
Their main finding was antiviral therapy - principally oseltamivir - initiated within 48 hours of onset, reduced the likelihood of severe outcomes, namely admission to a critical care unit or death, by 49 to 65%.
And lastly, for those who question the value of Tamiflu in a bird flu pandemic, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on 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.
Last January, after the Cochrane group released their analysis, the CDC responded with their rationale for continuing to recommend Tamiflu (reparagraphed for readability, bolding mine).
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 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.
Tamiflu isn’t a cure all, but it can reduce the severity of symptoms, particularly in severe infections. The other concern often heard regarding Tamiflu has been possible adverse effects (AEs), including psychiatric symptoms in adolescents.
In 2010 a review in the journal Eurosurveillance: Adverse Effects of Oseltamivir in Children, looked at the antiviral treatment of a number of students at a primary school in Sheffield, UK during the 2009 pandemic.
While none of the side effects reported were life-threatening, the nausea, vomiting, abdominal pain and other symptoms were bothersome enough that a minority of those who started the Tamiflu (< 10% ) stopped taking the drug.
More recently, in Study: Adverse Events Associated With Oseltamivir Outpatient Treatment, researchers writing in the journal Pharmacoepidemiology and Drug Safety, found that `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’
The safety record of Tamiflu has been reassuring enough that last month the FDA approved its use in infants as young as two-weeks (see FDA expands Tamiflu’s use to treat children younger than 1 year).
Despite the critics, the preponderance of evidence continues to show that antivirals – including Tamiflu – can have a substantial positive therapeutic effect on influenza, particularly in high risk patients.