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Acquisition of H274Y Tamiflu Resistance in Pandemic H1N1
Recombinomics Commentary 02:09
July 1, 2009

In the context of tracing contacts of a cluster of 3 imported cases in Denmark, a female contact who initially tested negative on PCR, was given prophylaxis with oseltamivir (75 mg per day). Five days later, despite reportedly having complied with treatment, she developed flu-like symptoms and was tested positive for A(H1N1)v. Sequencing of the virus showed a single mutation H275Y (H274Y in N2 nomenclature) in the neuraminidase gene. The presence of the resistance marker and the phenotypic (in vitro) resistance was confirmed by a WHO collaborating Centre. The virus is not a re-assortant and is presumed to remain susceptible to zanamivir (another neuraminidase inhibitor). All other virus isolated as part of this cluster investigation, including the presumed source patient, did not show the mutation.

According to the available epidemiological and virological data, this reported event in Denmark is almost certainly secondary resistance acquired during post-exposure prophylaxis. This is supported by the time sequence and the absence of similar genotypic markers in viruses isolated in the other cases of the cluster.

There is no evidence in this case that the isolated resistant virus has transmitted to other persons, meaning that the risk of spread of a resistant virus is nearly zero.

Secondary resistance, arising due to treatment, must not be confused with more complex mutations including the H274Y substitution resulting from primary resistance. Such primary resistance was first observed in seasonal A(H1N1) influenza virus in the 2007-2008. It spread worldwide generally displacing other seasonal A(H1N1) viruses (98% resistance in EU in 2008-2009

The above risk assessment by the European Centre for Disease Control indicates the oseltamivir resistance identified in a female contact of a pandemic H1N1 confirmed traveler was due to the acquisition of H274Y.  The report also indicates the sequence from the likely source of the pandemic H1N1 infection of the contact did not contain H274Y, supporting the acquisition during prophylactic treatment leading to a low risk assessment for spread.

However, there are alternate explanations for the failure to detect H274Y in the sequence from the traveling contact.  If the contact was infected with two versions of H1N1, sample collection prior to oseltamivir treatment would generate the sequence of the dominant wild type species.  The local contact, who developed symptoms five days after the start of treatment , would test positive for H274Y because the prophylactic treatment would lower the level of wild type RNA.  Thus, potential spread of resistance would reside in patients in the originating country, who could travel to Denmark and re-introduce the H274Y.

Alternatively, the local contact could have been infected by another source in Denmark, since there were no symptoms during the first five days of prophylactic treatment.  Although Denmark has reported a relatively low level of H1N1 in residents, like most countries in Europe, testing is focused on airport travelers and contacts, while testing for community spread is limited.  However, since many passengers will be infected shortly before flight, many will be asymptomatic.  Others will be asymptomatic because of an infection that does not produce a high fever, while others will have symptoms reduced because if medications. Thus, the number of passengers evading detection at airports will be large, leading to H1N1 spread in the community.

The evidence for H274Y acquisitions via recombination are linked to the recent patterns of spread in H1N1 seasonal flu.  Although the report notes the dramatic primary spread of H274Y between 2007-2009, it simply calls such spread complex and fails to address the appearance of H274Y on multiple genetic backgrounds in the absence of Tamiflu treatment.  It is the jumping of H274Y from one genetic background to another (recombination) that has raised concerns that such jumps will lead to acquisition of H274Y on a pandemic H1N1 background, because the H274Y level is near 100% in seasonal flu and pandemic H1N1 is accelerating its spread through the human population, increasing the frequency of dual infections involving swine and seasonal H1N1.

Thus, the acquisition of H274Y is expected and it is likely that there will be more examples of sequences like the resistance described in the above report.  Release of the sequences from the cluster would be useful, as would the travel history of the traveler thought to have infected the contact who developed resistance via H274Y.

These data should launch more aggressive surveillance worldwide.  Although countries have been promptly depositing sequences, the number of sequences remains low.  Denmark has only deposited one sequence, which was from a patient infected in April. 

The start of flu season in the southern hemisphere should lead to rapid evolution and the widespread acquisition of important polymorphisms, such as PB2 E627K, which was reported in Shanghai, but present only in the original sequence and the first clone, and NA H274Y, as found in the above patient from Denmark.

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