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Paradigm Shift Intervention Monitoring
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Transmission of H1N1 Tamiflu
One example involves sequences which have H274Y and D225E, This combination of Tamiflu resistance with a receptor binding domain change is of concern because prior fixing of Adamantane resistance, S31N, in seasonal H3N2, and Tamiflu resistance in seasonal H1N1 involved receptor binding domain changes. In H3N2 the two key RBD drivers were S193F and D225N. In seasonal H1N1 it was A193T followed by changes in flanking positions 187, 189, and 196.
Thus, when the first example, A/Hong Kong/2369/2009, of H274Y in a patient (San Francisco traveler to Hong Kong) who had no documented exposure to Tamiflu, had D225E, there was concern that this change would lead to more examples of this combination. The report led to increased surveillance in northern California, which failed to pick up additional examples ofH274Y or D225E. However, other countries screening passengers at border checks identified sequences with D225E, and most were passengers from the United States raising concerns that the US surveillance was missing milder cases with D225E, because most testing was directed at hospitalized patients.
However, a matching sequence, A/Tennessee/17/2009 was recently placed on deposit at GISAID by the CDC, supporting transmission of the sequence with H274Y over a wide area and extended time frame. This match was extended to Japan when the recent sequences from NIID were released. A sequence in Japan, A/SHIGA/43/2009 had the same set of HA and NA markers as well as H274Y suggesting transmission was extensive.
Moreover, phylogenetic analysis identified additional isolates in Japan (A/Nagasaki/HA-44/2009, A/Nagasaki/HA-52/2009, A/Nagasaki/HA-53/2009), but only HA sequences were released. However, recent sequences from Japan have a high frequency with H274Y and at least 28 isolates have been identified with H274Y. Therefore, it is likely that these isolates also have H274Y.
Markers were also identified in three isolates from Texas. However, NA sequences had a wild type codon for position 274. However, the presence of H274Y as a minor species remained open. Details on the sequencing of Hong Kong/2369 demonstrated that the original sample was a mixture of H274Y and wild type and the sequence in the database was from a clone that also had minor levels of wild type sequence. However, since the deposited sequence was a "consensus" sequence the minor wild type component was not reflected in the deposited sequence, even though it was present in the tracing that generated the consensus sequence.
The presence of mixtures raised concerns that H274Y linked to Tamiflu treatment was not "spontaneous" or due de novo synthesis, but instead represented selection of the minor population with H274Y. The minor species was supported by the rapid appearance of H274Y, which was dominant In as few as two days after the start of treatment, as seen in the first H274Y isolate from Singapore. Similarly, prophylactic treatment led to detection of H274Y in 5-6 days. The rapid appearance of H274Y indicated Tamiflu treatment was simply selecting a minor species that was already present in these patients.
The mixture could explain the data on two immunosupressed patients in Seattle. Although these cases were discussed as examples of H274Y develop after long term treatment of immno-suppressed patients, the data present did not eliminate selection of a minor population. Since the two patients developed symptoms within a few weeks of each other and were patients in the same hospital, the clustering could be due to a minor population circulating in the Seattle area. One patent converted from wild type to H274Y between days 4 and 11 post treatment start, while the other patient converted between days 1 and 18. Thus, neither was shown to develop H274Y after extensive treatment and samples collected on days 3 and 6 for the second patient were not tested. Release of sequence data demonstrated tyat the H1n1 from each patient belonged to the same sub-clade, which was circulating in the Washington area. However, additional sequences with H274Y in Japan (A/Osaka/180/2009 and A/Oits/126/2009), Texas (A/Texas/47/2009 and A/Texas/48/2009) and Illinois (A/Illinois/10/2009 also were the same subclade, providing additional evidence supporting H274Y widely circulating in the sub-clade linked to the immuno-suppressed patients.
This clustering of H274Y in multiple members of the same sub-clade support widespread transmission of H274Y in selected sub-clades leading to the emergence of H274Y via hitchhiking and recombination, as was seen in the fixing of H274Y in seasonal H1N1.
The recent explosion of H274Y indicates this fixing is developing rapidly.