Age and antivirals

The journal BMC Infectious Diseases has published research evaluating the age-prioritisation of antivirals during an influenza pandemic. The Daily Mail referred to the study in an article: “Will mass use of Tamiflu leave Britain all but defenceless as swine flu becomes resistant?”.

The newspaper voices the concerns of a representative from the British Medical Association, Dr Peter Holden, who has questioned the policy of giving the antiviral to people with mild symptoms. He said the policy places extra strain on the NHS, increases the possibility of the virus developing immunity to the drug and exposes people who would otherwise have a mild illness to potential side effects of the drug.

The debate over the widespread use of antivirals is complex. The Department of Health’s approach to treat symptomatic people is part of a well-considered treatment strategy to reduce the spread of infection in this country. Antiviral resistance is possible, but the government is monitoring this situation closely.

However, the study referred to in the news article has little relevance to the issue of antiviral resistance in the UK. The study aims to give some guidance on how to prioritise antiviral stockpiles if these are limited. Making some assumptions about the flu virus, the study concludes that treating all cases and providing prophylaxis to younger individuals is the only intervention resulting in "a significant reduction of the clinical attack rate and requiring a relatively small stockpile of antivirals". The Daily Mail has misinterpreted the findings of this study by suggesting that not giving Tamiflu to pensioners in UK would cut the chance of resistance.

Where was the article published?

The study was conducted by Dr Stefano Merler from the Fondazione Bruno Kessler and colleagues from the University of Trento and the Istituto Superiore di Sanita, Italy. It was published in the peer-reviewed medical journal BMC Infectious Diseases . Funding was provided by the European Union.

What kind of study was this?

The researchers used mathematical models to simulate the spread of an influenza pandemic in Italy and to evaluate the effectiveness of different strategies of prioritising antivirals by age.

The WHO recommends that governments should stockpile sufficient antivirals to treat 25% of their populations. However, some countries do not have sufficient stockpiles for this. For example, Italy currently has enough antivirals to treat seven million people, which is about 12% of the population. Meanwhile, other countries have more than enough antivirals to treat all cases and may therefore need to prioritise the use of the surplus supplies for treatment and prevention.

There are some relevant issues to highlight here:

Antivirals can be used both to treat infected people and to prevent infection in people who are exposed to cases. When being used to treat infection in a person they also reduce how easily that person transmits the virus to other people. Antivirals can also be given to people who are exposed to an infected case, reducing their susceptibility to infection.

The study makes use of a measure called the basic reproduction number (R0), which is used alongside other statistics to determine the impact of outbreaks, epidemics and pandemics. It is defined as the number of secondary cases that a single infected person would cause in a population that had no immunity to the disease (and no vaccines or treatments to control the infection). If the R0 is less than one (that is, only one other person becomes infected by an index case), the infection will not spread in a population. However, if the R0 is greater than one, the infection can spread. If the R0 is large it is harder to control an epidemic. A recent modelling published in BMC Medicine estimated that the R0 for the current pandemic (H1N1) 2009 virus is between 1.4 and 1.6, lower than that of the 1918 pandemic strain and similar to that of seasonal flu.

Modelling the impact of a pandemic

The model used in this study is complex, but essentially predicts the impact of the pandemic in Italy. As with all models, a number of factors are fed in and several assumptions need to be made. Broadly, these assumptions consider:

• The basic reproduction value. Here researchers assumed R0 values of 1.4 (as in similar past pandemics) and also a value of three (which was seen in some cities during the 1918-1919 Spanish influenza pandemic).
• How many cases are imported into the country.
• How easily the virus spreads in households, schools, workplaces and through random contacts in the population.
• How susceptible people are.
• How long symptoms last for.
• Absenteeism and attendance at work.
• Commuting.
• Death rates by age group (these were estimated from previous pandemics including the 1918 Spanish influenza pandemic and the 1969 pandemic in Italy).
• By how much antivirals (used as treatment and for prevention) would reduce infectiousness and symptomatic disease.

The researchers assumed that all infected people were treated with antivirals before these were used for prophylaxis.

What does the research say?

The researchers make a number of conclusions based on the outcome of their model.

• Before a vaccine becomes available some measures are key to delaying the epidemic in large countries. These include travel restrictions, social distancing measures (such as school closure and isolating cases), treatment of infected individuals with antivirals and giving prophylaxis antivirals to their close contacts.
• If age-specific case fatality rates are assumed to be the same as during the 1918 Spanish influenza pandemic, then the model suggests that only treating the elderly with antivirals does not significantly reduce the total deaths and that treating adults is more effective. However, if age-specific case fatality rates are assumed to be the same as in the 1969-1970 pandemic in Italy, then it is more effective to treat the elderly than adults.
• In addition, giving prophylaxis to close contacts of infected cases is a more effective way of reducing the spread of infection, but it requires a larger stockpile of antivirals.
• The model does not take into account potential antiviral resistance or selective treatment of people at higher risk of serious illness, for example hospitalised people and healthcare workers.
• Antiviral treatment and prophylaxis are less effective if they are given more than 48 hours after exposure. Late antiviral therapy is not helpful.
• If there are sufficient antivirals stockpiled to treat all cases (which is the situation in the UK), then the model suggests that using the excess to provide prophylaxis only to younger individuals is an option to be considered.

What are the implications of this study?

Other studies have also concluded that treating cases with antivirals and giving antivirals to their close contacts is the most effective single intervention strategy for preventing spread in the early stages of a pandemic. This is what the UK did at first during its containment phase.

On July 2, the UK moved to a treatment phase in which cases were diagnosed on the basis of clinical observation rather than laboratory testing. During this phase everyone with flu-like symptoms is assessed and offered antivirals to manage their illness. The Health Protection Agency (HPA) no longer traces close contacts or provides antivirals to limit spread. This is because public health interventions to reduce spread are no longer appropriate and the focus moves to the treatment of individual patients.

For countries with limited supplies of antivirals and still in the early phases of the pandemic, this study highlights the importance of stockpiling antivirals and how closely the number of required doses depends on the basic reproduction number of the virus. For all countries, the availability of the vaccine will reduce the amount of antivirals that will be needed.

This study’s findings regarding limiting treatment with antivirals to the elderly or adults have limited application for the UK. The results are based on assumptions fed into a model simulating the pandemic and different potential treatment strategies in Italy, which has enough antivirals to treat about 12% of its population. The situation is different in the UK, which has a large enough stockpile of antivirals to treat 50% of the population (and has ordered more to increase supplies up to levels needed to treat 80%), and which is not currently considering limiting treatment purely on an age-specific basis.

Resistance to antivirals is possible, and responsible use of Tamiflu is one way to avoid or delay this. The Department of Health recommendations to provide antivirals to people with symptoms of flu are sensible and are in line with this country’s approach to controlling infection. The HPA is monitoring the resistance situation. As of last week, 427 viruses have been analysed by the HPA for the marker commonly associated with resistance to oseltamivir in seasonal influenza (H274Y). None of the viruses have so far been found to carry this marker.