With Tamiflu in danger of causing more deaths than Swine Flu, and the European Medicines Agency extending its shelf life to prevent embarrasing disposals by European governments, the current outbreak of H1N1 is providential to say the least. Is the use of Tamiflu to control an essentially harmless illness likely to cause future problems in treating more serious illnesses? The investigation continues.
The widespread use of antivirals increases the risk of the virus mutating and developing a resistance to the treatment. With Tamiflu, during clinical trials it was noted that the resistance rate was 0.33% in adults, 4.0% in children and 1.26% overall. It should be noted, however, that clinical trials are limited in number and, just as Adverse Drug Reactions (ADRs) are not necessarily revealed across a limited sample, the same applies to viral resistance. At the clinical trial stage, it was noted that because Tamiflu is a neuraminidase inhibitor, it would block viral replication and therefore it was unlikely that strains of Influenza would develop immunity to a significant degree. It was confidently asserted that Tamiflu would prove more effective, and that virii would be less resistant to it than to the older anti-viral treatments, amantadine and rimantadine. Where resistance developed during the clinical trials, it involved a mutation of the virus which also weakened the ability of the virus to infect humans.
That was the theory. In practise, it was rather different. As early as 2005, during the H5N1 Avian flu outbreak it was discovered that Tamiflu resistant strains were becoming increasingly prevalent. Investigations in Vietnam discovered 2 cases of tamiflu resistance out of 8 cases studied, including at least one case where H5N1 was detected at an early stage, and Tamiflu treatment was completed. The problems appeared to be caused by dosage levels: while the recommended dosage was 2 x 75mg/day, at this level viral replication was not halted completely: indeed, it required 2 x 150mg/day to completely halt replication. This continued replication during treatment meant that in some instances resistance could develop during treatment. Both of the two resistant cases studied proved fatal to the patients. While during clinical trials it was found that a 300mg dosage level per day caused no increase in ADRs, it should be borne in mind that as discussed in the previous article, neuropsychiatric damage was not recognised as an ADR until the drug was widely used.
The 2005 study looked at resistance developed by the H5N1 strain of Influenza A. By 2007, resistance was developing in seasonal flu strains of the H1N1 strain to which Swine Flu belongs. The Centre for Disease Control in Atlanta warned in 2008 that Tamiflu may prove ineffective against Influenza A flu types, and studies into seasonal strains over the 2007-2008 flu season showed that resistance of H1N1 was running at 12.3%. this was consistent with WHO studies in Canada which showed 8 out of 81 samples were resistant to Tamiflu in the same year. By the following year, the situation had worsened considerably, and preliminary CDC data showed that H1N1 resistance had reached a staggering 98.5%. Interestingly, the report (referenced below) found that contrary to the findings of the clinical trials, Tamiflu resistant strains were no less virulent than non-resistant strains. Following this, in June of this year, Nature Biotechnology magazine published an article recommending the stockpiling of alternative treatments in the event that the Swine Flu strain developed resistance. Such warnings were met with varying degrees of action by governments who had invested heavily in Tamiflu stockpiles: studies showed that, due to lower usage, resistance rates to Relenza were markedly lower. Similar results were demonstrated in studies in Europe, and there as in Canada, Relenza remained effective.
Notwithstanding this, on the 22nd July this year, CBC News in Canada reported one case of Tamiflu resistant Swine Flu in a 60 year old man from Quebec, and noted 4 other cases had so far been reported in Denmark, Japan and Hong Kong. While there was no evidence to suggest that the Canadian patient had passed the resistant virus to anyone else, it was an entirely predictable turn of events.
So where does this leave us? The current strain of H1N1 causing Swine Flu is responding to Tamiflu treatment at the current time, although the emergence of a resistant strain is a matter of concern, or at least it would be had Swine Flu proved as serious as governments would have us believe. More to the point, the widespread use of self-prescribed Tamiflu in self-diagnosed cases of Swine Flu in the UK does increase seriously the chances of a more widespread propagation of Tamiflu resistant Swine Flu, particularly as the dosage levels are below those required to completely halt viral replication.
More importantly, there is a longer term trend here. Since the introduction of Tamiflu, and more rapidly since its widescale deployment to fight H5N1 in 2005, there has been increased resistance across all virus stains of Influenza A, while Japanese researchers also found resistance in Influenza B strains amongst those who had not previously been treated with Tamiflu at a prevalence of 1.7%.
The acid test will be the rate at which the mutated H1N1 Swine Flu tamiflu resistant strain spreads. As of 2 days ago, there were 5 cases: what rate will that reach over time, and what wider impact will it have on the effectiveness of Tamiflu as an anti-influenza medicine? There is an alternative in the form of the much less widely used Relenza, but that alternative is both expensive and difficult to administer: it can not be taken in either capsule or suspension form, only via an inhaler. The cost issue is, of course, one of the reasons why Tamiflu has to date been the preferred treatment.
In terms of the widespread (a) stockpiling and (b) current use of Tamiflu, the problems of increased resistance caused by essentially unregulated usage raises more questions. Are the 5 cases of resistance a true reflection of the level of resistance acquired by the H1N1 Swine Flu strain? It is almost impossible to tell, because the symptoms of Swine Flu in many of those infected are so mild as to be almost non-existent, but if the 'pandemic' continues at its current rate, and if viral resistance increases as it did among H1N1 seasonal flu virii over a 12 month period in United States, it is possible that the widespread early use of Tamiflu as a prophylaxis will, rather than combatting the illness, contribute to an equally virulent strain which can be treated effectively only with Relenza. The British governments last purchase of anti-viral medicines included only 20% Relenza to 80% Tamiflu, and yet the British government is creating the ideal conditions for the mutation of the strain into a resistant one.
References:
National Centre for Biotechnology Information: Oseltamivir (Tamiflu) and its potential for use in a pandemic:
http://www.ncbi.nlm.nih.gov/pubmed/15709056
New England Journal of Medicine: Oseltamivir resistance during treatment of Influenze A (H5N1), Dec22 2005, De Jong, Thanh and others:
http://content.nejm.org/cgi/content/full/353/25/2667
Got the flu? Tamiflu may not be much help, says the CDC:
http://www.physorg.com/news148968276.html
Journal of the American Medical Association: Infections with Oseltamivir resistant Influenza A (H1N1) Vrus in the United States, Dharan, Gubareva, Meyer et al
http://jama.ama-assn.org/cgi/reprint/301/10/1034
CBC News - Tamiflu resistant strain rare:
http://www.cbc.ca/health/story/2009/07/22/swine-flu-tamiflu-resistance.html
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