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

[HenryN]

Re: Third case of Tamiflu-resistant swine flu in Japan

OK, I'm lost in the translation. This is saying 28 people had cases of Tamiflu resistant some type of flu? I'm assuming even though they say avian flu they are not talking H5N1.

I added the translations for detail. I believe they indicate that 40 employees were given prophylatic Tamiflu because someone in the worlkplace was H1N1 positive. One worker developed symptoms on the 5th day of treatment. The sample was sent to NIID where they sequenced the isolate and found resistance (I assune H274Y). The infection was mild and the patient has recovered.

[AlaskaDenise]

Tamiflu resistance in pandemic influenza - historical compilation of news

Disease researchers have begun modeling how a future H1N1-09 swine-flu outbreak would spread throughout the world and have come up with some troubling scenarios. Infectious disease experts are beginning to describe modern efforts to quell seasonal and epidemic influenza with vaccines and anti-viral drugs using wording like "potentially dangerous," "worrisome," and "may do more harm than good."

This is striking in light of the multi-billion dollar worldwide effort to rapidly manufacture huge stocks of vaccines, up to an unprecedented 2 billion doses, against the 2008–09 late-flu season H1N1 swine flu epidemic. Public health officials are fearful this unusual strain of H1N1 influenza virus may mutate into a more lethal form in the fall as did the deadly Spanish flu pandemic of 1918.

Researchers at Shizuoka University in Japan, writing in a recent March 2009 issue of the Public Library of Science (PLoS One), are among the first to sound the alarm that the most relied upon weaponry against the flu, vaccines, may actually apply "immunological pressure on circulating strains of the flu which might engender the emergence of genetic variants with enhanced potential for pathogenicity in humans." Translation: mass vaccination, unless well monitored, may actually induce the dreaded gene mutation that could result in more cases, increased hospitalizations and a larger death toll.

Public health officials are just beginning to piece together how treatment-resistant forms of flu viruses develop. The paradox is that if the virulence of a vaccine-resistant flu strain is less than that of the vaccine-vulnerable strain, the epidemic might increase in proportion to the percentage of the population that elects to undergo vaccination. Researchers conclude that "a vaccination that is expected to prevent the spread of the disease can instead foster the spread of the disease."

Examples of the paradoxical effect


As an example, researchers point to a compulsory vaccination campaign for all poultry in China in 2005 involving the H5N1 influenza virus. Genetic analysis revealed that the H5N1 variant flu strain (Fujian-like influenza) emerged and subsequently became the prevalent variant in each of the 12 provinces of China, replacing previously established viruses.

In another example, H5N2 vaccines used in Mexico since 1995 appear to have promoted the emergence of various sub-strains of the flu after introduction of vaccines.

Type-A influenza viruses, which are the most common, are characterized by rapid mutation, that is, they learn to rapidly skirt around anti-viral agents. Efforts to quell flu outbreaks through vaccination in poultry may actually generate "a new pandemic virus that is dangerous for humans through a bird-human link," say researchers. All those animal influenza vaccination programs may actually increase the risk for a day when a highly virulent strain of bird flu wipes out large portions of the world’s human population.

The Skizuoka University researchers in Japan say they "remain skeptical that a vaccination program can reduce the number of total infectious individuals even if the vaccination protects against transmission of a vaccine-sensitive strain." [PLoS One 4(3):e4915, March 18, 2009]

Wagering one threat against another

While the H1N1-09 swine flu in circulation has spread rapidly, illnesses have been extremely mild and mortality rates low. But what lies ahead is unknown.

One the one hand, the H1N1-09 flu could mutate into a more virulent and deadly form and the vaccines would avert another 1918 Spanish-flu-like pandemic. But on the other hand, the vaccines currently in production against this unknown mutant variety may not confer immunity against the new variant flu virus and actually induce the very mutation that could kill millions of vulnerable humans, especially those who have little or no natural immunity or have compromised immunity due to age (very young, very old), existing disease or immune suppression.

Humanity is taking a big gamble. The impetus by public health officials and politicians to prepare human populations for mass vaccination may result in an avoidable calamity of unprecedented proportion.


2nd-Tier Anti-Viral Drugs May Induce The Same Problems

There is similar concern that over-use of anti-viral drugs, particularly early in the course of a flu outbreak, may worsen the spread and severity of a flu epidemic.

The second tier of defense against influenza is primarily comprised of anti-viral drugs known as enzyme (neuraminidase) inhibitors: oral Tamiflu tablets (oseltamivir) or nasally administered Relenza (zanamivir). Another class of anti-viral agents known as M2 ion channel inhibitors: amantidine and ramantadine, are lesser disregarded because they are ineffective against influenza-B viruses and rapidly induce drug resistance in influenza-A viruses.

Unexpectedly, resistance to Tamiflu by H1N1 flu viruses appears more common in countries with less use of the drug. Widespread under-dosing of Tamiflu can result in more drug resistant flu varieties. Of greater concern, young children appear to have greater resistance to treatment with Tamiflu than adults.

One drug not enough

In a similar manner to the newly expressed concerns over vaccines generating mutations that could worsen a flu epidemic, researchers at the Mayo Clinic now declare there is "worrisome evidence" of rapidly evolving resistance to anti-viral drugs. They now suggest the use of two different classes of anti-viral drugs at the same time so as to "prevent the development of new viral species that induce drug resistance."

The Mayo Clinic researchers say that the sequential use of one drug, such as Tamiflu initially, followed by amantidine when Tamiflu resistance occurs, is inherently flawed. The researchers say "the use of single-drug anti-viral drug therapy against influenza is unwise and dangerous." These strong comments, published in the May 2009 issue of Communicable Infectious Diseases, have drawn little or no attention from public news sources.

The cost of availability of two anti-viral drugs would further limit the number of communities that could adequately mount a defense against a deadly flu virus.

Will anti-viral drugs block or spawn a flu epidemic?

European researchers write in a report published in the October 30, 2008 issue of the Virology Journal that while the emergence of a drug resistant strain of flu virus may not necessarily be dangerous given that most prior treatment-resistant flu strains have been unlikely to spread, early surveillance data from the 2007–08 flu season in the northern hemisphere suggest the development of a type-A H1N1 Tamiflu-resistant flu virus that circulates in Europe and the US. The proportion of resistant infections ranges from 4 to 67 percent. Drug resistance occurs even without widespread use of Tamiflu. [Virology Journal 5: 133–39, October 2008]

In real numbers, not a simulation, the prevalence of Tamiflu-resistant H1N1 flu cases across Europe increased gradually over time, from near 0 in week 40 of 2007 to a startling 56% in week 19 of 2008! [Emerging Infectious Diseases 15: 552–60, April 2009] This means more than half of flu patients treated with anti-virals could face the end of their treatment options. Doctors will end up fighting the symptoms rather than the replicating virus.

Simulation of a drug-resistant flu epidemic


Flu researchers simulate a flu epidemic in a community of 100,000 people where there is no drug resistance and the flu outbreak causes 19,500 to seek doctors’ care and 258 hospitalizations.

If drug resistance develops naturally within subjects who receive the medicine, then an estimated 20,700 would seek doctors’ care and 312 would be hospitalized.

But if resistant forms of the flu are imported into the population within 21 days after onset of the epidemic, for example by people who travel by airplane from distant lands, then the infectious cases rise to 22,700 and the hospitalizations to 420.

If the drug-resistant flu strain is imported prior to the drug-sensitive strain, then the numbers rise to 25,100 who will seek treatment and 601 who require hospitalization.

This last scenario is quite troubling as it more than doubles the demand for in-hospital care. It is unlikely there are enough extra hospital beds, respirators and medicines in a community of 100,000 to treat such a flu outbreak.

Extrapolating this data into a metropolis of 8+ million people, like Los Angeles or New York City, and you have need for nearly 50,000 extra hospital beds. [Virology Journal 5: 133–39, 2008] In a country like the United States with a population of 300 million, nearly 2 million extra hospital beds would be required. God only knows what the demand for hospital beds, respirators and antibiotics would be worldwide.

Efforts by public health officials to calm public fears by claiming there are adequate stockpiles of medicines and respirators appear meager next to these horrific scenarios now being published by disease investigators.

Other researchers point to a scenario where even without any early preventive use of anti-viral drugs to prevent spread of the flu in a community, about 13.7% all drug-treated patients would be treated in vain due to resistant flu strains, and if 10–20% of the population actually do use anti-viral drugs to prevent infection, drug-resistant cases increase by 43 to 74 percent.

H1N1-09 flu virus has high transmissibility

The ability of these simulations to become reality is controlled by the capability of a drug-resistant strain to be transmitted from person to person. What has researchers concerned is that the current H1N1-09 flu is readily encircling the globe and therefore has high transmissibility. Researchers caution that the uncontrolled use of anti-viral drugs like Tamiflu could do more harm than good. Tamiflu should be restricted to treatment of active cases rather than used for prevention, say researchers. [BMC Infectious Diseases 9: 4–12, January 2009]

A problem is that many people have already acquired Tamiflu throughout the world and have stockpiled it in their home medicine chest for future use. They may elect to use it to prevent flu infection should an outbreak of the flu occur in their community. This uncontrolled use is what worries communicable disease experts.

Researchers at the University of Manitoba are concerned about an over-response to a flu outbreak where stockpiles of anti-viral drugs are depleted so rapidly early in the course of a developing epidemic that treatment cannot be completed which results in widespread drug-resistant flu strains. If drug treatment is employed too early during a flu outbreak a second wave of more severe infections can potentially occur. Controlled use of anti-viral drugs is required to prevent an epidemic of greater magnitude. [BMC Infectious Diseases 9: 8, January 22, 2009]

Current situation

What if the H1N1-09 flu virus now in circulation doesn’t mutate into a more virulent form that human populations have no immunity towards? Billions of dollars of vaccines and anti-viral drugs would only pose the potential of producing unwanted side effects and no health benefits.

Currently the H1N1-09 flu virus is running its course. Its symptoms are somewhat mild and mortality rates are low. This virus needs to mutate on time, right when H1N1-09 flu vaccines become available. The H1N1-09 vaccines won’t become available till after school starts in 2009.

Fortunately, we don’t currently have any available vaccines to induce viral mutations, but infected subjects are taking anti-viral drugs like Tamiflu which could induce resistant mutated flu strains.

There are billions of dollars of unused vaccines and anti-viral drugs ordered and stockpiled by governments and they need to unload these flu weapons onto the public, who will purchase them individually at flu clinics or through health plans.

All this has raised suspicion that vaccine makers could intentionally produce a mutated species and introduce it directly into the population, and what a better way than via vaccination.

The long dreaded H5N1 flu virus, with a 60% death rate, fizzled when it was found it is not transmitted very well from human to human. But suddenly a contaminated vaccine which combined the deadly H5N1 with more transmissible seasonal flu strains was found by Biotest, a vaccine distributor in the Czech Republic, when it was tested in ferrets and it killed all of them. [The Canadian Press February 27, 2009]

The maker of that H5N1/H1N1 contaminated flu vaccine, Baxter, had filed a patent a year prior describing a method to produce vaccines in multiple species using several different antigens (US patent: US 2009/0060950 A1). Safeguards should have prevented this contamination, which suggests the contamination was intentional.

It is just too coincidental that French President Nicolas Sarkozy visited Mexico and announced a new $126 million facility by French drug manufacturer Sanofi-Aventis at the same time the H1N1-09 swine flu outbreak broke onto the scene. President Barack Obama visited Mexico the week prior to the flu outbreak there.

There is a cozy relationship here where the World Health Organization prematurely declares a pandemic which coerces more than 80 governments to purchase flu vaccines and then public health authorities invoke mandatory flu vaccination programs for school children and become the free sales agents for the vaccine makers. The vaccine makers then funnel profits back to the vaccine makers in the form of political contributions which are veiled kickbacks.

What if vaccines and anti-viral drugs don’t work?

Should vaccines and anti-viral drugs be rendered useless by a treatment-resistant flu strain, the only backup plan is to limit the spread of the infection by quarantine and limitation of social contacts. A scenario where world commercial aircraft are grounded and schools and workplaces closed, would throw the world into economic turmoil. The masses would be grasping for any imagined flu remedy.

Researchers have begun to search for alternate treatments. Researchers in Germany write that "the increasing frequency of viral resistance to the four US Food and Drug Administration (FDA)-approved anti-influenza virus drugs underlines the urgent need for novel anti-virals to be prepared for future influenza epidemics or pandemics."

Modern medicine casts a blind eye towards strategies to boost human immunity. There are many over-the-counter products with proven ability to boost the immune response including vitamin D, Echinacea, beta glucan, vitamin C, nucleotides (RNA), selenium and zinc.

Among other non-drug agents now being explored are NF-Kappa-B inhibitors which limit viral production and resultant inflammation as well as viral resistance itself. [Journal Antimicrobial Chemotherapy 2009 July; 64(1):1–4]

Available natural NF-Kappa-B inhibitors are found in pomegranate, wine (resveratrol, quercetin), ginseng, turmeric (curcumin), ginger and vitamin D. [Mini Review Medicinal Chemistry 2006 Aug; 6(8):945–51]

http://www.lewrockwell.com/sardi/sardi114.html

[Giuseppe]

Tamiflu resistance in pandemic influenza - historical compilation of news

Eurosurveillance - Oseltamivir adherence and side effects among children in three London schools affected by influenza A(H1N1)v, May 2009 ? an internet-based cross-sectional survey

Eurosurveillance, Volume 14, Issue 30, 30 July 2009

Rapid communications

Oseltamivir adherence and side effects among children in three London schools affected by influenza A(H1N1)v, May 2009 ? an internet-based cross-sectional survey

A Kitching 1,2, A Roche 3, S Balasegaram 4, R Heathcock 5, H Maguire 3
1. European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden
2. Health Protection Agency (HPA), London Region Epidemiology Unit, London, United Kingdom
3. Health Protection Agency, South West London Health Protection Unit (HPU), London, United Kingdom
4. Health Protection Agency, North East and North Central London HPU, London, United Kingdom
5. Health Protection Agency, South East London HPU, London, United Kingdom

Citation style for this article: Kitching A, Roche A, Balasegaram S, Heathcock R, Maguire H. Oseltamivir adherence and side effects among children in three London schools affected by influenza A(H1N1)v, May 2009 ? an internet-based cross-sectional survey . Euro Surveill. 2009;14(30):pii=19287. Available online: http://www.eurosurveillance.org/View...rticleId=19287

Date of submission: 20 July 2009


This report describes the results of a cross-sectional anonymised online survey on adherence to, and side effects from oseltamivir when offered for prophylaxis, among pupils from one primary and two secondary schools with confirmed cases of influenza A(H1N1)v in London in April-May 2009. Of 103 respondents (response rate 40%), 95 were estimated to have been offered oseltamivir for prophylaxis, of whom 85 (89%) actually took any. Less than half (48%) of primary schoolchildren completed a full course, compared to three-quarters (76%) of secondary schoolchildren. More than half (53%) of all schoolchildren taking prophylactic oseltamivir reported one or more side effects. Gastrointestinal symptoms were reported by 40% of children and 18% reported a mild neuropsychiatric side effect. The results confirmed anecdotal evidence of poor adherence, provided timely information with which to assist decision-making, and formed part of the body of growing evidence that contributed to policy changes to restrict widespread use of prophylaxis for school contacts of confirmed cases of influenza A(H1N1)v.



Background

During April-May 2009, a number of London schools were advised to close due to confirmed cases of influenza A(H1N1)v in schoolchildren and antiviral prophylaxis (oseltamivir, Tamiflu?; a neuraminidase inhibitor) was offered to close contacts in the school setting. Anecdotal evidence (from family doctors in London) was suggestive of non-compliance (because of side effects) particularly when it was offered to children and adolescents. There was an urgent need to understand and provide preliminary information on adherence to, and side effects from oseltamivir, to assist decisions about strategic direction and operational policy in relation to antiviral use in United Kingdom schools.

The main objectives were: to measure the degree of adherence to oseltamivir; to measure the extent of self-reported adverse drug reactions (ADRs) to oseltamivir; and to describe reported ADRs.


Methods

We conducted a cross-sectional anonymised online survey among pupils from one primary and two secondary schools in London with confirmed influenza A(H1N1)v cases. The schools emailed a weblink to the questionnaire to parents, with a letter describing the study, seeking consent and participation. Parents/guardians were also offered the opportunity to complete the questionnaire with the child (e.g. for younger children). As the main method of communication of each school with parents or guardians was via email, internet access (email use) was not a decisive criterion in selecting participants. The selection process varied depending on which classes the confirmed cases were in, which year groups had been offered prophylaxis, and on negotiation with school management regarding feasibility. In two schools (one primary and one secondary school) we selected all classes who were offered prophylaxis, i.e. all pupils in the primary school (age range 4-11 years; n=122), and all of one year group in the secondary school (age range 13-14 years; n=68). In the other secondary school, while the whole school was offered prophylaxis, the questionnaire was offered only to pupils in two classes in the year group with the highest attack rate, and pupils in two classes in a year group with no confirmed cases (age range 11-13 years; n=66).

The questionnaire included questions on student class and year group; whether they took any oseltamivir if offered it and for what duration; presence or absence of influenza-like symptoms before taking oseltamivir; other medication taken with oseltamivir; and symptoms after taking oseltamivir (including specific gastrointestinal and neuropsychiatric symptoms). The questionnaire included a section for parental comments.

As preliminary information was required quickly, the weblink to the questionnaire was emailed to parents/pupils on the morning of Thursday 14 May asking for completion by midnight that night. Data from the initial responses was downloaded on Friday 15 May, and a preliminary report produced. The survey closed at 09.00 on Monday 18 May.

Due to concerns raised by the schools regarding deductive disclosure (i.e. discerning of an individual respondent's identity and responses through the use of known characteristics of that individual), particularly where there were small numbers of cases in a class or school, pupils were not directly asked if they had been prescribed oseltamivir for treatment or for prophylaxis. As previously stated, questions were asked about the presence or absence of influenza-like symptoms, the duration of oseltamivir course taken, and the school year and class of the respondent. This helped to determine those given oseltamivir for prophylaxis. Children without symptoms could not be a case (as they would not meet the clinical criteria for testing) and therefore would have been offered oseltamivir for prophylaxis; those with influenza-like symptoms could be a confirmed case (and offered 5-day treatment course) or a discarded case (and offered 10-day prophylaxis course). Hence, no symptoms or course duration of 6-10 days would imply a course of prophylaxis (according to a tiered weight-based dosing regimen, see Table). In addition, as the specific classes of all cases were known, pupils in other classes could not have been cases.

[Table. Tiered weight-based dosing regimen for 10-day course of oseltamivir prophylaxis in children]


Results

Response rate

The weblink was sent to 256 schoolchildren, with a final overall response rate of 40% (103/256); 35% (43/122) in the primary school, and 42% (28/66) and 47% (32/68) in the secondary schools respectively.


Adherence to oseltamivir when offered for prophylaxis

Ninety-five schoolchildren (41 in the primary, and 54 in the secondary schools) were estimated to have been offered oseltamivir for prophylaxis, of whom 85 (89%) actually took any. The ten children who took none of the prescribed course were all primary school pupils.

Two thirds (66%, 56/85) of those who took ?any oseltamivir? completed (or said they would complete) a full 10-day prophylaxis course. However, less than half (48%, 15/31) of primary schoolchildren completed a full course, compared to three-quarters (76%, 41/54) of secondary schoolchildren.


Adverse drug reactions (ADRs)

More than half (53%, 45/85) of all schoolchildren taking prophylactic oseltamivir reported one or more side effects. The most frequently reported symptom overall was nausea (29%), followed by stomach pain/cramps (20%) and problems sleeping (12%).

Gastrointestinal side effects (defined as one or more of the following symptoms - feeling sick/nauseous, vomiting, diarrhoea, stomach pain/cramps) were reported by 40%, and almost one in five schoolchildren (18%) reported a neuropsychiatric side effect (one or more of the following symptoms - poor concentration/unable to think clearly, problems sleeping, feeling dazed/confused, bad dreams/nightmares, behaving strangely). A neuropsychiatric side effect was more commonly reported by secondary (20%) than primary (13%) schoolchildren (see Figure).

[Figure. Main symptoms reported by schoolchildren taking oseltamivir for prophylaxis in three London schools, May 2009 (n=85)]


Parental comments

Comments showed that parents often made their own risk assessment as to the likely benefit of oseltamivir to their child. Despite oseltamivir (Tamiflu?) being recommended by healthcare professionals, parents often appeared sceptical of the need for medication, especially when the indication was to prevent onward transmission rather than give a specific benefit to the individual asymptomatic child. Many parents questioned the scientific basis of our advice, recognising that prophylaxis would not confer longer lasting immunity or protection. They also raised the possibility that we may be doing more doing more harm than good i.e. in relation to the ?risk? (potential side effects) from oseltamivir compared to the ?risk? from influenza A(H1N1)v. There were also comments on the need to have sufficient information about the type and nature of any potential side effects in order to enable parents to make informed decisions.


Discussion and conclusion

This study was undertaken in the containment phase of the response to influenza A(H1N1)v in the United Kingdom (UK). It provided preliminary information on adherence to, and side effects from oseltamivir in schools; and a useful snapshot of attitudes and behaviours regarding oseltamivir use.

Managing school incidents is always challenging, ensuring communications are appropriate and often managing high levels of anxiety. Containment through interventions at school level is hindered by the high level of mixing between children in schools (siblings in different years and/or different schools, facilities shared with other schools, children involved in complex inter-school networks due to shared after-school activities - formal and informal). Case identification, risk assessment, and organisation of mass prophylaxis will frequently be outside the 48 hours quoted in the literature for the use of oseltamivir for prophylaxis [1]. In addition, little is known about how children adhere to such prolonged treatment (5-day course) and prophylaxis (10-day course).

A key component of influenza therapy and prophylaxis is the possibility for development of resistance. The magnitude and duration of neuraminidase inhibitor concentrations at the site of infection are thought to be an important factor in determining the likelihood of drug resistance arising in influenza viruses [2]. Low drug concentrations which only partly block viral replication and result in suboptimal virus suppression could enhance the risk by providing an environment for drug-resistant virus to emerge [2,3]. In our study, not all who started a course of oseltamivir for prophylaxis completed that course. While some reported discontinuing the course due to side effects, others reported doing so due to concerns about the effectiveness of oseltamivir and its necessity. Such incomplete adherence to the recommended course of oseltamivir could contribute to the development of drug-resistant virus.

The commonest adverse effect reported in the literature on oseltamivir is dose-related nausea [4-8], which occurs twice as frequently (as with placebo) when used as prophylaxis [9]. In controlled clinical trials, approximately 10% of patients reported nausea without vomiting, and an additional 10% experienced vomiting [5,10]. Insomnia has also been reported [5].

In recent years, there have been a number of post-marketing case reports (mainly from Japan) of neuropsychiatric events (such as delirium, hallucinations, confusion, abnormal behaviour leading to injury, convulsions, and encephalitis [4,11]), particularly in children younger than 16 years [4]. While a review of the available information on the safety of Tamiflu? in paediatric patients by the United States (US) Food and Drug Administration (FDA) suggested that the increased reports of neuropsychiatric events in Japanese children are most likely related to an increased awareness of influenza-associated encephalopathy, increased access to Tamiflu? in that population, and a coincident period of intensive monitoring of adverse events [4], this prompted the addition of associated precautions to the US product label for oseltamivir [12]. A retrospective cohort study funded by Roche (who make Tamiflu?) noted a higher rate of episodic mood disorders among those aged 17 years and below receiving oseltamivir compared to those who received no antiviral treatment [12].

In our study, more than half of all schoolchildren taking prophylactic oseltamivir reported one or more side effects. The commonest symptoms reported were gastrointestinal, most frequently nausea, as in the published literature [4-8]. Although no serious neuropsychiatric events were described in our study (as have been described in Japanese case reports [4,11]), almost one in five respondents reported a neuropsychiatric symptom, most frequently difficulty sleeping, bad dreams/nightmares and poor concentration, which would impact on school and studying for those concerned. This may be of particular concern to exam-year students (and their parents).

The possibility of group psychological effects leading to an apparent cluster of symptoms has been suggested. The children are socially linked, and social contact may facilitate spread of ?psychogenic? symptoms [13,14], but not typical ?biological? symptoms. However, previous reports suggest such symptoms often remit with dispersion of the group [14]. The three schools in our study were closed for the period when children were taking oseltamivir prophylaxis.

Many of the children will have been told to take oseltamivir rather than seeking it out; this may also result in higher self-reported side effects. If it is rumoured that side effects are frequent, students may over-report through a desire to conform. However, while the possibility of ?autosuggestion? through discussion of symptoms on Facebook was raised by a parent of one secondary school pupil, there was no increased reporting of similar symptoms from other students in the same class.

While the high level of reported side effects may have had a ?psychogenic? component, e.g. children with high anxiety levels (due to the outbreak or due to other factors such as concomitant exams) might somatise and exhibit more nausea and vomiting, or have more difficulty sleeping, comments made by some parents regarding the nature of side effects experienced by their children (particularly in relation to observed disturbed sleep, altered behaviour, and being unusually tearful) are not likely to have been influenced by this. A telephone survey of 1,000 residents (over 18 years of age) of England, Scotland and Wales, carried out between 8 and 12 May just prior to our survey, explored public perceptions, anxiety and behaviour change in relation to the influenza A(H1N1)v outbreak [15]. Results from this survey suggest that anxiety among the general public about the outbreak at this time was low, with only 24% of participants reporting any anxiety and only 2% reporting high anxiety [15].

There are some striking similarities to the literature on adherence to antimicrobial prophylaxis (to prevent inhalational anthrax) among postal workers during the 2001 anthrax incidents in the United States [16,17]. In an environment characterised by uncertainty, and also by changing recommendations for screening or treating at-risk individuals as more was learned during the outbreak investigation, study participants in the anthrax incidents used multiple sources of information and support as they weighed the risk from anthrax against their perceptions of the advantages and disadvantages of antibiotics [16]. Anxiety [18], experiencing adverse events to prophylaxis [18], and following the advice of private physicians [16] who often contradicted public health recommendations regarding antibiotic prophylaxis, were all risk factors for discontinuing anthrax prophylaxis [16]. Changing recommendations were often perceived as conflicting information and advice [16].

In this study also, comments showed that parents often made their own risk assessment as to the likely benefit of oseltamivir to their child. It was suggested, in the comments in our survey, that some parents had on occasion received different advice from other healthcare professionals than that given by the Health Protection Agency. There was also a suggestion of a possible impact of changing recommendations, as in the anthrax studies [16].

A number of limitations apply to our study. The numbers are small. As the survey had to be done quickly, there was limited time for a full negotiation with schools regarding methodological issues, and limited time to give to pupils and their parents to complete the survey (initial responses were requested from pupils and their parents by the end of the same day they received the survey), which may have influenced the low response rate.

Regarding representativeness, the three schools surveyed were independent (non-state) schools, with a bias towards well educated parents from higher socio-economic groups, who are used to debate/negotiation (using information from multiple sources) before reaching an individual decision. They are thus not representative of the broader UK school population (but perhaps of pupils attending similar schools in London and elsewhere). The low uptake of antivirals seen in our study was also reflected in another outbreak in an independent boarding school in South East England, where estimated uptake of antivirals among those for whom it was recommended was only 48% [19].

However, while there may be sources of bias in the methodology and results, we believe the comments made by parents are legitimate and provide insight into parental attitudes and concerns. As such they are very helpful as they reflect factors which may have an influence on implementation of national policy in future. The use of an online questionnaire format (with internet-aware parents and pupils) enabled this survey to be done quickly, providing timely information with which to assist decisions about operational policy in an evolving incident.

The study findings formed part of the body of growing evidence that contributed to policy change in the UK. Current UK advice is to limit antiviral prophylaxis in schools to the small number of contacts considered most at risk. Further studies are planned in other schools in London and nationally to provide further information about attitudes, including child and parental perception of risks associated with Influenza A(H1N1)v, as well as behaviours and practical implementation of antiviral prophylaxis in the current influenza A(H1N1)v outbreak. In addition, these studies will explore the possible role of psychological mechanisms in generating ?adverse drug reactions?.


Acknowledgements

We would like to acknowledge the schools involved in this survey, and thank them for their patience and support.


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16. Stein BD, Tanielian TL, Ryan GW, Rhodes HJ, Young SD, Blanchard JC. A bitter pill to swallow: nonadherence with prophylactic antibiotics during the anthrax attacks and the role of private physicians. Biosecur Bioterror. 2004;2(3):175-85.
17. Shepard CW, Soriano-Gabarro M, Zell ER, Hayslett J, Lukacs S, Goldstein S, et al. Antimicrobial postexposure prophylaxis for anthrax: adverse events and adherence. Emerg Infect Dis. 2002;8(10):1124-32.
18. Jefferds MD, Laserson K, Fry AM, Roy S, Hayslett J, Grummer-Strawn L, et al. Adherence to antimicrobial inhalational anthrax prophylaxis among postal workers, Washington, D.C., 2001. Emerg Infect Dis. 2002;8(10):1138-44.
19. Smith A, Coles S, Johnson S, Saldana L, Ihekweazu C, O?Moore E. An outbreak of influenza A(H1N1)v in a boarding school in South East England, May-June 2009. Euro Surveill. 2009;14(27):pii=19263. Available from: http://www.eurosurveillance.org/View...rticleId=19263
-

<cite cite="http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19287">Eurosurveillance - View Article</cite>

[HenryN]

Re: Third case of Tamiflu-resistant swine flu in Japan

Tokushima Prefecture was confirmed in patients (30 man) for the avian flu was detected, indicating it H275Y Tamiflu resistance was reported from the National Institute of Infectious Diseases and the separation of the avian flu that mutated gene, the information provides an overview.

However, according to the ministry, with the mutant gene are resistant to Tamiflu, the severity of the virus (pathogenic) is a direct influence is not.


Profile of virus detection>

Contents of a genetic analysis by the National Institute of Infectious Diseases

H275Y oseltamivir resistance marker was detected.
The hybridization of seasonal influenza A/H1N1 virus with the genes that have
Was confirmed.

In the future, the National Institute of Infectious Diseases, drug susceptibility tests are being judged.


2 after the patient
Patients, the incidence of Tamiflu for prevention in the administration, immediately after weighting for the antipyretic treatment, a cure.
Then, to spread around, including a family is not approved.
The travel history of patients.

http://anshin.pref.tokushima.jp/infection/influenza.html?infection_influenza_id=2009_124877425121&news_year=2009

[Commonground]

Tamiflu resistance in pandemic influenza - historical compilation of news

Monday, 3/8/2009

Excerpt:

Also by Dr. Hien, Institute of Hygiene and cultural are conducting research, analyzing the nucleotide sequence of the HA gene of the vaccine virus, results in the virus initially shows: Gene influenza virus by HA's A/H1N1 and get in people in Vietnam have similar high level of the whole virus vaccine for pandemic influenza A/H1N1 in the current world from 99% -100%.

Results raising trees and the NA gene for sudden changes related to drug resistance to Tamiflu not detect sudden changes in position 274 and 294 relating to the resistance or lower level of the sensitive virus with Tamiflu pandemic A / H1N1. Activity monitoring of the circulating influenza virus vaccine in the community at 15 monitoring points in the country has strengthened and has detected a number of patients infected with influenza A/H1N1 in a monitor.

http://tinyurl.com/l6zxbl

[Shiloh]

Tamiflu resistance in pandemic influenza - historical compilation of news

Source: http://www.google.com/hostednews/afp...GE3KnYOs5DuTtA

Tamiflu-resistant swine flu found on US-Mexico border

(AFP) ? 1 hour ago

LA JOLLA, California ? A strain of swine flu that is resistant to treatment with the drug Tamiflu has been discovered near the US-Mexican border, the Pan-American Health Organization (PAHO) said on Monday.

"We have found resistance to Tamiflu on the border. We have observed some cases, few to be sure, in El Paso and close to McAllen, Texas," said Maria Teresa Cerqueira, head of the local PAHO office.

Cases of A(H1N1) that were resistant to the anti-viral medicine have now been found in the United States, Canada, Denmark, Hong Kong and Japan.

Experts gathered in La Jolla, California on Monday to discuss the response to the outbreak, said the resistance was likely due to overuse of antivirals like Tamiflu.

"In the United States Tamiflu is sold with a prescription, but in Mexico and Canada it is sold freely and taken at the first sneeze. Then, when it is really needed, it doesn't work," said Cerqueira.

Roche, the manufacturer of Tamiflu, has said it expects a 0.5 percent rate of case resistance based on clinical trials.

Cerquiera said one patient diagnosed with a Tamiflu-resistant strain had been treated with Zanamivir -- an anti-viral made by GlaxoSmithKline -- and another was given no alternative medication. Both survived.

Since the swine flu outbreak emerged earlier this year it has killed 353 people in the United States and 146 in Mexico, according to authorities from each country.

A large proportion of nearly 1,000 recorded deaths around the world since the virus was first identified in Mexico in April have involved people with underlying medical conditions.

World Health Organization chief Margaret Chan has urged countries to boost their drug stockpiles amid warnings of the virus's continued spread.

"Manufacturing capacity for influenza vaccines is finite and woefully inadequate for a world of 6.8 billion people, nearly all of whom are susceptible to infection by this entirely new and highly contagious virus," Chan said on July 14.

A vaccine against the disease is currently being tested for safety and effectiveness, and is expected to be ready in the next two to four months, although the precise date is unclear.

US officials have recommended that children and pregnant women be among the groups first in line for swine flu shots, but said they were unlikely to have enough vaccine for everyone once the drug is ready to be rolled out.

Greece has announced it will vaccinate all its 11-million-strong population, the first country to introduce such a broad measure amid the current pandemic.

With such pledges emerging, developing nations have expressed concerns they will be left out, as richer nations race to build stock piles.

UN Secretary General Ban Ki-moon has said developing countries could need about one billion dollars by the end of the year to fund measures against the swine flu pandemic, especially vaccines.

[HenryN]

Re: Tamiflu-resistant swine flu found on US-Mexico border

Source: http://www.google.com/hostednews/afp...GE3KnYOs5DuTtA

Tamiflu-resistant swine flu found on US-Mexico border

"We have found resistance to Tamiflu on the border. We have observed some cases, few to be sure, in El Paso and close to McAllen, Texas," said Maria Teresa Cerqueira, head of the local PAHO office.

These two locations are at opposite ends of the Texas border with Mexico. It is unclear if these patients had been treated with Tamiflu. I strongly suspect that the one that recovered without "alternative" (instead of "additional") treatment was NOT treated with Tamiflu.

[HenryN]

Re: Tamiflu-resistant swine flu found on US-Mexico border

Check the wording again. They said "few cases" not two cases. Perhaps I am reading the text too closely, but the way it was written implies it may be more than 2. Also:



Again, I may be reading plain English too literally, but they said "another", not "the other." People speaking in an official capacity really ought to be more careful with their wording.

It also says the other patient had "diagnosed" Tamiflu resistance and was treated with Relenza. It doesn't say that the patient developed Tamiflu resistance. I suspect that testing is up because FIT Tamiflu resistance has been found.

[Jeremy]

Re: Tamiflu-resistant swine flu found on US-Mexico border

Roche, the manufacturer of Tamiflu, has said it expects a 0.5 percent rate of case resistance based on clinical trials.

Niman,

Correct me if I am wrong but didn't the previous strain of H1N1 from last year have close to 100% Tamiflu Resistance?

If that is the case, this statement can't really be true can it?

[wotan]

Re: Tamiflu-resistant swine flu found on US-Mexico border

Niman,

Correct me if I am wrong but didn't the previous strain of H1N1 from last year have close to 100% Tamiflu Resistance?

If that is the case, this statement can't really be true can it?

I think that refers to de novo development.

[HenryN]

Re: Tamiflu-resistant swine flu found on US-Mexico border

Niman,

Correct me if I am wrong but didn't the previous strain of H1N1 from last year have close to 100&#37; Tamiflu Resistance?

If that is the case, this statement can't really be true can it?

The seasonal flu was at 100% resistant (had H274Y) but NOT linked to Tamifu use (which I suspect is the case in these patients).

[AlaskaDenise]

Re: Tamiflu-resistant swine flu found on US-Mexico border

Commentary

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

Commentary

Tamiflu Resistant Pandemic H1N1 Cases in Texas

Recombinomics Commentary 03:14
August 4, 2009

"We have found resistance to Tamiflu on the border. We have observed some cases, few to be sure, in El Paso and close to McAllen, Texas," said Maria Teresa Cerqueira, head of the local PAHO office.

Cerquiera said one patient diagnosed with a Tamiflu-resistant strain had been treated with Zanamivir -- an anti-viral made by GlaxoSmithKline -- and another was given no alternative medication. Both survived.

The above comments describe at least two oseltamivir resistant patients along the Texas / Mexico border. The cases are at opposite ends of the border (see map) and raise concerns that the resistance developed in the absence of Tamiflu treatment. One patient had "diagnosed" resistance and was treated with Zanamivir, while the other wasn't treated with Zanamivir, leaving open the possibility that neither were treated with oseltamivir. Moreover, the wording left open the possibility that there were more than two patients, suggesting fit swine H1N1 with H274Y was circulating over a wide area.

The emergence of fit swine H1N1 with H274Y is not a surprise. A case has already been reported in Hong Kong in a traveler from San Francisco. The precursor for this strain has been reported worldwide, although the only case reported in the US was in April in New Jersey, raising concerns that the fit strain was circulating silently, in part because the cases were mild and not being tested. The patient in Hong Kong, like one of the patients recovered without treatment with Relenza, indicating the cases were relatively mild.

The fact that these cases were reported simultaneously also raises concerns that a fit H274Y is circulating in the area.

Details on the number of cases, and release of sequences, would be useful.

.

[vinny]

Re: Resistant flu virus mutation to Relenza found in lab

Health officials said they had found cases of Tamiflu-resistant swine flu along the US border with Mexico, as India and South Africa announced their first deaths from the A(H1N1) virus.



"We have found resistance to Tamiflu on the border. We have observed some cases, few to be sure, in El Paso and close to McAllen, Texas," said Maria Teresa Cerqueira, head of the Pan-American Health Organization office in La Jolla, California.

Cases of A(H1N1) that were resistant to the anti-viral medicine have now been found in the United States, Canada, Denmark, Hong Kong and Japan.

Experts had gathered in La Jolla on Monday to discuss the response to the outbreak, and warned that resistant strains were likely emerging because of overuse of antivirals like Tamiflu.

"In the United States Tamiflu is sold with a prescription, but in Mexico and Canada it is sold freely and taken at the first sneeze. Then, when it is really needed, it doesn't work," said Cerqueira.

The Tamiflu-resistant cases were reported as South Africa and India both announced their first fatalities from the A(H1N1) virus, which emerged in Mexico in April and has since spread worldwide, gaining pandemic status.

In South Africa, health authorities said Ruan Muller, a 22-year-old student at Stellenbosch University near Cape Town, had died after contracting the virus.

"He died on the 28th (of July), but there had to be some testing done to ensure the cause of death. It was the A(H1N1) influenza," said Fidel Hadebe, spokesman for South Africa's Department of Health.

With the world's highest number of HIV/AIDS-affected people -- nearly 19 percent of a 49-million-person population -- South Africa is considered particularly at risk because people with compromised immunity are more likely to fall prey to the disease.

South Africa's swine flu caseload has increased fourfold since the country's first case was reported on June 14. The government has said its stockpile of Tamiflu will only be used for the seriously ill, but that schools may also be closed on a case-by-case basis.

In India, authorities said a 14-year-old girl in the western city of Pune became the country's first fatality from the virus.

The teenager first felt unwell on July 21, complaining of a sore throat, runny nose and headaches. She returned to school the following day after the general symptoms improved, the Ministry of Health and Family Welfare said.

She then developed a fever again on July 25 and two days later was admitted to a private clinic for treatment. She was put on a ventilator in an intensive care unit and was treated with Oseltamivir, a generic brand of Tamiflu.

"Her condition deteriorated again with multi-system involvement and (she) expired on the evening of 03.08.09," the ministry said in a statement.

Meanwhile, the Russian state health agency warned the country's football fans to stay away from the national team's World Cup qualifying tie with Wales in Cardiff on September 9.

"This would be an extremely unnecessary and inappropriate undertaking at a time of a flu epidemic," the head of Russia's state health agency Gennady Onishchenko said, according to local news agencies.

Onishchenko expressed fear that "the expressions of emotion on the part of football fans involving intense shouting" could lead to the airborne transmission of the flu virus.

Russia has to-date been relatively spared by the swine flu pandemic, with just 55 confirmed cases in the country.

Experts remain puzzled as to why different countries have not always been affected to the same degree, with England and Scotland both heavily hit proportionately, yet neighboring France's tally appearing light by comparison.

Some have argued that gargantuan sums being spent by rich economies on a disease that is no more lethal than seasonal flu are grotesquely disproportionate when thousands die each day of diseases which receive less media coverage.

http://uk.news.yahoo.com/18/20090804/thl-treatment-resistant-swine-flu-detect-5effa79.html

[HenryN]

Re: Tamiflu-resistant swine flu found on US-Mexico border

(Google translation)

Several patients were found to be resistant to antiviral near the border. "This is not a surprise, there was no worry," says Roche, which estimated that 0.5&#37; rate of resistance.


Boxes of Tamiflu (Sipa)
Cases of resistance to Tamiflu, the main antiviral drug used against influenza A (H1N1), were found near the border between the United States and Mexico, said Monday 3 August the Pan American Health Organization (PAHO). "We found cases of Tamiflu resistance to the border. We have seen some cases, few of which we are confident, El Paso and around McAllen, Texas," said Dr. Maria Teresa Cerqueira, responsible local office of PAHO, at a conference on influenza A. The persons concerned cross the border regularly and were autom&#233;dicament&#233;es, says the doctor.


Cases "isolated"
"In the U.S., Tamiflu is a prescription but it is widely available in Mexico and Canada and took the first sneeze. And when it is really useful, it does not work anymore", said Maria Teresa Cerqueira. She explained that a patient with a strain of influenza A (H1N1) viruses resistant to Tamiflu has been treated positively to Zanamivir, another antiviral drug, and another patient received no other treatment. Both patients survived, she argued.
In July, a case of resistance to Tamiflu had been found in Canada. It was the first case in North America, according to Dr. Guy Boivin, Center hospitalier de l'Universit&#233; Laval (CHUL) in Quebec, who had discovered this resistant strain. Cases of resistance to antiviral therapy were also recorded in Denmark, Japan and Hong Kong.
The World Health Organization (WHO) has estimated that these cases are "isolated" and that it maintains its recommendation for Tamiflu and Relenza.


"There is no worry for the moment"
The laboratory Roche, Tamiflu seller, said he expected at 0.5% of its antiviral resistance from the results of clinical trials.
"This is not a surprise," says the director of the pharmaceutical division of Roche, William Burns: "in the case of the flu season, about 0.4% of the organisms may be resistant. There not worried at the moment. " "We do not increase in these cases of resistance," adds the CEO of Roche Severin Schwan.
"It is not excluded that in a community where people are treated with Tamiflu, there are few cases of viruses that develop resistance and spread," explains Dr. Thierry Buclin, a medical assistant in the office clinical pharmacology and toxicology at the CHUV of Lausanne. "The real question is: who should take Tamiflu?" Dr. Buclin nuance. "What you win to deal with Tamiflu, if one can be cured with paracetamol?" Hits there.

http://tempsreel.nouvelobs.com/actualites/societe/20090804.OBS6428/des_cas_de_resistance_au_tamiflu_a_la_frontiere_america.html

[HenryN]

Re: Tamiflu-resistant swine flu found on US-Mexico border

(Google translation)

"We found cases of Tamiflu resistance to the border. We have seen some cases, few of which we are confident, El Paso and around McAllen, Texas," said Dr. Maria Teresa Cerqueira, responsible local office of PAHO, at a conference on influenza A. The persons concerned cross the border regularly and were autom?dicament?es, says the doctor.




http://tempsreel.nouvelobs.com/actua...e_america.html

This version of the AFP story suggest that resistance might have been linked to self-prescribed tamiflu. However, it doesn't state that it was, and also does state that the resistance was discovered because the patients received Tamiflu treatment from a doctor. Thus, the number of patients and details surrounding the "diagnosis" remain murky.