It is impossible to anticipate an influenza pandemic and, should a true influenza pandemic virus again appear as in 1918 — or even epidemics such as those experienced in the United States of America in 1976 and Hong Kong in 1997, there can be a rapid build up of public fear. Such fears create major challenges for health authorities. In order to better respond to such situations, WHO has devised an Influenza Pandemic Preparedness Plan (1).

The plan outlines the separate but complementary roles of WHO and national authorities when an influenza pandemic is imminent or actually occurs. The following abbreviated extract from the plan gives information on the drugs available to deal with outbreaks and includes information on the newly marketed anti-influenza drugs. However, vaccination remains the primary method of preventing and controlling influenza, and production and use of an influenza vaccine are discussed on pages 235-237.

Policies are needed on the role of antiviral drugs in pandemic situations. As part of planning, mechanisms should be in place to import, license and distribute these drugs and to maintain a supply for critical needs, such as for health care staff and laboratory workers who may be exposed to new strains.

Generally, antiviral drugs will be more readily available since a vaccine to combat a new strain will require a minimum of 8 months to produce. However, the issues which need to be considered before providing antiviral drugs are similar to those for vaccines: identification of target groups and distribution, dosage, availability, methods of response to a sudden increase of demand, and safety.

Until now, amantadine and rimantadine have been used to treat influenza type A and have been shown to be clinically effective when taken throughout the period of exposure in a normal epidemic or outbreak situation. They also reduce the duration of illness by 1-2 days when taken early after onset. Although their effectiveness is similar, rimantadine has a better safety record. Specifically, amantadine is excreted by the kidneys and can cause significant neurological side effects, particularly in those with diminished renal function, including generally healthy elderly persons. This does not appear to be a problem associated with rimantadine.

Both drugs interfere with the replicative cycle of influenza A (but not B) viruses through blocking the function of a membrane-spanning protein synthesized in influenza-infected cells. Each has been found to be >70% effective in preventing illness caused by influenza A virus (2). WHO recommends either drug for use when a vaccine is not yet available or has only just been administered (3).

The recommended dose of amantadine for prophylaxis and treatment is:

Adults: 200 mg daily
Children 10-15 years and adults over 65 years: 100 mg
Children 1-9 years: 2-4 mg/kg

Caution must be exercised in the event of decreased renal function. Occasional resistance to amantadine and rimantadine can develop in viruses present in persons using the drugs to treat symptoms (4) and such drug-resistant viruses may be transmitted to contacts (5).

Other anti-influenza drugs with a different mode of action to amantadine and rimantadine and active against influenza type A and B have recently become available. Oseltamivir and zanamivir have been licensed in the United States and some European countries (6). They are two closely related compounds which bind to the active site in a protein found on the surface of influenza viruses, the enzyme neuraminidase. The binding appears extremely strong and in human clinical studies both drugs interfere with viral replication to a high degree and provide protection similar to amantadine and rimantadine. However, evidence for use of these antiviral drugs to treat influenza is based principally on studies in patients with uncomplicated influenza.

There is no clear evidence to support safety and efficacy in persons with underlying respiratory or cardiac diseases, or persons with complications which can develop during an acute influenza episode, such as bacterial pneumonia (7).

Human clinical trials have not yet been undertaken in children under 12 years of age or the elderly. Important considerations therefore need to be taken and zanamivir, in particular, needs special caution in patients with underlying asthma or chronic obstructive pulmonary disease (8). The presence of primary or concomitant bacterial infections should also be considered when making treatment decisions in patients with suspected influenza.

References

1. Influenza Pandemic Preparedness Plan. Communicable Disease Surveillance and Response, World Health Organization. http://www.who.int/emc-documents/influenza/whocdscsredc991c.html

2. Dolin, R., Reichman, R.C., Madore, H.P. et al. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. New England Journal of Medicine, 307: 580-584 (1982).

3. Current status of amantadine and rimantadine as anti-influenza A agents: memorandum from a WHO meeting. Bulletin of the World Health Organization, 63: 51-56 (1985).

4. Belshe, R.B., Burk, B., Newman, F. et al. Resistance of influenza A virus to amantadine and rimantadine: results of one decade of surveillance. Journal of Infectious Diseases, 159: 430-435 (1989).

5. Hayden, F.G., Belshe, R.B., Clover, R.D. et al. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. New England Journal of Medicine, 321: 1696-1702. (1989).

6. WHO Drug Information, 13(3): 170 (1999).

7. Safe and appropriate use of influenza drugs. CDER Public Health Advisory, 12 January 2000.

8. FDA reminds prescribers of important considerations before prescribing flu drugs. FDA Talk Paper, T00-3 (2000).