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Emergence of H1N1 Relenza Resistance In New Jersey?
Recombinomics Commentary 20:32
July 22, 2008

The recent explosion of oseltamivir (Tamiflu) resistance in H1N1 has focused attention on the emergence of resistance against all approved anti-virals.  H5N1 clade 1 had two resistance markers for the amantadines, which included M2 S31N.  Several years ago S31N began to appear in H3N2 seasonal flu and approached 100% in most countries,  This was followed by appearance of S31N in H1N1, which has been limited to clade 2C (Hong Kong).  The S31N level in clade C in the United States appears to be near 100%. Resistance to Amantadines has been seen previously, but not at these levels, indicating S31N did not reduce the fitness of H3N2 or H1N1.

However, the emergence of H274Y in NA was a surprise because a fitness penalty had been previously described.  H274Y was also reported in H5N1 in patients treated with Tamiflu, as well as wild birds.  The presence of H274Y in wild birds indicated there was not a fitness penalty in H5N1, but the recent data on seasonal H1N1 indicated there was no penalty in H1N1 either.

H274Y began to appear in the 2006/2007 season in patients who had not been treated with Tamiflu.  Isolates from the United States had H274Y on a New Caledonia background (clade 1), while isolates in China had H274Y on a Hong Kong (clade 2C) background.  The presence of H274Y on two distinct genetic backgrounds suggested movement by homologous recombination.

However, this season H274Y levels exploded worldwide.  Initial reports cam from Norway, where more than50% of H1N1 isolates had H274Y.  High levels were also seen in Russia, France, and Canada, but many countries had levels above 10%.  Most recently the level rose to 100% in the first 23 samples tested in South Africa.  The explosion of H274Y was in Brisbane (clade 2B), although phylogenetic analysis identified multiple introductions into clade 2B, providing additional evidence for recombination.

In addition to oseltamivir resistance, additional H1N1 resistance was found in Asia.  This resistance (Q136K) was for zanamivir (Relenza) and was on a Solomon Island (clade 2A) background during the 2006/2007 season.  It then jumped to a clade 2B background in the 2007/2008 season. 

This season it also appeared as a mixture in a sample from Pennsylvania.  That sequence had a mixed signal of the first position of the 136 codon, signaling a mixture of wild type and Q136K.  More recently an isolate from New Jersey, A/New Jersey/08/2008, was identified which also had a mixed signal in the 136 codon.  However, in this patient the mixture was at the second position, signaling wild type and Q136R.  It is likely that this change will also generate Relenza resistance because both changes reflect a switch from an acidic to a basic amino acid.  The amino acid sequences from both isolates were identical except for position 136 raising concnerns that the deposited sequences may represent quasi-species.  Plaque purification and sequencing of the clones would be useful.

The appearance of Relenza resistance follows Tamiflu resistance and Amantadine resistance in H1N1, which creates significant pandemic concerns, since the above drugs represent the entire anti-viral arsenal currently approved for seasonal or avian influenza.

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