Indonesian bird flu less susceptible to Tamiflu than before

[Theresa42]

Hat-tip, DennisC!

Indonesian bird flu Tamiflu resistant
Canadian Press

June 21, 2007 at 9:07 PM EDT

TORONTO ? An Australian researcher says H5N1 avian flu viruses from Indonesia are markedly less susceptible to the antiviral drug Tamiflu than a previous line of the H5N1 family of viruses.

Jennifer McKimm-Breschkin says laboratory testing shows the viruses from Indonesia are 20 to 30 times less susceptible to the drug as compared to H5N1 viruses that circulated in Cambodia a couple of years ago.

Dr. McKimm-Breschkin, who's attending a conference on infectious diseases in Toronto, says the findings are not good news.

And she says they may help to explain the high death toll from H5N1 in Indonesia, where 80 of 100 patients have died of the disease.

A scientist from the World Health Organization says it's not clear what the impact of the reduced susceptibility to Tamiflu means for people from that part of the world who become infected with the virus.

Dr. Frederick Hayden says a lot of factors can have an impact on whether oseltamivir treatment of H5N1 patients is successful, including how much time passes between infection and the start of drug therapy.

http://www.theglobeandmail.com/serv...dHealth/?page=rss&id=RTGAM.20070621.wfluu0621

 

[gsgs]

Re: Indonesian bird flu less susceptible to Tamiflu than before

aren't there some corrupt people to sell us the sequences
or samples ?

 

[Gert van der Hoek]

Re: Indonesian bird flu less susceptible to Tamiflu than before

Indonesian bird flu viruses less susceptible to Tamiflu, scientists report

Helen Branswell, Canadian Press

Published: Thursday, June 21, 2007

TORONTO (CP) - H5N1 avian flu viruses from Indonesia - which has the highest H5N1 death toll and rate in the world - are markedly less susceptible to the antiviral drug oseltamivir (Tamiflu) than a previous line of the H5N1 family of viruses, an Australian researcher reported Thursday.

Jennifer McKimm-Breschkin told a major international influenza conference that testing conducted in her laboratory showed the viruses from Indonesia were 20 to 30 times less susceptible to the drug as compared to H5N1 viruses that circulated in Cambodia a couple of years ago.

The reduced sensitivity in the Indonesian viruses is an unwelcome development, McKimm-Breschkin said, given that oseltamivir already didn't appear to have a great track record against the family of viruses to which the Cambodian viruses belong. (The World Health Organization calls the group clade 1 viruses.)


This is not good news to see a decrease in sensitivity where we've already got dubious efficacy. It's certainly not the news we would want to hear," said the researcher, from Australia's CSIRO Molecular and Health Technologies. CSIRO is the Commonwealth Scientific and Industrial Research Organization.

She said the mutations that made the viruses less vulnerable to oseltamivir developed spontaneously in nature and were not a consequence of poor use of the drug. The viruses studied, which date back to 2005, were from collected birds.

McKimm-Breschkin said the findings highlight the advisability of governments stockpiling both Tamiflu and zanamivir (Relenza), so as not to get caught out if resistance to one or the other develops. "I would certainly advocate that you would have both drugs - because we don't know which way nature is going to go," she said.

Others cautioned that the way a virus acts in a lab doesn't necessarily tell you how it will act in a human.

"With a disease like H5N1, there are a lot of factors that impact on whether treatment will control replication and give benefit to the patient," said Dr. Frederick Hayden, an antiviral expert working with the World Health Organization.

For instance, Hayden noted that if a virus with reduced susceptibility replicates less well in an infected person, it might be easier to treat than a virus that replicates rapidly and with ease.

"One can't only look at the susceptibility. One also has to look at the fitness of the virus, the pathogenicity (virulence) of the virus," said Dr. David Reddy, pandemic task force leader for Hoffman-La Roche, the maker of Tamiflu.

The Eurasian H5N1 viruses are broken down into three groups or clades, each with its own molecular characteristics. They can be thought of like a large extended family with several branches. Some characteristics are shared across all branches, others are specific to a branch.

The clade 2 viruses are further divided into three subgroups. Indonesian viruses are classified as clade 2.1.

Scientists have wondered if the molecular variations between the clades and sub-clades translate into differences in attack rates or disease severity in people who become infected, looking for ways to explain why, for example, 80 of 100 cases in Indonesia have died while in Egypt only 15 of 36 cases have died. (Viruses in Egypt belong to a different subgrouping of clade 2 than those in Indonesia).

McKimm-Breschkin said the answer might not be that the Indonesian line of viruses cause more severe disease, but rather that people infected with them get less benefit from treatment with oseltamivir.

She said the findings also raise concern that viruses within this group could become resistant to oseltamivir.

The current recommended regimen for oseltamivir is based on treatment of human flu; experts worry that dose could be too low for the more severe illness caused by H5N1 infection. If an infected person is treated with drug doses that are too low, it will kill susceptible viruses, but could let viruses with reduced susceptibility escape death and evolve to become resistant to the drug.

"This is our concern about the H5N1 viruses," McKimm-Breschkin said.

"You're allowing the virus to continue to replicate and the longer it replicates, the more chance you have of (resistant) viruses being accidentally selected."

A research network of Southeast Asian clinicians, organized by the WHO and with support from Roche, is starting to test whether higher doses of oseltamivir, over a longer period, would be more effective in treating H5N1.

Another piece of research presented Thursday suggested there is reason to hope that might be useful.

Elena Govorkova of St. Jude Children's Hospital in Memphis, Tenn., reported that testing in ferrets showed that two and a half times the standard dose was needed to protect them against infection with a virus from Turkey, another clade 2 subgrouping.


http://www.canada.com/nationalpost/...996ead-8fb7-4122-a320-2c4ca63c458c&k=6658&p=2

 

[JJackson]

Re: Indonesian bird flu less susceptible to Tamiflu than before

Two points to note.

H5N1 recommended Tamiflu regime is a double dose for twice as long as seasonal flu; which should be taken into account when reading statements like 'The UK has stockpiled enough Tamiflu to treat 25% of the population'.

Tamiflu should be given within 48hrs of symptom onset and results are significantly better, with seasonal flu, if given in 24hrs. The current mean time after symptom onset in Indonesia is over 5 days.

 

[Vibrant62]

Re: Indonesian bird flu less susceptible to Tamiflu than before

Good points. One thing I do wonder about though is how they arrived at this statement.

"She said the mutations that made the viruses less vulnerable to oseltamivir developed spontaneously in nature and were not a consequence of poor use of the drug. The viruses studied, which date back to 2005, were from collected birds."

Initially in 2005/ 2006, bird and human viruses did not match and had a differing cleavage site. At this time, Tami was used widely amongst human contacts where human cases occurred. Over time, most bird virus distribution has altered and now match human ones in the majority of cases (in terms of cleavage site). This suggests to me that there is a possibility that infected humans were a possible cause of new bird infections, in at least some cases, seeding human virus amongst poultry populations. In this scenario Tami usage in humans would be a likely source of evolved resistance.

There is no way to prove such a supposition, or disprove it reterospectively, I think. So I wonder if this statement simply arises from the fact that all viral samples tested originated from birds.

Has there ever been any trial work to see if a human virus isolate can readily infect poultry? I think we need to know the answer to this question.

 

[gsgs]

Re: Indonesian bird flu less susceptible to Tamiflu than before

> Over time, most bird virus distribution has altered and now
> match human ones in the majority of cases (in terms of cleavage site).

not the majority. Just a few birds were found with the human virus,
the majority still have the avian virus, and so had the Karo-cluster

that's how it was in Jan., no data since then.

 

[Gert van der Hoek]

Re: Indonesian bird flu less susceptible to Tamiflu than before

Tamiflu May Be Losing Potency Against Bird Flu, Study Finds

By Jason Gale

June 22 (Bloomberg) -- Roche Holding AG's Tamiflu, the antiviral drug stockpiled in the event of an influenza pandemic, may be becoming less potent in Indonesia, where bird flu has killed the most people, a study of viruses showed.

Laboratory tests on six samples of the H5N1 strain of avian influenza collected from poultry in Indonesia in 2005 showed they were between 15 and 30 times less sensitive to Tamiflu than a family of the viruses collected in Southeast Asia a year earlier. The study, led by Jennifer McKimm-Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne, was presented at a conference in Toronto yesterday.

``The decrease in drug sensitivity does not appear to be drug-induced, but may be due to random mutations'' that have occurred as the virus has circulated among birds, McKimm- Breschkin said in her presentation.

Tamiflu is recommended by the World Health Organization as the first choice for doctors treating human cases of avian flu. Strains either resistant or less sensitive to Tamiflu have been linked to the deaths of at least five people in Vietnam and Egypt, raising concern that the drug won't work effectively in the event of a pandemic.

While the H5N1 virus has killed millions of poultry in about 60 countries, it is known to have infected only 313 people in a dozen countries since 2003, according to the WHO's tally, last updated June 15. Three of every five cases have been fatal.

Millions could die if H5N1 develops the characteristics of seasonal flu and begins spreading easily between people, touching off a global outbreak.

Vaccine Delay

A vaccine against pandemic flu isn't expected to be widely available until several months after the start of a pandemic, according to the WHO. Without a vaccine, antiviral drugs will be the first line of defense to limit sickness and deaths, and decrease the spread of the contagion.

Supplies of Tamiflu that would cover two-thirds of a country's population may cut deaths from flu by half in the event of a pandemic, Basel, Switzerland-based Roche said in an e-mailed statement today, citing a separate study presented at the flu conference in Toronto.

Tamiflu's active ingredient oseltamivir works by blocking neuraminidase -- one of the two surface proteins in influenza viruses and the ``N'' in H5N1 -- that allows the virus to spread from infected cells to other cells in the body.

The dominant strain of H5N1 circulating in poultry in Vietnam, Malaysia and Cambodia in 2004 was more sensitive to oseltamivir than a human seasonal flu virus known as H1N1.

Samples of the H5N1 virus from the Kandal region of Cambodia the following year showed a sixfold to sevenfold decrease in oseltamivir sensitivity, McKimm-Breschkin said.

`Step Ahead'

``Results suggest that nature may be a step ahead, and that relying solely on oseltamivir for stockpiles poses the risk that we will be left behind without an effective drug,'' she said.

The effectiveness of GlaxoSmithKline Plc's Relenza antiviral treatment was tested on the same samples in the study. There was no change in the sensitivity to the drug across the two main virus families, or clades, tested, McKimm-Breschkin said. Relenza, an inhaled medicine, is known scientifically as zanamivir and belongs to the same class of drugs as Tamiflu, neuraminidase inhibitors.

``As all H5N1 clades retain sensitivity to it, zanamivir should also form part of any pandemic stockpile,'' said McKimm- Breschkin, who was a member of a team of scientists that discovered the drug.

Resistance to neuraminidase inhibitors ``has been clinically negligible so far, but is likely to be detected during widespread use during a pandemic,'' WHO says on its Web site.

Roche recommends adults take 75 milligrams of oseltamivir twice a day for five days to reduce the severity and duration of symptoms for seasonal flu. Doctors are testing whether avian flu patients need a double dose.

Inadequate dosing with oseltamivir may lead to the emergence of high-level resistance of the drug, McKimm-Breschkin said. The problem could be exacerbated if it's given to patients who are infected with a less sensitive strain, such as that circulating in Indonesia, she said.

To contact the reporter on this story: Jason Gale in Singapore at j.gale@bloomberg.net

Last Updated: June 22, 2007

http://www.bloomberg.com/apps/news?pid=20601202&sid=aWDfAg6kux2I&refer=healthcare

 

[HenryN]

Re: Indonesian bird flu less susceptible to Tamiflu than before

> Over time, most bird virus distribution has altered and now
> match human ones in the majority of cases (in terms of cleavage site).

not the majority. Just a few birds were found with the human virus,
the majority still have the avian virus, and so had the Karo-cluster

that's how it was in Jan., no data since then.

Wrong

http://www.recombinomics.com/News/02120701/H5N1_Indo_Match.html

 

[HenryN]

Re: Indonesian bird flu less susceptible to Tamiflu than before

aren't there some corrupt people to sell us the sequences
or samples ?

Australia has been releasing Indonesia bird sequences for some time

http://www.recombinomics.com/News/10050602/H5N1_Indo_Match_Failures.html