Discussion: A/H1N1 with oseltamivir resistance
http://www.flutrackers.com/forum/showthread.php?t=51648
(The above raises a question and I have posted some preliminary thoughts below but would be interested in the thoughts of others.)
This is a predictable and not particularly surprising development. Resistance has been seen before in both seasonal flu and HP AI H5N1.
The question which needs to be addressed – preferably collectively and under the guidance of the WHO – is what do we use Tamiflu for?
Tamiflu was developed as a treatment for seasonal flu, with the threat of an HP AI zoonotic emergence it has become our only extant weapon against a far greater potential enemy: Pandemic HP H5N1. That there are several known mutations that reduce the effectiveness of Tamiflu is well know as is the fact that using any antiviral will give a selective advantage to those mutations, when they occur. The more Tamiflu continues to be used to treat seasonal flu the higher the proportion of the circulating virus that will show some resistance. How much this matters depends on how correct Dr. Niman is in his estimation of the importance of recombination as the primary means of flu’s evolution. If evolution is largely confined to Reassortment and random mutations then having resistance in the seasonal flu gene pool does not greatly increase the risk of resistance in a pandemic form. If however Recombination is common, and a pandemic form emerges without resistance, it is likely to quickly acquire it by swapping genetic material with seasonal flu in cases of dual infection and a pervasive Tamiflu blanket.
So we return to the question of how do we use Tamiflu, do we try and restrict its use in seasonal flu cases – where we know it can do good – to preserve its usefulness to fight a pandemic which may not occur in the short term, may not be susceptible to Tamiflu and only really matters if recombination is a significant factor.
Personally I would favour making all doctors aware of the dilemma and recommending extreme restraint in its use. Where resistant cases are know greater efforts should be employed in quarantining patients to reduce the prevalence of resistant strains.
JJ
Sorry if this was unclear.
Mixin, have you seen how the Biocryst shares went down ?
There must be more problems than just the needle length,
which could have been an excuse for other problems.
Actually, their testing went quite well until they decided to switch the size of the needle. Now...you would think that just maybe, with all the money that has gone into funding this research, someone would have thought for one second: I wonder if a shorter needle will work as well. A half inch is not very long and many people have that much extra fat on their arms.
They determined that about 1/3 of the participants did receive the injection deep into the muscle and the test results on those were good enough that they are continuing with the third phase:applause: May they not mess up this one.
http://www.fiercebiotech.com/story/biocrysts-peramivir-flunks-trial/2007-09-20
See here credit Dutchy.
INDONESIA: Scientists worry bird flu strain is drug resistant - 28/01/2008
Indonesia has the world's highest number of bird flu deaths and now scientists are trying to find out why. One theory being tested is that the Indonesian strain of the H5N1 virus is less susceptible to conventional antivirals.
Presenter - Joanna McCarthy Speaker - Professor Anne Kelso from the WHO Collaborating Centre for Influenza in Melbourne, Dr Deoraj Caussy, Epidemiologist, World Health Organisation.
http://www.radioaustralia.net.au/i/icon_listen.gif (http://www.abc.net.au/ra/connectasia/stories/m1532301.asx) listen windows media > (http://www.abc.net.au/ra/connectasia/stories/m1532301.asx)
First, they went back and did their homework on giving injections:
Additionally, pharmacokinetic studies have been completed that indicate that needle length impacts adequate and consistent systemic exposure to i.m. peramivir. These PK studies also provide guidance on the appropriate needle length to use in future studies to provide adequate drug exposure for subjects based upon an individual's body mass index (BMI) and gender.
Now they are putting off Phase III and rethinking doses. Maybe that's the reason for the stock drop? During a pandemic, a single dose would be far superior to having to go back for a second injection.
Based on these clinical results and virologic data, the Company believes that a single i.m. dose of 300mg peramivir can be a potentially clinically effective dose. Given the dose-response observed between the 150mg and 300mg doses in the Phase II trial, the Company also believes it is prudent to evaluate whether doses higher than 300mg provide additional efficacy. The Company has been limited in evaluating doses higher than 300mg due to the concentration of the formulation used in the Phase II trial. Alternative formulations are being developed, and should be available, that permit evaluation of a single dose higher than 300mg. BioCryst is now planning to initiate a Phase II clinical trial that will evaluate the 300mg dose and a higher dose of peramivir later this year. As a result, BioCryst will not continue to pursue a pivotal Phase III program for i.m. peramivir in the current influenza season.
Personally I would favour making all doctors aware of the dilemma and recommending extreme restraint in its use. Where resistant cases are know greater efforts should be employed in quarantining patients to reduce the prevalence of resistant strains.
JJ
Agreed, may be we can have a preview of what could happen, looking at the use of anti-biotics and MRSA and XDR-TB?
However it seems not easy for doctors looking at a patient being very ill - influenza can be really nasty - and refrain from administrating Tamiflu?
"Recommending extreme restraint" does not seem enough: guidelines, protocols should be developed?
leaving the treated human. No h2h2h... yet.
So, can it enter birds again, h2b ? Seems unlikely.
The European strain was reported to have been introduced at several
places independently, so if it was due to resistance-building, then this mutation
probably happened some time ago, maybe in Asia.
They might have recognized it .. but keep it secret. Not good to report
that you created a resistant strain . The sequences might shed some light
on the origin
shares of Biota and Biocryst didn't react.
Seems that peramivir doesn't work anyway ?
leaving the treated human. No h2h2h... yet.
So, can it enter birds again, h2b ? Seems unlikely.
The European strain was reported to have been introduced at several
places independently, so if it was due to resistance-building, then this mutation
probably happened some time ago, maybe in Asia.
They might have recognized it .. but keep it secret. Not good to report
that you created a resistant strain . The sequences might shed some light
on the origin
Do you think a combination might be more useful than a single anti-viral or is it likely that both will be useless by the time we might need them?
for Biocryst and Biota.
Bad news for Roche, but Roche has many other activities.
I'm not sure whether that mutation also affects
Zanamivir or Peramivir but I suppose not ?!?
There was a paper last year...
I have been arguing that far too many eggs have been put in the Tamiflu basket for some time. To leverage and protect this investment I would like to see reduced prescription for seasonal flu use, combination therapy with ion blockers and increased buildup of antibiotics for secondary pneumonia (and any other common secondary infections which caused such loses in 1918). I agree we are in danger of severely blunting the only tool in our box. I would like to see efforts now to protect it from becoming totally useless by the time we really need it.
Prepdeb
Good thinking see links below.
Low dose oral combination chemoprophylaxis with oseltamivir and amantadine
http://www.flutrackers.com/forum/showthread.php?t=28585&highlight=amantadine
Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice
http://www.flutrackers.com/forum/showthread.php?t=28074&highlight=amantadine
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inserito da cfz il 11 March 2010
