Antiviral agents for the prevention and treatment of influenza

Introduction
Influenza infection and its complication of pneumonia constitute by far the most significant cause of respiratory morbidity and mortality each year. In fact influenza and pneumonia are the sixth leading cause of death from any event in the United States.[1] Annual immunization with inactivated influenza vaccine can reduce infection rates by 75% to 80% in younger age groups and by 40% in elderly nursing home residents.[2] In spite of this, surveys indicate that even in patient populations at highest risk (for example, the elderly), vaccination rates through family doctors and medical specialists are not as high as they should be.[3,4]

In view of the variability in optimal immunization rates, even though this remains the mainstay of public health efforts to reduce influenza-related morbidity and mortality, strategies have been developed employing antiviral agents—some old, some new—to help improve prophylaxis and treatment of influenza.

Available antiviral agents for influenza are listed on Table 1. There are two classes of agents. Most physicians will be familiar with the adamantane agents, amantadine, and rimantadine (the latter available in the US but not in Canada). The other new class includes the viral neuraminidase inhibitors.

The initial clinical trials on neuraminidase inhibitors included patients of varying age groups. Further studies are required in the elderly, especially those in chronic care facilities. 

Amantadine
This agent acts by binding to a viral surface protein called “M2”, which is somehow integral to the uncoating of the influenza virus and entry into host respiratory columnar epithelial cells. Mutations in the M2 protein confer resistance to amantadine.[5] Amantadine is only effective against influenza A, not influenza B because the latter has no M2 protein.

Neuraminidase inhibitors
The second and most recent agents against influenza are the viral neuraminidase inhibitors. The influenza virus contains two major surface proteins, the hemagglutinin and neuraminidase, and both are pathophysiologically important. Viral neuraminidase cleaves neuraminic acid, a component of sialic acid in the host cell membrane, thereby aiding the release of virus from the cell. Influenza viruses are coated with cell receptors containing neuraminic acid because they bud off the cell membrane, and the cell receptors cause the virus particles to aggregate. Neuraminidase increases the efficiency of further cell infection by preventing clumping of virus particles. Early studies with neuraminidase vaccine (preparations that never reached commercial production) modified the infection to a milder, often subclinical form.[6]

Antineuraminidase drugs do the same thing, allowing only a mild or clinically inapparent infection. Unlike amantadine they are effective against both influenza A and B. Two agents have been fully evaluated so far: zanamivir (Relenza) and oseltamivir (Tamiflu).

Zanamivir was granted Health Canada approval on 2 November 1999 and oseltamivir on 24 December 1999. Both are now available as an influenza treatments.

Evidence for antiviral drug treatment of influenza
Table 2 lists efficacy of amantadine and the antiviral agents zanamivir and oseltamivir in preventing influenza and its complications, and the side effects of each.

Amantadine reduces illness rates by 75% to 90%.[7] Side effects are mainly an “amphetamine-like” effect of insomnia, sometimes nightmares, dizziness, and jitteriness. This can be a problem in elderly patients at the 100 mg twice a day dose. If insomnia or other side effects occur, the dose can be reduced to 100 mg daily, preferably in the morning. Because amantadine is excreted by the kidney, the dose must be further modified in patients with renal impairment and should also be adjusted in those with a history of seizure or psychiatric disorder. Table 3 provides detailed dosing guidelines.

Zanamivir, administered as a powder with an inhaler device, has reduced overall influenza rates by 67%, and febrile influenza by 84%, compared to a placebo.[8] Side effects were no different than placebo. There have been reports of bronchospasm following inhalation in patients with respiratory disease. The package insert contains precautionary information about this.

Oseltamivir, an oral agent previously designated as GS4104, had similar protective efficacy rates of 74% to 84%. Side effects noted were nausea and other gastrointestinal complaints and were mild (7% with placebo versus 9.7% at a once daily dose and 12.7% at a twice daily dose).[9]

Amantadine is currently the only antiviral licensed for prophylaxis against influenza in Canada. Strategies for its use in prevention include:

1. Institute the agent for those who cannot or will not receive vaccine, and continue it for the duration of the influenza period.
2. If influenza occurs without advance warning and one has an unvaccinated high-risk patient (e.g., one with congestive heart failure), institute drug prevention and at the same time vaccinate with influenza vaccine. The drug should be continued for 2 weeks until the person develops a protective antibody response, at which point it can be discontinued.
3. Continue the drug throughout the influenza season in severely immunosuppressed patients or patients who may not respond to vaccine with a sufficient antibody response (although influenza vaccine is still warranted for these patients).
4. Facility outbreak control (Influenza A and institutional outbreak control). Influenza A and institutional outbreak control—Changing standards of practice (J/F 2000)
5. Administer influenza antivirals to unvaccinated household contacts of a person with influenza, especially if they are at high risk for influenza complications.

Evidence for antiviral drug treatment of influenza
Amantadine, zanamivir, and oseltamivir have all been evaluated in controlled clinical trials for early treatment of clinical influenza, and all have a therapeutic effect. The data are summarized in Table 2. Although amantadine is only effective for influenza A, illness is modified to a milder form.[2] If given within 36 to 48 hours of the onset of symptoms, both antineuraminidase agents reduced symptomatic influenza significantly, usually by 1.5 to 2 days.[11-14] In febrile patients, one study of zanamivir for early treatment showed a reduction in major influenza symptoms from 7 to 4 days.[11] Data from the MIST trial with zanamivir in Australia, New Zealand, and South Africa showed a reduction in days of illness by 2.5 days in high-risk patients and demonstrated a 70% reduction in influenza complications such as pneumonia, and a 61% reduction in the use of antibiotics.[14] However, these data are based on small numbers and need to be confirmed in larger trials. Physicians need to be vigilant for the development of bacterial complications of influenza, against which these drugs are ineffective.

We are entering an exciting era of influenza antiviral chemotherapy. Influenza, the most dominant of viral illnesses, is now amenable to drug prevention and drug therapy on several fronts. Although influenza vaccination remains the mainstay of prevention, practising physicians and public health personnel can employ influenza antiviral agents in conjunction with immunization strategies. Most exciting are prelimanary data showing promise of effective treatment and reduction in complications in ill high-risk patients who suffer the most morbidity and mortality in influenza epidemics.

Antiviral agents for influenza: Key Concepts

Dr Stiver is a professor in the Division of Infectious Diseases at the University of British Columbia and acting head of the Division of Infectious Diseases at Vancouver General Hospital.