Dr Richard Lawson outlines the criteria for the use of the antiviral agents, oseltamivir and zanamivir, in patients with influenza

The annual wave of influenza that sweeps across the country in the winter months is not one of the highlights of the GP’s year. The fact that GPs now have at their fingertips some antiviral agents that can inhibit influenza A and B may be viewed with ambivalence by some, fearful that they may be swamped with calls to visit and cure their patients with influenza; this, however, is a reason why it is in the GP’s own interest, as well as that of his/her patients, to have a clear grasp on who should or should not be given antivirals for influenza.

Remit of the guidance

To help choose between the pharmacological options, NICE has issued Technology Appraisal 168 (TA168): Amantadine, oseltamivir and zanamivir for the treatment of influenza.1 It should be noted that TA168 does not cover a pandemic, impending pandemic, or a prevalent pandemic of a new influenza strain to which there is little or no community resistance. For example, it does not consider the serious influenza pandemic that might occur if the H5N1 virus mutates in such a way that there is a high rate of human-to-human transmission, nor does it provide advice on influenza A H1N1 (swine influenza). Guidance and advice for healthcare professionals on swine influenza is available on the Health Protection Agency website: www.hpa.org.uk

Technology Appraisal 168 sets the framework for the use of amantadine, oseltamivir, and zanamivir, replacing Technology Appraisal 58.2 The main changes from the previous guideline are that:

  • more patient types have been added to the at-risk group
  • children aged 5–12 years can be treated with zanamivir
  • people in long-term and residential nursing homes can be treated during localised outbreaks, if there is a high level of certainty that influenza is the causative agent.

In short, oseltamivir and zanamavir can be offered to people if all of the following conditions apply:1

  • influenza virus A and B is circulating as indicated by national surveillance schemes
  • the person is in an ‘at-risk’ group (see Box 1)
  • the patient presents with influenza-like illness and is able to commence treatment within 48 hours (or within 36 hours for zanamivir treatment in children) of the onset of symptoms as per licensed indications.

The NICE guidance emphasises that primary care should not stop providing vaccination just because antivirals are available. It is doubtful such worries are founded as vaccination is delivered by nurses in a routine mass programme, whereas antivirals would be delivered by harassed GPs often on home visits in the peak of an influenza outbreak; it is not difficult to see which is the preferred option.

Box 1: People defined as ‘at-risk’

Any patient with one or more of the following:
  • chronic respiratory disease (including asthma and chronic obstructive pulmonary disease)
  • chronic heart disease
  • chronic renal disease
  • chronic liver disease
  • chronic neurological conditions
  • diabetes mellitus
  • people who are aged 65 years or older
  • people who might be immunosuppressed

Symptoms and mortality rate

The acute phase of influenza lasts 3–4 days, with some symptoms persisting for 1–2 weeks; sequelae of bacterial otitis media, bronchitis, and pneumonia are common.1 It should be remembered that children may present with fatigue, irritability, diarrhoea, and vomiting rather than the classic adult symptoms of sore throat, malaise, aching, and high fever.1,2 In the UK, the average mortality rate of influenza is 600 deaths per year in a non-epidemic year and reaches between 12,000 and 13,800 deaths per year in an epidemic year.1

Drug treatment

The most straightforward part of the guidance is that regarding amantadine: it is not recommended for the treatment of people with influenza because it is only effective against influenza A and there is no clinical way of knowing that this is the causative agent rather than influenza B.1

Oseltamivir and zanamivir are both neuraminidase inhibitors that prevent the release of viral particles from infected cells. Both should be started within 48 hours of onset of illness, or 36 hours for the use of zanamivir in children. Comparisons of effectiveness between the two drugs are difficult to interpret with any great confidence. Both oseltamivir and zanamivir cost approximately £16 for the 5-day course.3

Oseltamivir
Oseltamivir is given at a dose of 75 mg twice daily for 5 days. It can be used (in proportional doses) in children as young as 12 months.1 Adverse effects are remarkably similar to the disease itself: gastrointestinal symptoms, bronchitis and cough, dizziness, fatigue, headache, insomnia, and vertigo. Skin rashes and allergic reactions and, rarely, disorders of the hepato-biliary system have been reported. Convulsions and neuropsychiatric disorders, mainly in children and adolescents, are possible but not established side-effects.2

Studies with oseltamivir showed overall reductions in:1

  • alleviation of symptoms by 0.7–1.0 days
  • median time to return to normal activity by 1.3–1.5 days
  • alleviation of fever by approximately 1.0 day.

There were little data on complications and only the use of antibiotics was significantly reduced.1

Zanamivir
Zanamivir is prescribed at a dose of 10 mg twice daily for 5 days for patients aged over 5 years.1 The medicine can only be received through the use of an inhaler; bronchospasm and allergic reactions are a risk,1 which suggests that it should not be the first-line treatment for patients with asthma. Apart from this, however, it has a much cleaner side-effect profile than oseltamivir. Zanamivir was, however, less effective on some illness parameters, with overall reductions in:1

  • alleviation of symptoms by 0.7–1.1 days
  • median time to return to normal activity by 0.4–0.7 days
  • alleviation of fever by 0–0.5 day.

Making a choice
Overall, data on complications were sparse and there was only a significant reduction for the use of antibiotics in those individuals who received oseltamivir compared with placebo. Data from direct comparisons of oseltamivir and zanamivir were not available, so an indirect comparison was made via their performance compared with placebo.2 Considering the difficulty in obtaining good clean data from patients with influenza, the subjective nature of the symptoms, and the effect that the condition has on the accurate completion of forms, it may be a good idea to pay more attention to the broader picture, and to not be restricted by the small print figures supplied by NICE.

One group of individuals who fall outside the remit of the guideline, but for whom it would be reasonable to consider for treatment ‘off guideline’ as it were, are front-line medical staff. In the height of an influenza epidemic, an unimmunised GP or hospital doctor, or a nursing colleague who develops a sore throat might be considered a suitable case for treatment by his or her colleagues.

Summary

Overall, this guideline is a helpful addition to our knowledge. Healthcare professionals have access to a reasonably cheap and effective duo of antiviral agents in these medicines. They are not likely to be overused because the scope for their use is fairly limited. Zanamivir should be avoided in patients with asthma and oseltamivir has a side-effect profile that might make GPs think twice before using it, for fear of being seen to make the illness even worse than it was before the script was handed over.

The drugs might find a useful place in the medical armamentarium if there is a significant mismatch between the antigenic profile of the virus and that year’s vaccine. They may also be very useful if the April 2009 outbreak of swine flu originating from Mexico becomes a serious epidemic or pandemic.

References

  1. National Institute for Health and Care Excellence. Amantadine, oseltamivir and zanamivir for the treatment of influenza. Technology Appraisal 168. London: NICE, 2009.
  2. GP notebook website. Clinical features. www.gpnotebook.co.uk/simplepage.cfm?ID=-1657470955&linkID=19504&cook=yes (accessed 29 April 2009).
  3. British National Formulary. BNF 57. London: Royal Pharmaceutical Society, 2009.G
For up-to-date information on investigating and managing probable/confirmed cases of swine influenza, visit: www.hpa.org.uk