Saturday, May 2, 2009

Multi-drug strategy could slow pandemic spread

How individual countries deploy their flu drugs may be key to determining the size of any pandemic that emerges from the current H1N1 outbreak. That's the conclusion of a mathematical model of flu transmission by an international team of researchers.
The findings also suggest that countries that stockpile just one of the two commonly used flu drugs may have trouble controlling a major pandemic.
"If you can hold off using your primary drug until the cumulative number of cases reaches a sufficiently high number, you reduce the spread of resistance and the final number of cases," says team member Joseph Wu at the University of Hong Kong.
"The key is to make sure the source population has good control of antiviral drugs, then all countries downstream benefit. If the source loses control then these strategies won't work," he says.

Resistance risk

Two anti-flu drugs are commonly stockpiled for use in a flu pandemic: oseltamivir, which is sold as Tamiflu, and zanamivir, which is sold as Relenza. Both work by inhibiting an enzyme called neuraminidase that the virus needs to replicate, but they act on different parts of the enzyme and resistance to one drug does not confer resistance to the other.
The Mexican H1N1 strain is currently sensitive to both drugs, but no one knows how long that will last.
The Wu team conducted their study after noticing that despite concerns about resistance, many countries stockpile just one drug, usually oseltamivir. There are some exceptions, however, including Australia and the UK, which stockpile both drugs.
Viruses are notorious for their ability to develop resistance to drugs. Last year, an H1N1 flu strain that caused some seasonal flu rapidly developed resistance to oseltamivir. By December, "close to 100 per cent of H1N1 in Australia and the US, and many other parts of the world, were resistant to Tamiflu", says Raina MacIntyre, an infectious disease expert at the University of New South Wales in Sydney, Australia.

One drug or two?

To work out whether initially treating patients from a smaller stockpile of a secondary anti-flu drug could delay the emergence of resistance, the Wu team ran a mathematical model of a flu outbreak in a theoretical "closed" population of 6.8 million – the size of Hong Kong.
In the model, doctors either prescribed just one drug, both drugs in combination, or prescribed one, then switched to the other when supplies of the first drug ran out.
The two strategies that used more than one drug decreased the number of people who finally became infected from 68 to 58 per cent. It also reduced the chance of resistance emerging from 38 to just two per cent, which would translate into a significant number of lives saved, says Wu.
When the model included international travel between the "index" population and 105 large cities to take into account the possibility that people might spread resistant strains, the two strategies that used more than one drug reduced the final number of people infected and the emergence of resistance to a similar degree.

Two-phase strategy

As the safety of using two drugs together has not been assessed, the most practical strategy would be to use a limited supply of one drug first, and then switch to the other, says Wu. Zanamivir, which is less popular because it has to be inhaled, is the obvious drug of choice for the limited-supply drug. However, it has not been approved to treat young children.
"Cross-resistance to both drugs at the same time is highly unlikely, so using the two drugs cleverly might be able to delay the emergence of resistance," says epidemiologist Jodie McVernon at Melbourne University, Victoria, Australia, who was not involved in the study.
McVernon's team have previously used mathematical modelling to show that resistance can also be delayed by using one of the drugs to treat active flu infections, and the other to prevent infection.
"In Australia, where the stock pile is enough for 40 per cent of population, we are keen to use drugs to prevent cases and spread early on, because it's far more effective at limiting the pandemic," she says.

Unethical solution

The Wu model only considers drug resistance that is caused by treatment with the drug, and not resistance that emerges from mixing of viruses, or natural mutation.
Wu points out that simply avoiding using either drug until numbers of sick people had reached a certain threshold would have the same effect as using two drugs in succession. "But medically that would be unethical, so you need to use a second drug," he says.
"In a scenario where lots of drugs are being used over a short period of time, drug resistance will probably emerge, and efficacy would be substantially weakened," says Wu.
The modelling study was carried with researchers from Harvard University and the Health Protection Agency in London, as well as the University of Hong Kong.
Journal reference: PLoS Medicine (in press)

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