Flu antiviral resistance forces new strategies

Feds expect hospitals to stockpile millions of doses

Antiviral resistance of one strain of influenza has altered this year's strategies for seasonal influenza. It also highlights mutability of the virus — and the need for careful pandemic planning, federal health officials say.

But it does not change the recent guidance from the U.S. Department of Health and Human Services that calls for employers — including hospitals — to stockpile millions of doses of antiviral medication for use during a pandemic, says Ben Schwartz, MD, former senior science adviser with the National Vaccine Program Office in Washington, DC, who coordinated the guidance development.

HHS has called for health care employers to stockpile almost 103 million doses of antiviral medication for pandemic preparedness (www.pandemicflu.gov/vaccine/antiviral_use.pdf.)

"It's important to note that this resistance is limited only to this one particular type of influenza. As such, it doesn't have any implications really for whether a new influenza virus that might cause a pandemic would be susceptible to oseltamivir (Tamiflu)," says Schwartz. "Our recommendations are to continue to plan and prepare for an influenza pandemic [with stockpiling of antiviral medications]."

In a health advisory issued on Dec. 19, 2008, the Centers for Disease Control and Prevention reported a high prevalence of H1N1 influenza A strains that are resistant to oseltamavir. If there is infection or exposure to influenza A (H1N1), zanamivir (Relenza) or a combination of oseltamivir and rimantadine should be used for treatment or prophylaxis, the CDC said.

Influenza A (H3N2) and influenza B remain susceptible to Tamiflu. CDC is recommending the use of rapid tests that can distinguish between types A and B. Tamiflu can still be used with influenza B strains. If a patient tests positive with influenza A, zanamivir (Relenza) or a combination of Tamiflu and rimantadine can be used.

Clinicians also can contact the local public health department to determine whether the prevailing A strain is H1N1 or H3N2, says Tony Fiore, MD, MPH, medical epidemiologist with CDC's influenza division.

The influenza resistance occurred through a mutation and not due to overuse of antiviral medication, Fiore says. The strain could once again become resistant, he says.

"There's not any difference in the viruses whether they're resistant or not, in terms of the types of syndromes they cause or the severity of symptoms or transmissibility," he says.

Antiviral medications remain a crucial part of pandemic preparedness, though health officials stress that hospitals should stockpile more than just Tamiflu.

"It points out ... the need for diversifying the number of drugs we have," says Fiore. "What if the virus showed up and it was resistant already? We can't turn to a single drug, even a drug that has been as useful as Tamiflu, and expect that to be the answer."

Antivirals are useful in ameliorating the symptoms of influenza and are more effective if given within the first two days of illness. Yet they are not commonly used, says Fiore. "There's a general lack of awareness of the benefits of treatments with antivirals," he says.

In the initial stages of a pandemic, when there is no vaccine yet available for a newly emerging strain, antiviral medications play a crucial role in protecting health care workers and first responders, public health officials say.

Employers are expected to provide those doses through their own stockpiles, according to HHS guidance. The national stockpile will be used to contain the spread of the virus and for treatment of patients, the guidance states.

Community outbreaks are expected to last 12 weeks, and no pandemic vaccine will be available for the first wave of infection, according to public health officials. Post-exposure prophylaxis requires a single dose daily for 10 days, and prophylaxis would require 8 of those 10-day regimens to cover the 12-week period, the guidance states.

Two-thirds of health care workers will have high-risk exposures to pandemic influenza, requiring 102.8 million regimens (10-day doses), HHS estimated. About 80% of the stockpile is in oseltamavir (Tamiflu) and 20% in zanamivir (Relenza), supplemented with a few million doses of rimantadine. Stockpiling even more Relenza might be warranted, says Schwartz.

Relenza, administered through inhalation, is not recommended for people with severe asthma or other chronic lung disorders and is approved for children 5 years old and older. Tamiflu is approved from the age of 1 year and older.

"If a hospital is planning to use antiviral drugs for prophylaxis, there are data published that show the effectiveness of Tamiflu and Relenza to be equal," Schwartz says. "Resistance is less likely to develop to Relenza. Therefore, if a hospital is planning to use a drug for prophylaxis and not for treatment, it wouldn't be unreasonable to stockpile a larger proportion of Relenza."

Hospitals will not be able to rely solely on rotating its stock of antiviral medications with ongoing use, he says. However, the pharmaceutical companies offer stockpiling programs for an annual fee that promise the delivery of regimens within 48 hours.

"It's an investment in preparedness. It's an investment in work force safety," says Schwartz. "And it's an investment in assuring that the hospital can protect the health of the public at the time a pandemic occurs."

Rethinking the stockpile

For some hospitals that already have invested in a stockpile, the news about antiviral resistance has spurred a reconsideration of strategy.

At Vanderbilt Medical Center in Nashville, TN, infectious disease expert William Schaffner, MD, has asked the laboratory to provide periodic updates on the prevailing subtype of influenza. "You need to know the predominant strain circulating in your community" to treat seasonal influenza, says Schaffner, who is chair of preventive medicine at the Vanderbilt University School of Medicine.

The hospital system also may expand its stockpile, he says. "I think people will want to very deliberately review all the data and will want to look again at what information we have regarding the current bird flu strain and its susceptibility to Relenza," he says.

The issue of resistance also underscores the need for better vaccine development, both for seasonal and pandemic influenza. "That serves to remind us that the research that's ongoing to develop better influenza vaccines is absolutely critical," he says.