# 8004
In clinical medicine there are a lot of things that we think we know – based on observational studies – but for which rigorous randomized controlled trials (RCTs) have not been conducted. Sometimes it is impractical (or even unethical) to subject patients to an RCT, especially if it involves withholding a potentially lifesaving drug from a `control’ cohort.
So we are often left to rely on less desirable, but still useful, observational studies to gauge the value of treatments or therapies.
Over the past decade one of the drugs that has fallen into this pharmaceutical limbo is oseltamivir (Tamiflu ®), a product of Roche laboratories, which has been stockpiled by many nations to combat a flu pandemic. Observational studies have shown that this drug can significantly reduce morbidity and mortality in severe cases of flu, and modestly reduce the duration of symptoms in uncomplicated seasonal flu.
But robust RCTs have not been conducted to quantify these benefits, and `RCT purists’ like this Cochrane group analysis – that do not consider `observational studies’ to be solid evidence - have found insufficient evidence to show whether the drug reduces influenza complications and transmission (see 2012 CIDRAP article Review renews questions about oseltamivir benefits).
Add to this a prolonged reluctance on the part of Roche laboratories to release all of their clinical trial data, and a not totally undeserved reputation of `Big Pharma’ to massage test results, and the result has been a vociferous backlash against the government stockpiling of Tamiflu in some quarters (see Dr. Ben Goldacre Opinion Piece).
While academics and activists tend to have a dim view of Roche and their antiviral drug, clinicians obviously see value in oseltamivir, and continue to prescribe it. The CDC continues to recommend its use – particularly for high-risk influenza patients - or for the treatment of novel flu (see 2012 blog The CDC Responds To The Cochrane Group’s Tamiflu Study).
With a new avian (H7N9) virus in the wings and H5N1 still simmering in Asia and the Middle East, the CDC recently reiterated their support for the use of oseltamivir in the treatment of severe, or novel, influenza infection (See H7N9: Updated CDC Guidance For Antiviral Treatment).
Yesterday, the CDC published a news release on an RCT conducted in Bangladesh on the benefits of Oseltamivir in uncomplicated seasonal flu. A category of illness where one would expect the least amount of benefit to taking an antiviral. A few excerpts, and a link to The Lancet Study, then I’ll return with a bit more.
CDC Research Confirms Benefits of Flu Antiviral Drugs, Even Beyond 2 Days After Symptoms Start
New research confirms benefits of the influenza antiviral medication oseltamivir in treating children with uncomplicated flu illness and shows that treatment can be beneficial even beyond the two-day window recommended as a cut-off for treatment in the drug’s package insert.
A new study on influenza (flu) antiviral drugs by CDC authors was released today in The Lancet Infectious Diseases. This study is the first clinical trial to note a significant reduction in the duration of illness and virus shedding in children when influenza antiviral treatment was initiated more than 2 days after the onset of influenza (flu) symptoms. These findings confirm the benefits of using the antiviral drug oseltamivir to treat flu illness and suggest that some children will benefit when treatment is initiated beyond 2 days, which is the recommended cut-off for treatment in the current package insert.
The patients in this double-blind, randomized, placebo-controlled study were mostly children (average age: 5 years) in an urban setting in Bangladesh with laboratory-confirmed influenza infection and no additional flu-related complications. Patients were treated with either oseltamivir (a type of flu antiviral drug known as a “neuraminidase inhibitor”) or a placebo (e.g., a shot of saline). Researchers observed when patients began oseltamivir treatment — either less than 48 hours or 48 hours or more after illness onset — and collected information about the duration of flu symptoms using standardized forms collected from daily household visits. In addition to documenting the duration of flu symptoms, researchers also measured viral shedding, which is virus detection at various times after the patients were enrolled. The detection of live virus in respiratory secretions is thought to be associated with how contagious a person is to others.
Among all children receiving oseltamivir within 5 days of illness onset, researchers found that overall flu symptoms were reduced by one day compared with those treated with placebo (3 days versus 4 days). This finding is consistent with results from other flu antiviral studies that started treatment within 2 days of illness onset. The results also show that oseltamivir treatment reduced the amount of live virus that was isolated from respiratory specimens by 12% to 50% compared with placebo regardless of whether treatment was started before or after 2 days since illness onset. This finding is especially important because no other study has shown reduced viral shedding in similar proportions regardless of whether treatment is started less than or more than 48 hours after flu symptoms begin.
The article is available in The Lancet Infectious Diseases: “Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial
.”
Of course, governments aren’t stockpiling Tamiflu for uncomplicated seasonal flu. They have purchased millions of doses in anticipation of a severe pandemic. And while RCTs on treating severe influenza with the drug are scant, we have seen some pretty compelling observational and anecdotal data.
In 2010 an observational study appearing in JAMA (see Study: Antivirals Saved Lives Of Pregnant Women) 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.
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 an avian 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.
While today’s study may not completely mollify 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.
