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PostPosted: Fri Aug 28, 2009 9:11 am 
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niman wrote:
wotan wrote:
I think this is new. Tamiflu resistance confirmed in California?
http://www.cdph.ca.gov/programs/vrdl/Documents/InfluenzaUpdate082009.pdf

Quote:
During this week, the CDPH Viral and Rickettsial Diseases Laboratory detected a specimen with the H275Y resistance mutation (associated with oseltamivir resistance); the result was confirmed by the CDC. This is the first time that this mutation has been detected by the VRDL and provides strong evidence for the importance of enhanced surveillance for antiviral resistance testing. The specimen was obtained from a hospitalized patient in Northern California. To date, 308 specimens have been tested at VRDL for the resistance mutation; all but one have tested negative for the mutation. VRDL and CDC will continue prospective antiviral resistance testing from a sampling of pandemic (H1N1) 2009 influenza viruses through the summer and the 2009-10 influenza season.

Yes, this is new and of course northern California (San Francisco) is the origin of the case in Hong Kong where the traveler had a mild case and recivered with no Tamiflu resitance. It is not clear if this is the first hospitalized patient in the US who is not immunocompromised, since the above doesn't give details on the patient.

The UK is also listing a summary of WHO notified cases, and they show 4 from Japan, which is an increase of one over the cases I know of.


This report was released silently and apparently after hours yesterday. All the more interesting, this is California's week 32 surveillance. CDC's week 32 surveillance had the 2 in Washington and the announcement of 2 more in NC. The CDC has not updated their week 32 surveillance to reflect this report. Furthermore, I have seen no news coverage of this as of yet.

If I read it correctly, California reported 0 cases of seasonal flu in week 32.

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PostPosted: Fri Aug 28, 2009 4:42 pm 
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http://www.cdc.gov/flu/weekly/

The CDC is reporting 6 cases of Tamiflu resistance but I can only account for 5 so far. 2 in Washington, 2 in NC, 1 in CA. Five of the 6 were receiving Tamiflu treatment, the sixth is being researched.

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PostPosted: Fri Aug 28, 2009 4:46 pm 
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wotan wrote:
http://www.cdc.gov/flu/weekly/

The CDC is reporting 6 cases of Tamiflu resistance but I can only account for 5 so far. 2 in Washington, 2 in NC, 1 in CA. Five of the 6 were receiving Tamiflu treatment, the sixth is being researched.


The table says 6 cases but the text says 7:

Quote:
The majority of 2009 influenza A (H1N1) viruses are susceptible to the neuraminidase inhibitor antiviral medication oseltamivir, however rare sporadic cases of oseltamivir resistant 2009 influenza A (H1N1) viruses have been detected worldwide, including seven viruses in the United States. All tested viruses retain their sensitivity to the other neuraminidase inhibitor zanamivir. Additional information on antiviral recommendations for treatment and chemoprophylaxis of 2009 influenza A (H1N1) infection is available at http://www.cdc.gov/h1n1flu/recommendations.htm All 2009 influenza A (H1N1) viruses tested to date are resistant to the adamantane antiviral medications, amantadine and rimantadine. Antiviral treatment with either oseltamivir or zanamivir is recommended for all patients with confirmed, probable or suspected cases of 2009 influenza A (H1N1) virus infection who are hospitalized or who are at higher risk for seasonal influenza complications.

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PostPosted: Fri Aug 28, 2009 5:05 pm 
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I can't account for two of the cases of Tamiflu resistance. Last week the CDC was reporting 4. Today it is 7. One of the new cases should be the one from California.

Texas has still not released their week 32 surveillance. A few weeks back there were reports of at least 2 cases of Tamiflu resistance in Texas that were later denied....

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PostPosted: Fri Aug 28, 2009 7:58 pm 
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wotan wrote:
I can't account for two of the cases of Tamiflu resistance. Last week the CDC was reporting 4. Today it is 7. One of the new cases should be the one from California.

Texas has still not released their week 32 surveillance. A few weeks back there were reports of at least 2 cases of Tamiflu resistance in Texas that were later denied....

Yes, I suspect these are Texas, but I am not sure Texas will admit it.

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PostPosted: Fri Aug 28, 2009 8:04 pm 
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wotan wrote:
I can't account for two of the cases of Tamiflu resistance. Last week the CDC was reporting 4. Today it is 7. One of the new cases should be the one from California.

Texas has still not released their week 32 surveillance. A few weeks back there were reports of at least 2 cases of Tamiflu resistance in Texas that were later denied....

Texas has tested THREE pandemic H1N1 isolates for antiviral resistance for the ENTIRE season (through week 31) and that is three above their credibility level.

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PostPosted: Fri Aug 28, 2009 11:37 pm 
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Quote:
the H275Y resistance mutation


I may have missed something earlier on this, but the 274 has been referenced before and this is 275. What does that mean? I haven't seen anyone specifically address the change from 274 to 275. Thank you.


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PostPosted: Sat Aug 29, 2009 12:15 am 
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gjs0708 wrote:
Quote:
the H275Y resistance mutation


I may have missed something earlier on this, but the 274 has been referenced before and this is 275. What does that mean? I haven't seen anyone specifically address the change from 274 to 275. Thank you.

Dr. Niman can give a better answer but it is the same mutation, just using a slightly different notation. Perhaps think of it as like counting starting at either 0 or 1, the same offset but i off from each other (fencepost error).

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PostPosted: Sat Aug 29, 2009 3:23 am 
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gjs0708 wrote:
Quote:
the H275Y resistance mutation


I may have missed something earlier on this, but the 274 has been referenced before and this is 275. What does that mean? I haven't seen anyone specifically address the change from 274 to 275. Thank you.

The number is reaally related to the numbering "system". Much of the early structural work on influenza was based on H3N2, so many use an H3 numbering system for H and an N2 numbering system for N. For H1N1, some use an H1 numbering system for H and and N1 numbering for N. The change that confers Tamiflu resistance is H274Y in an N2 numbering system, while the same change designated H275Y in an N1 numbering system, so both names refer to the same change (and there is a different numbering for H5N1 because the N1 has a 20 aa deletion, but all changes are for the same position, and H changes to Y).

In fact the Tamiflu resistance in seasonal H1N1 and pandemic H1N1 all trace back to the change in H5N1 in Vietnam in 2005.

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PostPosted: Sun Aug 30, 2009 10:07 am 
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Genomic Diversity of Oseltamivir-Resistant Influenza Virus A (H1N1), Luxembourg, 2007–08
To the Editor: The prevalence of oseltamivir-resistant influenza viruses A (H1N1) (ORVs) increased dramatically worldwide during the winter of 2007–08 (1). Recent reports indicated that by early 2009 most influenza virus (H1N1) strains were resistant to oseltamivir (2). Resistant viruses were transmitted readily and were as viable and pathogenic as oseltamivir-sensitive viruses (OSVs) (3,4). The His275Tyr (N1 numbering) mutation in the neuraminidase (NA) genes of influenza virus A (H1N1) that confers resistance to oseltamivir has previously been associated with impaired virus replication, infectivity, and pathogenicity (5,6).
We investigated the genetic diversity in all 8 gene segments of representative ORVs and OSVs collected during December 2007–March 2008 by the National Influenza Sentinel Surveillance System in Luxembourg (www.lns.public.lu/statistiques/grippe). Phylogenetic analyses were performed by using MEGA version 4.0 (7). Tree topology and posterior probabilities were calculated by using MrBayes version 3 (8). The sequences have been submitted to GenBank (accession nos. FM174406–60, FN401430–45, and FN401487–FN401518).
Among 140 viruses, 34 strains (24.3%) had the oseltamivir-resistant genotype (Tyr275) in the NA gene. Bayesian analyses of NA genes showed that ORVs formed a distinct cluster supported by high posterior probability (1.00) on the common node (Figure). One resistant strain (LNS-365) was more closely related to OSVs (minimal Kimura distance 0.3%, 4 nt) than to ORVs (minimal Kimura distance 0.5%, 6 nt). In NA protein 33, ORVs showed the common Asp354Gly substitution in addition to the Tyr275 mutation. The resistant outlier LNS-365
Page 1 of 5
encoded Asp354 like all other OSVs (n = 106). Similarly, only 4 other resistant strains from Europe from the same season shared Asp354 with all 2007–08 sensitive influenza virus (H1N1) strains (n = 251) available in public databases.
A total of 18–44 selected sequences from each of the other genes of ORVs and OSVs were generated to investigate which other genetic markers cosegregated with the resistant genotype. Sequences derived from most of the other genes (PB1, polymerase A, hemagglutinin, nucleoprotein, matrix, nonstructural) of ORVs and OSVs were phylogenetically interspersed with no distinct clustering. In contrast, matching the phylogeny of NA, PB2 sequences of genotypically resistant strains (n = 14) formed a distinct cluster supported by high posterior probabilities (1.00) and separate from all OSVs (n = 16) and the resistant outlier LNS-365 (Figure). On the PB2 amino acid level, all OSVs and the resistant outlier LNS-365 shared Pro453, whereas all ORV encoded serine at the same position (Ser453). The outlier LNS-365 differed only by 2 aa from OSVs but by 4 aa from the closest resistant strain.
All published PB2 sequences for influenza virus (H1N1) strains collected since 1918 (n = 720) encoded either Pro453 or His453. Until the emergence of ORVs in 2007, Ser453 was only present in 3 other strains (A/Wilson-Smith/1933 and 2 strains from 1976 and 1988). Located on the surface of the PB2 cap-binding domain (9), the Pro453Ser mutation may influence polymerase function and virus replication. The fact that PB2 sequences of ORVs and OSVs are phylogenetically segregated suggests a link between the genetic background and the unexpected fitness of ORVs. There was no amino acid mutation in any of the other genes that segregated in the same way between ORVs and OSVs other than Ser453 (PB2).
Only 1 OSV strain from Luxembourg in 2007–08 (LNS-110) was derived from subclade 2C, unlike the other 139 influenza virus (H1N1) strains (subclade 2B, Figure). Like many other subclade 2C strains, which were recently identified, this virus encoded the amantadine-resistance marker Asn31 in the matrix 2 protein (10). Although we did not identify any reassortments between ORVs and OSVs, double-resistant strains may result from co-circulation of amantadine-resistant and OSVs in the same region.
The phylogeny of ORVs identified worldwide (2) indicates multiclonal emergence of resistance, which suggests that OSVs may contain low levels of ORV subpopulations. Using pyrosequencing, we determined the incidence and level of mixed alleles in codon 275 of the NA
Page 2 of 5
gene (CAT, sensitive and TAT, resistant). In 98 clinical specimens (78 sensitive and 20 resistant strains) no minority alleles were reliably detected above the 3% threshold of the assay. Six OSVs with values between 2.1% and 2.9% were further analyzed by cloning of partial NA genes. No evidence of ORVs was found (Tyr275) in 227 clones.
In summary, we have described amino acid markers in NA (Gly354) and PB2 (Ser453) proteins, which were present in ORVs but absent in all OSVs from Luxembourg in 2007–08. ORVs without this background spread as efficiently and were rarely found in Europe. At least 1 resistant virus was more similar to OSV, which suggests >2 clones of resistant viruses in Luxembourg, potentially with different viral fitness. We speculate that the unexpected fitness of the 2007–08 influenza viruses (H1N1) may be caused by a new genetic background that is most likely encoded in the PB2 gene.
Acknowledgments
We thank Emilie Charpentier, Aurélie Sausy, and Sébastien de Landtsheer for technical assistance, and the clinicians who participated in the Influenza Sentinel Surveillance in Luxembourg.
N.A.G. was supported by an Aides à la Formation-Recherche fellowship of the Ministry of Research and Higher Education, Luxembourg.
Nancy A. Gerloff, Jacques R. Kremer, Joël Mossong, Matthias Opp, and Claude P. Muller
Author affiliations: National Health Laboratory, Luxembourg, Luxembourg
References
1. Recommended composition of influenza virus vaccines for use in the 2009 southern hemisphere influenza season. Wkly Epidemiol Rec. 2008;83:366–72. PubMed
2. World Health Organization. Influenza A(H1N1) virus resistance to oseltamivir—2008/2009 influenza season, northern hemisphere [cited 2009 Mar 25]. Available from http://www.who.int/csr/disease/influenz ... te20090318 ed_ns.pdf
3. Meijer A, Lackenby A, Hungnes O, Lina B, van der Werf S, Schweiger B, et al. Oseltamivir-resistant influenza A (H1N1) virus, Europe, 2007–08 season. Emerg Infect Dis. 2009;15:552–60. PubMed DOI: 10.3201/eid1504.081280 Page 3 of 5
4. Rameix-Welti MA, Enouf V, Cuvelier F, Jeannin P, van der Werf S. Enzymatic properties of the neuraminidase of seasonal H1N1 influenza viruses provide insights for the emergence of natural resistance to oseltamivir. PLoS Pathog. 2008;4:e1000103. PubMed DOI: 10.1371/journal.ppat.1000103
5. McKimm-Breschkin J, Trivedi T, Hampson A, Hay A, Klimov A, Tashiro M, et al. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother. 2003;47:2264–72. PubMed DOI: 10.1128/AAC.47.7.2264-2272.2003
6. Yen HL, Herlocher LM, Hoffmann E, Matrosovich MN, Monto AS, Webster RG, et al. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother. 2005;49:4075–84. PubMed DOI: 10.1128/AAC.49.10.4075-4084.2005
7. Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol. 2007;24:1596–9. PubMed DOI: 10.1093/molbev/msm092
8. Ronquist F, Huelsenbeck JP. MRBAYES 3: Bayesian phylogenetic inference under mixed models. Bioinformatics. 2003;19:1572–4. PubMed DOI: 10.1093/bioinformatics/btg180
9. Guilligay D, Tarendeau F, Resa-Infante P, Coloma R, Crepin T, Sehr P, et al. The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol. 2008;15:500–6. PubMed DOI: 10.1038/nsmb.1421
10. Niman H. Emergence and fixing of antiviral resistance in influenza A via recombination and hitch hiking. 2009 Feb 10 [cited 2009 Mar 25]. Available from http://hdl.handle.net/10101/npre.2009.2832.1
Address for correspondence: Claude P. Muller, Institute of Immunology, National Health Laboratory, 20A, Rue Auguste Lumière, L-1950 Luxembourg, Luxembourg; email: claude.muller@lns.etat.lu Page 4

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