Anti-viral resistance in 2009 A/H1N1 flu - historical compilation of news

[HenryN]

Re: Two Tamiflu-resistant swine flu cases reported in Washington

Two cases of swine flu resilient to the drug Tamiflu were diagnosed over the weekend, the U.S. Centers for Disease Control and Prevention said yesterday. Tamiflu and Relenza were the only two medications that had thusfar proven effective in treating the virus (also known as H1N1), which already proved resilient to other seasonal flu remedies.

Tamiflu had been particularly popular, as it is ingested orally. Relenza, which is inhaled, is therefore not recommended for patients with respiratory conditions. Both drugs work by disabling an enzyme the virus needs in order to grow. Many governments in the world, including Israel's, have stockpiled Tamiflu in large quantities since the swine-flu pandemic began. <TABLE border=0 cellSpacing=0 cellPadding=0 align=right><TBODY><TR><TD rowSpan=2></TD><TD class=t9></TD></TR><TR><TD align=right></TD></TR></TBODY></TABLE>
Reports of Tamiflu-resistant strains of swine flu began in late June. In patients with weakened immune systems the virus might stay active for longer periods, acquiring resistance to Tamiflu and potentially spreading to others.

http://www.haaretz.com/hasen/spages/1107725.html

At the end of June, a representative of the Swiss pharmaceutical company Roche, which manufactures Tamiflu, said a Danish patient infected with a strain of the virus was not responding to the medicine. Earlier studies on Tamiflu indicated that 0.4 percent of adults and 4 percent of children afflicted with normal seasonal flu were likely not to respond to the drug.

Ten more such patients were identified in the world since June, with three in Japan, one in Singapore, one in China, one in Denmark, one in Canada, and two in the United States. However, no patient-to-patient transmission of the Tamiflu-resistant strain has yet been documented.

The two U.S. cases reported over the weekend were documented in Seattle. The swine flu patients were said to be suffering from leukemia and a depleted immune system. One patient is a young man who received a marrow transplant in May, and was said to be recovering at home; the other is a woman in her forties, who is still hospitalized. The two were said to have not been in contact, nor has it been documented that they have infected family members or medical staff with the Tamiflu-resistant strain.

The World Health Organization said it was following the reports, but no changes were yet made to its guidelines on treating the virus.

No Tamiflu-resistant strains have been recorded in Israel, where five more labs for testing for the disease are soon to be allocated by the health ministry. "The spread of a drug-resistant strain is usually slow, and by the time it spreads significantly vaccines against the disease will, in all likelihood, be developed. However, Tamiflu is one of the only medicines that can slow or weaken the disease, so it's crucial that swine flu react to it," said Dr. Amnon Kiro, chief of influenza research at the Israeli Pediatric Association research network.

At the moment, checks for swine flu are only carried out at the Health Ministry laboratory in Tel Hashomer, and in a laboratory at Hadassah University Hospital, Ein Kerem in Jerusalem. The checks are only meant to identify the virus, rather than test its response to Tamiflu.

Thirteen Israelis are presently in intensive care due to swine flu, and seven fatalities have so far been reported.
</TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE>

[HenryN]

Re: Two Tamiflu-resistant swine flu cases reported in Washington

Local swine flu patients resistant to Tamiflu

<!----><!-- cc -->By JENNIFER FARRINGTON
MyNorthwest.com staff


Two patients being treated for H1N1 virus (swine flu) have been found to be resistant to the antiviral Tamiflu used to treat the infection, according to Seattle and King County Public Health.
The two patients, a male teenager and a female in her 40s, are believed to have no connection with one another. Both patients have been identified as having compromised immune systems, raising their risk of developing an infection and antiviral resistance. One patient has recovered while the other has ongoing symptoms and is currently being treated with zanamivir, another antiviral medication.
"Viruses can develop drug resistance over time. It's important that antiviral treatments only be used as recommended by a health care provider, to minimize drug resistance and preserve an important tool against the illness for those who need it," said Dr. David Fleming, Director and Health Officer for Public Health Seattle & King County in a news release. "The vast majority of people with H1N1 virus continue to be treatable with Tamiflu, and in cases where it becomes ineffective, other options are available." The health department says the general public's risk is very low and there is no evidence that health care workers in contact with the patients became infected. However, local and state officials are working with the Center for Disease Control and are taking precautionary measures to monitor for other antiviral drug resistant influenza cases.

http://www.mynw.com/?nid=189&sid=200937

[AlaskaDenise]

Re: China, Singapore report Tamiflu-resistant H1N1 viruses

Commentary

http://www.recombinomics.com/News/08...O_See_NOT.html

Commentary

WHO Failure to See Spread of Tamiflu Resistant Pandemic H1N1

Recombinomics Commentary 15:19
August 16, 2009

China and Singapore have found Tamiflu-resistant pandemic viruses, Charles Penn, a scientist with the Geneva-based agency, said in an interview with The Canadian Press.

He revealed that the WHO has also been alerted informally to the discovery of a small number of other Tamiflu-resistant viruses. He would not say where they were found or how many there were in total.

"It's a small number. It certainly doesn't change the scale of what we're seeing," Penn said.

The above comments were issued in response to queries about osletamivir resistance in Singapore and Hunan, China, as indicated by sequences made public at GISAID and Genbank. Those two instances were acknowledged, but the rationale behind the withholding of additional cases remains unclear. At the time Thailand had already acknowledged at least one case, and additional reports from Hong Kong and an MMWR Dispatch describing two immuno-compromised patients in Washington State were made public on Friday. Cases in Texas along the border with Mexico are still being denied, although the initial report included detail on two of the cases, suggesting the denials were largely based on semantics.

The cases in Texas would change the inferred scale, because the cases were at opposite ends of the border and had much in common with the initial H1N1 described in southern California. Those cases were unlinked to each other or swine, yet the sequences were virtually identical, indicating the virus was widespread. The same conclusion could be made from the cases in Texas, which may be related to the withholding of the information associated with these cases.

However, the detail that has come out in the past few days has left little doubt that the WHO's "scale of what we are seeing" is false. The failure to see the true scale of the H274Y spread is due to the limited testing, which is largely focused on samples collected prior to Tamiflu treatment, which can be "seen" in results from patients on prophylactic Tamiflu treatment or in samples collected a few days after the start of Tamiflu treatment in symptomatic patients.

The Hong Kong case described Friday was another patient who became symptomatic while on prophylactic Tamiflu. Earlier detail on patients in Denmark and Japan indicated they became symptomatic on day 5 of prophylactic treatment. Since the incubation period of influenza is in the range of 2-4 days, the slightly longer time period indicated the H274Y was already present when Tamiflu treatment began, but because it was a minor component, disease onset was delayed by 1-2 days. The recent patient in Hong Kong developed symptoms on day 6.

However, the confirmatory data on silent spread of H274Y came from Singapore, where additional data on first confirmed case was disclosed. The sequence was from a May 30 sample from a 28F, but the detailed reports at the MOH indicated the patient (American working in Singapore who arrived late on May 26 after becoming symptomatic during flight, but passed fever scans, but was hospitalized on May 27 and confirmed on May 28). The recent comments indicated the patient was initially Tamiflu sensitive (May 28 test), and resistance was discovered after patient improved (she was discharged May 31). Thus, the resistance in the May 30 sample was present only a few days after the start of treatment and the sequences (on HA, NA. MP) had no evidence of a mixture, indicating the resistant sequence quickly replaced the wild type sequence, signaling silently spread of H274Y.

Thus, the WHO failure to see the resistance was linked to limited and delayed testing of samples collected a few days after the start of treatment, and the standard testing / sequencing failed to detect the H274Y transmitting as a minor population. The HA Singapore sequence has a polymorphism that was found in isolates in the US, Sweden, China, and Argentina, raising concerns that the H274Y was creating additional problems in Tamiflu treated patients as seen in the two immune-compromised patients in Washington State as well as rising fatalities being reported worldwide.

.

[GennieF]

Re: Two Tamiflu-resistant swine flu cases reported in Washington

Drug-resistant swine flu cases discovered in patients in Seattle

By SANDI DOUGHTON
The Seattle Times
Published: Saturday, Aug. 15, 2009 - 7:03 pm
Last Modified: Sunday, Aug. 16, 2009 - 5:08 am

SEATTLE -- The country's first cases of drug-resistant swine flu were discovered in two leukemia patients in Seattle, the U.S. Centers for Disease Control and Prevention reported Friday.

Both patients, who had weakened immune systems from chemotherapy and stem-cell transplants, developed flu strains resistant to the anti-viral drug oseltamivir, sold as Tamiflu.

There was no connection between the cases and no threat to the public, said Dr. Jeff Duchin, chief of communicable-disease control for Public HealthSeattle & King County. None of the patients' family members, or the health workers who cared for them, contracted the disease.

The Seattle cases bring to 11 the worldwide total of people diagnosed with Tamiflu-resistant infections of the H1N1 virus.

"These are rare, isolated types of phenomena," Duchin said. "It's not something we expect is going to lead to widespread drug resistance in the community."

But the cases underscore the need for judicious use of anti-viral drugs to ensure resistant strains do not become more common, he said.

Last month, CDC officials warned summer camps to stop the practice of handing out Tamiflu to healthy children in an effort to ward off infection.

"Anti-viral drugs should be used to treat an infection after it's occurred - once the cat is out of the bag," Duchin said. "The more promiscuous use ... the more chances we have to develop resistant viruses."

Patients with weakened immune systems are most vulnerable because their bodies are not able to join forces with the drugs to fight off the virus. That means the virus persists longer in the presence of the anti-viral drugs, which is a recipe for the evolution of drug-resistant bugs.

One of the patients is a teenage boy who received a stem-cell transplant in May. He contracted the flu virus later that month and has since recovered.

The second patient, a woman in her 40s who relapsed after an earlier stem-cell transplant, remains hospitalized.

Genetic analysis showed that over several weeks of Tamiflu treatment, the flu bugs in their bodies mutated and were no longer sensitive to the drug.

The account of the cases, published in CDC's Morbidity and Mortality Weekly Report, identifies the hospitals as Seattle Children's and the University of Washington Medical Center.

Local and state health officials are working with the CDC to boost monitoring for drug-resistant flu viruses.

http://www.sacbee.com/847/story/2112883.html

[HenryN]

Re: Two Tamiflu-resistant swine flu cases reported in Washington

Drug-resistant swine flu cases discovered in patients in Seattle

Genetic analysis showed that over several weeks of Tamiflu treatment, the flu bugs in their bodies mutated and were no longer sensitive to the drug.

http://www.sacbee.com/847/story/2112883.html

The above statement is quite misleading (as was the MMWR dispatch). Although both patients initially tested as tamiflu sensitive, and one patient was still senstive on day 4 (June 4) after the start of treatment (June 1), there is no data supporting development of resistance "over several weeks". The first patient developed resistance between days 4 and day 11 (June 11 collection had H274Y) of treatment (clearly NOT over SEVERAL weeks) and the second patient developed resistance between day 1 (June 26) and day 18 day (July 14 sample had H274Y). i.e. resistance may have been detected on day 1 of treatment if such a sample was collected and TESTED. The detection on day 18 was of the FIRST REPORTED result on a sample collected after the start of treatment (the report was SILENT on samples collected earlier in July and did not indicate that such samples were sent to the CDC for testing).

[HenryN]

Re: Two Tamiflu-resistant swine flu cases reported in Washington

The above statement is quite misleading (as was the MMWR dispatch). Although both patients initially tested as tamiflu sensitive, and one patient was still senstive on day 4 (June 4) after the start of treatment (June 1), there is no data supporting development of resistance "over several weeks". The first patient developed resistance between days 4 and day 11 (June 11 collection had H274Y) of treatment (clearly NOT over SEVERAL weeks) and the second patient developed resistance between day 1 (June 26) and day 18 day (July 14 sample had H274Y). i.e. resistance may have been detected on day 1 of treatment if such a sample was collected and TESTED. The detection on day 18 was of the FIRST REPORTED result on a sample collected after the start of treatment (the report was SILENT on samples collected earlier in July and did not indicate that such samples were sent to the CDC for testing).

The specifics on the second case indicate her initial treatment was between June 26-July 1 and the initial testing was on samples collected June 21 (prior to treatment and no H274Y) and July 28 (day 27 after the 5 day treatment course and having H274Y). However, additional samples were sent and although samples were collected on July 3, 6 and 14 it is not clear what was sent, other than July 14, which had H274Y. Thus, it is not clear that the July 3 and 6 samples were sent, if they were tested, or if tested, whether they did or did not have H274Y.

[HenryN]

Tamiflu resistance in pandemic influenza - historical compilation of news

GP diary: beware Tamiflu panic

Updated on 14 August 2009
By Channel 4 News

Dr Peter Stott, writing for Channel 4 News from his surgery in Surrey, explains why irresponsible Tamiflu use could boost the spread of swine flu.


I was chatting about swine flu to one of my patients today and we got on to the subject of Tamiflu.
"I've already got some," she said. "I rang the flu advice line and pretended to have symptoms. They gave me a number to get some from the chemist.
"I wanted to take some with me on holiday just in case."
I told her that I thought this was the height of irresponsibility and that I was surprised that one of my apparently sensible patients should have behaved in this way.
Tamiflu works by stopping the virus multiplying in the body and it does this in a very clever way.
Viruses are effectively parasites which use mechanisms inside human or animal cells to replicate.
The new viruses buds off from the surface of the infected cell and is released to infect others.
This process requires a chemical called neuraminidase and Tamiflu blocks the action of this chemical.
So the virus cannot escape and stays inside the first cell. Tamiflu has to be taken early in the infection before too many cells have been affected.
After this time, the host's natural immune mechanisms like interferon will kick in and give protection.
In clinical trials Tamiflu reduces the duration of symptoms by approximately one day - a benefit that many consider may not be worth the cost and effort for patients who have only a mild illness.
The flu virus however is very clever and very quickly develops ways to become resistant to antivirals.
It is rather like trying to find your way to your favourite restaurant in a city centre. Even if they close one road, there are always other routes. It may take a little time to find it, but you will do eventually.
Similarly, there are lots of types of neuraminidases - lots of ways for the virus to get out of the cell and eventually the flu virus will mutate and be able to produce one.
We categorise neuraminidases as N1, N2, N3 etc but there are also sub-types. Swine flu is one of the H1N1viruses which are usually the nasty ones.
Tamiflu has been used for several winters now, given to patients with normal H1N1 winter strains and we are already beginning to see signs of resistance.
In the fourth quarter of 2008, the World Health Organisation reported that of that winter?s circulating influenza A (H1N1) flu virus, 95 per cent were resistant. We have only seen one resistant case of swine flu this year, in Denmark.
Happily this has not spread, but the fear of scientists is that swine flu will combine with one of these resistant strains, a change which would render Tamiflu ineffective.
So back to my patient. Why was I so upset?
First using Tamiflu for mild cases in fit people is probably not necessary. Second, widespread use will lead to increased resistance because the virus will get used to Tamiflu and it may be ineffective when we might really need it ? if the virus mutates to become more pathogenic.
Last, it's costing a lot of money for only minimal benefit. We have stockpiled 33m doses of Tamiflu which at normal pharmacy prices is worth over half a billion pounds - money that could be better spent on lots of other things.
There is a direct corollary between antivirals and antibiotics. Everyone understands that antibiotics have to be used responsibly. Otherwise resistance will develop and they will become ineffective. This will inevitably happen for antivirals too.
The government and the Department of Health have made antivirals very easily available through this flu epidemic, much more easily available than antibiotics have ever been.
You can get them immediately, on the phone, online and without a doctor's prescription. Be assured they will be there if you need them.
It is everyone's duty to use these medicines responsibly in the correct people, in the correct circumstance and for the correct illness.
Not to do so will only encourage viral resistance and could as a result, put the whole population at increased risk.
Dr Peter Stott is a GP at the Tadworth Medical Centre in Surrey.
<!--googleoff: index-->http://www.channel4.com/news/article...+panic/3308757

[Giuseppe]

Tamiflu resistance in pandemic influenza - historical compilation of news

Changing seasons herald a new phase in the H1N1 pandemic (The Lancet Infectious Diseases, excerpt, edited)

The Lancet Infectious Diseases, Volume 9, Issue 9, Page 529, September 2009

doi:10.1016/S1473-3099(09)70214-2


Changing seasons herald a new phase in the H1N1 pandemic

Priya Shetty


As the northern hemisphere gears up for a new influenza season, the looming question is whether or not there will be a vaccine available by autumn. The issue has taken on a new urgency with the realisation that the spread of the pandemic means that attempts at containment are pointless and that there have been cases of drug resistance to oseltamivir (tamiflu), one of the key anti-H1N1 drugs. Europe is pushing hard to develop a vaccine, and the European Medicines Agency (EMEA) has said it will fas ...

(...)
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</previous>

<cite cite="http://www.thelancet.com/journals/laninf/article/PIIS1473309909702142/fulltext?rss=yes">Changing seasons herald a new phase in the H1N1 pandemic : The Lancet Infectious Diseases</cite>

[AlaskaDenise]

Re: China, Singapore report Tamiflu-resistant H1N1 viruses

Commentary

http://www.recombinomics.com/News/08...Locations.html

Commentary

WHO Withholding Tamiflu Resistant Pandemic H1N1 Locations

Recombinomics Commentary 13:55
August 17, 2009

He revealed that the WHO has also been alerted informally to the discovery of a small number of other Tamiflu-resistant viruses. He would not say where they were found or how many there were in total.

"It's a small number. It certainly doesn't change the scale of what we're seeing," Penn said.

The above comments by WHO are curious. WHO is funded by member nations and has a mandate to protect citizens of member nations. The withholding of important information such as the number and location of Tamiflu resistant pandemic H1N1 virus is not consistent with that mission. Tamiflu is widely used and recommended by WHO, so the withholding of information on resistance leads to inappropriate use of the antiviral, and places patient care and health care systems at risk.

This type of risk was easily seen in the two immuno-suppressed patients detailed in the recent MMWR dispatch. WHO has maintained that resistance is rare and due to spontaneous mutations selected in Tamiflu treated patients. However, recent data, including that from the patients in Washington state suggested that the limited number of reports is related to limited and delayed testing, which is compounded by the withholding of information on identified isolated.

The MMWR describe patients who were H1N1 infected in June. The patients were treated with Tamiflu and detectable resistance developed quickly. However, treatment was increased and resistance was not confirmed until August, after one patient developed a Tamiflu resistant recurrence and the other patient continues to be hospitalized in spite of treatment with Tamiflu, Relenza, and ribavirin. The ability of Tamiflu resistant pandemic H1N1 to persistence in such aggressively treated patients increases concerns that the recent worldwide rise in patient deaths and hospitalizations is linked in part to such resistance.

When WHO stated it was withholding the information on resistance, there had already been 8 examples in patients which were supported by sequence data. Another example (in Thailand) had already been described in media reports and shortly after the proclamation by WHO, Hong Kong reported another cases of resistance in a patient being treated prophylatically and the two patients in Washington State were detailed. Moreover, additional information on the American patient in Singapore provided compelling data that H274Y was silently circulating because the vast majority by WHO and consultants involved samples collected prior to Tamiflu treatment, which were failing to detect the H274Y present as a mixture in the H1N1 samples being sequenced.

The WHO should be encouraging countries to promptly report resistance and expand testing to patients who have been briefly treated with Tamiflu. A true accounting of H274Y in pandemic H1N1 is long overdue.

.

[AlaskaDenise]

Re: Two Tamiflu-resistant swine flu cases reported in Washington

Commentary

http://www.recombinomics.com/News/08...4Y_Fit_US.html

Commentary

Fit Tamiflu Resistant Pandemic H1N1 in the United States

Recombinomics Commentary 11:20
August 17, 2009

Genetic analysis showed that over several weeks of Tamiflu treatment, the flu bugs in their bodies mutated and were no longer sensitive to the drug.

The above comment on the recent MMWR dispatch warning of prolong shedding of oseltamivir resistant pandemic H1N1 in immunosuppressed patients is in error. The two patients from Washington state were the first confirmed cases of H274Y in swine H1N1 in the United States, but the presentation of the resistance data helped create the above misconception that the H1N1 muted within the patients over a period of several weeks. MMWR dispatches are used to quickly alert physicians to significant medical concerns and the inclusion of August 11 data in the August 14 publication signals the rapid publication of such data as well as the urgency of such reports. However, the description of the resistance could easily be misinterpreted and lead to the false conclusions stated in the above media report.

Recent data on the detection of H274Y in pandemic H1N1 has supported the silent spread of the polymorphism which is usually detected in patients treated with osletamivir. Since the H274Y is present as a mixture, sequence analysis of untreated patients produces a "Tamiflu sensitive" genotype, with H274. Indeed, the only reported case of H274Y in a patient who was not treated with Tamiflu was a San Francisco resident who was identified in Hong Kong through routine surveillance. However, multiple examples of H274Y in patients who have been briefly treated with Tamiflu support a relatively high level of H274Y prior to treatment. Published sequences are a consensus and represent the dominant nucleotide at a given position, so samples with H274Y in 10-20% of the virions will not be represented in the published sequence. When levels approach 50% the consensus sequence will show a mixed signal at the position, but sequences published to date have either had wild type or H274Y at position 274. This is due in part by the ability of the Tamiflu, in combination with and the host's immune system, to rapidly clear the wild type sequences (and most patients can clear the H1N1 without antiviral treatment)..

This type of data was most clearly presented in the recently released sequence from an American traveling from Honolulu to Singapore. The patient developed symptoms during the flight, but successfully passed through the thermal scanner. However, her condition did not improve and she was hospitalized the next day, May 27. The H1N1 was confirmed on May 28 and the sequence indicated the virus was Tamiflu sensitive. The infection was mild and the patient was discharge on May 31. However, a sample was collected on May 30, and the associated sequence had H274Y, signaling the rapid appearance of the resistance, and the rapid clearing of the wild type sequence (the sequence had no mixed signals).

This rapid appearance of H274Y was also seen in multiple patients on prophylactic Tamiflu. These were asymptomatic contacts of confirmed cases infected with Tamiflu sensitive H1N1. However patients in Denmark and Japan developed symptoms after 5 days of treatment and a patient from Hong Kong developed symptoms on day 6. Since the incubation period of influenza is 2-4 days, the slightly longer than normal incubation period indicated the H274Y was silently spreading as a minor component, which was subsequently detected after brief Tamiflu treatment.

In the two patients in Washington, the clearance of wild type was likely delayed somewhat by their immuno-compromised state. The first patient responded to Tamiflu treatment, but then had an H1N1 recurrence which had H274Y. Testing of samples collected earlier showed that prior to treatment the virus was sensitive, as was the sample from treatment day 4. However, H274Y was identified on day 11 after the start of treatment, indicating the H274Y reached a detectable level between days 4-11 post initiation of treatment, and the H1N1 was evolutionarily fit and produced a recurrence in the patient.

Data from the second patient produced similar results, but that H1N1 with H274Y has produced a persistent infection which has not been cleared by aggressive Tamiflu treatment or treatment with inhaled and intravenous Relenza, as well as ribavirin. The patient remains hospitalized with H274Y positive H1N1, again demonstrating the virus is evolutionarily fit. Data on earlier collections indicated that the H1N1 was sensitive prior to treatment and H274Y was detected on day 18 after the start of treatment. However results on earlier collections on day 3 and 6 of treatment were not disclosed, so the H274Y reached detectable at some time between day 1-18 post treatment. Testing of samples collected on days 3 and 6 could help resolve the initial date of detectable H274Y.

However, the above data clearly show that H1N1 is evolutionarily fit and can cause significant medical problems linked to prolonged shedding, as well as the condition of infected patients. These data increase concerns that H1N1 with H274Y could be linked to the increased number of fatal and hospitalized patients, who are frequently treated with Tamiflu.

Testing of samples collected after the start of Tamiflu treatment would be useful because, as seen in recently released data, virus which is Tamiflu sensitive prior to treatment can be quickly replaced by Tamiflu resistant H1N1, leading to significant complications.

.

[AlaskaDenise]

Re: U.S. - First Tamiflu-resistant swine flu (Singapore ex-Hawaii)

Commentary

http://www.recombinomics.com/News/08...Confirmed.html

Commentary

Silent Spread of Tamiflu Resistant Pandemic H1N1 Confirmed

Recombinomics Commentary 14:26
August 15, 2009

A Health Ministry spokesperson said that the isolated case involved a patient who fell sick towards the end of May and was admitted to hospital for isolation and treatment.

The patient was infected by a Tamiflu-susceptible strain of the virus and treated with Tamiflu. The resistant strain emerged during treatment and was detected through laboratory testing but by then the patient had already improved clinically.

The above comments provide additional detail on the first confirmed case of Tamiflu resistance in a swine pandemic H1N1 case. The H274Y was identified in an NA sequence, A/Singapore/57/2009, which was recently deposited by the CDC, along with the HA and MP sequences. All three were clearly from the swine H1N1 pandemic strain, but the presence of H274Y in NA signaled oseltamivir resistance. The sample was from a 28F and was collected May 30, consistent with the description of the above Health Ministry spokesperson.

The MOH website provided a great deal of detail on the initial confirmed cases and contacts. The first confirmed case was May 27, and the third confirmed case matched the description associated with Singapore/57. The only 28F confirned patient ib Singapore in late May / early June was an American who was working in Singapore, She arrived from Honolulu via Tokyo on a flight that arrive just before midnight (23:53) on the night of May 26. Although she did not feel well during the flight, she was not detected by the fever scanners at the airport. However, the next she was transported by ambulance and arrive at the hospital in the afternoon of the 27th, and tested H1N1 positive on the afternoon (16:10) of the 28th.

The NA sequence from the 28th has not been made public, but the comments above indicate the sample was Tamiflu sensitive, It is not clear if treatment began the 27th (upon admission to the hospital), or the 28th, following confirmation of H1N1, because the MOH website does not mention Tamiflu treatment. The patient was described as having a mild case, and was discharged May 31st.

However, the sample collected on May 30th had H274Y, which was 3 days after admission or 2 days after confirmation, indicating the H274Y was silently spreading since it was not detected in the May 28th sample. Detection in the May 30th sample indicates that the H274Y was already present in May 28, but not detected, based on the comments by the spokesperson above, supporting silent spread which is detected in samples collected after Tamiflu treatment.

Although the May 28th sample was Tamiflu sensitive, the May 30th sample had H274Y in the NA sequence, as well as a polymorphism in the HA sequence that was subsequently detected in California and New York in the US, as well as Guangdong Province in China, Mexico City, Stockholm, and the first fatal case in Sao Paulo, Brazil (see list here), raising concerns of silent spread of H274Y worldwide.

The presence of H274Y in a minor species would explain the failure to find H274Y in the above locations, but its presence just below the detection level in untreated patient may explain the recent increases in fatalities. Agencies have repeatedly cited the lack of H274Y detection, leading to the widespread use of Tamiflu in H1N1 in positive cases, including the two immuno-suppressed patents in the state of Washington, where H274Y was detected for the first time in the United States. In those two patients H274Y was not detected until the patients either had a reoccurrence of symptoms or a failure to respond to treatment. The resistance was found in August, even though both patients developed resistance weeks or months earlier. These detection delays and recent reports of patients, who were resistant in May and June, raise concern that the number of samples with H274Y is significantly higher that the 11 confirmed cases thus far. Media reports have described in at least one patient in Thailand, and earlier media reports described multiple cases in Texas along the Mexican border.

However, the detection of H274Y in the sample collected a few days after the start of treatment in the patient in Singapore suggests the actual incidence is much higher than the reported or withheld cases described by WHO, and a more intense screening program is critical, especially of samples collected after the start of osletamivir treatment and the increasingly common fatal cases.

.

[Giuseppe]

Tamiflu resistance in pandemic influenza - historical compilation of news

Oseltamivir- and Amantadine-Resistant Influenza Viruses A (H1N1) (EID, abstract, edited)

[Original Full Document: LINK. EDITED.]

DOI: 10.3201/eid1506.081357
Suggested citation for this article: Cheng PKC, Leung TWC, Ho ECM, Leung PCK, Ng AYY, Lai MYY, et al. Oseltamivir- and amantadine-resistant influenza viruses A (H1N1). Emerg Infect Dis. 2009 Jun; [Epub ahead of print]

Oseltamivir- and Amantadine-Resistant Influenza Viruses A (H1N1)

Peter K.C. Cheng, Tommy W.C. Leung, Eric C.M. Ho, Peter C.K. Leung, Anita Y.Y. Ng, Mary Y.Y. Lai, and Wilina W.L. Lim

Author affiliation: Centre for Health Protection, Hong Kong Special Administrative Region, People?s Republic of China


Surveillance of amantadine and oseltamivir resistance among influenza viruses was begun in Hong Kong in 2006. In 2008, while both A/Brisbane/59/2007-like and A/Hong Kong/2652/2006-like viruses (H1N1) were cocirculating, we detected amantadine- and oseltamivir-resistance among A/Hong Kong/2652/2006-like viruses (H1N1), caused by genetic reassortment or spontaneous mutation.

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[Giuseppe]

Tamiflu resistance in pandemic influenza - historical compilation of news

WHO | Pandemic (H1N1) 2009 - update 62 (revised 21 August 2009)

Weekly update

As of this week, there have been more than 182,000 laboratory confirmed cases of pandemic influenza H1N1, 1799 deaths, in 177 countries and territories have been reported to WHO.

As more and more countries have stopped counting individual cases, particularly of milder illness, the case number is significantly lower than the actually number of cases that have occurred. However, through the WHO monitoring network, it is apparent that rates of influenza illness continue to decline in the temperate regions of the southern hemisphere, except in South Africa where pandemic influenza H1N1 appeared slightly later than the other countries of the region. Active transmission is still seen in some later affected areas of Australia, Chile and Argentina even as national rates decrease.

Areas of tropical Asia are reporting increasing rates of illness as they enter their monsoon season, as represented by India, Thailand, Malaysia, and Hong Kong, four places in the region which have active surveillance programs. Tropical regions of Central America, represented by Costa Rica and El Salvador, are also seeing very active transmission.

In the northern temperate zones, overall rates are declining in both North America and Europe though the virus is still found across a wide area throughout both regions and pockets of high activity are being reported in 3 U.S. states and a few countries of Western Europe.

It has been noted throughout the temperate zones of the southern hemisphere, which are now passing out of their winter season, that when pandemic H1N1 began to circulate, the relative importance of seasonal strains, represented by H3N2 in nearly all countries, rapidly diminished and pandemic H1N1 became the dominant strain. Some seasonal H1N1 strains were reported but were even less common than seasonal H3N2. It is too early to tell if this co-circulation of multiple strains will continue into the coming season of the Northern Hemisphere but it appears very likely that pandemic H1N1 will be the dominant influenza virus in the early part of the winter months.

Many countries including Australia, Canada, New Zealand, and the U.S. have noted that their indigenous peoples appear to be at increased risk of severe disease related to pandemic influenza. While it still has not been clearly determined how much of the increased risk observed in these groups is due to issues related to access to care, high rates of chronic medical conditions that are known to increase risk, or other factors, countries with indigenous and other vulnerable populations should carefully evaluate the situation and consider ways to mitigate the impact of the pandemic in the coming season in these populations.

WHO has also been notified of 12 cases of oseltamivir resistant virus. These isolates have a mutation in the neuraminidase (referred to as H275Y) that confers resistance to oseltamivir, though the viruses remain sensitive to zanamivir. Of these 8 have been associated with oseltamivir post exposure prophylaxis, one with treatment of uncomplicated illness, and two have been from immunocompromised patients receiving oseltamivir treatment. These isolated cases have arisen in different parts of the world (Japan 4, USA 2, China, Hong Kong SAR China 2, and 1 in Denmark, Canada, Singapore and China), and there are no epidemiological links between them. There is also no evidence of onward transmission from these cases.
-

<cite cite="http://www.who.int/csr/don/2009_08_21/en/index.html">WHO | Pandemic (H1N1) 2009 - update 62 (revised 21 August 2009)</cite>

[sharon sanders]

Tamiflu resistance in pandemic influenza - historical compilation of news

Flu antivirals: the good news (they work), the bad news (not very well), the good news in the bad news (we're not likely to lose much)

Category: Antivirals ? Influenza treatment
Posted on: August 11, 2009 6:53 AM, by revere


Yesterday (today as I am writing this) the British Medical Journal published another Cochrane meta-analysis on the efficacy of neurimminidase inhibitor antivirals (the only two in use now, being oseltamivir [Tamiflu] and zanimivir [Relenza]). Their conclusions have made the news, so I guess I should cast my baleful eye on their handiwork. I think there is less here than meets the eye, but first let's look at what meets the eye.


This is a meta-analysis, that is, an analysis of other analyses, the other analyses in this case being drug trials of Tamiflu or Relanza in children. So it's an observational study of experimental studies, if you follow me.



"Experimental" in this context means studies on children where the investigators control the treatment assignment (an antiviral or a placebo or no treatment). In essence, it is a review article of other studies where the authors employ various qualitative and quantitative techniques to combine results to come up with a summary of the studies, taken together. It's more complicated than that, but that's the general idea. It's potentially better than the kind of reviews of the literature commonly done because it is very explicit about what kinds of analyses will be included and the methods of weighting the results are also explicit and often quite sophisticated. I say potentially better because it takes a very narrow view of the subject, only allowing data from scientific studies of a particular kind. The Cochrane consortium last looked at this question in 2005 and this article looks at what has been learned in the interim, clearly with an eye on the swine flu pandemic now underway. All of the analyses they looked at were for seasonal flu, not pandemic flu. How generalizable this is to pandemic flu is unclear, but it is reasonable to think it has relevance.


There were only four studies meeting their strict eligibility criteria in this time period using antivirals to treat flu in children, two for each antiviral. The total number of children in the treatment studies was just under 1800, about two thirds of whom had virologically confirmed flu. Two thirds of those had influenza A. The rest had flu B. There was no differentiation of flu A subtypes. Three more studies used antivirals (two Relenza, one Tamiflu) as post exposure prophylaxis (just under 900 children). The studies were randomized trials involving children less than 12 who had flu (either clinically suspected or virologically confirmed) but not sick enough to be hospitalized. Thus the conclusions say nothing about the efficacy of these drugs for really sick children, although this is not clear from the news reports (example from the BBC: "The antiviral drugs being used to treat swine flu do not appear to work well in children, say UK researchers." This also fails to mention this was not a study of the use of these drugs for swine flu.)


I've never been much of a fan of antivirals as a way to deal with pandemic flu, but that's because I'm a public health person, not a clinician. My interest is in things that work on the population level, not applied at the level of the individual. In addition I was never impressed by how well these drugs worked. At times I even wondered if they worked at all were we to take a hard look at them (many of the studies were financed by the drug companies and we now know this is often a tainted source). Antivirals aren't like antibiotics, where you can sometimes work almost miraculous cures. If they work, they work at the margins. With those prejudices of mine as background, I can state that one clear message of the 2005 review and this one is that both of these drugs work to some extent. You wouldn't get that idea at all if all you read was the news headlines (the BBC again: Flu drugs 'unhelpful' in children). They not only work, but they work on every single measure examined: reduction of time with symptoms (.5 days to 1.5 days); time of illness (.4 days to 1.5 days), where this was defined as resolution of all symptoms and resolution of fever and return to school or normal activities; reduction in cough or fever (1.3 days for Tamiflu, "reduced incidence of moderate or severe cough" at day five with Relenza); reduction in asthma exacerbation; improvement in pulmonary function; reduction in antibiotic use; reduction in otitis media (middle ear infection) at day 10; and in confirmed secondary cases with an infected index case (reduction in transmission of about 8%).



In some of these outcomes the differences were not statistically significant, but in no instance -- not a single one I was able to see in this paper -- was there an outcome that wasn't consistent with the drugs working. Remember that the authors were surveying less than 3000 children divided up into seven studies, each of varying quality and different outcomes. The most plausible explanation for a lack of statistical significance given the consistent pattern and the biology is that there was insufficient statistical power. It is certainly false and absolutely incorrect to say that the outcomes that were not statistically significant showed no effect. In every instance they showed an effect of the drug in the right direction. In some instances the alternative explanation of random variation remained on the table along with a real effect.


In trying to make the jump from this review to the current swine flu situation there are other issues to contend with. Anywhere from 2% to 20% of the children in these trials had gotten seasonal flu vaccination, which could well have modulated the severity of their illness and the response to antivirals. This is especially pertinent in trying to extrapolate to populations of children in the initial stages of this pandemic, where none of them will have been vaccinated. Second, as already noted, none of these children were sick enough to be hospitalized. The marginal improvement in these community residing patients may look very different in very sick children who are on the margin between needing vents or no vents or even a fatal outcome. Nor do we know much about children with serious underlying medical conditions. That is work that remains to be done and some of it is happening now. Third, we know little about the efficacy of these drugs across flu A and flu B or between subtypes of flu A. Are there significant differences? We know that the neuriminidase protein on the virus looks different in different subtypes (there are at least two main NA subgroups) but we don't know much about the effect of those differences on antiviral efficacy. Moreover it is likely that many of these children were infected with viruses resistant to Tamiflu. So far the swine flu virus remains sensitive.


While we fear this paper will lead to misinterpretation and we think it has been oversold, it does raise some very important questions. It presents clear evidence these drugs work, but do they work well enough? In the Big Picture, for most patients the improvement is not very significant (although for individuals a day or more gained without symptoms is not just a tunafish sandwich). Tamiflu has some adverse effects, most commonly nausea and vomiting. That's not fun, either. When told of this, my daughter declined the Tamiflu she was offered when she came down with the virus.



Finally, there is the prospect that unwise use will promote resistance and deprive us of one of the few therapies we have for swine flu. This is not a simple issue. To have the greatest chance of success these drugs should be used relatively early in the course of the illness, often before anyone knows which direction it is headed. If we wait to use them only when the patient goes sour, they will have lost much of their potential efficacy. On the other hand, suppose we do lose their use because the virus develops resistance. The current seasonal H1N1 is almost entirely resistant to Tamiflu (but not Relenza) and we have managed quite well without it. That's the silver lining to the fact these are not miracle drugs. If you lose them, you aren't losing the ability to work a miracle. It's the good news in the bad news.


The real take home lesson in the BMJ paper is that for seasonal flu these drugs work for children but not well enough to rely on them for much. We don't know whether this is also true for swine flu and for very sick children, but studies now underway which will likely provide some data. How much of what this paper provides will turn out to be of any use remains to be seen.
Meanwhile, caveat lector.

[Treyfish]

Tamiflu resistance in pandemic influenza - historical compilation of news



By MARIA CHENG
ASSOCIATED PRESS

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• LONDON ? Healthy people who catch swine flu do not need antivirals like Tamiflu, but the young, the old and the pregnant surely do, the World Health Organization declared today in new advice to doctors.

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The UN health agency said people who are otherwise healthy with mild to moderate cases of swine flu or regular flu don?t need the popular drug, calling the medical evidence for giving it to those people ?low quality.?
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But people thought to be at risk for complications from swine flu ? children less than five years old, pregnant women, people over age 65 and those with other health problems like heart disease, HIV or diabetes ? should definitely get the drug, WHO said.



WHO also recommended that all patients, including children, who have severe or worsening cases of swine flu, with breathing difficulties, chest pain or severe weakness, should get Tamiflu immediately, perhaps in higher doses than now used.

The advice contradicts some current government policies, such as those in England, whose health agency liberally hands out Tamiflu to healthy people with swine flu. Since the British set up a national flu service in July to deal with the surge of swine flu cases, Tamiflu has been available to anyone suspected of having the disease, including healthy people.


At its summer peak, British authorities guessed there were about 110,000 new cases of swine flu, also known as H1N1, every week. The number of new cases dropped last week to about 11,000, but the fall/winter flu season has not yet begun.

Boasting that Britain had the world?s largest supply of Tamiflu, enough to cover 80% of its nearly 61 million people, Health Minister Andy Burnham promised the drug would be available to anyone who needed it.

Britons who call the national flu line can get Tamiflu without ever seeing a doctor ? it is given out by call center operators who have no medical training. Scotland, Northern Ireland and Wales decided not to participate in the swine flu phone line.

On its swine flu Web site, the Department of Health says ?the government has decided to offer the antivirals Tamiflu or Relenza to everyone confirmed with swine flu.?

To stop people fraudulently getting Tamiflu, the web site says ?the government is relying on the public to use the system responsibly.?

Some experts have criticized that approach, warning that blanketing the population with Tamiflu increases the chances of resistant strains emerging.

Flu expert Hugh Pennington of the University of Aberdeen called the strategy ?a very big experiment? and said England?s approach was out of step with the rest of the world. The U.S. Centers for Disease Control and Prevention, for instance, says antivirals must be prescribed by a health care professional.

Pennington called for the national flu line to be dismantled because Tamiflu should be used more sparingly.

?This approach increases the likelihood of a resistant strain and that is not a risk worth running,? Pennington said.

Officials have already found widespread drug resistance in seasonal strains of H1N1 flu and worry that might also crop up with swine flu. So far, only a handful of Tamiflu-resistant swine flu strains have been found.


WHO said most patients infected with swine flu worldwide recover within a week without any medical treatment. Still, about 40% of the severe swine flu cases are occurring in previously healthy children and adults, usually under 50 years of age.
WHO has estimated that as many as 2 billion people could become infected over the next two years with swine flu ? nearly one-third of the world?s population.http://www.freep.com/article/2009082...te=fullarticle