Antivirals: New interest in second line of defense

40 million doses available for flu season

While influenza antiviral medications comprise an important second line of defense during a troubled flu season, the Centers for Disease Control and Prevention (CDC) is reluctant to promote the drugs as a solution to the vaccine shortage.

"We are not looking at them as a big alternative to vaccination," said Scott Harper, MD, medical epidemiologist in the CDC influenza branch. "Part of that is because we want to get the message out that vaccine is still far and away the best way to prevent influenza in the population."

Still, with vaccine doses at a premium, interest in antivirals is likely as high as it’s ever been. Indeed, with the threat of pandemic influenza looming, one positive side of the current vaccine shortage is that antivirals will draw more interest from both clinicians and the public.

"In general, if we are to really to provide for an effective response to a pandemic threat with antiviral drugs, we have to foster use of these agents in the interpandemic period," said Frederick Hayden, MD, professor of internal medicine and pathology at the University of Virginia in Charlottesville.

"Just as for vaccine, the greater use of these influenza drugs in the upcoming and subsequent influenza season will provide not only a greater amount of drugs available in the event of a pandemic, but also greater familiarity on the part of practitioners with their use and effective applications," he added.

With about 40 million doses available nationally, the CDC is recommending antivirals be prioritized for use according to general guidelines recently issued for the 2004-2005 flu season. For example, antivirals generally are not recommended for healthy individuals who want to use them as chemoprophylaxis during flu season.

"That is sort of the lowest risk," Harper says. "That would be like your 35-year-old healthy office worker. There is no recommendation that that person should go on antiviral medications because influenza is in their community."

But what about an otherwise healthy, nonrisk group person who starts having flu symptoms? Can they seek antiviral treatment under the guidelines? "It depends [on local availability] and also just clinician and patient judgement," Harper adds. "In these recommendations, there are priority groups [for whom] CDC recommends [antivirals] really should be used for either treatment or prophylaxis."

The prime rule is that any person experiencing a potentially life-threatening influenza-related illness should be treated with antiviral medications.

Four meds of choice

In the United States, four antiviral medications (amantadine, rimantadine, oseltamivir, and zanamivir) are approved for treatment of influenza, though limited supplies of zanamivir are currently available, according to the CDC.

Amantadine and rimantadine are chemically related antiviral drugs known as adamantanes with activity against influenza A viruses but not influenza B viruses. Amantadine was approved in 1966 for chemoprophylaxis of influenza A (H2N2) infection and later was approved in 1976 for treatment and chemoprophylaxis of influenza type A virus infections among adults and children age 1 year and older.

Rimantadine was approved in 1993 for treatment and chemoprophylaxis of influenza A infection among adults and prophylaxis among children. Although rimantadine is approved only for chemoprophylaxis of influenza A infection among children, certain specialists in the management of influenza consider it appropriate for treatment of influenza A among children, the CDC reports.

Zanamivir and oseltamivir are chemically related antiviral drugs known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for treating uncomplicated influenza infections. Zanamivir is approved for treating people 7 and older, while oseltamivir is approved for treatment for those 1 year and older. In 2000, oseltamivir was approved for chemoprophylaxis of influenza among people 13 and older.

The four drugs differ in pharmacokinetics, side effects, routes of administration, approved age groups, dosages, and costs. When used for treatment within the first two days of illness, all four antiviral medications are similarly effective in reducing the duration of illness by one or two days. Only three antiviral medications (amantadine, rimantadine, and oseltamivir) are approved for chemoprophylaxis of influenza. In its latest recommendations, the CDC encourages the use of amantadine or rimantadine for chemoprophylaxis and use of oseltamivir or zanamivir for treatment as supplies allow — in part, to minimize the development of adamantane resistance among circulating influenza viruses.

"Currently, the drug that has received, by far, the greatest use in the United States and really worldwide is oseltamivir, " Hayden said during a recent audio conference held by Thomson American Health Consultants, publisher of Hospital Infection Control. Commercially available rapid influenza assays can be used to guide clinical decisions about whether to administer antivirals, he said. Noting that the combination of fever and cough is highly predictive of influenza, Hayden said the tests are used to confirm diagnosis before administering antiviral treatment.

"This allows us to determine which patients might benefit from antiviral therapy even in they are presenting somewhat later in the course of illness," he said.

"It also, of course, facilitates their appropriate isolation in institutions where there is a shortage of beds cohorting with other positive patients. We do routinely back up our antigen testing with cultures if the assay is negative, particularly in adults because we do know that the performance of these tests is associated with lower sensitivity in adults as compared to children. The assays [also] can be very useful in outbreak investigations, whether in nursing homes, chronic care facilities, or acute settings like hospitals," Hayden added.

Good for chemo, less so for treatment

In general, antivirals can be used to lessen the duration of infection and prevent new infections.

"While the antivirals work very well for chemoprophylaxis; they work less well for treatment," Harper said.

"So if you develop influenza, if you start treatment within the first two days, you can reduce duration of symptoms by one to two days. There is some evidence in newer data the use of oseltamivir or zanamivir — the neuraminidase inhibitors — will reduce severe complications. There are no data to suggest that with amatandine or rimantidine, but those studies really haven’t been done so we don’t know if that is the case with them or not."

The interim recommendations primarily are aimed at reducing the impact of influenza in people at high risk for developing severe complications secondary to infection.

"Antivirals will be used by different facilities in different kinds of ways," Harper said. "The message for patient care is that if you are a patient at high risk of complications of the flu and you haven’t received the vaccine, if you develop influenzalike symptoms, then you should seek medical attention because there are antivirals that can be used. For health care professionals, there is guidance out there now for use of antivirals if you are taking care of [high-risk] populations."

In addition, health care workers who have not been able to obtain flu vaccine may be indicated for chemoprophylaxis if an influenza outbreak erupts in their facility.

"If there is an outbreak in an institution going on, they would clearly [take antivirals]," Harper said. "[Otherwise], they would not be a priority group, but [antivirals] can be considered for health care workers with direct patient care responsibilities who cannot obtain vaccine. So, yes, they can consider going on them."