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Tamiflu Resistant Pandemic H1N1 Surveillance Failures in US
Recombinomics Commentary 14:41
July 11, 2009

The recent report of osletamivir resistant pandemic H1N1 in Hong Kong in a traveler (16F) from San Francisco, A/Hong Kong 2369/2009 raised concerns because the traveler had not take osletamivir and her case was mild.  She recovered without any antiviral treatment, but the presence of H274Y raised concerns that resistant virus was silently circulating because most mild cases in the United States were no longer tested or reported.

The publication of the sequence increased concerns, because the NA sequence, except for H274Y, exactly matched the sequence from the first case in New Jersey, A/New Jersey/1/2009, a Bergen county women (22F) infected in April.  Since the Hong Kong case was in June, the identity between the two sequences indicated that the virus had spread across the United States undetected between April and June, and was only detected when it was exported to Hong Kong, through routine osletamivir resistant testing of pandemic isolates.

The sequence in Hong Kong  matched a sequece from Japan, A/Sapporo/1/2009, which was published in Genbank a few days later.  Like New Jersey, the Japan sequence did not have H274Y, but it also was detected in a traveler (20M) from the United States (Hawaii), increasing concerns that this sequence was transmitting in the United States undetected.

The next day, two more sequences were released.  One was a partial NA sequence from Catalonia, Spain (A/Catalonia/387/2009), which also exactly matched the sequence from New Jersey and Japan, while the other was from Vastra Gotalands , Sweden (A/Stockholm/37/2009), which also matched the above sequences, but had one additional change.  The isolate from Sweden was also from a traveler (2M) from the United States.  Both isolates were also from patients infected in June, so the Tamiflu flu resistant sequence, or precursor, was detected in Hong Kong, China, Sapporo, Japan, Catalonia, Spain, and Vastra Gotalands, Sweden in the month of June, and at least three of the four isolates were from patients traveling from the United States.  However, the only match in isolates from the United States was in a New Jersey patient infected in April.

The export of infections from a country not reporting corresponding infections signals a poor surveillance system.  Although the number of sequences from the United States is the highest in the world, the failure to identify the oseltamivir resistant precursor sequences matching those found worldwide in travelers from United States is cause for concern. 

After the resistant isolate was announced, assurances were given, citing on the lack of detection of resistance in the United States.  This failure however may be due an emphasis on severe cases and lack of testing of mild cases.  Moreover, even if precursor sequences are detected, a low abundance version would not be identified in a consensus sequence.

In any event, the failure to identify the precursor since April, when the sequence is detected worldwide in June travelers from the United States, raises serious concerns about surveillance programs which focus efforts on severe cases and largely ignore milder cases.

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