# 5919
The acquisition of antiviral resistance by influenza strains is a constant worry, given their long history of eventually finding their way around our pharmaceutical defenses.
Not so long ago Amantadine (an M2 ion channel blocker) was the preferred influenza antiviral. It was cheap, plentiful, and effective.
But by the mid 2000s Amantadine began to lose its ability to combat the H3N2 seasonal flu virus along with some strains of the H5N1 bird flu.
It has been suggested that the prophylactic use of Amantadine by Chinese poultry farmers (who supposedly included it in their chicken feed for several years) may have contributed to this sudden resistance.
But whatever the cause, by January of 2006 the CDC had issued a warning to doctors not to rely on Amantadine (or Rimantadine) to treat influenza.
Oseltamivir (Tamiflu) – a newer neuraminidase (NA) inhibitor drug introduced in 1999 - while far more expensive, became the new treatment standard.
But by 2008 seasonal H1N1 began to show growing resistance to Oseltamivir as well (although H3N2 remained sensitive).
By the spring of 2009, - in the space of just about a year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant.
The arrival of the novel 2009 H1N1 pandemic virus was a game changer, in that it – unlike seasonal H1N1 – was still sensitive to oseltamivir (but not Amantadine).
Since then, we’ve been watching to see if – like its seasonal cousin – A/H1N1/2009 learns to evade oseltamivir and/or zanamivir as well.
So far, the news has been generally good.
Only 1%-2% of samples tested have shown the most common mutation known to convey oseltamivir resistance; H275Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275.
(Note: some scientists use 'N2 numbering' (H274Y) and some use 'N1 numbering' (H275Y))
Of course, resistance to antivirals is usually a matter of degree. A virus may become strongly resistant, rendering an antiviral all but useless, or just mildly resistant, which may simply reduce the drugs effectiveness.
We’ve a report appearing in Eurosurveillance this week which looks at the emergence of an H1N1 mutation that is mildly resistant to oseltamivir and zanamivir due to a different sort of mutation; S247N (serine (S) to asparagine (N)) mutation at the neuraminidase position 247.
This emerging mutation has been appearing with some frequency in Australia, Brunei and Singapore.
Eurosurveillance, Volume 16, Issue 23, 09 June 2011
Rapid communications
A C Hurt, R T Lee, S K Leang, L Cui, Y M Deng, S P Phuah, N Caldwell, K Freeman, N Komadina, D Smith, D Speers, A Kelso, R T Lin, S Maurer-Stroh, I G Barr
A novel influenza A(H1N1)2009 variant with mildly reduced oseltamivir and zanamivir sensitivity has been detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia during the early months of 2011.
The variant, which has also been detected in other regions of the Asia-Pacific, contains a S247N neuraminidase mutation. When combined with the H275Y mutation, as detected in an oseltamivir-treated patient, the dual S247N+H275Y mutant had extremely high oseltamivir resistance.
In and of itself, this mutation may not be enough to produce clinical resistance to oseltamivir and zanamivir, as the reduction in sensitivity observed was just 6 fold and 3 fold respectively.
But when combined with the better known H275Y mutation, a virus with the S247N mutation proved 10 times more resistant than with the H275Y mutation alone.
The concern is that this mutation, which appears to be biologically fit and easily transmissible, may team up with other mutations known to produce varying degrees of resistance – and together they could prove far more problematic.
While the entire article is well worth reading, the authors conclude with:
If the S247N variant spreads globally, the greatest concern is that other NA mutations which may have previously caused only mild reductions in NAI susceptibility (e.g. mutations at the I223 residue) could instead cumulatively decrease NAI sensitivity to levels that may be clinically significant and affect treatment efficacy.
Laboratories should consider screening currently circulating specimens and isolates for the S247N NA mutation to determine whether the variant is spreading into other regions.
Although our antiviral arsenal remains largely effective against the new H1N1 virus, over time, that could change.
All of which points towards the wisdom of getting a flu shot every year. While not 100% protective, the yearly influenza vaccine can significantly reduce your chances of catching the flu.
After all, it is nearly always better to try to prevent an illness, than to have to treat one.
