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Evolutionarily Fit Tamiflu Resistance in Northern California
Recombinomics Commentary 10:13
August 31, 2009

Six of the seven patients had documented exposure to oseltamivir through either treatment or chemoprophylaxis, and the remaining patient is currently under investigation to determine exposure to oseltamivir. Occasional development of oseltamivir resistance during treatment or prophylaxis is not unexpected. Enhanced surveillance is expected to detect additional cases of oseltamivir resistant 2009 influenza A (H1N1) viruses and such cases will be investigated to assess the spread of resistant strains in the community.

The above comments from the week 33 CDC report identify three more cases of osletamivir resistance in the United States.  Two of the new cases have documented exposure to Tamiflu, as was seen in the two immuno-compromized patients in Seattle, who developed resistance during treatment, and two summer campers in North Carolina, who developed symptoms while on prophylatic Tamiflu.

The patient without documented exposure to Tamiflu is likely to be the hospitalized patient described in the latest weekly report from California.  The northern California patient was hospitalized, suggesting H274Y was identified through routine surveillance.  Earlier, a San Francisco traveler to Hong Kong also had no documented exposure to Tamiflu, but had a mild case of pandemic H1N1 with H274Y.  Thus, the H1N1 was evolutionarily fit and could produce mild disease in patients not talking Tamiflu.

However, the hospitalized patient in northern California raises concerns that a more aggressive evoltionarily fit H1N1 may be circulation. Many locations, including California, have reported a dramatic increase in hospitalized and fatal cases and the rapid appearance of resistance in prophylatic patients raised concerns that the more severe cases involved Tamiflu resistance that had been silently circulating as a minor population that was missed in routine sequence analysis.  These isolates represented a variant of pandemic H1N1 sub-clade, and raised concerns that a dominant H274Y positive sub-clade would emerge, as was seen in seasonal H1N1 last season.

This concern was also voiced in the US Presidential report on pandemic H1N1 which raised the possibility of the emergence of H274Y via recombination ("Resistance to these agents, especially oseltamivir as a result of mutation or genetic recombination, can be a major factor limiting antiviral effectiveness"). 

In seasonal flu, recombination moved H274Y from one genetic background to another until the H274Y paired up with HA A193T and other key changes acquired from clade 2C via recombination.  The genetic hitchhiking of H274Y lead to fixing in seasonal H1N1, which created a large genetic reservoir for the transfer of H274Y from seasonal H1N1 to pandemic H1N1.

More detail on the H1N1 from the hospitalized patient in northern California, including full sequences, would be useful.

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