# 7344
One of the concerns during a severe pandemic is our finite supply of antiviral medications. The standard adult dose of oseltamivir (Tamiflu ®) is 75mg twice a day for 5 days, or a course of 10 pills.
But as we’ve seen in Southeast Asia with H5N1 (and more recently with H7N9), many patients have required larger antiviral doses for a longer period of time, and yet many still do not survive.
In 2007, at the height of the H5N1’s expansion, some doctors began treating patients with double the dose for double the time, essentially 40 pills over 10 days (see Prudence and the Pill).
A rate that is sustainable when cases are few, but would quickly exhaust our stockpiles of antivirals in a severe pandemic.
Which makes the headline being carried by the media this morning, stemming from a study that appeared in the BMJ yesterday, of particular interest:
No benefit of double dose antiviral drug for severe influenza
Findings have major implications for stockpiling drugs during pandemics, say experts
And if you stop there, or simply read the press release, you might come away with the idea that a double dose of oseltamivir (Tamiflu ®) is a waste of time, and valuable resources, when treating an avian flu patient.
But that’s not exactly what the study says.
First, a link to the open access double-blind randomized trial, conducted across 13 hospitals in four southeast Asian countries between 2007 and 2010, comparing the relative effectiveness of the standard dose of oseltamivir (Tamiflu ®) vs a double dose.
Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial
BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3039 (Published 30 May 2013)
Cite this as: BMJ 2013;346:f3039
This is actually an impressive, well mounted study, certainly worth reading in its entirety. There were 326 patients, mostly children under the age of 15, enrolled in the trial.
The press release describes their methodology:
Patients received either standard dose oseltamivir (75 mg twice a day or children's equivalent) or double dose (150 mg twice a day or children's equivalent) for five days. Nose and throat swabs were then taken to test for virus levels.
Other outcomes including death, admission to intensive care, and help with breathing (mechanical ventilation) were also assessed.
The researchers found no differences between the treatment groups in virus levels on day five. There were also no differences in deaths or rates of adverse events between the different doses.
The authors mention a few important limitations to this study, including:
- Most of the patients were children under 15
- Most of the patients had low or normal BMI
- Only about 1/5th had underlying conditions
- Very few adults were included in the study
- Only 17 (of 326 cases) were H5N1, and of those, only 3 survived to day 5 of the trial.
- The average delay for treatment for H5N1 patients was 7 days vs. 5 days for seasonal flu
- All H5N1 cases met the criteria for clinical failure
The authors caution:
Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology.
One is left to wonder how well these results would translate to a much older population, one likely to have a higher average BMI, far more (and different) underlying conditions, and in all likelihood would seek treatment sooner than did the patients in this study (average 5-7 days).
But assuming that these factors would not make huge differences in outcomes, the biggest limitation remains the lack of data on H5N1 avian influenza.
Only 17 patients were enrolled, treatment began (on average) a week after falling ill – well beyond the optimal `48 hour window’ - and only three patients survived.
So, while this trial found no value to doubling the dose for seasonal flu, there is insufficient evidence to judge whether doubling the dose for H5N1 (or presumably H7N9) would improve patient survival.
And in an accompanying editorial, Ian Barr and Aeron Hurt of the WHO Collaborating Centre for Reference and Research on Influenza, would appear to agree:
What is clear is that double dose oseltamivir is unlikely to significantly improve the clinical outcomes of severe cases of seasonal influenza, although there were probably insufficient data to determine if this was also true for people infected with A(H5N1).
It is worth noting that last month, in CDC Interim Guidance On H7N9 Antiviral Treatment, we saw the CDC’s recommendation that for hospitalized patients:
The optimal duration and dose of therapy are uncertain in severe or complicated influenza. Pending further data, longer courses of treatment (e.g., 10 days of treatment) should be considered for severely ill hospitalized H7N9 patients.
And in a discussion this morning on this study between Gregory Hartl – spokesperson for the World Health Organization and FluTrackers – Hartl had this to say.
While the success rate of treatment with oseltamivir for avian flu has been less than stellar, 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.
And importantly, most of these patients did not receive antivirals within the first critical 48 to 72 hours of infection.
Over the next few months I suspect we’ll get a much better idea of the efficacy of oseltamivir for treating avian flu, and optimal dosing in adult patients, from China’s experience with the H7N9 virus.
