Controlling Avian Flu
Emergency Plan Movies
Human implications of influenza
Control of Avian Flu
Avian Flu Medicines
Model of Avian Flu Outbreak
Cats catch Avian Flu
1918 Influenza Epidemic
Oseltamivir - Tamiflu
Rimantadine - Flumadine
World Virus Maps
May to October
Avian flu special: What's in the medicine cabinet?
By Alison Abbott
Alison Abbott is Nature's senior European correspondent.
Drugs that could lessen the death toll in a flu pandemic do exist.
But global stockpiles are too small, and the countries at most immediate
risk are among the worst prepared. Alison Abbott reports.
The pharmaceutical company Roche
didn't have huge commercial expectations for its influenza drug oseltamivir
when it was licensed under the brand name Tamiflu in 1999. Flu is
a fact of life, and doctors have been advising aspirin, hot lemon
and bed-rest for generations. In most countries they continue to do
so, reserving the drug for vulnerable groups such as the elderly.
Rows of antiviral flu drugs fill Roche's
warehouse but stocks would not meet demand in
But in the past year or so, Roche has
quadrupled its Tamiflu production capacity. The reason: developed countries
are now stockpiling the drug against the threat of a pandemic flu virus
that could arise at any time. Given the difficulty of rapidly producing
an effective vaccine, drugs will be the first line of defence. But even
after Roche's moves to boost Tamiflu production, experts say that global
stockpiles are woefully inadequate.
What's more, no one knows for sure
the answers to several key questions. How many deaths could antiviral
drugs prevent? To what extent would they slow the spread of a pandemic?
Could they, as some mathematical modellers claim, even stamp out the
disease as it emerges? "There is a lot of uncertainty, but that is
no reason not to plan their use," says Marc Lipsitch, an infectious-disease
epidemiologist at the Harvard School of Public Health in Boston.
Although the pandemic will be global, defence plans are so far strictly
national. Thanks mostly to prodding by the World Health Organisation
(WHO), about 50 countries have drawn up pandemic-preparedness plans.
Most are still very sketchy, but include strategies for stockpiling
antiviral drugs. Only a handful of nations, including Britain and
Canada but notably not the United States have given
their plans legal status.
Worryingly, the list of relatively
well-prepared nations includes few of those countries in Asia where
a pandemic strain is most likely to emerge. Historically, the WHO
has found it hard to persuade even rich countries to produce a pandemic
plan: many governments have proved reluctant to pay for a stock of
drugs that may not be used during their terms of office. Only now
that the alarm bells are ringing about the H5N1 avian flu virus have
official minds been focused.
Experts agree that Tamiflu is the
best of the four currently available anti-influenza drugs. A course
costs between US$10 and $30, but national stockpilers have negotiated
prices in the lower range. Roche is also making the powdered active
ingredient available at a cheaper price than tablets. The powder would
be dissolved in water and drunk when needed nasty-tasting but
still effective, and stable in solution for several days.
Tamiflu, and the chemically related
zanamivir, marketed by GlaxoSmithKline as Relenza, belong to a class
of drugs called neuraminidase inhibitors. They do not eliminate the
virus, but they reduce its release from infected cells by blocking
a key viral enzyme. If taken within 48 hours of the onset of symptoms
the earlier, the better they reduce the duration of
symptoms by at least a day1, 2.
They also limit the severity of symptoms in non-pandemic flu: patients
succumb less frequently to acute bronchitis or pneumonia1.
That should be good news if the same applies to a pandemic strain,
as patients who cough less will spread the virus less effectively.
Relenza is less helpful because
it has to be taken by inhaler, which is not very practical if a patient's
breathing is impaired. But both neuraminidase inhibitors have so far
generated few problems with drug resistance: mutations in the flu
virus that confer resistance seem rare, and generally seem to weaken
it3. (But an H5N1 virus sample from one
Vietnamese patient has recently been shown to be less susceptible
to Tamiflu, so experts are not complacent.) Side effects are also
mild, and the drugs can be kept on the shelf for at least ten years
without losing their activity.
The older, off-patent drugs amantadine
and rimantadine belong to a different class and interfere with a viral
protein called M2, which stops the virus from entering its target
cells. They seem to be as clinically effective as the neuraminidase
inhibitors, but resistance arises very rapidly and the drugs can have
disturbing side effects, including psychotic episodes. Although such
reactions are rare, they would be highly unwelcome in the already
panicky atmosphere of a flu pandemic.
Bitter pill: governments will have
to make tough decisions about who should receive Tamiflu.
Indeed, the potential for social
unrest is a major concern for those laying pandemic plans. And demand
for Tamiflu could exacerbate the problem. Who will, and who will not,
be treated with this scarce but valuable resource? "It's not easy
we know there won't be enough for everyone," says Theresa Tam
of the Public Health Agency of Canada. Britain, which is among the
best-prepared countries, has ordered enough for about 25% of its population;
Canada has stocks for just over 5% of its people; the United States
currently cannot even cover 1%.
In practice, a significant proportion of supplies might be used for
prophylactics of healthcare workers for up to two months as
the influenza wave passes through leaving less for treating
the sick. "It is not a happy situation," says Klaus Stöhr, the
WHO's chief influenza expert. Canada, wary of the potential for a
public backlash if health workers were perceived to be saving their
own skins, included an ethicist on its Pandemic Influenza Committee.
The WHO recommends that antiviral drugs should be available for the
early treatment and prophylactics of "those groups at highest risk
of infection" and "essential workers". But defining these people,
and matching their number to the doses available, is difficult.
Ultimately, how you define your strategy depends on what you want
to achieve, says clinical virologist Fred Hayden of the University
of Virginia in Charlottesville. Most countries are aiming to keep
the death toll as low as possible, but for others, maintaining the
economy may be at least as high a priority. So the definition of essential
workers will vary. Those deemed nonessential will be able to do little
but don a protective face mask which provides no guarantee
But the biggest challenge to any plan is the intrinsic biological
uncertainty: just how nasty will a pandemic virus be? "We have so
many unknowns about how many people of what age groups would
get ill, just how ill they would get, just how fast the virus would
transmit so it is hard to be firm about the best strategy for
prioritising treatment groups," Hayden says.
Of course, the larger the stockpiles,
the easier the choices will be. This is why the WHO is using all its
persuasive powers to get governments to place orders now. Once a pandemic
breaks out, it will be too late. Roche has promised not to profiteer
by hiking prices during a pandemic, but it is not simply a question
of money. The firm has no spare production capacity and batches take
up to a year to make.
In addition to encouraging stockpiling,
experts are trying to find other ways of driving up the supply of
antiviral drugs. They argue strongly, for example, for the wider prescription
of antivirals against non-pandemic influenza. "This would allow companies
to increase their routine manufacturing capacity without fear of losing
money," says Stöhr. Other countries should follow the example
of Japan, which consumes three-quarters of the Tamiflu prescribed
each year, he argues. Most of the rest is used in the United States,
with only 3% being prescribed in the rest of the world.
VIPs: in some countries, will drugs
be earmarked for 'essential' construction workers?
S. T. WONG/CORBIS
"It would be very good for physicians
in these other countries to have experience with the drug before a
pandemic arrives, so that they learn how best to treat patients,"
agrees Hayden. It's important for patients to be hit with the drug
early, he says, but doctors may accept this only through clinical
experience. The wider use of antivirals during annual flu epidemics
would also stimulate companies to develop new drugs. This is currently
not a priority for the pharmaceutical industry because the market
is too small.
There is still of plenty of work
to be done to further our understanding of Tamiflu's pharmacology.
"There are gaps in our knowledge that we need to fill so that physicians
can use it more effectively in a pandemic," says Hayden. For example,
Tamiflu is not licensed for infants under one year old, because of
the ethical difficulties of running trials in very young children
yet this age group proved exceptionally vulnerable in the severe
pandemic of 1918.
Pharmacologists also want more biological data on patients who are
treated with Tamiflu after being infected with the H5N1 virus now
circulating in Asia. This will help them epitomise dosing regimes.
They complain that not enough is being done to gather these data from
the relatively few patients who have so far been given the drug. Animal
studies would also help, but this has similarly not yet been made
an official priority.
are gaps in our knowledge that we need to fill so that
physicians can use Tamiflu more effectively in a pandemic.
University of Virginia in Charlottesville
Animal models could be used to
investigate the use of Tamiflu in drug combinations, which may help
avoid any problems with resistance. Pandemic planners are considering
stockpiling amantadine and rimantadine as back-ups, despite their
disadvantages, because they are cheap and were shown to have some
prophylactic activity in the milder 1968 pandemic4.
Now is the time to begin investigating the merits of using both major
classes of anti-flu drugs together, says Hayden.
Finally, experts urge that the
few new candidate drugs coming up should be given serious consideration,
even if they don't seem ideal. For example, peramivir, another neuraminidase
inhibitor was developed by BioCryst Pharmaceuticals of Birmingham,
Alabama, but abandoned because it has to be injected. Nevertheless,
its very long half-life in the body means that it needs to be given
only once or twice a week and so might be useful prophylactically.
For most developing countries,
meanwhile, creating a national stockpile would simply break the bank.
So some public-health experts are calling for an international supply
of Tamiflu that could be deployed by the WHO when a pandemic threatens.
In unpublished work, Ira Longini, a biostatistician at Emory University
in Atlanta, Georgia, has calculated that about 120,000 courses of
Tamiflu, if deployed rapidly to treat the sick and protect their families
and if combined with strict quarantine of their houses
could even nip a pandemic in the bud at its point of origin.
Stöhr thinks the idea of ring-fencing
outbreaks in this way is "well worth investigating". But Longini's
model depends on assumptions about transmissibility and initial death
rate that may prove to be wrong. And given the poor infrastructure
in many of the Asian countries in which a pandemic virus is most likely
to arise, such measures might prove hard to implement in practice.
Before embarking on an effort to persuade sceptical governments to
invest in such a plan, says Stöhr, there has to be much more
confidence in the possibility that it could be made to work.
Uncertainty, unfortunately, is the name of the pandemic flu game.
And the problem, for those trying to work out how to organise the
first line of defence, is that politicians are averse to spending
large sums of money when they don't know the odds or even whether
they'll still be in post when the bet comes in.
- Ternary, J. J. et al. J. Am.
Med. Assoc. 283, 1016 - 1024 (2000). | Article | ChemPort |
- Cooper, N. J. et al. Br. Med.
J. 326, 1235 - 1239 (2003). | ChemPort |
- Zambon, M. & Hayden, F. G. Antivir.
Res. 49, 147 - 156 (2001). | Article | PubMed | ChemPort |
- Hayden, F. G. Phil. Trans. R. Soc.
Lond. B 356, 1877 - 1884 (2001). | Article | ChemPort |
- Fowler, R. A. et al. J. Am.
Med. Assoc. 290, 367 - 373 (2003). | Article |
- Seto, W. H. et al. Lancet 361,
1519 - 1520 (2003). | Article | PubMed | ISI | ChemPort |