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Influenza viruses resistant to oseltamivir, news and updates

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

I was wondering if someone could confirm the following summary of the situation:

"?If those resistant strains begin to propagate, then that?s when we?re going to be in trouble, because we don?t have any antivirals active against them,? said Rommie Amaro, a postdoctoral fellow in chemistry at UC San Diego."

Source: http://www.medicalnewstoday.com/articles/113847.php

I wasn't aware that there were viable strains of H5N1, or any influenza resistant to Relenza? Isn't Relenza "active against them"?
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

miso said:
I was wondering if someone could confirm the following summary of the situation:

"“If those resistant strains begin to propagate, then that’s when we’re going to be in trouble, because we don’t have any antivirals active against them,” said Rommie Amaro, a postdoctoral fellow in chemistry at UC San Diego."

Source: http://www.medicalnewstoday.com/articles/113847.php

I wasn't aware that there were viable strains of H5N1, or any influenza resistant to Relenza? Isn't Relenza "active against them"?
Click to expand...
There are human influenza strains (in Asia, Africa, and Australia) resistant to Relenza, but H5N1 has not been reported.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

miso said:
I was wondering if someone could confirm the following summary of the situation:

"?If those resistant strains begin to propagate, then that?s when we?re going to be in trouble, because we don?t have any antivirals active against them,? said Rommie Amaro, a postdoctoral fellow in chemistry at UC San Diego."

Source: http://www.medicalnewstoday.com/articles/113847.php

I wasn't aware that there were viable strains of H5N1, or any influenza resistant to Relenza? Isn't Relenza "active against them"?
Click to expand...
LOCUS CY030873 1396 bp cRNA linear VRL 17-MAR-2008
DEFINITION Influenza A virus (A/Thailand/39/2008(H1N1)) segment 6 sequence.
ACCESSION CY030873
VERSION CY030873.1 GI:170026929
KEYWORDS .
SOURCE Influenza A virus (A/Thailand/39/2008(H1N1))
ORGANISM Influenza A virus (A/Thailand/39/2008(H1N1))
Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
Influenzavirus A.
REFERENCE 1 (bases 1 to 1396)
AUTHORS Hurt,A.C., Kelso,A. and Barr,I.G.
TITLE Community cases of zanamivir-resistant human influenza viruses with
a novel mutation in the neuraminidase gene
JOURNAL Unpublished
REFERENCE 2 (bases 1 to 1396)
AUTHORS Hurt,A.C., Deng,Y.-M. and Komadina,N.
TITLE Direct Submission
JOURNAL Submitted (14-MAR-2008) WHO Collaborating Centre for Reference and
Research on Influenza, 45 Poplar Rd, Parkville, Victoria 3052,
Australia
FEATURES Location/Qualifiers
source 1..1396
/organism="Influenza A virus (A/Thailand/39/2008(H1N1))"
/mol_type="viral cRNA"
/strain="A/Thailand/39/2008(H1N1)"
/serotype="H1N1"
/isolation_source="gender:M; age:23"
/specific_host="Human"
/db_xref="taxon:511421"
/segment="6"
/lab_host="MDCKX passage(s)"
/country="Thailand"
/collection_date="02-Jan-2008"
gene 1..>1396
/gene="NA"
CDS 1..>1396
/gene="NA"
/codon_start=1
/product="neuraminidase"
/protein_id="ACB05991.1"
/db_xref="GI:170026930"
/translation="MNPNQKIITIGSISIAIGIISLMLQIGNIISIWASHSIQTGSQN
NTGICNQRIITYENSTWVNHTYVNINNTNVVAGEDKTSVTLAGNSSLCSISGWAIYTK
DNSIRIGSKGDVFVIREPFISCSHLECRTFFLTKGALLNDKHSNGTVKDRSPYRALMS
CPLGEAPSPYNSKFESVAWSASACHDGMGWLTIGISGPDNGAVAVLKYNGIITGTIKS
WKKQILRTQESECVCMNGSCFTIMTDGPSNKAASYKIFKIEKGKVTKSIELNAPNFHY
EECSCYPDTGIVMCVCRDNWHGSNRPWVSFNQNLDYQIGYICSGVFGDNPRPEDGEGS
CNPVTVDGANGVKGFSYKYDNGVWIGRTKSNRLRKGFEMIWDPNGWTNTDSDFSVKQD
VVAITDWSGYSGSFVQHPELTGLDCIRPCFWVELVRGLPRENTTIWTSGSSISFCGVN
SDTANWSWPDGAELP"
ORIGIN
1 atgaatccaa atcaaaaaat aataaccatt ggatcaatca gtatagcaat cggaataatt
61 agtctaatgt tgcaaatagg aaatattatt tcaatatggg ctagtcactc aatccaaact
121 ggaagtcaaa acaacactgg aatatgcaac caaagaatca tcacatatga aaacagcacc
181 tgggtgaatc acacatatgt taatattaac aacactaatg ttgttgcagg agaggacaaa
241 acttcagtga cattggccgg caattcgtct ctttgttcta tcagtggatg ggctatatac
301 acaaaagaca acagcataag aattggctcc aaaggagatg tttttgtcat aagagaacct
361 ttcatatcat gttctcactt ggaatgcaga accttttttc tgaccaaagg cgctctatta
421 aatgacaaac attcaaatgg gaccgtaaag gacagaagtc cttatagggc cttaatgagc
481 tgtcctctag gtgaagctcc gtccccatac aattcaaagt tcgaatcagt tgcatggtca
541 gcaagcgcat gccatgatgg catgggctgg ttaacaatcg gaatttctgg tccagacaat
601 ggagctgtgg ctgtactaaa atacaacgga ataataactg gaaccataaa aagttggaaa
661 aagcaaatat taagaacaca agagtctgaa tgtgtctgta tgaacgggtc atgtttcacc
721 ataatgaccg atggcccgag taataaggcc gcctcgtaca aaattttcaa gatcgaaaag
781 gggaaggtta ctaaatcaat agagttgaat gcacccaatt ttcattatga ggaatgttcc
841 tgttacccag acactggcat agtgatgtgt gtatgcaggg acaactggca tggttcaaat
901 cgaccttggg tgtcttttaa tcaaaacttg gattatcaaa taggatacat ctgcagtgga
961 gtgttcggtg acaatccgcg tcccgaagat ggagagggca gctgcaatcc agtgactgtt
1021 gatggagcaa acggagtaaa agggttttca tacaaatatg ataatggtgt ttggatagga
1081 aggaccaaaa gtaacagact tagaaagggg tttgagatga tctgggatcc taatggatgg
1141 acaaataccg acagtgattt ctcagtgaaa caggatgttg tagcaataac tgattggtca
1201 gggtacagcg gaagtttcgt ccaacatcct gagttaacag gattggactg tataagacct
1261 tgcttctggg ttgagttagt cagagggctg cctagagaaa atacaacaat ttggactagt
1321 gggagcagca tttctttttg tggcgttaat agtgatactg caaactggtc ttggccagac
1381 ggtgctgagt tgccat
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

I was only able to find reports of Relenza resistance to one influenza virus: type B, which I believe hadn't shown antiviral resistance before this year. I hadn't heard about Relenza resistance.

I've wondered if substandard dosing is the culprit behind sudden rise of geographically distinct, but not distant (as in Paris and Southern France) resistance of H1N1 to tamiflu.

(the following is purely speculative babble)...

Maybe there is something in the food or regional favorite drink that either inhibits the esterase cleavage of precursor form of Tamiflu or enhances its drug metabolism, clearing it from the system before it has a chance to work properly. Provence and Parisian/Bordeaux cuisine are quite different.

Tamiflu is, after all, derived from natural product (unlike Relenza, which is purely synthetic and I believe active in its administered form, although it has poor uptake when administered orally).

The spice it is most like is burned as incense in Japan, and consumed elsewhere in Arabic and European cooking/appertifs.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

do we have improved numbers for resistance in H3N2 and B
meanwhile ? If they are also increased we have another
pessimistic indication for its development due to drug use.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

The WHO preliminary summary accompaigning PDF demonstrate that H3N2 and B strains reimain susceptible to oseltamivir.

Further, for example, in Hong Kong isolates 16 per cent remain susceptible to adamantanes (H1N1) (for the H3N2 100% are resistant).

Cross-resistance against zanamivir isnt' demonstrated, thus H1N1 remain susceptible to this drug as stated by both ECDC/EISS and WHO.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

thanks. So the 6% above was probably an error

> But only 6 percent of H3N2 and influenza B samples tested
> in North America had genetic mutations giving resistance to Tamiflu,
> she said.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Just to emphasize another transparency problem is that we're not getting needed info on resistant patterns. This needs both sequence analysis to look for known genetic variations and live virus to use in tests with the actual antivirals to look for other patterns of resistance

http://66.102.1.104/scholar?hl=en&l...al+susceptibility+monitoring+activities+..."+

A Meijer (a.meijer@nivel.nl)1 2, A Lackenby3 4, A Hay3 5, M Zambon3 4
European Influenza Surveillance Scheme (EISS) Co-ordination Centre, Nederlands Instituut voor Onderzoek van de Gezondheidszorg (Netherlands Institute for Health Services Research, NIVEL), Utrecht, the Netherlands
Laboratory for Infectious Diseases and Screening, Rijksinstituut voor Volksgezondheid en Milieu (National Institute of Public Health and the Environment, RIVM), Bilthoven, the Netherlands
European Surveillance Network for Vigilance against Viral Resistance (VIRGIL)
Respiratory Virus Unit, Centre for Infection, Health Protection Agency, London, United Kingdom
World Health Organization Collaborating Centre for Reference and Research on Influenza, National Institute for Medical Research, London, United Kingdom


--------------------------------------------------------------------------------

Due to the influenza pandemic threat, many countries are stockpiling antivirals in the hope of limiting the impact of a future pandemic virus. Since resistance to antiviral drugs would probably significantly alter the effectiveness of antivirals, surveillance programmes to monitor the emergence of resistance are of considerable importance.

During the 2006/2007 influenza season, an inventory was conducted by the European Surveillance Network for Vigilance against Viral Resistance (VIRGIL) in collaboration with the European Influenza Surveillance Scheme (EISS) to evaluate antiviral susceptibility testing by the National Influenza Reference Laboratories (NIRL) in relation to the national antiviral stockpile in 30 European countries that are members of EISS.

All countries except Ukraine had a stockpile of the neuraminidase inhibitor (NAI) oseltamivir. Additionally, four countries had a stockpile of the NAI zanamivir and three of the M2 ion channel inhibitor rimantadine. Of 29 countries with a NAI stockpile, six countries' NIRLs could determine virus susceptibility by 50% inhibitory concentration (IC50) and in 13 countries it could be done by sequencing. Only in one of the three countries with a rimantadine stockpile could the NIRL determine virus susceptibility, by sequencing only. However, including the 18 countries that had plans to introduce or extend antiviral susceptibility testing, the NIRLs of 21 of the 29 countries with a stockpile would be capable of susceptibility testing appropriate to the stockpiled drug by the end of the 2007/2008 influenza season.

Although most European countries in this study have stockpiles of influenza antivirals, susceptibility surveillance capability by the NIRLs appropriate to the stockpiled antivirals is limited.


Since the widespread emergence of antiviral resistance would likely have a significant impact on clinical effectiveness of antiviral therapy and prophylaxis, it is important to track resistance through regional and national surveillance programmes. In addition, it is important that these surveillance programmes are appropriate to the antivirals being stockpiled. Therefore, VIRGIL and EISS, as the European public-funded consortia working on these subjects, carried out this study in order to evaluate the actual and future antiviral susceptibility testing activities by the NIRLs in relation to the national antiviral stockpile in the 30 European countries that are members of EISS.

All European countries (except Ukraine) that participated in this study indicated that antiviral stockpiles are available. This is an encouraging observation as it relates directly to national pandemic preparedness activities. However, the number of countries in which NIRLs performed influenza antiviral susceptibility testing appropriate to the stockpiled antivirals was limited.

The creation of antiviral stockpiles involves substantial allocation of resources, and in the event of a pandemic it will be important to use such resources efficiently. Emerging information about the potential for the development of resistance against influenza antiviral drugs suggests that information about susceptibility of circulating strains should be taken into consideration for decisions on recommending drug use,

Antiviral susceptibility testing should exist to support the stockpiling of antiviral drugs, to analyse the susceptibility of viruses to the stockpiled antivirals in the early stages of a pandemic and to assess possible treatment failure.

Most NIRLs test for NAI resistance by sequencing, indicating that this type of analysis is much more widespread, compared with phenotypic susceptibility testing that is dependent on working with virus isolates. However, phenotypic NAI susceptibility analysis is still necessary to fully evaluate NAI resistance, given the uncertainty of purely genotypic methods for assessment of resistance as only a few mutations conferring NAI resistance have been described so far, and several more are likely to emerge. Therefore, we recommend that if a surveillance programme for NAIs is developed, both genotypic and phenotypic methods are used and data combined from both methods.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

gsgs said:
do we have improved numbers for resistance in H3N2 and B
meanwhile ? If they are also increased we have another
pessimistic indication for its development due to drug use.
Click to expand...
The whole point is the resistance is limited to H1N1 , is only for H274Y, and appeared SUDDENLY.
That's why "random mutations" are headed for the circular file.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

gsgs said:
thanks. So the 6% above was probably an error

> But only 6 percent of H3N2 and influenza B samples tested
> in North America had genetic mutations giving resistance to Tamiflu,
> she said.
Click to expand...
6% is utter nonsense and the reporter should find another line of work.
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Oracle said:
I was only able to find reports of Relenza resistance to one influenza virus: type B, which I believe hadn't shown antiviral resistance before this year. I hadn't heard about Relenza resistance.

I've wondered if substandard dosing is the culprit behind sudden rise of geographically distinct, but not distant (as in Paris and Southern France) resistance of H1N1 to tamiflu.

(the following is purely speculative babble)...

Maybe there is something in the food or regional favorite drink that either inhibits the esterase cleavage of precursor form of Tamiflu or enhances its drug metabolism, clearing it from the system before it has a chance to work properly. Provence and Parisian/Bordeaux cuisine are quite different.

Tamiflu is, after all, derived from natural product (unlike Relenza, which is purely synthetic and I believe active in its administered form, although it has poor uptake when administered orally).

The spice it is most like is burned as incense in Japan, and consumed elsewhere in Arabic and European cooking/appertifs.
Click to expand...
The recent spread of H274Y has NOTHING to do with Tamiflu or any derivatives.
 
typo , Henry.

typo , Henry.

:surrender:

It's the tropism shift that's allowed the HA/NA balanced action to be maintained (changes in glycosylation) while reducing NA susceptibility as an emerging phenotype, independent of tamiflu use.

It's why antiviral phenotypes were detected in a few influenza isolates obtained long before these drugs were introduced into use.

I thought it amusing to ponder the public outcry, should the highly popular Provencal beverage, Pastis, be forbidden. The Norwegians are more stoic - plus they have a variety of Aquavit flavors to choose from.

Anise metabolism involves esterases and causes neutrotoxicty in infants and children but that's beside the point.

This report of widespread antiviral resistance is about cellular tropism shift *maybe* associated with prior years of vaccines or from global circulating strain exposure, between 2003-2006: selection for A/ New Caledonia/20/99 (H1N1)-like viruses that caused death with neurological complications.

Severe Morbidity and Mortality Associated with Influenza in Children and Young Adults --- Michigan, 2003

http://www.cdc.gov/MMWR/PREVIEW/MMWRHTML/mm5235a2.htm

I'm sure you will correct technical misconceptions.
 
Last edited by a moderator:
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

niman said:
The recent spread of H274Y has NOTHING to do with Tamiflu or any derivatives.
Click to expand...

I agree although I am not surely a specialist in this field...

I would like to point out another strange behaviour of these resistant viruses: why do they ciruclated in southern France and not in northern Italy?

Are there some biases in testing methodics, samples collection and storage, something different in the operational practices among EU countries?

I think the single viral isolation in Italy may be taken with caution...

However, it is also noteworthy that the two countries share common borders, with continuous and massive humans and animals movements, via road, railways, airplanes. During the influenza epidemic in the winter, a person infected in Paris who travelled to Milan or Rome probably infected a lot of Italians...

It is hard to understand for me. Thus, I hope someone among the experts at Ft may clarified a bit this strange situation, also for people like me that cannot share the same level of knowledge.
 
Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

some years after increased use of Amantadine we got resistant strains.
Nothing all the decades before.
Same with Oseltamivir.

There are often only a few introductions into one country in a season which
survive and spread. It depends on just some (super) spreaders.
Who happens to travel from where to where in November,December.
Random movement vs. predictable relocation theory.

Oracle, without the typos it's hard to understand. You mean host-cell
suspectability of the virus changed ? But how does that produce H274Y ?
 
Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

Re: _|ANTIVIRALS RESISTANCE BAFFLED SCIENTISTS|_

ironorehopper said:
I agree although I am not surely a specialist in this field...

I would like to point out another strange behaviour of these resistant viruses: why do they ciruclated in southern France and not in northern Italy?

Are there some biases in testing methodics, samples collection and storage, something different in the operational practices among EU countries?

I think the single viral isolation in Italy may be taken with caution...

However, it is also noteworthy that the two countries share common borders, with continuous and massive humans and animals movements, via road, railways, airplanes. During the influenza epidemic in the winter, a person infected in Paris who travelled to Milan or Rome probably infected a lot of Italians...

It is hard to understand for me. Thus, I hope someone among the experts at Ft may clarified a bit this strange situation, also for people like me that cannot share the same level of knowledge.
Click to expand...
H274Y in the past season is almost exclusively in the Brisbane/59 strain (designated 2B on the various trees). However, there is a difference in disitibution of the 2B version (as well as genetic composition). One version led to the initial cases, and this version initially was primarily found in the north, including Norway. The levels in various locals, especially at the end of 2007 beginning of 2008, was dependent on this version (labeled Northern EU-like). This held for the US and Canada also (as well as Russia, England and northern France).

A seond version emerged later, labeled "Hawiian". Although this version was first found in Hawaii in 2007, it did not spread as rapidly. In the US, it is in Hawaii, Caliifornia, with another version in Florida (all are southern locations). This version is also in Thailand, southern France, Greece, and Japan. This "southern" version emerged later and the most cases so far have been in Japan. Data on this "southern version" however is not as complete (although it involves multiple independent introductions) as the "northern EU version", which is dominant in the US and probably Canada, as well as countries to the north like Russia.
 
Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

why do you think it emerged later ?
 
Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

lots of samples with H274Y from 2007, but they first mentioned
it in late Jan.2008, do they collect the isolates but only
sequence them weeks/months later ?

274Y:
Arizona/03/07
England/557/07
Hawaii/21/2007 Oct @
Hawaii/28/07
Illinois/10/2007 Dec @
Lyon/1337/2007 Dec @
New Jersey/15/07
New Jersey/16/2007 Dec @
Norway/1630/2007 @
Norway/1687/07
Norway/1701/07
Norway/1731/07
Norway/1736/07
Norway/1743/07
Norway/1745/07
Norway/1747/07
Paris/0577/07
Paris/0644/07
 
Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

gsgs said:
why do you think it emerged later ?
Click to expand...
It had to recombine with the northern version to acquire H274Y and it look awhile for the two to meet.
 
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