Tamiflu Update | Pandemic Preparedness
Frontline defense against swine flu... but for how long?
There are now several confirmed cases of swine flu resistant to Tamiflu. Overall, more than ten have been reported, as of August 2009, in various countries, including Canada, China, Japan, Hong Kong, Denmark, Singapore and the US. Further spread could result in the medication becoming ineffective–a worrying scenario, given that Tamiflu is the most widely used medicine for the prevention and treatment of swine flu.
Dangers of stopping treatment
The growing concern over Tamiflu resistance is supported by evidence that, in the past two years, the seasonal flu H1N1 virus has changed into a form almost completely resistant to the drug. Why and how, exactly, this happened is unknown, but it is reasonable to expect that the same thing might occur with the swine flu H1N1 virus.
One suggested reason for resistance is patients not finishing their treatment course; a phenomenon also referred to as medication noncompliance.
The recommended treatment course for swine flu is two 75mg capsules a day for five days. When patients start taking Tamiflu, the first H1N1 strains to die are those highly susceptible to the medication, followed by those less susceptible – that is, the more resistant.
A whole treatment course ensures that both highly and less susceptible strains are killed. But, if patients stop taking Tamiflu, the less susceptible strains survive in the body, where they continue to replicate and may, potentially, originate a strain completely resistant to the drug.
Patients, who don’t finish their treatment course are about 20 percent of all those on Tamiflu, according to researchers at Imperial College London, UK. These patients could be the key agent for transmission of resistant forms of the virus, enabling them to rapidly spread through populations. The good news is there is no evidence, so far, indicating that Tamiflu-resistant strains of H1N1 can be transmitted from person to person.
A single-dose alternative?
A solution to the problem of compliance could be a treatment that is taken only once. A strong candidate, in this regard, is Laninamivir, a swine flu medication administered through inhaler, which, according to recent findings from clinical trials conducted in Asia, is also effective at treating seasonal and avian influenza.
Manufactured by the Australian pharmaceutical company Biota Holdings Limited, Laninamivir – like Tamiflu and the other medication used for swine flu, Relenza – belongs to a class of drugs called neuraminidase inhibitors, which act early in the virus’ replication cycle, “so effectively creating a ‘still birth’ of the new virus,” says the company’s chief executive, Peter Cook.
Laninamivir, which Cook expects to be licensed for marketing in Japan, Europe and the US by next year, could represent a significant improvement in the treatment of swine flu. Not only has it been shown, in studies, to be as effective as Tamiflu, it also has the advantage that, as a single-dose medication, it is easier and less costly to stockpile, and–most importantly–potentially crucial in preventing the virus from becoming resistant due to patients not finishing their treatment.
Widespread use not the best strategy
An important contributing factor to the development to Tamiflu-resistant strains of H1N1 is the mass use of the drug, which is given for prophylaxis (prevention) also to individuals with no symptoms of swine flu.
In the attempt to make it easier for the public to obtain the medication, and avoid placing further strain on already stretched healthcare services, some governments have implemented measures to ensure access to Tamiflu for everyone. For example, in the Netherlands, the drug is distributed for free to anyone with a physician’s prescription and, in the UK, it is sold over the counter in most any store.
But, experts urge caution. Widespread access to Tamiflu may not be the best strategy. Why? Because it speeds up the spread of resistant mutations, increasing the risk of the virus becoming resistant – globally. As a result, Tamiflu would become useless. And if this happens in the fall, when a more powerful strain of H1N1 is likely to circulate, the consequences could be disastrous.
Strategies have been put forward that could, potentially, help prevent the phenomenon of Tamiflu resistance from becoming global. These, according to findings in the journal BioMed Central Infectious Diseases, include not giving Tamiflu to people over 65 – the age group supposedly at least risk of swine flu.
However, mass Tamiflu use is causing another problem. People on the drug develop side effects for which they require medical attention. And this puts additional pressure on healthcare systems worldwide.
A study published this month in the British Medical Journal shows children are a category particularly at risk. The researchers, from Oxford University, say the side effects (mostly vomiting, which may lead to potentially life-threatening complications, like dehydration) are so severe and frequent that physicians should consider giving Tamiflu only to children with underlying health problems. Those with a mild form of the infection should be given paracetamol.
What’s the advice?
In summary, swine flu has been found resistant to Tamiflu in sporadic cases, which may indicate that the threat of a global resistance to the drug is real and that strategies – like improving the drug’s compliance and limiting its use to certain patient groups – to prevent, or delay, H1N1 from becoming completely resistant may be worth considering. However, currently most patients respond well to the drug.
So, what’s the advice? In a briefing note issued on August 21, the World Health Organization (WHO) says: “Worldwide, most patients infected with the pandemic virus continue to experience typical influenza symptoms and fully recover within a week, even without any form of medical treatment. [Thus] healthy patients with uncomplicated illness need not be treated with antivirals.”
However, “for patients who initially present with severe illness or whose condition begins to deteriorate WHO recommends treatment with oseltamivir [Tamiflu] as soon as possible. Studies show that early treatment, preferably within 48 hours after symptoms onset, is strongly associated with better clinical outcome. For [these patients] treatment should be provided even if started later.”
The same recommendation applies to all children younger than five years, pregnant women and individuals with pre-existing health problems. These, too, should be given Tamiflu as soon as possible.
Since approximately 40 percent of cases of progression to severe illness occur in previously healthy individuals – mostly adults younger than 50 and children – the WHO recommends that clinicians, caregivers, and the patients themselves be particularly alert for signs of deterioration of the infection (e.g., chest pain, confusion, difficult breathing, blue skin, low blood pressure, persistent high temperature, colored sputum) “and take urgent action, which should include treatment with oseltamivir.”
“In cases of severe or deteriorating illness, clinicians may consider using higher doses of oseltamivir, and for a longer duration, than is normally prescribed.”
References
Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/h1n1flu [Accessed 08.18.2009].
Merler S., Ajelli M., Rizzo C. “Age-prioritized use of antivirals during an influenza pandemic,” BMC Infectious Diseases, July 28, 2009, 9:117.
Shun-Shin M., Thompson M., Heneghan C., Perera R., Harnden A. “Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomized controlled trials,” British Medical Journal, August 10, 2009, 339:b3172. doi: 10.1136/bmj.b3172
World Health Organization (WHO). http://www.who.int/csr/disease/swineflu/en/. [Accessed 08.18.2009].
World Health Organization (WHO). Recommended use of antivirals. Pandemic (H1N1) 2009 briefing note 8. August 21, 2009. http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_20090820/en/index.html. http://www.who.int/csr/disease/swineflu/en/. [Accessed 08.26.2009].
By Lorena Tonarelli, MSc
There are now several confirmed cases of swine flu resistant to Tamiflu. Overall, more than ten have been reported, as of August 2009, in various countries, including Canada, China, Japan, Hong Kong, Denmark, Singapore and the US. Further spread could result in the medication becoming ineffective–a worrying scenario, given that Tamiflu is the most widely used medicine for the prevention and treatment of swine flu.
Dangers of stopping treatment
The growing concern over Tamiflu resistance is supported by evidence that, in the past two years, the seasonal flu H1N1 virus has changed into a form almost completely resistant to the drug. Why and how, exactly, this happened is unknown, but it is reasonable to expect that the same thing might occur with the swine flu H1N1 virus.
One suggested reason for resistance is patients not finishing their treatment course; a phenomenon also referred to as medication noncompliance.
The recommended treatment course for swine flu is two 75mg capsules a day for five days. When patients start taking Tamiflu, the first H1N1 strains to die are those highly susceptible to the medication, followed by those less susceptible – that is, the more resistant.
A whole treatment course ensures that both highly and less susceptible strains are killed. But, if patients stop taking Tamiflu, the less susceptible strains survive in the body, where they continue to replicate and may, potentially, originate a strain completely resistant to the drug.
Patients, who don’t finish their treatment course are about 20 percent of all those on Tamiflu, according to researchers at Imperial College London, UK. These patients could be the key agent for transmission of resistant forms of the virus, enabling them to rapidly spread through populations. The good news is there is no evidence, so far, indicating that Tamiflu-resistant strains of H1N1 can be transmitted from person to person.
A single-dose alternative?
A solution to the problem of compliance could be a treatment that is taken only once. A strong candidate, in this regard, is Laninamivir, a swine flu medication administered through inhaler, which, according to recent findings from clinical trials conducted in Asia, is also effective at treating seasonal and avian influenza.
Manufactured by the Australian pharmaceutical company Biota Holdings Limited, Laninamivir – like Tamiflu and the other medication used for swine flu, Relenza – belongs to a class of drugs called neuraminidase inhibitors, which act early in the virus’ replication cycle, “so effectively creating a ‘still birth’ of the new virus,” says the company’s chief executive, Peter Cook.
Laninamivir, which Cook expects to be licensed for marketing in Japan, Europe and the US by next year, could represent a significant improvement in the treatment of swine flu. Not only has it been shown, in studies, to be as effective as Tamiflu, it also has the advantage that, as a single-dose medication, it is easier and less costly to stockpile, and–most importantly–potentially crucial in preventing the virus from becoming resistant due to patients not finishing their treatment.
Widespread use not the best strategy
An important contributing factor to the development to Tamiflu-resistant strains of H1N1 is the mass use of the drug, which is given for prophylaxis (prevention) also to individuals with no symptoms of swine flu.
In the attempt to make it easier for the public to obtain the medication, and avoid placing further strain on already stretched healthcare services, some governments have implemented measures to ensure access to Tamiflu for everyone. For example, in the Netherlands, the drug is distributed for free to anyone with a physician’s prescription and, in the UK, it is sold over the counter in most any store.
But, experts urge caution. Widespread access to Tamiflu may not be the best strategy. Why? Because it speeds up the spread of resistant mutations, increasing the risk of the virus becoming resistant – globally. As a result, Tamiflu would become useless. And if this happens in the fall, when a more powerful strain of H1N1 is likely to circulate, the consequences could be disastrous.
Strategies have been put forward that could, potentially, help prevent the phenomenon of Tamiflu resistance from becoming global. These, according to findings in the journal BioMed Central Infectious Diseases, include not giving Tamiflu to people over 65 – the age group supposedly at least risk of swine flu.
However, mass Tamiflu use is causing another problem. People on the drug develop side effects for which they require medical attention. And this puts additional pressure on healthcare systems worldwide.
A study published this month in the British Medical Journal shows children are a category particularly at risk. The researchers, from Oxford University, say the side effects (mostly vomiting, which may lead to potentially life-threatening complications, like dehydration) are so severe and frequent that physicians should consider giving Tamiflu only to children with underlying health problems. Those with a mild form of the infection should be given paracetamol.
What’s the advice?
In summary, swine flu has been found resistant to Tamiflu in sporadic cases, which may indicate that the threat of a global resistance to the drug is real and that strategies – like improving the drug’s compliance and limiting its use to certain patient groups – to prevent, or delay, H1N1 from becoming completely resistant may be worth considering. However, currently most patients respond well to the drug.
So, what’s the advice? In a briefing note issued on August 21, the World Health Organization (WHO) says: “Worldwide, most patients infected with the pandemic virus continue to experience typical influenza symptoms and fully recover within a week, even without any form of medical treatment. [Thus] healthy patients with uncomplicated illness need not be treated with antivirals.”
However, “for patients who initially present with severe illness or whose condition begins to deteriorate WHO recommends treatment with oseltamivir [Tamiflu] as soon as possible. Studies show that early treatment, preferably within 48 hours after symptoms onset, is strongly associated with better clinical outcome. For [these patients] treatment should be provided even if started later.”
The same recommendation applies to all children younger than five years, pregnant women and individuals with pre-existing health problems. These, too, should be given Tamiflu as soon as possible.
Since approximately 40 percent of cases of progression to severe illness occur in previously healthy individuals – mostly adults younger than 50 and children – the WHO recommends that clinicians, caregivers, and the patients themselves be particularly alert for signs of deterioration of the infection (e.g., chest pain, confusion, difficult breathing, blue skin, low blood pressure, persistent high temperature, colored sputum) “and take urgent action, which should include treatment with oseltamivir.”
“In cases of severe or deteriorating illness, clinicians may consider using higher doses of oseltamivir, and for a longer duration, than is normally prescribed.”
References
Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/h1n1flu [Accessed 08.18.2009].
Merler S., Ajelli M., Rizzo C. “Age-prioritized use of antivirals during an influenza pandemic,” BMC Infectious Diseases, July 28, 2009, 9:117.
Shun-Shin M., Thompson M., Heneghan C., Perera R., Harnden A. “Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomized controlled trials,” British Medical Journal, August 10, 2009, 339:b3172. doi: 10.1136/bmj.b3172
World Health Organization (WHO). http://www.who.int/csr/disease/swineflu/en/. [Accessed 08.18.2009].
World Health Organization (WHO). Recommended use of antivirals. Pandemic (H1N1) 2009 briefing note 8. August 21, 2009. http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_20090820/en/index.html. http://www.who.int/csr/disease/swineflu/en/. [Accessed 08.26.2009].
By Lorena Tonarelli, MSc
Labels: h1n1, pandemic preparedness, stats statistics BBC News swine flu infections national flu service, tamiflu
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