The researchers assumed in their model that there is an outbreak of flu in a closed community of 500 people, for example in a school or hospital. Firstly they studied how the flu develops if no specific medication is used. Secondly, however, they also wanted to know how the disease develops within the population if the patients are treated with oseltamivir, i.e. Tamiflu, or if, in parallel to this treatment method, the people who are not yet ill are also given it as a precaution. Finally, the model is also intended to show the dynamics of resistance to this flu treatment in the viruses.

Tamiflu hardly shortens the flu outbreak

At the start of the outbreak of the disease, the number of patients increases relatively quickly, reaching a peak after 10 days and then gradually declining. If the patients showing symptoms are treated with oseltamivir, their numbers are only slightly reduced, and the duration of the flu outbreak is also barely any shorter. The model shows a different outcome if the drug is also given for preventive treatment. The number of cases of illness is dramatically cut by this prophylactic anti-flu treatment, and the flu outbreak only lasts half as long.

All well and good, you might think. If a flu pandemic breaks out, you give those at risk Tamiflu prophylactically and this will keep the virus under control. However, there is another side to the coin, say the two population biologists Sebastian Bonhoeffer and Roland Regoes of the ETH Institute for Integrative Biology: “Prophylaxis increases the number of viruses resistant to oseltamivir that are in circulation in the population.”

Transmission fitness is critical

If only those people showing flu symptoms are treated with oseltamivir, then the proportion of viruses which newly acquire resistance to the drug increases only slowly. The model shows a different picture when oseltamivir is used not only to treat the ill but also prophylactically. This increases the pressure on the virus on a broad front. To survive, it has to adapt to the new conditions quickly. It is as if preventive treatment with drugs intervenes in the natural battle between the non-resistant original virus and the resistant viruses – in favour of those which are resistant. After all, only resistant viruses can infect people who have been treated prophylactically. If, by means of certain mutations, the transferability of the resistant viruses – the so-called transmission fitness – is also improved, then the proportion of these within the virus population can increase sharply, because their strategy is more successful than that of the original disease germs. The resistant viruses are bound to succeed. According to the model, this transmission fitness plays a key role in the successful spread of resistant flu viruses.

From the point of view of population biology, vaccination is preferable to prophylactic treatment with flu drugs, because it does not increase the selective pressure on the virus so much. large

Als weniger wichtig für die Verbreitung von resistenten Viren gilt die Rate der von Grund auf neu erworbenen Resistenzen, so genannten de novo Resistenzen. „Sie schien uns wichtig, das Modell zeigte aber, dass dem nicht so ist“, sagt Roland Regoes.

Resistance on the increase

The model is supported by observations in the field. Around the world, 12 per cent of the flu viruses that are in circulation are resistant to a certain class of flu drugs, the M2 inhibitors, while in certain regions of China and Hong Kong the figure is as high as 74 per cent. At the start of the last flu season in the USA, nine out of ten flu viruses of the sub-type H3N2 were resistant to M2 inhibitors. These drugs are intended to prevent viruses from penetrating the cell and releasing their genetic material there.

“For a long time, the level of resistance to M2 inhibitors remained low. In the last three to four years, though, it has shot up remarkably quickly,” says Sebastian Bonhoeffer. However, this can only happen so quickly if the virus remains easily transferable despite having become resistant – or if it can become easily transferable by mutation. Scientists can only speculate about the reasons for this. The ETH professor believes that the rise we have seen is due to the fact that in many countries M2 inhibitors are available without a prescription.

Fight flu, but with reservations

The aim of fighting an epidemic should be to prevent fatalities and new cases of the disease, says Regoes. Although this primary aim would be achieved very effectively by relying on prophylactic treatment, the approach is problematic in terms of the development of resistance. Prophylaxis causes a drug to become useless more quickly, but developing a new drug is also difficult. “It can take decades before something new appears on the market. And it has to be something entirely new,” he stresses.

With bird flu at our door, the results of the two biologists are sobering. It is no longer possible to imagine that no resistance would develop if flu drugs were used on a massive scale. “Nevertheless, despite our reservations, it is still right to use these drugs prophylactically in the case of a pandemic,” emphasises Bonhoeffer. Drugs are clearly the first line of defence in the battle against a pandemic, and hopefully by treating it anti-virally, time could be gained in which to develop a vaccine. He prefers the vaccination approach, because the evolutionary pressure on the pathogen is less. The disadvantage of a vaccine is the long lead-time, and the fact that the vaccine has to match the virus, but you can’t know the exact characteristics of the virus until it arrives.