# 5028
Pharmacological victories over continually evolving pathogens are often fleeting at best.
No sooner do researchers release a new generation of antibiotics or antivirals, than these organisms begin to find ways to work around them.
History shows that if we create a better mousetrap, nature immediately goes to work building a better mouse.
Amantadine managed to remain an effective treatment and/or prophylaxis against influenza A for four decades, although it was used only sparingly for the first 30 years or so.
Overuse of Amantadine, particularly its inclusion into chicken feed during the late 1990s to combat bird flu in Asia – has been credited with a dramatic rise in influenza’s resistance to the drug by 2005.
Tamiflu (oseltamivir), released in 1999 proved extremely effective against influenza until 2008, when a resistant version of seasonal H1N1 appeared and quickly spread around the world.
Seasonal H3N2, along with the pandemic strain of H1N1, remain largely susceptible to the drug. As does H5N1.
At least for now.
We’ve a new study in Plos Medicine that takes a look at the best use (monotherapy or as a combination) of two well known antivirals used for treating seasonal (and by extension, pandemic) influenza.
The two antivirals in question are both neuraminidase inhibitors; Roche Laboratories Tamiflu (oseltamivir) and GlaxoSmithKline’s Relenza (zanamivir).
The study, which comes up with a somewhat surprising answer, is called:
Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial
Duval X, van der Werf S, Blanchon T, Mosnier A, Bouscambert-Duchamp M, et al. 2010 Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial. PLoS Med 7(11): e1000362. doi:10.1371/journal.pmed.1000362
Over the 2008-2009 (pre-pandemic) influenza season, researchers enlisted the aid of 145 general practitioners across France, and conducted a randomized placebo-controlled study on adult patients with a positive influenza A rapid test and reporting flu-like symptoms for less than 36 hours.
Those that fell into that criteria were randomized into one of 3 groups who received either:
(1) oral oseltamivir 75 mg twice daily plus zanamivir 10 mg by inhalation twice daily
(2) oral oseltamivir 75 mg twice daily plus inhaled placebo, or
(3) zanamivir 10 mg by inhalation twice daily plus oral placebo.
The assessment of each treatment regimen was evaluated virologically and clinically. The participants in this study were all blinded to the individual treatment protocols.
Using reverse transcription (RT)-PCR testing, they monitored nasal viral shedding levels, while clinical evaluation included the amount of time to resolution of illness and the incidence of secondary complications of influenza.
Most (85%) of these patients were assumed to have had H3N2 seasonal influenza, which predominated that year. The study was supposed to involve 900 patients, but was cut short by the emergence of the novel H1N1 virus in the spring of 2009, and so only 541 patients were enrolled.
The goal was to determine what worked best.
Tamiflu alone
Relenza alone
Or a combination of the two.
While a more expensive treatment option, many scientists have suggested that a combination of antivirals – instead of using a single drug - might help prevent the creation of new antiviral resistant strains.
It has also been assumed that a combination of two antivirals might prove more effective as well.
Today’s study – while limited in scope and size – seems to call both of those ideas into question.
When the blinds were removed researchers discovered that by the 2nd day of treatment, 62.5% of those receiving Tamiflu alone saw a significant reduction in viral load compared to just 40.5% of those receiving Relenza.
Additionally, the study found:
(reparagraphed from the study):
Overall the oseltamivir-zanamivir combination was both virologically and clinically significantly less effective than the oseltamivir monotherapy.
In addition, the clinical effects of the oseltamivir-zanamivir combination on time to resolution of symptoms were not significantly different from that of zanamivir monotherapy, suggesting that oseltamivir does not add clinical benefit to zanamivir monotherapy.
The combination of antivirals was also linked to a slightly increased incidence of side effects.
For ethical reasons, there was not a double-placebo arm to this study.
In other words, we have no comparison of outcomes between those who received no antivirals and those who received one of the protocols above.
The authors sum up their study this way:
Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower efficiency of the oseltamivir-zanamivir combination found in this study calls for caution in its use in clinical practice.
Thus, also considering the superiority of oseltamivir monotherapy over zanamivir monotherapy observed in this trial, oseltamivir should be the recommended primary anti-influenza treatment during influenza seasons with predominant H3N2 viruses naturally susceptible to oseltamivir.
These results would need to be confirmed for the 2009 H1N1 pandemic virus and in the coming years, for future circulating influenza viruses.
The entire open access study is available here.
Interesting findings that will need to be analyzed (and repeated) by others, particularly since the strain of H3N2 in circulation in 2008 is no longer with us.
The results may not be the same with other virus strains.
This study also doesn’t resolve ongoing questions over whether single-antiviral drug treatment exacerbates the development of resistant strains.
Given the limited number of influenza antivirals available now or in the pipeline, finding ways to protect the ones we have remains a serious consideration.
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