Flu Found Resistant to Main Antiviral Drug

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

EID Journal Home > Volume 15, Number 4?April 2009
<!-- InstanceEndEditable --> <!-- content_starts_here //--> <!-- InstanceBeginEditable name="Article Content" --> Volume 15, Number 4?April 2009

Research

Oseltamivir-Resistant Influenza Virus A (H1N1), Europe, 2007?08 Season


Abstract
In Europe, the 2007?08 winter season was dominated by influenza virus A (H1N1) circulation through week 7, followed by influenza B virus from week 8 onward. Oseltamivir-resistant influenza viruses A (H1N1) (ORVs) with H275Y mutation in the neuraminidase emerged independently of drug use. By country, the proportion of ORVs ranged from 0% to 68%, with the highest proportion in Norway. The average weighted prevalence of ORVs across Europe increased gradually over time, from near 0 in week 40 of 2007 to 56% in week 19 of 2008 (mean 20%). Neuraminidase genes of ORVs possessing the H275Y substitution formed a homogeneous subgroup closely related to, but distinguishable from, those of oseltamivir-sensitive influenza viruses A (H1N1). Minor variants of ORVs emerged independently, indicating multiclonal ORVs. Overall, the clinical effect of ORVs in Europe, measured by influenza-like illness or acute respiratory infection, was unremarkable and consistent with normal seasonal activity.

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Once again the independent introductions are noted (and such independent introductions are OBVIOUS to anyone who can read a phylogenetic tree).

[Shiloh]

Re: Flu Found Resistant to Main Antiviral Drug

Source: http://www.usatoday.com/news/health/...sistance_N.htm

Drug-resistant flu strains throw doctors a curve
By Anita Manning, Special for USA TODAY

Not long ago, when infectious-disease specialist Connie Price saw a patient hospitalized with flu at Denver Health Medical Center, she had a powerful weapon at hand: a drug that could shorten the course of the illness and lessen its misery.

Now, the strength of that weapon, Tamiflu, has been undermined by a widely circulating flu strain, type A H1N1, that has developed the ability to resist the drug.

Even as this year's flu season winds down, doctors say the implications of the spread of drug-resistant flu strains could resonate in seasons to come, affecting treatment and highlighting the need for faster flu tests, new drugs and global monitoring of flu viruses.

TAMIFLU: Virus growing resistant to key weapon

Tamiflu, whose medical name is oseltamavir, is one of two drugs in a relatively new class of anti-flu medications that reduce the duration and severity of flu. Because it is easily taken in pill or liquid form, it quickly became the antiviral of choice for treating both seasonal flu and potential pandemic flu strains, such as H5N1, known as bird flu. Another drug in the same class is Relenza, or zanamavir, which has similar flu-fighting effects but is taken as an inhaled powder, which makes it difficult for some people to use, especially people who have lung problems such as asthma.

FIND MORE STORIES IN (go to the source to access links) : Japan | Food and Drug Administration | Prevention | Human Services | Department of Health | University of Virginia | Tamiflu | Relenza | Denver Health Medical Center | Infectious Disease Society of America | Bill Sheridan

Stockpiling for pandemic

In recent years, because of rising concern about the potential for a flu pandemic, governments around the world have been stockpiling millions of doses of Tamiflu, along with smaller amounts of Relenza and older antivirals, amantadine and rimantadine.

Tamiflu still is effective against bird flu in most cases, though some variants show signs of reduced sensitivity, says Frederick Hayden of the Infectious Disease Society of America's Pandemic Flu Task Force. "It's important that we monitor susceptibility patterns, not only in humans but also in avian viruses."

Meanwhile, for doctors treating patients with regular flu, this season has been dizzyingly complicated. Type A H1N1 flu, the predominant strain circulating now, is the one resistant to Tamiflu; the two others in circulation, type A H3N2 and type B, are not.

Patients who have H1N1 flu can be treated with Relenza if they can inhale the medicine. If not, they can take amantadine or rimantadine. But if they have either of the other two flu strains, they can take only Tamiflu or Relenza, because H3N2 flu is resistant to amantadine and rimantadine, and those drugs don't work against type B flu.

The trouble is, most doctors don't know which flu strain is infecting their patients. The symptoms are the same. Rapid flu diagnostic tests may be able to tell if it's influenza A or B, but can't identify type A subtypes, such as H1N1 or H3N2. The gold-standard test, a viral culture, takes about a week to produce results.

Difficult choices

Price says that given the inability to quickly know exactly what flu strain is present, she issued a "blanket recommendation" for doctors treating patients with flu at her hospital. She advised them to use Relenza, if possible, and if not, to always combine Tamiflu with one of the older drugs, such as rimantadine.

That is "never desirable," she says, because it means some patients will be overmedicated and subject to drug side effects, such as nausea, loss of appetite, nervousness or dizziness.

The sickest patients who could benefit most from antiviral treatment, she says, are often those who are elderly or who have underlying health problems that put them at higher risk for flu complications. "Now, to give them two more drugs that may interact with other therapies, it makes it more complicated," to treat, Price says.

The U.S. Centers for Disease Control and Prevention says this has been a milder flu season than in previous years. But the most recent report shows flu is widespread in 30 states, and 32 children have died because of the flu since the season began last September. In the 2007-08 season, 88 children died of illnesses associated with flu.

Drugmakers are working on new antivirals, including a potent injectable that could be used for hospitalized patients. The drug, peramivir, developed by BioCryst with $102.6 million from the Department of Health and Human Services, "is a major public health priority," says Bill Sheridan, chief medical officer. Clinical trials are underway in Japan and the USA, but testing at least through next flu season is needed before the drug can be considered by the Food and Drug Administration.

Other medications are being developed, but they're not expected to be available for years, which leaves annual flu vaccination as the best defense, says Hayden, a flu researcher at the University of Virginia. "Make sure you get vaccinated," he says, "and use common sense in terms of reducing exposure to the virus."

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

Docs struggle with drug-resistant flu


Published: March 23, 2009 at 1:37 PM

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WASHINGTON, March 23 (UPI) -- The drug-resistance of the widely circulating type A H1N1 flu virus highlights the need for new flu drugs and faster tests, U.S. researchers said. Type A H1N1 is resistant to Tamiflu, the anti-viral that until now been the first choice for treating both seasonal flu and bird flu, USA Today reported Monday. Tamiflu is still effective against most cases of bird flu, the report said.
Doctors still have options for treating type A H1N1 influenza. Relenza, also known as zanamavir, is in the same class as Tamiflu but the inhaled powder is difficult for some people to use. Older anti-virals, amantadine and rimantadine, will also work against that particular strain. The problem is that doctors don't often know which flu strain is making their patient ill. The other two common flu viruses this season, type A H3N2 and type B, are not resistant to Tamiflu but H3N2 is resistant to amantadine and rimantadine and won't work against type B flu.
Rapid flu diagnostic tests can't identify type A subtypes and a viral culture test takes nearly a week to identify the flu type, USA Today said.

http://www.upi.com/Science_News/2009/03/23/Docs_struggle_with_drug-resistant_flu/UPI-58711237829826/

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

Source: http://www.usatoday.com/news/health/...sistance_N.htm

Drug-resistant flu strains throw doctors a curve
By Anita Manning, Special for USA TODAY



Drugmakers are working on new antivirals, including a potent injectable that could be used for hospitalized patients. The drug, peramivir, developed by BioCryst with $102.6 million from the Department of Health and Human Services, "is a major public health priority," says Bill Sheridan, chief medical officer. Clinical trials are underway in Japan and the USA, but testing at least through next flu season is needed before the drug can be considered by the Food and Drug Administration.

Other medications are being developed, but they're not expected to be available for years, which leaves annual flu vaccination as the best defense, says Hayden, a flu researcher at the University of Virginia. "Make sure you get vaccinated," he says, "and use common sense in terms of reducing exposure to the virus."

H274Y is problematic for peramivir.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

Commentary at

http://www.recombinomics.com/News/03230902/H274Y_Global_Confirmed.html

[miso]

Re: Flu Found Resistant to Main Antiviral Drug

H274Y is problematic for peramivir.

H274Y is characterised as resistant to Peramivir but is 7x more resistant to Tamiflu. Biocryst claim to have overcome resistance simply by increasing the concentration of peramivir used. I'm sceptical because,

""In order for oseltamivir or peramivir to bind in the influenza A virus NA active site, a conformational change has to take place to accommodate the bulky hydrophobic group of these two drugs. The reorientation of residue E276 allows it to form a salt link with R224, which thereby creates the hydrophobic pocket required to accommodate the large hydrophobic group of the drugs ."

<b>Characterization of recombinant influenza B viruses with key neuraminidase inhibitor resistance mutations</b> J. Antimicrob. Chemother. Jackson et al. 55 (2): 162.

http://jac.oxfordjournals.org/cgi/reprint/55/2/162

and that doesn't change with concentration.


Biocryst claims success in phase II clinical trials having increased the dose of injectable Peramivir to 600mg. One of the end-points measured in the trial was the change in viral titre in individuals two days after injection with peramivir, but I can't find if results for individuals have been published. Does anyone have a link?
If even one subject treated with peramivir had a higher viral titre after two days that would indicate a wild strain of influenza is already resistant at 600mg, of that the therapy resulted in a mutation conferring resistance. A repeat of early trial results for Tamiflu that were ignored, and put us in the position we are currently in.

P.S. It doesn't bode well that peramivir has been in development for over ten years and they're still tinkering with the effective dose.

[AlaskaDenise]

Re: Flu Found Resistant to Main Antiviral Drug

Commentary at

http://www.recombinomics.com/News/03...Confirmed.html

Commentary

Confirmation of Global H1N1Tamiflu Resistance

Recombinomics Commentary 19:43
March 23, 2009

During this period, a total of 30 countries from all WHO regions reported oseltamivir resistance for 1291 of 1362 A(H1N1) viruses analysed. The prevalence of oseltamivir resistance was very high in the following countries/territory: Canada (52 of 52 tested), Hong Kong SAR (72 of 80), Japan (420 of 422), the Republic of Korea (268 of 269) and the United States of America (237 of 241).

The resistance prevalence was relatively low in China (6 of 44 tested). In Europe, H1N1 circulation was low during this period while the resistance prevalence was high: France (12 of 12tested), Germany (66 of 67), Ireland (9 of 10), Italy (16 of 16), Sweden (11 of 12) and the United Kingdom (61 of 62).

The above comments from the latest WHO update on Tamiflu resistance confirm that H274Y has become fixed in clade 2B (Brisbane/59) in the northern hemisphere, and similar levels will be expected in the upcoming flu season in the southern hemisphere. The only northern hemisphere country with lower levels is China, which is due to high levels of clade 2C. However, clade 2C has been largely replaced by 2B in all northern hemisphere countries, and many, especially those in Asia, previously had relatively high levels of clade 2C last year. Levels in the US were approximately 10% of H1N1, while this year levels are below 1%.

The dominance of clade 2B with H274Y not only creates treatment problems for patients with seasonal flu, but also raises concerns regarding the acquisition of H274Y by H5N1 via reassortment or recombination. Examples of exchanges between H1N1 clade 2B and clade 2C have been documented. One isolate from Hong Kong had a clade 2C HA and a clade 2B NA (with H274Y). Moreover, recombination has led to hitch-hiking of H274Y across multiple sub-clades (2C, 1, and 2B) as well as within each of the above sub-clades. Moreover, the H1N1 that led to the fixing of H274Y acquired additional clade 2C polymorphsms, including A193T, which is now present in all clade 2B isolates with H274Y.

This acquisition has been accompanied by additional changes in HA and NA, especially those that are adjacent to A193T. Multiple changes have been reported at positions 187, 189, and 196, an isolates with these changes have spread widely and rapidly, and are likely for vaccine resistance in Japan, Taiwan, and Italy.

The acquisition of these changes via recombination between H1N1 sub-clades raises concerns of H274Y acquisition in hosts co-infected with H1N1 and H5N1. These concerns have been increased by reports of mild H5N1 infections in Egypt. All eight H5N1 cases in 2009 have survived H5N1 infections, and the course of disease in several patients is short and mild, raising concerns of a significant number of unreported cases due to recovery with or without Tamiflu treatment for seasonal flu.

Acquisition of H274Y by H5N1 would create serious concerns, especially in countries like Indonesia, where the high case fatality rate suggests many milder cases are unreported.

.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

New NA tree from Japan

http://idsc.nih.go.jp/iasr/rapid/graph/pf35032.pdf

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

Ferret data

http://idsc.nih.go.jp/iasr/rapid/graph/pt35032.gif

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

Commentary

http://www.recombinomics.com/News/03250902/H274Y_Vaccine_Mismatch_2009.html

[AlaskaDenise]

Re: Flu Found Resistant to Main Antiviral Drug

Commentary

http://www.recombinomics.com/News/03...atch_2009.html

Commentary

Accelerated H1N1 Tamiflu Resistance Via Vaccine Mismatch

Recombinomics Commentary 23:11
March 25, 2009

The Japan NIH has released a new NA phylogenetic tree of H1N1 this season. Included are nine isolates from 2009, which all map with the major sub-clade in Japan. The tree also includes isolates from South Korea which map to the same dominant branch. HA sequences from these isolates have A193T and the flanking polymorphism of G189A. These sequences are also in a small number of isolates from the US and match the first five H1N1 isolates from Italy, as well as isolates from Taiwan.

Also included are isolates from Japan that were associated with an elementary school in the fall, which matches the dominant H1N1 sub-clade in the US. HA sequences from these isolates have A193T with G189V and H196R.

Japan NIH also released titers of 18 isolates against ferret reference anti-sera. These data clearly demonstrate significant drift of the recent isolates from last year?s H1N1 vaccine target, A/Solomon Islands/3/2006 (clade 2A). However, last season there was little clade 2A in circulation, raising concerns that the drift was accelerated by a poorly matched vaccine. Although the 18 test antigens represented multiple recent sub-clades, with HA sequences with A193T plus one or two additional changes at flanking positions 187, 189, and 196, all had reductions in titers when tested with the clade 2A reference anti-sera. Two were reduced four fold, but the remainder had reductions ranging from eight to thirty-two fold.

Similar results were generated for clade 2C, which was represented by recent anti-sera against A/Shiga/8/2008. One isolate was reduced four fold while the rest were reduced eight to thirty-two fold. These lower titers help explain the spread of clade 2B in Asia, where clade 2C was widespread last season.

However, reduced titers were also seen for A/Brisbane/59/2007 (clade 2B), although results were more complex. Two reference sera were used. One was directed against Brisbane/59 grown in eggs and like last season, the anti-sera had significant cross reactivity with the reference sera as well as the recent isolates. The mammalian cell isolate however discriminated between the reference sera, especially for clade 2C, where the titer was reduced eight fold. This level of reduction was also seen for four of the test isolates. Three were the dominant sub-clade in Japan, while the other was the dominant sub-clade in the US. These titer reductions support reports of vaccine failures in Asia and North America.

The recent announcement that the H1N1 target for the 2009/2010 will remain unchanged raises concerns of more vaccine failures next season.

.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

INFLUENZA A(H1N1) VIRUS, OSELTAMIVIR RESISTANCE (02): NORTHERN HEMISPHERE
************************************************** ***********************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>

Date: Sat 21 Mar 2009
Source: WHO Epidemic and Pandemic Alert and Response (EPR), Influenza [edited]
<http://www.who.int/csr/disease/influ...18%20ed_ns.pdf>


Influenza A(H1N1) virus resistance to oseltamivir -- 2008/2009
influenza season, northern hemisphere
--------------------------------------------------------------
During weeks 1-4 (28 Dec 2008-24 Jan 2009), the level of overall
influenza activity in the world increased. In Europe, most countries
reported regional or widespread activity with influenza A(H3) viruses
predominating. Widespread influenza A activity (H1 and H3) was
reported in Japan. In Canada, Hong Kong SAR, and the United States,
influenza activity increased but remained relatively low. Sporadic
influenza activity was observed in Brazil (A), Croatia (H1, H3, B),
Greece (H1, H3, B), Iran (H1, H3), Mongolia (A), Portugal (H1, H3,
B), Serbia (H1, H3, B), Singapore (H1, H3, B), Slovakia (H3), and
Turkey (H3, B).

During this period, a total of 30 countries from all WHO regions
reported oseltamivir resistance for 1291 of 1362 A(H1N1) viruses
analysed. The prevalence of oseltamivir resistance was very high in
the following countries/territory: Canada (52 of 52 tested), Hong
Kong SAR (72 of 80), Japan (420 of 422), the Republic of Korea (268
of 269), and the USA (237 of 241).

The resistance prevalence was relatively low in China (6 of 44
tested). In Europe, H1N1 circulation was low during this period while
the resistance prevalence was high: France (12 of 12 tested), Germany
(66 of 67), Ireland (9 of 10), Italy (16 of 16), Sweden (11 of 12)
and the United Kingdom (61 of 62).

WHO is collecting global data about this phenomenon from multiple
laboratories participating in Global Influenza Surveillance Network
[<http://www.who.int/csr/disease/influ...rveillance/en/>]. Data
from European countries participating in EISS [European Influenza
Surveillance Scheme, <http://www.eiss.org/>] were provided by the
EISS and VirGil [vigilance against viral resistance] project
[<http://www.virgil-net.org/about-virgil>]. This summary table will
be updated regularly (every 4 weeks).

Oseltamivir resistance results were based on phenotypic and/or
genotypic analyses.

A comprehensive table of influenza A(H1N1) virus resistance to
oseltamivir (4th quarter 2008-31 Jan 2009) can be found [at the URL
above.]

--
Communicated by:
ProMED-mail
<promed@promedmail.org>

[It should be noted that in Europe as of week 11 [9-15 Mar] 2009 all
influenza A(H3N2) viruses tested (the predominant epidemic virus)
were resistant to M2 inhibitors but sensitive to oseltamivir and
zanamivir (<http://www.eiss.org/cgi-files/bulletin_v2.cgi>).
Consequently the appearance of oseltamivir resistance is dependent on
virus genotype and may not be a direct response to the use of
anti-neuraminidase antivirals. - Mod.CP]

[see also:
Influenza A(H1N1) virus, oseltamivir resistance: Korea 20090113.0136
2008
----
Influenza A (H1N1) virus, oseltamivir resistance (10): CDC 20081224.4054
Influenza A (H1N1) virus, oseltamivir resistance (09): USA 20081220.4013
Influenza A (H1N1) virus, oseltamivir resistance (08): Europe 20081025.3375
Influenza A (H1N1) virus, oseltamivir resistance (07): Europe 20080906.2783
Influenza A (H1N1) virus, oseltamivir resistance (06): S. Hemisphere
20080825.2648
Influenza virus, oseltamivir resistance (06): Japan 20080228.0812
Influenza A (H1N1) virus, oseltamivir resistance (05): China (HK)
20080203.0438
Influenza A (H1N1) virus, oseltamivir resistance (04): CA, USA 20080202.0428
Influenza A (H1N1) virus, oseltamivir resistance (03): corr. 20080203.0430
Influenza A (H1N1) virus, oseltamivir resistance (03): Europe 20080201.0399
Influenza A (H1N1) virus, oseltamivir resistance (02): Europe 20080129.0371
Influenza A (H1N1) virus, oseltamivir resistance - Norway 20080128.0361
2006
----
Avian influenza, human (162): oseltamivir resistance 20061010.2907]
........................................cp/mjs/jw
</pre>

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

INFLUENZA A(H1N1) VIRUS, OSELTAMIVIR RESISTANCE (02): NORTHERN HEMISPHERE
************************************************** ***********************


[It should be noted that in Europe as of week 11 [9-15 Mar] 2009 all
influenza A(H3N2) viruses tested (the predominant epidemic virus)
were resistant to M2 inhibitors but sensitive to oseltamivir and
zanamivir (<http://www.eiss.org/cgi-files/bulletin_v2.cgi>).
Consequently the appearance of oseltamivir resistance is dependent on
virus genotype and may not be a direct response to the use of
anti-neuraminidase antivirals. - Mod.CP]

CP is just over a year late in stating the obvious.

[gsgs]

Re: Flu Found Resistant to Main Antiviral Drug

> may not be a direct response to the use of ..antivirals.

yes, there was never strong evidence for this response, so
excluding other possibilities was never reasonable.

OTOH the connection to antiviral use cannot excluded either.

"may not be" , how much makes that in % subjective probability ?

for me it's almost 50-50 whether Tamiflu use was the main factor
to drive the current widespread resistance.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

> may not be a direct response to the use of ..antivirals.

yes, there was never strong evidence for this response, so
excluding other possibilities was never reasonable.

OTOH the connection to antiviral use cannot excluded either.

"may not be" , how much makes that in % subjective probability ?

for me it's almost 50-50 whether Tamiflu use was the main factor
to drive the current widespread resistance.

50-50!!!
That is a VERY conclusive comment.