Antiviral medications: a refresher for the 2004-2005 influenza seasons

November 2004

The current vaccine shortage affecting the United States will certainly result in suboptimal vaccination coverage for the 2004-2005 influenza season. For those who will not be able to receive vaccine, there are therapeutic alternatives that are effective for treatment of influenza and can help prevent disease. Four antiviral medications are approved by the FDA for influenza. These fall into two main drug categories: the amantadine derivatives and the neuraminidase inhibitors.

Amantadine derivatives

Amantadine and rimantadine are the two oldest antiviral agents with activity against influenza on the U.S. market. They exhibit anti-influenza activity through interference with a membrane ion channel protein of influenza virus. This results in viral uncoating, inhibited viral replication and, therefore, decreased viral shedding. Their spectrum of activity is limited to influenza A, not influenza B. The latter is responsible for fewer than 5% of infections in the United States.

These agents are approved for both treatment and prophylaxis of influenza in adults. In pediatric patients, experience is limited for the prevention of influenza.

The major adverse events associated with this class of medications are gastrointestinal (GI) disturbances and neurologic effects. All adverse effects are noted more often in patients older than 65 years. Rimantadine and amantadine have also been linked to an increased risk of seizures in patients with a history of epilepsy.

Neuraminidase inhibitors

The neuraminidase inhibitors were approved in the late 1990s for treatment of influenza. One of the most notable differences between these agents and the amantadine derivatives is the expanded spectrum of activity against influenza A and B. This is provided by the ability of these agents to block the active site of the viral enzyme neuraminidase, which is common to these two strains of the influenza virus. This inhibition results in viral aggregation and a decreased amount of virus shed from the infected cell.

The two agents available in this class are zanamivir (Relenza, GlaxoSmithKline) and oseltamivir (Tamiflu, Roche). Zanamivir is administered by inhalation, which has made this agent the less frequently used of the two. Due to this route of administration, patient counseling regarding administration technique is essential. Also, as bronchospasm and other pulmonary reactions were reported in clinical trials, this drug should be used cautiously in patients with underlying pulmonary disease such as chronic obstructive pulmonary disease and asthma.

Overall, the adverse effect profile of the neuraminidase inhibitors is quite mild. Outside of the pulmonary reactions already discussed, most treatment-related adverse events were mild and transient. For zanamivir, these included nasal symptoms, diarrhea, nausea, headache, cough, sore throat, dizziness and nosebleeds. In most instances, these were difficult to distinguish from influenza virus infection itself and occurred just as frequently in patients receiving placebo. For oseltamivir, the most frequently reported adverse effects were nausea and vomiting. While these did occur more frequently in those receiving oseltamivir compared with placebo, in nearly all cases these resolved despite a continuation of therapy. Neither of these agents appears to be associated with neurologic toxicities, which may make these agents preferable in patients older than 65.

Therapy duration

When using these antiviral medications to treat patients with documented influenza, prompt initiation of treatment is the key to therapy. For all four agents, initiation of therapy within 48 hours of the start of symptoms is required. When given at the outset of symptoms, the duration of illness can be reduced by approximately one to two days. For the amantadine derivatives, therapy is slightly longer (seven days for rimantadine; until 24 to 48 hours after resolution of symptoms for amantadine) than for the neuraminidase inhibitors (five days).

Prophylaxis

Only three of the four agents are indicated as prophylaxis for influenza (amantadine, rimantadine and oseltamivir). Furthermore, only the amantadine derivatives are approved for this indication in children between the ages of 1 and 13 years. When started quickly after documentation of an outbreak, these drugs can be more than 75% effective in reducing spread of influenza during community outbreaks. The duration of the prophylaxis regimen varies based on the length of the at-risk period. When preventing disease during a community outbreak, a six-week course of prophylaxis has been studied for all three agents. When the goal is to prevent spread to household contacts of a sick individual, shorter courses of seven days may be appropriate.

Resistance

Resistance has been reported with all four of the anti-influenza medications; however, overall rates of resistance remain low. It is known that resistance can rapidly develop to both amantadine and rimantadine during therapy, after only two to three days of treatment. The mechanism is the same for both of these agents; therefore, cross-resistance does occur.

There is no evidence that resistance to the amantadine derivatives results in cross-resistance with the neuraminidase inhibitors. While experience with these agents is less extensive than with the amantadine derivatives, clinical resistance has been reported in individuals after prolonged treatment courses.

Special considerations for 2004-2005

The CDC has issued interim guidelines regarding use of these agents in the setting of the influenza vaccine shortage during the 2004-2005 influenza season. Specifically, these guidelines recommend targeting amantadine or rimantadine for prophylaxis of disease and reserving oseltamivir and zanamivir for treatment of influenza as supplies allow. The recent attention focused on this issue has resulted in decreased availability of all of these agents. Given these concerns, the CDC guidelines further suggest that priority for these drugs be given to high-risk individuals who may gain the most benefit from treatment. The complete recommendations can be found at www.cdc.gov.

For more information:

• Elizabeth Dodds Ashley, PharmD, BCPS, is from the Division of Infectious Diseases, Duke University Medical Center, Durham, N.C.