Wednesday, March 29, 2006

Figuring out Tamiflu

The one antiviral people hope will work in H5N1 prophylaxis (and marginally for early treatment) is oseltamivir (Tamiflu). Yet there is much uncertainty about how to use it and its efficacy for this virus. Helen Branswell reports on a meeting this week in Geneva where available clinical reporting on its use in H5N1 infections will be picked over and wrung out for as much information as possible. There are no clinical trials of the drug in H5N1.
"Clearly we need more information on how the drugs work in the actual prevention and treatment of avian influenza," said Dr. John Treanor, author of a number of scientific papers on neuraminidase inhibitors, and a professor at the University of Rochester, N.Y.

"We've extrapolated everything from what has been done with conventional flu. And it's very likely, or at least possible, that the response to treatment with H5 would be different in several different ways."
Tamiflu is not the only drug of its class. Zanamivir (Relenza) also works through the same mechanism, but has to be administered by inhalation because its active form is not absorbed. Tamiflu, by contrast, is actually a "pro-drug" that is converted to active form after absorption. Tamiflu can therefore be given orally, an advantage which has made it considerably more popular. Some believe that Relenza may have been overlooked in the process:
"To me, a really big question is: What about Relenza? And I really hope that gets talked about a lot," said Dr. Anne Moscona, an infectious diseases specialist at Weill Medical College at Cornell University in New York.


[A] number of experts, including Moscona, believe its potential has been under-explored.

For one thing, they suggest the drug's design makes it less vulnerable to the emergence of resistant viruses. To date there have been no reported cases of resistance to zanamivir, whereas oseltamivir resistance has been seen in low numbers both with human flu strains and in cases of H5N1 infection.
I am not sure what the evidence is for a lesser propensity to resistance in Relenza. But while it works by the same mechanism as Tamiflu, the occasional examples of H5N1 reported resistant to Tamiflu were still sensitive to Relenza, so at least resistance to one is not perfectly correlated with resistance to the other.

Then there are the older M2 blockers, the adamantanes. There is variable resistance to these drugs in different H5N1 lineages, so they may be useful in some places or some circumstances. Resistance to this class of drugs develops more readily, however, and it is not clear to what extent the Geneva meeting will discuss these drugs.

In fact it isn't clear exactly what will be on the table in the Geneva meeting. The discussion is clearly important for clinicians. But these drugs are not going to stop a pandemic that is underway. Nothing will do that. It is important to be clear about that.

Unfortunately WHO is not always as clear as it could be on this count. Maybe it is time they said so unambiguously.