Mitigating the effects: antiviral
drugs
5.7. If the virus were to be introduced into
the United Kingdom, various strategies could be used to mitigate
its effects and limit or slow down its spread. The most promising
of these involve the use of antiviral drugs either to treat those
infected with influenza or as prophylaxis for those who are at
risk of infection. The options were summarised at our seminar
by Professor Ferguson:
- Treatment-only use of antiviral drugs;
- Blanket prophylaxis;
- Treatment plus limited prophylaxis (e.g. "household
prophylaxis");
- Treatment plus limited prophylaxis plus control
of large gatherings, closure of schools or workplaces, and so
on.
5.8. The backdrop to all these options is the
Government's order of 14.6 million courses of the antiviral drug
oseltamivir (Tamiflu). This order, which will be fulfilled by
autumn 2006, is based on the assumption that the disease will
have a 25 percent "attack rate"in other words,
that one quarter of the population will be infected, and that
for each person infected one course of the drug will be required.
5.9. A "treatment-only" approach is
thus the Government's preferred option. Assuming that the virus
does not develop resistance to the drug, cases would be less severe,
and hospitalisation and mortality correspondingly lower. However,
for the drug to have an effect the course has to start within
48 hours of the onset of symptomsthe earlier the better.
At the peak of pandemic, with around one million new cases each
day, there would be huge strains on the health service in diagnosing
new cases and getting drugs to patients within this timescale.
We look at this issue in more detail in our next chapter. In addition,
we are seriously concerned over the robustness of the assumptions
made regarding the "attack rate" of a new virus, which
in reality could be either significantly below or above 25 percent.
If the latter were to be the case, supplies would simply run out.
5.10. At the other extreme, blanket prophylaxis
does not appear feasible. Antivirals provide protection only as
long as they are being taken, and each course of oseltamivir lasts
five days. It would be prohibitively expensive for the whole population
to be provided with antiviral drugs until such time as a vaccine
was available against the pandemic strain, possibly up to nine
months after the initial outbreak. Even if this approach were
affordable, the limited supply of antivirals globally would prevent
it.
5.11. Targeted or "household" prophylaxis
in the initial stages of a pandemic falls between the two extremes
of blanket prophylaxis and treatment-only. We have already noted
that antivirals are particularly effective when taken preventatively.
The object of limited prophylaxis would thus be to target the
first cases, identifying close contacts (such as family members
and healthcare workers) and prescribing antivirals in such a way
as to slow down the spread of the disease. In principle this could
buy more time which could be used for the development of a vaccine.
5.12. At our seminar Professor Ferguson estimated
that "household prophylaxis" could lead to a reduction
of around 30 percent in the number of cases of infection over
the first 180 days of a pandemic. The HPA were more tentative,
but accepted that if the first importation of the virus could
be identified targeted prophylaxis "might just slow [the
virus] down for a few weeks which gives us time". However,
in the absence of evidence from well-conducted trials, or the
experience of an actual epidemic, these projections remain somewhat
speculative. (Q 116)
5.13. Despite the views of the HPA, the Government
have not publicly committed themselves to using antiviral drugs
as prophylaxis to target the first cases. The Minister, indeed,
said in terms that "we believe that this should be used for
treatment and not used prophylactically". The Contingency
Plan, while noting that "short term prophylaxis" could
be used to delay the establishment of a pandemic, states that
this would be "done on a case by case basis and is
not the main use of antiviral drugs" (p. 46). Moreover, whereas
the Government's order for 14.6 million courses leaves little
or no spare capacity for prophylactic use, a strategy of "household
prophylaxis" would require from 30 to 100 percent more antivirals
than are currently on order. Not only would there be significant
cost implications, but there could be a substantial delay between
an order being made and the delivery of the drugs. (Q 222)
5.14. "Household prophylaxis" could
also be combined with limits on public gatherings, for instance
the closure of schools or workplaces, suspension of football matches,
and so on. Targeted at the initial outbreaks, such additional
measures could significantly delay the spread of the disease,
albeit at the expense of considerable social disruption. The Contingency
Plan simply states that they are "being kept under review"
(p. 48). It is worth noting that under the terms of the Civil
Contingencies Act 2004 the Government have very wide powers in
the event of a national emergency (which could include a pandemic)
to take steps of this kind at short notice.
5.15. There is an overarching issue of cost.
The Government have committed £200 million to the existing
order for oseltamivir. The drug has a limited shelf-life (five
years), so if there is no pandemic within this time-frame the
stockpile will have to be discarded and (assuming the world remains
on pandemic alert) replaced. Yet so far as we were able to ascertain
from the Minister this commitment has been made without any cost
benefit analysis (see QQ 222-223). It is difficult to predict
what such analysis would revealit might show that household
prophylaxis, although more expensive in absolute terms, represented
a more cost-effective strategy than treatment-only. In the absence
of comprehensive modelling of the best and most cost-effective
way to use antiviral drugs, the Government's open-ended commitment
of considerable sums to their purchase is a matter of serious
concern.
5.16. Finally, there remains the possibility
that the virus could develop resistance to oseltamivir. We have
already alluded to the fact that some H5N1 strains in south east
Asia have developed resistance to M2 inhibitors such as amantadine,
and that research is being undertaken into the optimum combinations
of antiviral drugs in order to minimise further development of
resistance. Although there is no confirmed case of resistance
to oseltamivir, it would be prudent for the Government to consider
a back-up plan, possibly involving zanamivir (Relenza) or combination
use of oseltamivir with M2 inhibitors.
CONCLUSIONS
5.17. Once an influenza pandemic is established,
in south east Asia or elsewhere, there is no realistic prospect
of preventing its spread to the United Kingdom. Travel restrictions,
quarantine or screening at airports, while they would be highly
visible, would only delay the spread of the virus.
5.18. The early and targeted use of antiviral
drugs, not only to treat the first cases in this country, but
to provide prophylactic protection to close contacts such as family
members or health workers, could both delay and lower the peak
of a United Kingdom pandemic. This would reduce the strain on
health services, and give more time for the production of a vaccine.
5.19. We are therefore extremely concerned
at the lack of clarity in the Government's policy on prophylactic
use of antiviral drugs, and at the possibility that the Government's
order of only 14.6 million courses of oseltamivir may have tied
them into a treatment-only policy on using the stockpile.
5.20. We recommend that the Government work
together with the HPA and the research community to establish
the optimal strategy for the use of antiviral drugs, and that
further orders, if required, should as a matter of urgency be
placed to allow this strategy to be implemented. We further recommend
that this strategy should incorporate a rigorous cost-benefit
analysis.
5.21. We recommend that the Government develop
back-up plans in case resistance to oseltamivir emerges. These
should encompass possible combination therapies or the acquisition
of reserve stocks of zanamivir.
11 "Entry screening for severe acute respiratory
syndrome (SARS) or influenza: policy evaluation", BMJ 2005;331:1242-1243
(September 2005). Back