# 323
The big news overnight, of course, is the revelation that two patients in Egypt who died in December of the H5N1 virus developed Tamiflu resistance. Rumors to this effect have been circulating on the web for a couple of weeks, prompted in part by the recent high mortality rate experienced in Egypt.
While none of this is good news, before we get our knickers in a bunch, it may not be quite as bad as it sounds. First, the article from the New York Times, and then a bit of discussion.
New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug
Published: January 18, 2007
A strain of avian flu that is resistant to the antiviral drug oseltamivir has been isolated from two family members in Egypt, the WHO (World Health Organization) said yesterday.
The development is potentially dangerous because oseltamivir, commonly sold under the name Tamiflu, is the chief weapon against the flu strain, H5N1, which many worry could mutate into a strain that could set off a worldwide pandemic.
The health organization emphasized that it was too early to tell whether the resistant strain had developed independently in the two patients, who were both under treatment with the drug, or whether they had picked it up from birds or from each other. The resistant strain did not spread to anyone else, including a third family member who also had avian flu.
“Given the information we have, we don’t see any broad public health implications,” said Dick Thompson, a spokesman for the organization.
Mr. Thompson was unsure which Egyptian cluster of flu infections the patients were part of. But another source said it was one in Gharbiya Province, roughly 50 miles north of Cairo, in which flu killed three people last month in a 33-member family living in one compound.
News of a Tamiflu resistant strain of the H5N1 virus swept the headlines a little over a year ago, when two patients in Vietnam reportedly developed resistance after receiving the drug.
The operative words here are `after receiving the drug’. The virus, isolated when they were first admitted into the hospital, wasn’t resistant, but mutated during the course of treatment and developed resistance.
It is expected that in a certain percentage of patients, Tamiflu resistance may develop. The New England Journal of Medicine (NEJM), December 22, 2005 edition’s article entitled Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection, states the following regarding Tamiflu (oseltamivir) resistance in normal (seasonal) influenza.
The emergence of resistant influenza A (H5N1) variants during oseltamivir treatment should not be surprising. In adults with influenza A (H1N1) or (H3N2) virus infection, the development of resistance to oseltamivir is rare, but resistant viral variants have been detected in up to 18 percent of children who receive oseltamivir.12,13,14 The difference in resistance rates between adults and children may be explained by the occurrence of a primary infection in children associated with higher rates of viral replication owing to a lack of previous immunity. Since humans have no previous immunity to influenza A (H5N1) virus, all human infections with this virus are primary infections. In addition, studies in animals indicate particularly high levels of replication of current influenza A (H5N1) strains.15,16
Tamiflu resistance is therefore expected to develop in a certain (as yet, unknown) percentage of patients. With Avian flu, it is thought that percentage might be higher than with seasonal flu, because of its high rate of replication and our lack of previous exposure.
What we don’t know at this juncture is if these two patients in Egypt developed the resistance after receiving the drug, or acquired a mutated strain of the virus already resistant to Tamiflu. While it may make little difference to the patient in question (a bad outcome is a bad outcome), it makes a big difference to the world at large.
Right now, there are simply too many unknowns in this report to draw any conclusions.
We don’t have details as to the dosage of Tamiflu that was administered, or the duration, or how far along in the illness either patient was when they started to receive treatment. We don’t know if the virus was genetically sequenced prior to treatment, and if it showed markers that would indicate resistance then, or if it was done after treatment was begun.
Frankly, this report is remarkable for its lack of detail. No fault on the part of the reporter, I'm sure. Hopefully authorities will be more forthcoming with information soon.
A resistant strain in the wild would be, obviously, of greater concern than occasional patients developing resistance. But even then, that strain would have to be the one to acquire pandemic caliber transmissibility before that became a huge problem.
It is of concern that we have so few options for antiviral treatments of the H5N1 virus. Basically, beyond Tamiflu, we have Relenza, and Amantadine/Rimantadine. The amantadines are older drugs, with occasionally serious side effects, that have in recent years have lost effectiveness against seasonal influenza. Relenza is expensive, and is more difficult to deliver to the patient, as it is an inhaled powder.
Two factors that may come into play in helping the virus develop resistance are the timing of the treatment, and the dosage administered. The earlier in the course of the illness the antivirals are given, the more effective they are. And there is evidence that the optimal dosage may be higher than the 10 pills over 5 days treatment currently advocated.
Again, from the NEJM article mentioned above:
Our observations suggest that at least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop.
Should additional cases of Tamiflu resistance continue to show up, or if a resistant virus strain is isolated in the wild, then we may be facing a bigger problem.
But the truth is, for most of the world (including many of those who live in western societies) should a pandemic erupt, Tamiflu resistance is going to be a moot point. Our strategic national stockpiles of this drug are only such that perhaps 20 million people in the United States could be treated now, and that assumes the 10-pill course of treatment.
More Tamiflu is on the way, but we are two years away from having enough for 25% of the nation, once again at the lowest dose. For most of the world, if a pandemic begins, Tamiflu simply won’t be part of the equation.
It’s a sobering reality.
We have no magic bullet for a novel influenza virus. There are treatments under investigation that show promise; statins, prednisolone, and even the faint hope of a vaccine, among others.
But we need more research, and a genuine commitment to finding the answers.
Most of all, we need time.
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