Wednesday, March 19, 2014

The Lancet: Effectiveness Of NAI Antivirals In Reducing Mortality In Hospitalized H1N1pdm09 Cases




# 8387


If you want to start a row on the Internet, simply say something positive about Roche’s neuraminidase inhibitor (NAI) antiviral Tamiflu ® (oseltamivir). 


Between large government outlays for stockpiles of the drug, an inherent distrust of `Big Pharma’,  a lack of Randomized Controlled Trials (RCTs) to gauge the effectiveness of the drug, a Cochrane group analysis that found insufficient evidence to show whether the drug reduces influenza complications and transmission, and the apparent reluctance of Hoffmann-La Roche  to release unpublished trial data . . .

Suffice to say its an easy drug to disparage - at least - until you need it (see Dec 2013’s Spot Shortages Of Tamiflu Reported In Some Regions). 


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 overrated, a waste of money, and not worth risking the (usually mild) side effects.

Yet despite these critics, the CDC continues to recommend its use (as do many other public health agencies around the world), and as recently as last week, the CDC released a fresh set of antiviral guidelines for clinicians:


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 critics such as the Cochrane group often discard 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.  Over the years we’ve looked at a number of them,  including:


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%.


Today The Lancet presents a new observational study (funded by F Hoffmann-La Roche), conducted by researchers at The University of Nottingham – that reviewed more than 29,000 hospitalized H1N1pdm cases across 38 countries between 2009 and 2011, and found that the administration of NAI antivirals was associated with a 19% reduction in mortality compared to receiving no NAI treatment at all.


And among those who received the NAI antiviral within the first 48 hours of admission, the mortality risk was halved. Pregnant women who received the drug swiftly saw a 54% reduction in mortality.

While funding was received from Roche for the study, the researchers stated that `No data were requested from nor provided by pharmaceutical companies.’ .  First a link to the study (which contains much more detail), followed by a link to an accompanying commentary from Alicia M Fry of the CDC’s Influenza Division.


Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

Jonathan S Nguyen-Van-Tam, et. al.



We included data for 29 234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70—0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41—0·56; p<0·0001).

Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37—0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18—1·28]; p<0·0001 for the increasing HR with each day's delay).


We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection.

(Continue Reading Full Text)

The related commentary may be read at:


Effectiveness of neuraminidase inhibitors for severe influenza

Alicia M Fry aEmail Address

The neuraminidase inhibitors (NAIs) were licensed for use for the treatment of uncomplicated influenza on the basis of results from phase 3 placebo-controlled, randomised clinical trials and are the only influenza-specific treatment option recommended for use. 1 However, the greatest potential clinical and public health benefits of NAI treatment are associated with more severe influenza-associated illness and outcomes, including admission to hospital and death. Thus, in the absence of placebo-cont ...

(Continue . . . )

Today’s study adds to the preponderance of evidence that oseltamivir (and other NAI antivirals) provide substantial benefits – particularly when administered early and in cases of severe influenza.  For on this topic you may wish to review these earlier blogs.

CDC Research On Benefits Of Antivirals For Uncomplicated Influenza
New Scientist: Don’t Stop Stockpiling Tamiflu
The CDC On The Value Of Antivirals


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