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Anti-viral resistance in 2009 A/H1N1 flu - historical compilation of news
Even though Tamiflu resistance is Tamiflu resistance irrespective of how acquired, reassortment with a new NA segment would mean an antigenic novel Swine Flu virus. In other words, the vaccines being developed around CA/07 would likely be much less effective against such a pathogen.
Wrong. The acquiring a Brisbane/59 H and N would produce a strain similar to seasonal H1N1 (population would already have antibodies). Its hopes and dreams on steroid.
It has already happened in Saskatchewan with another triple reassortant.
Tamiflu Resistant Pandemic H1N1 in Washington State
Recombinomics Commentary 03:20
August 15, 2009
On June 1, the patient was enrolled in an influenza antiviral treatment study and he began a 10-day course of oseltamivir.
A novel influenza A (H1N1) virus isolate from a specimen collected on May 31 was identified as susceptible to oseltamivir by pyrosequencing at CDC, but viruses isolated from specimens collected on June 11 and July 14 had the H275Y mutation, indicating oseltamivir resistance.
Antiviral treatment with high-dose oseltamivir (150 mg orally, twice a day) and rimantadine (100 mg orally, twice a day) was administered during June 26--July 1.
On August 10, CDC received other previously collected virus isolates from this patient for testing, and pyrosequencing of a virus isolated from a specimen collected on July 14 had the H275Y mutation, confirming oseltamivir resistance.
The above comments are from today's MMWR dispatch describing two immune-suppressed patients, who represent the first two confirmed cases of oseltamivir resistance in H1N1 pandemic swine flu in the United States. Both patients were from King County in Washington State and initial isolates from both patients were sensitive. In one patient, virus with H274Y was first detected in a sample collected 10 days after the start of treatment, while in the other patient, resistance was detected in a sample collected 18 days after the start of treatment. Because these patients were symptomatic at the start of treatment, the date of detectable resistance is unknown, in contrast to earlier patients who were asymptomatic at the start of prophylactic treatment and became symptomatic 5-6 days later. In the patients treated prophylatically, the appearance of symptoms in the short time frame after the start of treatment suggests the resistant virus was present as a minor population, and the treatment led to detection.
In the two immune-suppressed patients it is harder to draw a conclusion because of the longer time period between the start of treatment and confirmation of resistance. However, the report of two patients from the same area, who began treatment in June, raises concerns that H1N1 with H274Y is silently circulating. In patients who are not immune-compromised, virus is usually cleared with or without Tamiflu treatment and therefore minor populations with H274Y would go undetected. In immuno-compromised patients, as well as those who are on prophylactic Tamiflu, detections of resistance is more common because of the development of symptoms in patients who were previously asymptomatic, or in patients treated with Tamiflu over and extended time frame.
The report on these two patients follow reports of resistance in Hong Kong this week, as well as Singapore, China, and Thailand last week, in addition to media reports last week of resistance in patients in Texas at widely separated locations along the Mexican border, as well as comments from WHO on reports of resistance in an undisclosed number of patients at undisclosed locations.
These continuing reports of resistance at the same genetic position, H274Y, continue to increase concern of widespread resistance silently circulating as a minor population which is not discovered until patients are treated with oseltamivir.
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
HOUSTON, Aug. 14 (Xinhua) -- The Seattle health department said on Friday that two immuno suppressed patients being treated for A/H1N1 flu had been identified as resistant to Tamiflu.
One case involved a male teenager with leukemia who received a stem cell transplant in early May, according to local health experts. While recovering in hospital in a single room he contracted A/H1N1 flu, they said, adding the boy has recovered.
The second case involved a woman in her 40s, who also has leukemia and had a stem cell transplant late last year, the health experts said. That woman remains in hospital and is being treated with an intravenous form of the only other flu drug available, Relenza, and another antiviral drug, ribavirin, they disclosed, saying the two patients have no links to each other.
Local health officials also said that there is no evidence indicating that people who came in contact with the two patients became infected with a Tamiflu-resistant virus.
Since the pandemic began, 11 cases of Tamiflu resistance have been reported. Three of those were reported Friday -- the two in Seattle and a new case in Hong Kong.
Japan and China have each reported three. In the case of China, one case occurred in Hunan province on the mainland and two in Hong Kong. Canada, Denmark and Singapore have each found one. Most of these cases have occurred in people who took the drug as treatment for the flu or to prevent infection with the flu.
The sole exception so far is the case of the California teenager who traveled to Hong Kong. She had not previously taken Tamiflu, suggesting she was infected from the start with a resistant virus. The source of her infection was not found and no other cases of resistance have been reported from the San Francisco area, where she lives. "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 of Seattle & King County. "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," Dr. Fleming said.
SINGAPORE, Aug. 14 (Xinhua) -- Singapore's Ministry of Health on Friday confirmed that the country has found its first Tamiflu-resistant A/H1N1 case.
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.
"Patients can recover from their illness even if they are infected with a Tamiflu-resistant influenza strain because the immune system plays an important part in clearing the body of the virus," the spokesperson said.
The spokesperson did not reveal the age and gender of the patient. "So far, we have not detected any other cases of antiviral resistance. We will continue to conduct surveillance for antiviral resistance," the spokesperson said. Singapore reported its first confirmed case of flu A/H1N1 on May 27. The country's first A/H1N1 related death case was reportedon July 18. The country has reported 11 A/H1N1 related death cases so far.
Re: Two Tamiflu-resistant swine flu cases reported in WA
To my knowledge none of the other instances of Tamiflu resistance have been in people with immune system problems, but it seems very likely that segment of the population has received a fair amount of Tamiflu. Really, what is the likelihood that two people in the same county developed it spontaneously?
Wotan (pronounced Voton with the ton rhyming with on) - The German Odin, ruler of the Aesir.
I am not a doctor, virologist, biologist, etc. I am a layman with a background in the physical sciences.
a CP story by Helen Branswell: US swine flu patients on immunosuppressant drugs develop Tamiflu resistance. Excerpt:
Two cases of Tamiflu-resistant swine flu have been found in the United States, in leukemia patients who were highly immunosuppressed, the U.S. Centers for Disease Control reported Friday.
The cases, both from Seattle, are not linked. And there is no evidence either person transmitted drug-resistant pandemic viruses to either the health-care workers looking after them or their personal contacts.
But the findings underscore the reality that people who are highly immunocompromised and who contract the novel H1N1 virus could generate and spread drug resistant variants of the pandemic virus.
"That's a legitimate public health concern," said Dr. Frederick Hayden, an antiviral expert at the University of Virginia.
These are the first cases of Tamiflu-resistant swine flu found in the United States, though not the first to arise there. Last month it was reported that an California teenager quarantined with swine flu immediately after arriving in Hong Kong was found to be infected with a Tamiflu-resistant strain. She contracted the flu before leaving San Francisco, where she lives.
These new cases highlight the catch-22 of treating pandemic influenza in people who are severely immunosuppressed. These patients should be given flu drugs because their immune status leaves them highly vulnerable to severe illness.
But giving them the drugs raises at least the theoretical risk that they will develop and spread antiviral resistant strains of the novel H1N1 flu.
To my knowledge none of the other instances of Tamiflu resistance have been in people with immune system problems, but it seems very likely that segment of the population has received a fair amount of Tamiflu. Really, what is the likelihood that two people in the same county developed it spontaneously?
As the frequency of detection / reporting increases, the likelihood that these acquistions are due to random mutations becomes increasingly remote. The best data for the silent spread actually is the Singapore patient, which was said to be sensitive in the initial test, which was on May 28. The resistance was on a May 30 sample, too soon for "spontaneous" generation.
H274Y is clearly spreading silently, and detection rates will increase (which will be very clear very soon, unless the data is withheld, as was announced by WHO earlier this week).
any such reassortment is dangerous since it could change virulence.
e.g. it could acquire PB1 with a functional PB1-F2
reassortment means prolonged evolution. Once it goes loose
the virus may get other ideas how to change
It "could" do a lot of things. However, swine H1N1 that acquires human N almost always also acquires human H. In Sasketchewan, 2 or 3 farm workers were infected with a triple reassortant that was Tamiflu resistance because the virus had acquired the N1 from Bisbane/59, which had H274Y. However, it also acquired H1 from Brisbane/59, so the resulting virus had a human H1N1 serotype, but a pandemic strain is defined by a new serotype. Brisbane/59 H1N1 is not new (and most humans have immunity by virtue of earlier H1N1 seasonal flu infections and earlier vaccination with Brisbane/59 H1N1).
Wrong. The acquiring a Brisbane/59 H and N would produce a strain similar to seasonal H1N1 (population would already have antibodies). Its hopes and dreams on steroid.
It has already happened in Saskatchewan with another triple reassortant.
I take it by this very surprising response that it is your view that the existing Swine Flu cannot reassort with Seasonal Flu to acquire only the NA segment making it Tamiflu resistant.
Otherwise, none of this makes any sense, or you have just misinterpreted the question posed.
Many of us in our responses agree with you on your recombination theory of Tamiflu resistance acquisition, but a reader would not necessarily get that impression by the way you respond to our posts on this forum. You simply say "no" or "wrong" to anything anyone else posts.
I take it by this very surprising response that it is your view that the existing Swine Flu cannot reassort with Seasonal Flu to acquire only the NA segment making it Tamiflu resistant.
Otherwise, none of this makes any sense, or you have just misinterpreted the question posed.
Many of us in our responses agree with you on your recombination theory of Tamiflu resistance acquisition, but a reader would not necessarily get that impression by the way you respond to our posts on this forum. You simply say "no" or "wrong" to anything anyone else posts.
There is quite a bit of data on swine H1N1 acquiring H and N human genes. I don't know of any instance where one was acquired without the other, Swine H3N2 is now fairly widespread and both the H3 and N2 are human. In the earlier series on Canadian swine in 2003/2004, most isolates had human PB1 with seven other swine genes. Two had human H and N (I believe they were both H1N2), and one had all 8 gene segments (thus none had a human H with a swine N or a human N and a swine H). Same is true for the recent "novel" isolate in Sasketchewan. It was a triple reassortant (it wasn't clear if it was H3N2 or H1N1 prior to the acquisition of human H1 and N1) and acquired Bribane/59 H1 AND N1 (and the N1 had H274Y).
I didn't say that picking up N1 without H1 was likely and I know of any such example (human N1 with swine H1 or swine H3).
If you know of such and example, post it. I asked GS for an example and he posted ZERO.
I didn't say human N1 with swine H1 made sense. WHO and CDC did, as did media reports, but they are fixated on reassortment and as seen by the nonsense about a concern that acquisition of N1 from brisbane/59, they have no current examples (without also acquiring a human H1), and I doubt that they have any prior examples.
I admit to being confused even after Niman explained.
By the little summary I posted, I thought it was clear that the resistance developed "in" both people and was not the result of seasonal combining with panflu (or silent spreading). Considering that a certain percent of people will normally develop a resistance to Tamiflu, I just imagined this was much better than if it had combined.
It wasn't at all clear that the resistance developed "in" the patient. It just expanded in the patients (like Singapore, were the resistance was present 2-3 days after the start of treatment - too soon for de novo H274Y).
The more we talk about this, the less clear the issue becomes to me. People talk about this like it's a reality but here he calls the risk theoretical. It can't be both.
There is a ton of evidence from Japan that shows when you take Tamiflu, the target virus soon learns how to wire around the meds and become resistant. This is especially true for children (who normally have immature immune systems) that have been given the drug. Even Roche, the manufacturer of the drug admits to this and even provides a percentage of how often it occurs.
The "new" theory is that the resistance has just been silently hiding in the background all along, and therefore was not previously detectable.
Please provide some scientific basis to go along with this novel theory to go along with our continuing spreading and ever more resistant novel virus.
To distinguish between a de novo mutation instead the selection of a minor population requires some tight collection dates. In Singapore the patient developed symptoms on May 26, was hospitalized on May 27, and was tamiflu sensitive on May 28. Treatment began on May 27 or 28 and collection on May 30 was resistant. The 2-3 period is too short for detection of de novo resistance. The patient was infected with a mixture and the H274Y was obvious (no wild type detected) a few days after the start of Tamiflu treatment.
There is a ton of evidence from Japan that shows when you take Tamiflu, the target virus soon learns how to wire around the meds and become resistant. This is especially true for children (who normally have immature immune systems) that have been given the drug. Even Roche, the manufacturer of the drug admits to this and even provides a percentage of how often it occurs.
The "new" theory is that the resistance has just been silently hiding in the background all along, and therefore was not previously detectable.
There is a big difference between earlier data in Japan and the H274Y seen in seasonal or pandemic H1N1. In Japan, sub-optimal levels produced resistance in H3N2 as well as H1N1 and at multiple positions (and only in patients being treated).
In the past several years there have been NO reports of Tamiflu resistance in H3N2. In addition, all resistance in H1N1 has been H274Y.
This pattern alone suggest that the H274Y isn't due to selection of random errors because only one "error" is selected. Moreover, in seasonal flu, almost all cases of resistance were in patients not taking Tamiflu (and have no such selection).
In pandemic H1N1, the detection has been too quick for de novo. In asymptomatic patients, incubation times are normallly 2-4 days. Patients have been developing symptoms in 5 days. The slightly longer time period indicates a lower than normal level of virus, because the virus with H274Y is a minor population (at 1-10% of the infectious virus). As a result, it takes a day or two longer to produce symptoms. For Singapore, the patient already had symptoms prior to treatment, but the detected virus switched from sensitive to resistant in a couple of days, which is too short for detection of a virus that starts from a recent copy error.
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