Risk Wise

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Stockpiling and use of antivirals

Currently there are two groups of specific antiviral drugs

against influenza, which specifically interfere with the

replication of the virus in the body: the adamantanes

and the neuraminidase inhibiters, which have different

working mechanisms. The first group, to which the

drugs amantadine and rimantadine belong, has been

known and used to treat seasonal influenza for a long

time. These drugs however have some major limitations

and disadvantages. They cause considerable adverse

effects (less so for rimantadine), are not effective against

influenza B viruses (the cause of part of seasonal

influenza) and most importantly, influenza viruses

rapidly develop resistance against them.

The neuraminidase inhibitors, to which the drugs

oseltamivir and zanamivir belong, have been developed

more recently and were introduced in the last decade.

These drugs cause less side effects, are also effective

against influenza B viruses and limited or no resistance

development was observed initially when they were used

clinically to prevent or treat influenza. In cell culture

and in animal models it was demonstrated that they

were also active against avian influenza viruses.

Oseltamivir has been used so far in a limited number of

patients with severe symptoms of avian influenza (HPAI-

H5N1). Since the antiviral drugs have to be used as early

as possible during infection for the optimal effect, and

for seasonal influenza definitely before 48 hours, the

actual therapeutic effect of the neuraminidase inhibitors

in avian influenza of humans cannot be estimated to

date. On basis of the preclinical data it may be expected

that the neuraminidase inhibitors may indeed be effec-

tive against an emerging pandemic influenza virus.

Consequently several countries have now stockpiled

oseltamivir and some have complemented this stockpile

with that of zanamivir.

While oseltamivir is currently the most widely used

antiviral drug against seasonal influenza, oseltamivir

resistant viruses were found at a low rate and the resis-

tant viruses did not replace the sensitive viruses in the

population. Also in patients treated with oseltamivir

against avian influenza (HPAI-H5N1) resistant viruses

were shown to emerge, without further spread of these

resistant viruses. In the past year the situation with

respect to oseltamivir resistance has changed consid-

erably, when it became apparent that one of the

seasonal influenza A (H1N1) viruses had developed

resistance against this drug. This was first noted in

Europe where in spite of very limited use of the drug,

the resistant virus largely replaced the sensitive

influenza A (H1N1) virus.

Subsequently in the winter season of the southern

hemisphere and in the following winter season in North

America, the oseltamivir resistant influenza A (H1N1)

virus also replaced the sensitive one. Fortunately the

oseltamivir resistant H1N1 viruses still proved to be

susceptible to zanamivir, the other neuraminidase inhib-

iter and to amantadine. Since the use of antiviral drugs

against influenza viruses may be life saving for high-risk

this risk. Avian influenza A viruses are repeatedly crossing the avian-

mammalian barrier, but have so far not succeeded to become

efficiently transmissible from human to human. Unfortunately it is

impossible to predict with current knowledge when it will happen

and which virus will be involved.

With the advent of modern scientific insights and novel tech-

nologies it is possible in principle, to efficiently combat all forms

of influenza, including pandemic influenza. Besides non-medical

intervention strategies, like the implementation of hygienic

measures and social distancing, which both may significantly reduce

viral spreading, there are three medical intervention strategies

which, especially when used in combination, may reduce the burden

of seasonal, avian and pandemic influenza drastically: influenza

surveillance, as well as the use of influenza virus-specific antiviral

and vaccination strategies.

Surveillance of influenza in humans and animals

By far the best surveillance system for any infectious disease in

humans is the global surveillance network for seasonal influenza.

This was initiated over 50 years ago by the establishment of an ever-

increasing collaborative network of national and regional

collaborative influenza centres, established and maintained under

the auspices of the World Health Organization (WHO). It is based

on the regular reporting of seasonal influenza activity and charac-

teristics of the human influenza viruses that continuously spread

around the globe. It forms the basis for the bi-annual selection of

influenza virus strains that should be represented in the seasonal

influenza vaccines.

The recent implementation of mathematical modelling of the

data as they emerge and the associated antigenic cartography, has

recently added an important and novel dimension to the func-

tioning of the network. It contributes to the identification of novel

vaccine virus strains, and also provides novel insights in the way

in which these viruses spread geographically over time. In spite

of the major achievements of this network, it should be realized

that there are still significant gaps in its global geographical cover-

age. As this surveillance network also currently plays a role in

following the spread of avian influenza viruses in humans and in

the characterization of these viruses, it will also function as an

early warning system for an emerging pandemic influenza virus.

This makes the issue of geographical coverage even more impor-

tant, since in several areas where this could reasonably be

expected to happen, this coverage is far from satisfactory.

Influenza surveillance should not be limited to surveillance in

humans, but should also include surveillance in birds and other

animals, as they play an important role in the emergence of

pandemic influenza viruses.

In several geographical areas like North America, Eurasia and

Africa, combined activities between virologists, ornithologists and

data managers have been started in the past decade to map the spread

of avian influenza A viruses in waterfowl and the threat they may

pose to other wildlife, domestic poultry, other domestic animals and

eventually mankind. The value of these activities besides the

mapping of the spreading and the associated risk is that it generates

a large and continuously updated repository of avian influenza A

viruses. This may allow the continuous development of an updated

repository of seed viruses for eventual pandemic vaccine produc-

tion, which will save precious time in developing a vaccine when

the next pandemic emerges.