Drug-Resistant Flu Strain Turns Up In Denmark but Doesn't Last Long
2Jun 29, '09 by Lovely_RNhttp://www.nytimes.com/2009/06/30/health/30glob.html
June 30, 2009
Drug-Resistant Flu Strain Turns Up In Denmark but Doesn't Last Long
By DONALD G. McNEIL Jr.
The first case of swine flu resistant to the antiviral drug Tamiflu has been found in Denmark, according to Danish health officials.
The patient appears to have recovered without infecting anyone else, and experts said the recent history of Tamiflu resistance made it unlikely that the short-lived Danish strain would have been good at spreading to others.
An executive of Roche, the Swiss maker of Tamiflu, held a telephone news conference to describe the progress of the Danish patient, who apparently developed the resistant strain while being protectively treated with a low Tamiflu dose because a close contact had the swine flu. Doctors switched treatment to a different but related drug, Relenza, and the patient recovered.
In the past, Tamiflu-resistant strains of the seasonal flu have been found in Japan, which has used more than half the world's supply of the drug each year. But those strains were weak and did not spread. A Tamiflu-resistant strain of the H5N1 bird flu was also isolated from a Vietnamese patient being treated with low-dose Tamiflu in 2005, but it also died out.
Tamiflu resistance that did spread in seasonal flu emerged last year from a spontaneous mutation known as H274Y on the N gene. The mutant strain dominated the seasonal H1N1 flu during the past flu season in the United States, before swine flu was discovered in Mexico.
Virologists fear swine flu will soon pick up resistance by merging with seasonal H1N1 flu, perhaps in the Southern Hemisphere, where the flu season is just beginning.
0it has been known from the beginning of this outbreak that this virus would eventually develop resistance to tamiflu. roche's press conference has dismissed this recent case as insignificant. they say that it's just one case, and it's all over with. have they shown us any evidence that this is true? well no, not really...making a reassuring announcement is not proof of anything.
let's look at what is known thus far about this, and get the benefit of another view of what may be going on by following a conversation over at flutrackers:
Quote from www.flutrackers.com
i´m danish, and i have now read several of the tamiflu resistant patient reports in danish, and i belive fully that this is the correct info due to what has been reported on statens serum institut website and elsewere.
the tamiflu resistent person "a" (a woman, according to newsreport) had not been abroad.
"a" had been in contact with a person, we name him/her "b"
"b" had recently been abroad and had gotten infected with h1n1
therefore "a " was given tamiflu as a precausionn treatment
after "a" had been taking tamiflu for 5 days she devloped flu symptoms
a test showed that "a" was infected with h1n1
additional tests at statens serum institut showed that the virus in question, h1n1, had mutated. it (the h1n1) is resistent to tamiflu but is still sensetive to relenza.
Quote from www.flutrackers.comhttp://www.flutrackers.com/forum/sho...9&postcount=94
thanks for the clarification. that would narrow down the source of the woman's infection, and the 5 day delay included the time to get infected by the traveler contact, who was in denmark (the classic 5 day gap in disease onset). however, even though the source was in denmark, it still sounds like there was no data for the h1n1 from the source to show that the source was wild type. this is infered because the source recovered and was probably treated with tamiflu, but many recover without tamiflu treatment, so the recovery of the source does not signal wild type. however, the failure of the contact to recover in spite of treatment does signal resistance, so that sample was sequenced and was resistant (almost certainly h274y). thus, without the sequence from the traveler, there is still no evidence that the traveler didn't also have resistant h1n1 (or that the travel was the actual source of h1n1, since the only sequence described was from the patient who failed to respond to tamiflu).
Quote from www.flutrackers.comhttp://www.flutrackers.com/forum/sho...1&postcount=98
originally posted by niman
do the reports indicate that she "suddenly" developed symptoms (at day 5)? the sudden development would also suggest that she was infected with h1n1 that was already resistant. the prophylatic tamiflu did nothing. she was exposed for 5 days and the sudden onset suggests that she had a significant exposure, leading to sudden disease onset, instead of a milder infection that became more severe as the tamiflu sensitive h1n1 declined due to tamiflu treatment and was replaced by resistant h1n1.
yes that first scenario is correct; she "suddenly" developed symptoms at day 5 (after 5 days on prophylatic tamiflu) and she had been in close contact with "b" who had been infected abroad.
Quote from www.flutrackers.comhttp://www.flutrackers.com/forum/sho...=113101&page=4
wild type is the scientific term for the "normal" gene. in this case, it would be an na gene that is not tamiflu resistant.
as far as information is concerned, most countries have been very withholding of specifics, citing privacy laws. however, countries in europe, including denmark, have done a very minimal level of testing. they have focused on imported cases and contacts, as described in this case/cluster, but little real data has been released.
although sequences have been released promptly, the number from denmark remains at one. it was collected in late april and released promptly in early may, but of course it is almost july, so there is no public data on sequences from denmark for almost the past 2 months.
thus, the recent spread of tamiflu resistance in denmark would not be seen in public sequences, and many other european countries also have limited positives and even fewer sequences.
in all liklihood, there is no sequence from the contact, which is why statements include "probably" and "appears". there is no data showing that the h1n1 in the contact who traveled overseas was infected with tamiflu sensitive (wild type) h1n1, and the only reason the h1n1 was collected from the female patient was becasue she developed flu-like symptoms while taking tamiflu.
Quote from www.flutrackers.comoriginally posted by theforeigner
i´m not sure if this has any significance, but on the danish statens serum institut report about the tamiflu resistent patient "a", they also added this statement:
a corresponding development of resisitant twards oseltamivir (tamiflu®) has been observed in the winter-influenzavirus a h1n1, which has circulated the last to vinter seasons
yes, that is how they say h274y without saying h274y. this change was predicted, based on the high level in seasonal flu, and the ability of the change to jump from one genetic background to another via recombination. those in denial about recombination think it will jump via reassortment in which the entire human na gene from h1n1 replaces the swine na gene. however, in this case there was no reassortment.
roche maintains that the h274y was a "random mutation" selected by the tamiflu treatment (and wasn't in the contact or the patient intially - this is well into the "hopes and dream" category).
if the resistance is due to h274y, their argument is diminished, because h274y jumped from one h1n1 seasonal flu genetic background to another in patients not taking tamiflu, because the seasonal h1n1 with h274y was evolutionarily fit. all of the tamiflu resistance in seasonal flu was in h1n1 and all involved h274y.
a re-run in swine h1n1 is roche's worst nightmare (and that development is pretty high on the nightmare list for most others).
i suspect more countries will start looking harder and h274y will be found in many isolates from patients not taking tamiflu in the very near future.
Quote from www.flutrackers.comhttp://www.flutrackers.com/forum/sho...&postcount=107
originally posted by theforeigner
ok let me ask you if i´v got this right? (i don´t have knowhow concerning the technical part of the virus )
the tamiflu resistant patient "a" possibly/proably got/developed a virus where swine flu virus and preexisting tamiflu resistant sesonal flu virus h274y had mixed into a new tamiflu-resistant swine flu variation ?
is that close? or am i totaly off ?
you are close. you have described how the resistance formed, but it was probably not in patient a or b. it has been circulating undetected. the overseas traveler was infected, but recovered even though the tamiflu played no role (many recover without tamiflu treatment). he infected the denmark contact and the tamiflu also didn't help her, but she needed antiviral help, so when she developed symptoms while taking tamiflu, the drs knew there was a good chance that the h1n1 was resistant, so they isolated it. they also switched treatment to relenza, which worked.
the bottom line is the resistant strain is circulating, but surveillence is poor and the only reason it was detected was because the contact develped symptoms while taking tamiflu and she responded to relenza.
however, now countries will look harder and find h274y in patients not taking tamiflu and realize it has been silently spreading (as happened with seasonal flu in 2007/2008. it had been circulating for months prior to detection in norway (and for years at low levels prior to that - in patients that were not taking tamiflu).
Quote from scienceblogs.comThe Editors of Effect Measure are senior public health scientists and practitioners. Paul Revere was a member of the first local Board of Health in the United States (Boston, 1799). The Editors sign their posts "Revere" to recognize the public service of a professional forerunner better known for other things.
Currently the only antiviral drugs effective against the swine flu (novel H1N1) virus are the two neuriminidase inhibitors, oseltamivir (trade name Tamiflu) and zanamivir (trade name Relenza). Relenza is in active form at the outset and cannot be absorbed orally. It must be inhaled, leading to asthmatic reactions in some, ineffective dosage in those with breathing difficulties, and no drug at sites beyond the respiratory tract. Despite these drawbacks, it has so far produced little or no viral resistance. Tamiflu is absorbed orally and converted by the liver into the active form, so it gets to other organs and can be taken by people unable to inhale Relenza. But it has other problems. One is a tendency for the flu virus to become resistant to it. Until today, however, there have been no reports of Tamiflu resistance in swine flu isolates, although most flu experts were waiting for the other shoe to drop. Today may have been the day we heard it fall:
Scientists have established the first case of the new H1N1 influenza strain showing resistance to Tamiflu, the main antiviral flu drug, Danish officials and the manufacturer said on Monday.
It was expected that the strain would at some point show resistance to Tamiflu, Denmark's State Serum Institute said. The patient was now well and no further infection with the resistant virus had been detected.
"It does not constitute a risk to public health and does not cause changes to the recommendations for the use of oseltamivir (Tamiflu)," the institute said in a statement. (Reuters)
It's not exactly clear what a lack of risk to public health means in this context. I agree at this point it doesn't affect the extent of infection in the population, but if Tamiflu resistance becomes widespread it will alter treatment options for those who are infected and since Tamiflu treatment can reduce viral shedding also affect transmission within small groups, like households. Still, we don't know much about the reported resistance. Seasonal H1N1 is already resistant, so if novel H1N1 reassorted and swapped out its own H1 for a seasonal H1 when both viruses co-infect a host cell, that would be one mechanism. More likely, the HA of the the swine flu virus suffered a mutation that produces Tamiflu resistance (H274Y is the commonest, but others are possible). We don't know any details yet.
Details aside, this development is not a surprise, although its ultimate significance is unclear. Antivirals, especially when given early in the course of the illness, do seem to be of some benefit, but it's not dramatic. They reduce the symptomatic duration of illness by a day or two and with it viral shedding. They may also have some prophylactic effect for those known to be exposed. But if your model is the often dramatic effect that antibiotics have on bacterial infections, these antivirals are effective only on the margins and they are not without adverse reactions.
So the other shoe may have dropped but if it did, we don't yet know the consequences. People get over flu because their bodies are able to do it on their own. For some, although not most, an antiviral might make a vital difference. But the main protections are not to get infected to begin with, and if you do, to be in good shape, to have good care, and to have good luck. If you have the last of these, you don't need antivirals. If you don't, they probably won't help.
Meanwhile, it is what it is. Whatever that is.
dr. niman continues to defend his position. it is too soon to say if he is right. only time will tell, but in the meantime we will be watching for these expected changes to occur. remember that tamiflu drug resistant strains occurred in people infected with seasonal flu, h1n1, that were not even taking this drug. the strains were already resistant.
i corrected his typos because they drive me nuts.
Quote from www.flutrackers.comhttp://www.flutrackers.com/forum/sho...&postcount=125
originally posted by mamabird
please carefully read the ecdc assessment of the danish resistant virus, appended to their daily swine flu update:
this has been categorized as a secondary resistant virus due to the use of tamiflu administered to the patient. it is not a primary virus, ie., one that was acquired from another infected person. this is based on the isolation of the viruses in the cluster of contacts around the danish woman. none of those sequences revealed the na mutation causing tamiflu resistance.
the report is rather vague on who and how many were in the cluster, as well as how hard they looked. if the overseas traveler had a mixture, the tamiflu may have selected h274y in the patient who developed symptoms after being on tamiflu for 5 days, while the other isolates may have been collected prior to treatment, keeping the resistant sequence at a low level.
this is somewhat like the data for s227n in h5n1 in turkey. the index case had s227n, but his sister didn't. webridge said the s227n developed in the index case but subsequently two more sequences were release[d] from others in turkey (they would [not] say from who) and one had s227n while the other didn't. in all likelihood all four had s227n and the published sequence represented what grew out in cluture. of the four sequences two had s227n and two didn't.
the same thing happened in the sars outbreak. all of the polymorphisms really originated with the index case, but many were absent from the sequence from the index case and many jumped contacts
i will still predict that h274y will soon start appearing in swine h1n1, including patients who are not taking tamiflu.
notice that this group still can't explain how h274y in seasonal flu managed to jump from genetic background to genetic background in the absence of tamiflu and just calls it "complex".
Quote from www.flutrackers.comquote:
originally posted by mamabird
i guess we can expect the release of all the related danish genetic sequences in very short order, expecially since this case apparently resolved itself earlier in the month.
the tracing will likely be more informative than the sequence, unless the sequence has mixed signals. it is of note that this incident apparently happened some time ago, but to date there is a total of one sequence, collected in april, that is public.Last edit by indigo girl on Jun 30, '09
0Jul 2, '09 by indigo girlJapan Finds Tamiflu Resistant Case Of H1N1
WHO must have known about this when the Danish case was made public, surely.
Quote from afludiary.blogspot.com
A second case of Tamiflu resistant H1N1- this time from Japan - has made the news. On Monday,the media reported the first known case - in Denmark.
What is a bit surprising is that this case occurred sometime in May, and we are just now learning about it.Last edit by indigo girl on Jul 2, '09
0Jul 2, '09 by indigo girljapan reports tamiflu-resistant h1n1 influenza case
if they are going to announce that everything is fine, they should be able to demonstrate that this patient's flu strain did not contain h274y by releasing the viral sequence. just announcing that everything is fine without proving it is not very reassuring.
we know that they tested this patient for swine flu before treatment with tamiflu was given so what are the chances that they have this data?
if this virus has h274y, it means that the tamiflu resistance did not develop as a result of taking tamiflu. the virus would already have had this trait before the patient ever took the drug. that would be very bad news, and nobody wants to admit that this could have happened this soon into the pandemic.
Quote from www.flutrackers.com
originally posted by mamabird
in osaka, the patient apparently had been diagnosed with swine flu before the administering of tamiflu. see below:
a genetic mutation of swine flu that is resistant to the anti-viral tamiflu has been discovered in japan, the first such case in the country, the health ministry said.
it was found in a patient who had been given tamiflu since first being diagnosed with h1n1 around two weeks ago, kyodo news agency reported thursday, citing the health, welfare and labour ministry."
so, perhaps we will have a before and after genetic sequence of na for comparative purposes.
in any event, these "isolated" incidents are already getting tiresome.
this will also be h274y and if it was in the initial sample, prior to treatment, then the acquisition (independent of recent treatment, will have been confirmed, roche's handwaving notwithstanding).
Quote from www.flutrackers.com
originally posted by wotan
unfortunately they don't seem to mention if they have samples from before tamiflu treatment with which to perform the necessary testing.
yes they have the sample (and probably the sequence) because the patient was diagnosed with h1n1 before treatment. thus, the sample that was h1n1 positive was collected prior to treatment (and if that sample has h274y, the swine h1n1 with h274y is evolutionarily fit).
0Hong Kong: Detection of human swine influenza virus resistant to Tamiflu
This is the third case we are finding out about. Notice the dates of discovery of all of these cases.
This article makes note of the other two cases,"Denmark and possibly Japan."There is no possibly. The Japanese case is documented. This latest case flew in from San Francisco, and was never on Tamiflu, but she already had a resistant strain of the virus.
None of these sequences are available for viewing, btw, so none but a few select scientists who are not talking, can say if H274Y appears in any of these viruses.
Quote from www.flutrackers.com
A spokesman for the Department of Health (DH) said the department's Public Health Laboratory Services Branch (PHLSB) today (July 3) detected a strain of human swine influenza (HSI) virus which was resistant to oseltamivir (Tamiflu).
The virus was identified during PHLSB's routine sensitivity test of HSI virus to oseltamivir and zanamivir, the spokesman said.
"This is the first time Tamiflu resistance in HSI virus found in Hong Kong," he said, adding that similar cases were also reported in Denmark and possibly Japan.
"Tests showed that this strain is sensitive to zanamivir (Relenza)," he said.
The virus was isolated from the specimen taken from a 16-year-old girl coming from San Francisco. She was intercepted by Port Health Office at the Hong Kong International Airport on June 11 upon arrival. The girl was then admitted to Queen Mary Hospital for isolation. She was tested positive to HSI but opted not to take tamiflu. She had mild symptoms and was eventually discharged upon recovery on June 18.
The spokesman noted that PHLSB conducted routine sensitivity tests on specimens taken from confirmed HSI patients.
"This is the only Tamiflu-resistant strain so far among some 200 HSI samples tested in Hong Kong. Further tests are underway," he said.
Hong Kong has maintained an antiviral stockpile of both Tamiflu and Relenza.
The case will be reported to the World Health Organization (WHO), the spokesman said. He reiterated that Hong Kong had an intensive influenza surveillance system on antiviral resistant influenza viruses.
"We will closely liaise with WHO and overseas health authorities and monitor the global development of antiviral resistant HSI virus," he said.Last edit by indigo girl on Jul 3, '09
0surveillance flaws drive silent spread of tamiflu resistant h1n1
Quote from www.recombinomics.com
the virus was isolated from the specimen taken from a 16-year-old girl coming from san francisco. she was intercepted by port health office at the hong kong international airport on june 11 upon arrival. the girl was then admitted to queen mary hospital for isolation. she was tested positive to hsi but opted not to take tamiflu. she had mild symptoms and was eventually discharged upon recovery on june 18.
the above comments from a hong kong doh press release on tamiflu resistance in pandemic h1n1 highlight severe limitations in worldwide surveillance. although this case was identified by routine surveillance of h1n1 positive patients in hong kong, it is an effort largely focused on travelers. like countries outside of the americas, most efforts have focused on travelers and largely ignored local community spread. the recent explosion in cases in the uk has led to a focus on the community spread there, but many other counties in europe are reporting low numbers of confirmed pandemic h1n1 because of limited testing in the community.
in the us, efforts are focused on the community, but severe cases are targetted. most states have stopped reporting and testing mild cases, so real monitoring of this group is minimal. however, the case in hong kong originated in san francisco and was mild. the united states has not reported any tamiflu resistance. the cdc has tested over 200 isolates and failed to identify h274y.
this may be due in part to virus mixtures. in denmark and japan the h274y was discovered in patients undergoing tamiflu prophylactic treatment. the tamiflu treatment would reduce wild type h1n1 and allow a minor population with h274y to expand and be detected. therefore, it is likely that the h274y is spreading silently and under the radar of the sequencing efforts, which are focused on the dominant (consensus) sequence.
the acquisition of h274y by pandemic h1n1 was not unexpected. h274y has a history of jumping from one sub-clade to another, as well as jumping to multiple different backgrounds within a subclade via recombination and genetic hitchhiking. this has produced resistance that is limited to h1n1 and h274y within h1n1. the co-circulation of human h1n1 seasonal flu with swine h1n1 in humans, has created a favorable environment for the jump of h274y from seasonal flu to pandemic flu. moreover, the widespread use of tamiflu in patients infected with pandemic h1n1 will drive the rate of spread in pandemic h1n1.
although countries have been placing sequences on deposit in a timely manner, there are still major deficiencies in the surveillance program, as described above. moreover, the recent reports of tamiflu resistance in isolates in denmark, japan, and hong kong have not lead to the release of these sequences.
an increase in surveillance and release of full sequences is still necessary. the pandemic h1n1 is now rapidly spreading in the southern hemisphere, which is just beginning its flu season. sequences from fatal and mild cases are required to determine important changes in pandemic h1n1 associated with increased virulence as well as increased spread.
a serious comprehensive surveillance program is long overdue.
0Tamiflu-Resistant Swine Flu Virus Found in Hong Kong (Update2)
Quote from www.bloomberg.com(hat tip Avian Flu Diary)
This marks the first known case of Tamiflu resistance in a swine flu patient not treated with the drug, which has been stockpiled by governments worldwide to fight pandemic influenza. The specimen was collected from a 16-year-old girl who flew from San Francisco and was intercepted by officials at Hong Kong International Airport on June 11, according to the statement.
“Picking it up in a patient who was not treated is a cause for concern,” Malik Peiris, professor of microbiology at Hong Kong University, said in an interview. “One case doesn’t change the world, but if we are seeing more and more cases in patients who are not treated, then I think it would be more serious.”
The patient, who was admitted to Queen Mary Hospital for isolation, tested positive for the new H1N1 flu strain and opted not to take Tamiflu, Hong Kong’s health department said. She had mild symptoms and was discharged upon recovery on June 18.
Basel, Switzerland-based Roche said on June 29 that a swine flu patient treated with Tamiflu in Denmark showed resistance to the drug for the first time. Japan’s health ministry reported a case of resistance yesterday in a woman from Osaka who had taken a 10-day course.
Studies have shown that Tamiflu-resistant bugs develop in 0.4 percent to 4 percent of adults and children treated for seasonal influenza, Claudia Schmitt, a spokeswoman at Roche, said by phone from Basel today.
It’s likely the few reported cases of drug-resistant swine flu emerged independently, Hong Kong University’s Peiris said.
“The key point is whether the strains will become dominant and then we will have a problem,” he said. “At this moment, I don’t think there is cause for alarm. There is certainly cause for heightened surveillance.”
The new H1N1 pandemic virus and a seasonal H1N1 variant are more likely to develop resistance to Tamiflu than other common flu strains, Peiris said. About 95 percent of the H1N1 seasonal flu viruses circulating around the world evade the Roche pill, according to a March 21 World Health Organizationreport.
No widespread resistance to GlaxoSmithKline Plc’s flu drug Relenza has been reported in seasonal flu, and there have been no reports of resistance in swine flu.
“Constant, random mutation is the survival mechanism of the microbial world,” WHO Director-General Margaret Chan said in an address to a meeting on the flu pandemic in Cancun, Mexico, yesterday. “Like all influenza viruses, H1N1 has the advantage of surprise on its side.”
Tamiflu and Relenza, an inhaled powder, reduce the severity and the duration of flu symptoms by 24 to 30 hours if treatment is started within the first two days of illness, according to the companies.
Both drugs work by blocking a protein on the surface of influenza particles called neuraminidase, which allows the virus to spread from infected cells to other cells in the body.
Scientists say mutant H1N1 viruses have evolved to evade Tamiflu through a single mutation in the neuraminidase that prevents the medicine from clinging to the viral protein, enabling the pathogen to spread.
The case in Hong Kong indicates that the mutant virus is capable of being transmitted among people, said Jennifer McKimm- Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne.
“It’s very disturbing that, fresh into the human population, this one appears now to be able to retain fitness despite having the mutation and to be able to spread,” she said in a telephone interview today.
0Jul 4, '09 by indigo girlPossible case of “resistant” A (H1N1) virus
This is the 3rd case of a person who had flown in from the states, demonstrating Tamiflu resistance.
Quote from www.thehindu.com[hat tip Avian Flu Diary]
The State health authorities have been asked to send a blood sample of the infected person to the National Institute of Virology (NIV), Pune.
The patient, a man who had flown in from the U.S. in the third week of June, had tested positive along with his wife.
They were quarantined at the Communicable Diseases Hospital (CDH) here and started on a course of Tamiflu. “This was through the Directly Observed Treatment Short-course method, which means we know he took every tablet and did not miss out on even a single dose. Missing on doses can lead to resistance, but that is not the case with this patient,” Director of Public Health S. Elango said.
While his wife recovered and tested negative for A (H1N1) after about 10 days, the husband continued to test positive even after the treatment was completed.
Though he showed no symptoms, his tests kept coming back positive, Dr. Elango said.
“This is a case to be studied, definitely. The virus should not remain in his blood after the treatment. It is possible that it is a mutation of the virus. I have instructed the officials at the NIV to sequence the strain [from the samples] as soon as possible. Once we have that, we can have the alternative drugs to treat the patient,” Dr. Katoch explained.
He said the patient at the CDH could be treated on recommended doses of the drug ‘Relenza’ available in India.
When told that the patient was anxious to go home, Dr. Katoch categorically said that he could not be discharged as long as he continued to test positive, even if he was not symptomatic.
“He is certainly a carrier and can spread the virus to members of his family, and thereby take it into the community. That should not be allowed to happen. Indigenous transmission of the virus from this person will lead to a huge public health problem,” Dr. Katoch said.
The issue would be sorted out as soon as the sequence was drawn up. “That way we will also be ready for any future occurrences.”Last edit by indigo girl on Jul 4, '09