Cases of Tamiflu (or other anti-viral resistance)

wotan · **Posted:** Wed Aug 19, 2009 12:45 pm

The map is not specifically tracking confirmed or reported incidents of Tamiflu resistance in pandemic H1N1, so this thread will hopefully hold those so we can gain a better idea of where it has been found.

niman · **Posted:** Wed Aug 19, 2009 1:09 pm

So far the only confirmed cases in the US were immunospupressed patients in Seatle, but I have heard a rumor (and at this point it is JUST a rumor), that the outbreak in southern Georgia is NOT responding to Tamiflu.

niman · **Posted:** Wed Aug 19, 2009 1:14 pm

The outbreak in southern Geogia (Kingsland and St Mary's) will appear at link below in new map update

http://flutracker.rhizalabs.com/flu/gma ... 125&zoom=9

lifeless · **Posted:** Wed Aug 19, 2009 2:41 pm

Theres a wiki page about it

http://en.wikipedia.org/wiki/Tamiflu_re ... u_pandemic
_________________________________________________________________________________________________________

«Lifeless»

niman · **Posted:** Fri Aug 21, 2009 2:59 pm

Sequences from cases in Seattle have been released at GISAID.

EpiFlu Isolate IDEPI_ISL_34537Name and synonymsA/Washington/28/2009
Type/subtype lineageA/H1N1 swlPassage historyXSample collection date2009-07-14HostHumanLocationUSA - Washington stateFirst submission2009-08-21

EpiFlu Isolate IDEPI_ISL_34538Name and synonymsA/Washington/29/2009
Type/subtype lineageA/H1N1 swlPassage historyXSample collection date2009-07-28HostHumanLocationUSA - Washington stateFirst submission2009-08-21Last update

Angel_B · **Posted:** Fri Aug 21, 2009 9:54 pm

Tamiflu-resistant H1N1 may have spread in Singapore

SINGAPORE, Aug 22 — Resistance to Tamiflu has been detected in a patient in Singapore who was down with the pandemic Influenza A (H1N1) bug. Similar cases have also emerged in Hong Kong, China, Japan, Canada, the United States and Denmark.

When the novel strain first appeared in April, the antiviral worked well against it. The World Health Organisation (WHO) feels that these instances of it not working are isolated cases of resistance that have developed because Tamiflu had been used at lower, prophylactic doses in people who might have been exposed to the bug.

Because these so-called contacts were, in fact, already infected, the lower doses turned out to be suboptimal, which allowed resistance to emerge. There is no proof that resistance is circulating in the community at large, the WHO asserts.

Yet there is at least one documented case of a 16-year-old girl who fell ill while travelling from San Francisco to Hong Kong on June 11. Though she declined Tamiflu, an isolate from her was found to carry the H274Y mutation, which signals Tamiflu-resistance.

She was, however, not the world’s first case of such resistance, an honour belonging to a woman seen in Denmark in late June. When she got home from Britain, she was given Tamiflu prophylaxis. Yet she still fell ill on the fifth day of taking Tamiflu. H274Y was detected in her isolate.

Could she have been infected in Britain by someone carrying mainly Tamiflu-sensitive bugs but also a small population of resistant bugs? In that case, suboptimal Tamiflu dosage might have suppressed enough of the sensitive bugs to prevent any clinical symptoms. Over the five days, however, the resistant bugs could have replicated enough to predominate and thus cause clinical illness.

But if this is so, then the mutation must already have been circulating in Britain — which, however, has not reported any cases of Tamiflu resistance yet. Alternatively, she might have caught the resistant bug in Denmark itself, during the five days when she was well and ambulant.

One reason for suspecting community circulation of the resistant bug is that 98 per cent of all seasonal H1N1 bugs now carry H274Y. If patients are infected with both strains, that mutation could jump from seasonal flu to pandemic flu. But the WHO insists there is no evidence this has occurred, so all resistant cases must have emerged because of suboptimal Tamiflu dosages.

There are signs of community circulation in the US, at least. First, the genomics of the Hong Kong isolate where no Tamiflu was used suggests that the infection originated in the US.

Second, it was revealed only this month that a May 30 isolate taken from a young American woman returning to Singapore from Honolulu carried H274Y.

Flying on May 26, she fell ill on board the plane, was hospitalised here on May 27, was confirmed to be a H1N1 case on May 28, but was discharged on May 31 feeling well.

Although her May 28 sample was Tamiflu-sensitive, her May 30 sample had H274Y. Two days is probably too short an interval for resistance to develop from any suboptimal dosages of Tamiflu. At any rate, as a confirmed case, she would have been given the full dosage.

Thus it is entirely possible that she was infected in the US with both the sensitive and resistant strains, which her immune defences could have cleared quickly, so she was discharged fairly quickly.

Third, on Aug 15, the US authorities sent out an urgent report to physicians that two intensive care patients in Washington state who had been infected last month and treated aggressively with Tamiflu were found to have bugs with H274Y.

These four cases suggest that H274Y may already be circulating in the US. It is possible we are seeing relatively few of these isolates for a technical reason: All published genomes are consensus sequences of DNA. That is, the base that is considered to occupy a specific position on the genome is the one that occurs most frequently. But it needs do so 100 per cent of the time.

If a base occurs in only 10 per cent of viral particles, it isn’t likely to show up in the published sequence. It is only when a base occurs in, say, half the cases that it might appear in the consensus sequence.

If H274Y were found in, say, 10 per cent of viral particles, it won’t appear in the consensus sequence of samples taken from a patient prior to Tamiflu being used. Once Tamiflu is employed, the population of sensitive bugs would be drastically reduced. However, those with H274Y would flourish.

Thus, although it was already around prior to Tamiflu being used, the resistant bug would not be detected. After the drug is employed, however, the resistant bugs can grow to greater numbers than the sensitive ones, rendering them detectable.

Of course, if more samples are taken before Tamiflu is used, H274Y might be detected more often. Such comprehensive surveillance, however, would consume too much resources.

History suggests it was limited testing that enabled Tamiflu-resistance in seasonal Influenza A (H1N1) to creep up on the world unawares. The first instance of that was detected in Norway in spring last year.

By the 2008/2009 season, however, it was found in 98 per cent of bugs worldwide. Yet a re-testing of old samples showed that H274Y was already widespread by the autumn of 2007. This means it was circulating in the community before it was first detected in Norway last year.

Is history repeating itself? If so, Singapore should be stocking up on Relenza, the other antiviral that still works. — Straits Times

http://themalaysianinsider.com/index.ph ... -singapore

Angel_B · **Posted:** Fri Aug 21, 2009 10:04 pm

Quote:

The pocket for oseltamivir is created by the rotation of E276 and bonding of the amino acid to R224 — events that are prevented by the mutations R292K, N294S, and H274Y and therefore result in resistance to oseltamivir. An E119V mutation may permit the binding of a water molecule in the space created by the smaller valine, also interfering with oseltamivir binding.

http://content.nejm.org/cgi/content/full/353/25/2633

Dr. Niman...does this mean there are more mutations we need to look for other than just the H274Y?

wotan · **Posted:** Fri Aug 21, 2009 11:36 pm

CDC week 32 lists 4 Tamiflu resistant viruses, and then in a different place just mentions the 2 in Washington. Huh?

http://www.cdc.gov/flu/weekly/

Quote:

Antiviral Resistance:

Since October 1, 2008, 1,146 seasonal influenza A (H1N1), 245 influenza A (H3N2), 650 influenza B, and 376 2009 influenza A (H1N1) viruses have been tested for resistance to the neuraminidase inhibitors (oseltamivir and zanamivir). Also, 1,151 seasonal influenza A (H1N1), 245 influenza A (H3N2), and 431 2009 influenza A (H1N1) viruses have been tested for resistance to the adamantanes (amantadine and rimantadine). The results of antiviral resistance testing performed on these viruses are summarized in the table below.
Samples tested (n) Resistant Viruses,
Number (%) Samples tested (n) Resistant Viruses, Number (%) Samples tested (n) Resistant Viruses, Number (%)
Oseltamivir Zanamivir Adamantanes
Seasonal Influenza A (H1N1) 1,146 1,141 (99.6%) 1,146 0 (0) 1,151 6 (0.5%)
Influenza A (H3N2) 245 0 (0) 245 0 (0) 245 245 (100%)
Influenza B 650 0 (0) 650 0 (0) N/A* N/A*
2009 Influenza A (H1N1) 853 4** (0.5) 376 0 (0) 431 431 (100%)
*The adamantanes (amantadine and rimantadine) are not effective against influenza B viruses.
**Two screening tools were used to determine oseltamivir resistance: sequence analysis of viral genes or a neuraminidase inhibition assay.

2009 influenza A (H1N1) viruses were tested for oseltamivir resistance by a neuraminidase inhibition assay and/or detection of genetic sequence mutation, depending on the type of specimen tested: original clinical samples were examined for a single known mutation in the virus that confers oseltamivir resistance in currently circulating seasonal influenza A (H1N1) viruses, while influenza virus isolates were tested using a neuraminidase inhibition assay that determines the presence or absence of neuraminidase inhibitor resistance, followed by the neuraminidase gene sequence analysis of resistant viruses. Of the four oseltamivir resistant 2009 influenza A (H1N1) viruses, two were original clinical samples detected by the neuraminidase inhibition assay, and two were viral isolates detected by sequence analysis of a neuraminidase gene.

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 two 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.

Three seasonal influenza A (H1N1) viruses collected between February 8 and May 11, 2009, were found to be resistant to both oseltamivir and the adamantanes (amantadine and rimantadine). All seasonal influenza A (H1N1) viruses tested retain their sensitivity to zanamivir. The three dually-resistant viruses represent less than 1% of all seasonal influenza A (H1N1) viruses tested during the 2008-09 influenza season, and as a result, no changes to the influenza antiviral treatment or prophylaxis recommendations will be made at this time. CDC will continue to monitor trends in antiviral resistance over the summer and throughout the upcoming 2009-10 influenza season.

niman · **Posted:** Sat Aug 22, 2009 7:23 am

LOCUS GQ499337 1410 bp cRNA linear VRL 21-AUG-2009
DEFINITION Influenza A virus (A/Washington/28/2009(H1N1)) segment 6
neuraminidase (NA) gene, complete cds.
ACCESSION GQ499337
VERSION GQ499337.1 GI:256383636
DBLINK Project:37813
KEYWORDS .
SOURCE Influenza A virus (A/Washington/28/2009(H1N1))
ORGANISM Influenza A virus (A/Washington/28/2009(H1N1))
Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
Influenzavirus A.
REFERENCE 1 (bases 1 to 1410)
AUTHORS Deyde,V., Sheu,T., Okomo-Adhiambo,M., Hillman,M., Barnes,J.,
Garten,R., Klimov,A., Gubareva,L. and Cox,N.
TITLE Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection in
Immunosuppressed Patients Receiving Oseltamivir Therapy
JOURNAL Unpublished
REFERENCE 2 (bases 1 to 1410)
AUTHORS Deyde,V., Sheu,T., Okomo-Adhiambo,M., Hillman,M., Barnes,J.,
Garten,R., Klimov,A., Gubareva,L. and Cox,N.
TITLE Direct Submission
JOURNAL Submitted (21-AUG-2009) WHO Collaborating Center for Surveillance,
Epidemiology and Control of Influenza, Influenza Division, Centers
for Disease Control and Prevention, 1600 Clifton Road, N.E.,
Atlanta, GA 30333, USA
COMMENT Swine influenza A (H1N1) virus isolated during human swine flu
outbreak of 2009. For more information, see http://www.cdc.gov/.

Some of the information does not have GenBank feature identifiers
and is being provided in the comment section.

##EpifluData-START##
Isolate A/Washington/28/2009
Subtype H1N1
Segment_name NA
Host_gender M
Host_age 18
Passage_history X
Adamantane_resistance resistant
Zanamivir_resistance sensitive
Oseltamivir_resistance resistant
Country USA
State/Province Washington state
Collection_day 14
Collection_month 7
Collection_year 2009
Isolate_note Human case of H1N1 pandemic influenza with
Oseltamivir Resistance.
EPI_accession EPI191936
Lineage swl
##EpifluData-END##
FEATURES Location/Qualifiers
source 1..1410
/organism="Influenza A virus (A/Washington/28/2009(H1N1))"
/mol_type="viral cRNA"
/strain="A/Washington/28/2009"
/serotype="H1N1"
/host="Homo sapiens; gender: M; age: 18"
/db_xref="taxon:667724"
/segment="6"
/country="USA: Washington state"
/collection_date="14-Jul-2009"
gene 1..1410
/gene="NA"
CDS 1..1410
/gene="NA"
/codon_start=1
/product="neuraminidase"
/protein_id="ACU78208.1"
/db_xref="GI:256383637"
/translation="MNPNQKIITIGSVCMTIGMANLILQIGNIISIWISHSIQLGNQN
QIETCNQSVITYENNTWVNQTYVNISNTNFAAGQSVVSVKLAGNSSLCPVSGWAIYSK
DNSVRIGSKGDVFVIREPFISCSPXECRTFFLTQGALLNDKHSNGTIKDRSPYRTLMS
CPIGEVPSPYNSRFESVAWSASACHDGINWLTIGISGPDNGAVAVLKYNGIITDTIKS
WRNNILRTQESECACVNGSCFTVMTDGPSNGQASYKIFRIEKGKIVKSVEMNAPNYYY
EECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEYQIGYICSGIFGDNPRPNDKTGS
CGPVSSNGANGVKGFSFKYGNGVWIGRTKSISSRNGFEMIWDPNGWTGTDNNFSIKQD
IVGINEWSGYSGSFVQHPELTGLDCIRPCFWVELIRGRPKENTIWTSGSSISFCGVNS
DTVGWSWPDGAELPFTIDK"
ORIGIN
1 atgaatccaa accaaaagat aataaccatt ggttcggtct gtatgacaat tggaatggct
61 aacttaatat tacaaattgg aaacataatc tcaatatgga ttagccactc aattcaactt
121 gggaatcaaa atcagattga aacatgcaat caaagcgtca ttacttatga aaacaacact
181 tgggtaaatc agacatatgt taacatcagc aacaccaact ttgctgctgg acagtcagtg
241 gtttccgtga aattagcggg caattcctct ctctgccctg ttagtggatg ggctatatac
301 agtaaagaca acagtgtaag aatcggttcc aagggggatg tgtttgtcat aagggaacca
361 ttcatatcat gctcccccty ggaatgcaga accttcttct tgactcaagg ggccttgcta
421 aatgacaaac attccaatgg aaccattaaa gacaggagcc catatcgaac cctaatgagc
481 tgtcctattg gtgaagttcc ctctccatac aactcaagat ttgagtcagt cgcttggtca
541 gcaagtgctt gtcatgatgg catcaattgg ctaacaattg gaatttctgg cccagacaat
601 ggggcagtgg ctgtgttaaa gtacaacggc ataataacag acactatcaa gagttggaga
661 aacaatatat tgagaacaca agagtctgaa tgtgcatgtg taaatggttc ttgctttact
721 gtaatgaccg atggaccaag taatggacag gcctcataca agatcttcag aatagaaaag
781 ggaaagatag tcaaatcagt cgaaatgaat gcccctaatt attactatga ggaatgctcc
841 tgttatcctg attctagtga aatcacatgt gtgtgcaggg ataactggca tggctcgaat
901 cgaccgtggg tgtctttcaa ccagaatctg gaatatcaga taggatacat atgcagtggg
961 attttcggag acaatccacg ccctaatgat aagacaggca gttgtggtcc agtatcgtct
1021 aatggagcaa atggagtaaa aggattttca ttcaaatacg gcaatggtgt ttggataggg
1081 agaactaaaa gcattagttc aagaaacggt tttgagatga tttgggatcc gaacggatgg
1141 actgggacag acaataactt ctcaataaag caagatatcg taggaataaa tgagtggtca
1201 ggatatagcg ggagttttgt tcagcatccg gaactaacag ggctggattg tataagacct
1261 tgcttctggg ttgaactaat cagagggcga cccaaagaga acacaatctg gactagcggg
1321 agcagcatat ccttttgtgg tgtaaacagt gacactgtgg gttggtcttg gccagacggt
1381 gctgagttgc catttaccat tgacaagtaa

niman · **Posted:** Sat Aug 22, 2009 7:24 am

LOCUS GQ499335 1410 bp cRNA linear VRL 21-AUG-2009
DEFINITION Influenza A virus (A/Washington/29/2009(H1N1)) segment 6
neuraminidase (NA) gene, complete cds.
ACCESSION GQ499335
VERSION GQ499335.1 GI:256383632
DBLINK Project:37813
KEYWORDS .
SOURCE Influenza A virus (A/Washington/29/2009(H1N1))
ORGANISM Influenza A virus (A/Washington/29/2009(H1N1))
Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
Influenzavirus A.
REFERENCE 1 (bases 1 to 1410)
AUTHORS Deyde,V., Sheu,T., Okomo-Adhiambo,M., Hillman,M., Barnes,J.,
Garten,R., Klimov,A., Gubareva,L. and Cox,N.
TITLE Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection in
Immunosuppressed Patients Receiving Oseltamivir Therapy
JOURNAL Unpublished
REFERENCE 2 (bases 1 to 1410)
AUTHORS Deyde,V., Sheu,T., Okomo-Adhiambo,M., Hillman,M., Barnes,J.,
Garten,R., Klimov,A., Gubareva,L. and Cox,N.
TITLE Direct Submission
JOURNAL Submitted (21-AUG-2009) WHO Collaborating Center for Surveillance,
Epidemiology and Control of Influenza, Influenza Division, Centers
for Disease Control and Prevention, 1600 Clifton Road, N.E.,
Atlanta, GA 30333, USA
COMMENT Swine influenza A (H1N1) virus isolated during human swine flu
outbreak of 2009. For more information, see http://www.cdc.gov/.

Some of the information does not have GenBank feature identifiers
and is being provided in the comment section.

##EpifluData-START##
Isolate A/Washington/29/2009
Subtype H1N1
Segment_name NA
Host_gender F
Host_age 47
Passage_history X
Adamantane_resistance resistant
Zanamivir_resistance sensitive
Oseltamivir_resistance resistant
Country USA
State/Province Washington state
Collection_day 28
Collection_month 7
Collection_year 2009
Isolate_note Human case of H1N1 pandemic influenza with
Oseltamivir resistance.
EPI_accession EPI191938
Lineage swl
##EpifluData-END##
FEATURES Location/Qualifiers
source 1..1410
/organism="Influenza A virus (A/Washington/29/2009(H1N1))"
/mol_type="viral cRNA"
/strain="A/Washington/29/2009"
/serotype="H1N1"
/host="Homo sapiens; gender: F; age: 47"
/db_xref="taxon:667723"
/segment="6"
/country="USA: Washington state"
/collection_date="28-Jul-2009"
gene 1..1410
/gene="NA"
CDS 1..1410
/gene="NA"
/codon_start=1
/product="neuraminidase"
/protein_id="ACU78206.1"
/db_xref="GI:256383633"
/translation="MNPNQKIITIGSVCMTIGMANLILQIGNIISIWISHSIQLGNQN
QIETCNQSVITYENNTWVNQTYVNISNTNFAAGQSVVPVKLAGNSSLCPVSGWAIYSK
DNSVRIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLMS
CPIGEVPSPYNSRFESVAWSASACHDGINWLTIGISGPDNGAVAVLKYNGIITDTIKS
WRNNILRTQESECACVNGSCFTVMTDGPSNGQASYKIFXIEKGKIVKSVEMNAPNYYY
EECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEYQIGYICSGIFGDNPRPNDKTGS
CDPVSSNGANGVKGFSFKYGNGVWIGRTKSISSRNGFEMIWDPNGWTGTDNNFSIKQD
IVGINEWSGYSGSFVQHPELTGLDCIRPCFWVELIRGRPKENTIWTSGSSISFCGVNS
DTVGWSWPDGAELPFTIDK"
ORIGIN
1 atgaatccaa accaaaagat aataaccatt ggttcggtct gtatgacaat tggaatggct
61 aacttaatat tacaaattgg aaacataatc tcaatatgga ttagccactc aattcaactt
121 gggaatcaaa atcagattga aacatgcaat caaagcgtca ttacttatga aaacaacact
181 tgggtaaatc agacatatgt taacatcagc aacaccaact ttgctgctgg acagtcagtg
241 gttcccgtga aattagcggg caattcctct ctctgccctg ttagtggatg ggctatatac
301 agtaaagaca acagtgtaag aatcggttcc aagggggatg tgtttgtcat aagggaacca
361 ttcatatcat gctccccctt ggaatgcaga accttcttct tgactcaagg ggccttgcta
421 aatgacaaac attccaatgg aaccattaaa gacaggagcc catatcgaac cctaatgagc
481 tgtcctattg gtgaagttcc ctctccatac aactcaagat ttgagtcagt cgcttggtca
541 gcaagtgctt gtcatgatgg catcaattgg ctaacaattg gaatttctgg cccagacaat
601 ggggcagtgg ctgtgttaaa gtacaacggc ataataacag acactatcaa gagttggaga
661 aacaatatat tgagaacaca agagtctgaa tgtgcatgtg taaatggttc ttgctttact
721 gtaatgaccg atggaccaag taatggacag gcctcataca agatcttcar aatagaaaag
781 ggaaagatag tcaaatcagt cgaaatgaat gcccctaatt attactatga ggaatgctcc
841 tgttatcctg attctagtga aatcacatgt gtgtgcaggg ataactggca tggctcgaat
901 cgaccgtggg tatctttcaa ccagaatctg gaatatcaga taggatacat atgcagtggg
961 attttcggag acaatccacg ccctaatgat aagacaggca gttgtgatcc agtatcgtct
1021 aatggagcaa atggagtaaa aggattttca ttcaaatacg gcaatggtgt ttggataggg
1081 agaactaaaa gcattagttc aagaaacggt tttgagatga tttgggatcc gaacggatgg
1141 actgggacag acaataactt ctcaataaag caagatatcg taggaataaa tgagtggtca
1201 ggatatagcg ggagttttgt tcagcatccg gaactaacag ggctggattg tataagacct
1261 tgcttctggg ttgaactaat cagagggcga cccaaagaga acacaatctg gactagcggg
1321 agcagcatat ccttttgtgg tgtaaacagt gacactgtgg gttggtcttg gccagacggt
1381 gctgagttgc catttaccat tgacaagtaa

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