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H1N1 Tamiflu Resistance At 100% in Honduras and Guatemala? Recombinomics Commentary 20:47 August 31, 2008
With respect to neumon?a, Sanchez needed that 260 people died in which goes of the year, among them 127 smaller children of five years and 96 greater adults of 50, the most vulnerable groups to the respiratory affections. Between the diseases that have begun to appear in the last months it appears influenza type AH1 N1, that causes high fevers, cough, muscular pains and in some cases diarrea pictures, it explained.
The above translation describes recent deaths Nicaragua, that were linked to H1N1 infections. The comments expressed concerns that influenza from Honduras was spreading into Nicaragua.
HA sequences from H1N1 isolates from Honduras and Guatamala were recently released at GenBank as part of a US military (Air Force) surveillance program. These sequences were in addition to a large series released a few months. The H1N1 sequences were collected in 2007/2008 season, and the five recent isolates from Honduras and Guatemala listed below are Brisbane/59 and closely related to each other.
Phylogenetic analysis places these isolates on a branch with H1N1 isolates that have H274Y. Recently sequences from South Africa were released, where the frequency of H274Y in H1N1 cases were at 100%, suggesting the sequences provided a selection advantage. The HA sequences from South Africa fell into two major groups. One had a cluster on newly acquired polymorphisms onto a genetic background that was common among H274Y isolates in the United States. The second group was related bur fell onto a branch with H274Y isolates from France.
The isolates from Honduras and Nicaragua form a new branch from the second branch described above. This new branch also has an isolate from France, which has H274Y, strongly suggesting that there recent isolates from Guatemala (collected in early June) and Honduras (collected in early and late July) also have H274Y, raising concern that the frequency of H274Y in recent isolates in Guatemala and Honduras are also near 100% Tamiflu resistant, which may now also be true for Nicaragua.
The NA sequence from these patients as well as additional isolates would be useful. All recent isolates also have K99N, which was also present in sequences from a Siberian Lake, which were closely related to human H1N1 from the 1930?s.
These data raise concerns that high frequencies of Tamiflu resistance have also come to North America. In South Africa, the first 107 H1N1 sequences this season had H274Y, as did the first 10 sequences from Australia.
"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
H1N1 Tamiflu Resistance Emergence and Evolution Recombinomics Commentary 16:41 September 2, 2008
The recent reports from South Africa and Australia have increased concerns that H1N1 oseltamivir resistance (H274Y) is becoming widespread during the current flu season in the southern hemisphere. Similarly, the recent HA sequences released by the US Air Force surveillance program has raised concerns that H274Y is also becoming dominant in the Americas.
Tamiflu resistance can be assessed indirectly through phyogenetic analysis of HA sequences which include sequences from isolates known to contain H274Y. In the United States, there is a dominant HA sequence associated with H274Y on NA. The 2008 sequences from the Air Force, A/New JerseyAF1291/2008 and A/Texas/AF1960/2008 both map to this branch, indicating the isolates are likely to contain H274Y. Similarly, another branch has H274Y positive isolates from Wyoming and Arizona, indicating the co-mapping sequence from A/Oklahoma/AF1901/2008, is also from an isolate positive for H274Y. Another branch has H274Y positive sequences from Illinois, Indiana, and Minnesota, indicating A/Alabama/AF1952/2008 is also H274Y positive. Yet another branch, which has A/Paris/1208/2008, also has the five recent isolates from Guatemala and Honduras, raising concerns that H274Y is present at high frequencies in H1N1 isolates in North America.
These isolates from Honduras and Guatemala are closely related to each other ands the French isolate, and were collected in June and July, raising concerns that this sub-clade is gaining dominance. Moreover, the other isolates above demonstrate how the established sub-clades continue to increase in number and increasing geographic reach. This was also seen in the sequences from South Africa, as well as phylogenetic analysis of isolates from Japan.
These new branches with H274Y isolates support new acquisitions of H274Y onto various genetic backgrounds, raising concerns that the dramatic increase of H274Y levels in H1N1 seasonal flu, which may be linked to the vaccine mismatch, will lead to transfer of H274Y onto new backgrounds via recombination, in addition to backgrounds that evolve from existing sequences.
The genetic background jumping was seen in prior seasons. H274Y was first reported on a Hong Kong (clade 2C) background in China in the 2005/2006 season, which was followed by New Caledonia (clade 1 in 2006/2007). The first reported cases on the Brisbane (clade 2B) background were in 2007 in Hawaii, which was followed by acquisition by the dominant B sub-clade in the United States and northern Europe.
The above expansion was in patients who were not taking Tamiflu, raising concerns that the fixing of H274Y in H1N1 will continue to increase, as seen in recent isolates from South Africa and Australia, as well as likely acquisitions in the Americas.
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
Spread of H1N1 Tamiflu Resistance Recombinomics Commentary 18:41 September 3, 2008
The recently released HA sequences from Guatemala and Honduras have raised concerns that like South Africa and Australia, the level of oseltamivir (Tamiflu) resistance in H1N1 in circulation this summer is 100%. This increase to 100% has been rapid, raising questions about the mechanism underlying the increase as well as the stability of the change in future H1N1 isolates, as well as related H5N1 isolates.
Although oseltamivir was approved in 1999, the spread of resistance in patients who are not receiving oseltamivir has only been reported recently. The highest usage is in Japan, and there have been prior outbreaks of resistance in children receiving sub-optimal doses. However, these cases were being actively treated with oseltamivir and the resistance appeared in H1N1 and H3N2 and involved multiple polymorphisms. In contrast the recent cases have only involved H1N1 and have all be H274Y, encoded by the same single nucleotide polymorphism. This change matches the change linked to resistance in H5N1, which was reported initially in oseltamivir treated patients in Vietnam in 2005.
A matching sequences downstream from H274Y has been reported for H1N1 in the United States this year, A/Indiana/01/2008 (clade 2B), but the first reported human cases were in patients in China in the 2005/2006. These patients were not receiving oseltamivir, and the H1N1 was the Hong Kong strain (clade 2C). In the following season, H274Y was reported in the New Caledonia strain (clade 1). By the end of 2007, H274Y was reported in the Brisbane strain (clade 2B) in Hawaii. The downstream sequence of clade 1, 2B, and 2C match facilitating transfer of H274Y from one genetic background to another.
However, the transfer of H274Y sequence with an altered downstream region put H274Y on a subclade that was becoming dominant in the United States and Europe allowing H274Y spread to increase markedly. However, in addition to this common sub-clade, H274Y continued to be appended onto multiple clade 2B sub-clades.
Thus, there were two mechanisms of H274Y. One involved independent introductions only new clade 2B backgrounds, while a second mechanism involved spread and evolution of a common clade 2B background. These backgrounds include isolates from France, which were precursors for a subset of the resistance in South Africa, as well as the recent sequences from Guatemala and Honduras. The other sub-set in South Africa links back to the isolates in the United States, but this sub-set in South Africa has acquired a cluster of changes in HA, These changes are in the dominate H1N1 sub-clade in South Africa, raising concerns of additional resistance to the new H1N1 vaccine, which targets clade 2b (Brisbane/59).
The ability of H274Y to jump from clade to clade, as well as multiple sub-clades in 2B, as well as the rapid evolution of the 2B sub-clades, raises concerns of another vaccine mismatch, as well as the associated increase in H274Y in the H1N1 gene pool. Moreover, the match between H5N1 and the recent H1N1 isolate from Indiana raises concerns that oseltamivir resistance would develop quickly after H5N1 transmission efficiencies in humans increase, regardless of oseltamivir usage.
The rapid spread of H274Y in seasonal flu and the recent reports of increases to 100% continue to be cause for concern in seasonal and pandemic flu evolution and spread.
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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