EID Journal: Revisiting The Oseltamivir Effectiveness Debate

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Over the past 10 years we've been witness to both the repeated demonization and the resultant defense (by public health agencies) of the neuraminidase inhibitor (NAI) antiviral oseltamivir, better known as Tamiflu(c).


The British press, in particular, have excoriated the drug using hyperbolic headlines such as the Daily Mail's: Ministers blew £650MILLION on useless anti-flu drug.

Fueling this media frenzy have been a number of Cochrane group analyses that found insufficient evidence that oseltamivir substantially reduces seasonal influenza complications in healthy adults. 

And for mild to moderate seasonal influenza - in healthy adults - the advantages of taking the drug do appear to be modest at best.  A reduction, on average, of less than a day of symptoms.

But in severe influenza, the benefits have been far more pronounced. 

The problem is, while robust Randomized Controlled Trials (RCTs) exist for mild influenza, they do not (and ethically, cannot) be mounted for severe, life threatening flu.  We are therefore left to draw our conclusions based on less rigorous, yet still compelling, observational data. 

• The Study: Antivirals Saved Lives Of Pregnant Women strongly suggested that Tamiflu was life saving for some patients with pandemic flu.
• In BMJ: Efficacy of Oseltamivir In Mild H1N1,a study suggested oseltamivir significantly reduced pneumonia among otherwise healthy pandemic H1N1 patients.
• In Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic we looked at a meta-analysis of 90 observational studies that found NAIs - principally oseltamivir - initiated within 48 hours of onset, reduced the likelihood of severe outcomes by 49 to 65%.
• And most impressively . . .in Study: Antiviral Therapy For H5N1, out of 308 H5N1 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.

Because of these (and other) studies, we’ve seen a push back by public health agencies against the negative perceptions of antivirals, and advocacy for their early use in cases of severe flu:

ECDC: Expert Opinion On Effectiveness of NAI Antivirals For Influenza

Wellcome Trust/AMS Report On Antivirals For Influenza

 

The CDC Responds To The Cochrane Group’s Tamiflu Study 

The Conversation: The Rise & Fall Of The Challenge To Tamiflu

CDC Research On Benefits Of Antivirals For Uncomplicated Influenza

 
All of which brings us to a new Perspective article published today in the EID Journal that reviews the both the existing RCT data along with an abundance of observational data, and offers some intriguing hints that oseltamivir might also modulate excess cytokine production (cytokine storm) in patients with severe flu infection.

The authors argue that the existing trials based on patients with relatively mild disease should not be used to drive policies on the treatment of severe influenza.  

I've only posted the abstract from a much larger discussion, so follow the link to read the review in full.

Volume 22, Number 6—June 2016 Perspective

Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza

Aeron C. Hurt  and Heath Kelly 

Author affiliations: World Health Organization Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia (A.C. Hurt); University of Melbourne, Parkville, Victoria, Australia (A.C. Hurt); The Peter Doherty Institute for Infection and Immunity, Melbourne (H. Kelly); Australian National University, Canberra, Australian Capital Territory, Australia (H. Kelly)

 

Abstract

A debate about the market-leading influenza antiviral medication, oseltamivir, which initially focused on treatment for generally mild illness, has been expanded to question the wisdom of stockpiling for use in future influenza pandemics. 

Although randomized controlled trial evidence confirms that oseltamivir will reduce symptom duration by 17–25 hours among otherwise healthy adolescents and adults with community-managed disease, no randomized controlled trials have examined the effectiveness of oseltamivir against more serious outcomes. 

Observational studies, although criticized on methodologic grounds, suggest that oseltamivir given early can reduce the risk for death by half among persons hospitalized with confirmed infection caused by influenza A(H1N1)pdm09 and influenza A(H5N1) viruses. However, available randomized controlled trial data may not be able to capture the effect of oseltamivir use among hospitalized patients with severe disease. 

We assert that data on outpatients with relatively mild disease should not form the basis for policies on the management of more severe disease.

(Continue . . . )