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Frequent H1N1 Tamiflu Resistance In Delaware and Maryland

Recombinomics Commentary 23:05
May 11, 2011

40M Sussex County
  4M Sussex County
27M Sussex County
44F New Castle County

Typically, the public health division sends about five samples every other week to the CDC as part of the federal agency's routine monitoring of antiviral-resistant flu cases.

The federal Centers for Disease Control and Prevention, which runs tests to determine whether those cases are resistant, requested that Delaware increase its surveillance in March.
The above data has the demographics for the four most recent H274Y cases, which increased the Delaware total for the season to 14, suggesting that a high percentage of H1N1 cases are Tamiflu resistant. 

Recently the CDC released 2011 H1N1 sequences, which included H274Y positive isolates from four patients in Delaware and four patients in Maryland.

The collection dates for the four cases in Delaware were in the first two weeks of February which is close to the number of samples sent for testing.  Two more positives were reported prior to this week and the eight additional cases reflect an increase in testing, but would still represent a high frequency, supporting efficient transmission.

The efficient transmission is supported by the sequence data.  The first three cases (A/Delaware/04/2011,  A/Delaware/06/2011, A/Delaware/07/2011) were from two counties (Kent and Sussex) but all three sequences had the rare combination of S188T and A189T and were very closely related to each other indicating transmission.  Similarly, the fourth case, A/Delaware/08/2011 was another sub-clade, which had S188T.  However, it was virtually identical to A/Maryland/06/2011, again representing transmission across state lines instead of county lines.  Moreover, another Maryland isolate, A/Maryland/04/2011, represented another sub-clade (Chihuahua) which was virtually identical to seven other isolates in the United States as well as the 12 Chihuahua isolates in Mexico and four isolates in Ecuador. It was also collected in early February.  The remaining two cases from Maryland also had S188T, but were distinguishable from the other six cases. The most recent sample was collected on March 2, so all eight samples were collected in a one month period, indicating the high frequency of positives in Delaware was also found in Maryland.

Thus, the sequence data, as well as the time and space concentration of H274Y cases in Delaware and Maryland in February and early March signals efficient transmission, and the presence of H274Y on distinct sub-clades signals recombination between these sub-clades.

This pattern is remarkably similar to the fixing of H274Y in seasonal flu in 2008.  Norway reported resistance levels that were close to 60%, but the frequency varied widely in early 2008.  However, in mid-2008 the frequency rose to 100% in South Africa where the dominant sub-clade had A193T and additional changes at positions 187 and 189.  At the beginning of the 2008/2009 season in the northern hemisphere, the 100% frequency spread worldwide and  virtually all sequences had A193T and one or more additional changes at positions 187, 189, or 196.
The high frequency of H274Y in Delaware and Maryland raises concerns that a similar emergence will dominate the upcoming flu season in the southern hemisphere, leading to fixing in the northern hemisphere next season, when the only available vaccine targets California/07 isolated in the spring of 2009.

Release of sequences from the additional H274Y isolates from Delaware and Maryland would be useful.

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