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Paradigm Shift Intervention Monitoring
Resistance in the United States
The recently released H1N1pdm09 NA sequences from Mexico confirm widespread transmitting oseltamivir (Tamiflu), H274Y, resistance in Mexico in 2012. Although most of the eight sequences were partial, all covered position 274, and all had Y at that position. Earlier sequences from Mexico City had H274Y and were closely related to each other and recent sequences from the United States (Texas, California, Illinois). The recent sequences from Mexico had associated characterization sheets which included location, as well as collection date for the 8 sequences, which were collected between Jan 2 and Feb 28, 2012. The earliest case was from Puebla, just south of Mexico City, but subsequent sequences were from cases located throughout the country, from Veracruz on the eastern coast, and central Mexico, as well as Hidalgo City, near the Texas border.
Similar sequences were also found in Texas, as demonstrated by the sequences released by the CDC and described above. Most of these isolates were from cases who had no exposure to oseltamivir, and at least one of the three samples from patients with exposure were collected a day after the start of treatment, raising concerns that a subset of the sequences that had H at position 274, also had Y at that position at concentrations below 50% of the signal (samples with H274Y at a level below 50% are reported as wild type).
Phylogenetic analysis of the full (1410 BP) NA sequences raised concerns that samples with H274Y were markedly higher than the sixteen cases described above by the CDC or the 10 sequences released by Biologia Molecular y Validacion de Tecnicas in Mexico. Nine of the NA sequences (from 7 patients) matched at all 1410 positions (listed below as H274Y consensus match) and were collected in 2012 (Mexico City / Veracruz City in Mexico and Texas / Illinois in the United States). Related sequences (Mexico City / San Luis Potosi City in Mexico and Texas / California in the United States) are listed below as H274Y consensus related.
However, in addition to the full sequences with H274Y, are NA sequences that match at all 1409 of the consensus positions other than C823T, which codes for H274Y. These isolates (274H consensus match) were seen in late 2011 / early 2012 isolates in Mexico, but are also present throughout the United States, as well as one sequence from France (Paris), raising concerns that H274Y is widespread in North America.
Additional related sequence (274H consensus related) are also widespread. Most 2011 sequences are from Mexico, but sequences are widespread in the United States (California and Pennsylvania) and the earliest sequences was from an isolate in France (Grenoble). 2012 sequences are also widespread outside of the United States (Mexico and Guatemala) as well as throughout the United States (with Texas representing the sate with the most isolates).
The listed sequences suggest the H274Y was initially in Mexico and Texas in a sub-clade that could efficient spread and become dominant. The number of related 2012 cases in the United States raises concerns that the spread of H274Y in H1N1pdm09 in early 2012 will mimic the worldwide fixing of H274Y in seasonal influenza A in the 2008/2009.season in the northern hemisphere.
H274Y consensus match
H274Y consensus related
274H consensus match
EPI357955 A/New Mexico/01/2012
274H consensus related
EPI362981 A/New York/03/2012
EPI356270 A/North Carolina/04/2012
EPI358134 A/North Carolina/06/2012
EPI368436 A/North Carolina/09/2012
EPI362966 A/North Dakota/01/2012
EPI362993 A/North Dakota/02/2012
EPI368673 A/Rhode Island/04/2012
EPI368429 A/South Carolina/08/2012