Data drive debate over antivirals, theory vs. practice

Much of the focus on influenza in fall typically surrounds vaccination, which the CDC now recommends for everyone 6 months of age and older. Experts, however, would also like physicians to prepare to treat those patients who will catch the disease, vaccinated or not. Reading about the latest evidence and recommendations—and educating patients about them—could make flu season a slightly easier time of year for all, they said.

For example, a study published in Clinical Infectious Diseases in July found that recent years' treatment patterns have not matched guidelines on drug therapy for flu. “We wanted to better understand antiviral prescribing patterns. We knew they were underutilized,” said lead author Fiona Havers, MD, MHS, a medical epidemiologist in the influenza division of the National Center for Immunization and Respiratory Diseases at the CDC.

She and her colleagues looked at more than 6,000 outpatients suspected of having flu in the winter of 2012-2013. Of the 35% who were later confirmed to have influenza, 16% got an antiviral medication and 30% got an antibiotic.

“We weren't particularly surprised to see fairly high rates of antibiotic prescribing. We were maybe a little bit surprised about how low the antiviral prescribing was in high-risk patients,” Dr. Havers said.

The CDC and the Infectious Diseases Society of America (IDSA) recommend oseltamivir or zanamivir for all outpatients at higher risk for complications from influenza. That means elderly people, pregnant women, patients with certain chronic conditions, the severely obese, nursing home residents, American Indians, Alaska Natives, and children under 2. The study found that only 19% of these patients received an antiviral.

There are a number of explanations for this gap between guidelines and practice, said experts, who also offered their advice on optimizing influenza treatment.

For example, every physician knows that antibiotics don't cure the flu, but many find reasons to prescribe them anyway, said Andrew T. Pavia, MD, ACP Member, chief of pediatric infectious diseases at the University of Utah in Salt Lake City.

“‘The patient is pretty sick ... I need to prescribe something. Let me give them an antibiotic so they'll be happier,’” said Dr. Pavia. Others prescribe antibiotics out of “an abundance of caution. We know a small proportion of patients with flu will also get a bacterial infection, although we also have good data that prescribing antibiotics up front to patients with flu makes no difference,” he said.

Physicians may also be uncertain about whether a patient has the flu. Dr. Havers and her research colleagues had the benefit of hindsight, since they were comparing prescriptions for antibiotics to results of influenza polymerase chain reaction (PCR) tests, which the treating physicians couldn't always access. Flu tests are improving in accuracy, but the latest technologies aren't widespread in outpatient care yet, the experts said.

If practices do have rapid flu testing, the results may not be much better than a physician's clinical judgment. “During the peak of flu season, use of symptoms can be almost as accurate as the less-good tests,” said Dr. Pavia, noting that a fever and cough or sore throat during flu season are about 75% predictive in adults.

While physicians shouldn't prescribe antibiotics to patients who definitely have only the flu, the guidelines don't require such certainty to prescribe antivirals. “It's not just laboratory-confirmed flu, it's ones where there is suspicion, particularly in those who are hospitalized, who have serious or progressive disease, who have underlying risk conditions ... they should also be treated,” said Frederick G. Hayden, MD, FACP, professor of medicine and pathology at the University of Virginia in Charlottesville, Va.

The low rate of adherence to this advice, found in the study and experts' observations, may result from different factors. “There is a lack of awareness of all the data there is to support use of antivirals, particularly in high-risk groups,” said Dr. Havers.

There's also some controversy over the data. In April, several articles published in The BMJ, including Cochrane reviews of oseltamivir and zanamivir, suggested that antivirals had less benefit than previously thought. The reviews found that the drugs reduced the duration of influenza illness only modestly (less than a day) and that there wasn't significant evidence of a reduction in complications.

“The assumptions about the ability of the drug to prevent hospitalization are not supported by the clinical trial evidence,” said oseltamivir review co-author Peter Doshi, PhD, assistant professor of pharmaceutical health services research at the University of Maryland and associate editor for The BMJ. “What we have in the end is really a modest drug that may reduce the time to first alleviation of symptoms by a small amount, around a day, and carries with it, like all drugs, a range of potential harms.”

Experts agree that these findings are true of healthy patients who catch the flu. “For somebody who has a low risk of being hospitalized or being very sick, a reduction of a day in the complete resolution of all symptoms is nice, but it's not a major health outcome. So people were probably justifiably not enthusiastic about treating symptoms,” said Dr. Pavia.

Side effects are also an issue to consider. “Most of the studies suggest that about 10% of patients overall will have enough nausea with oseltamivir that they won't finish it,” said Dr. Pavia. Meanwhile, he said, coughing and wheezing are the most prominent risks associated with zanamivir. “Like all drugs we use, you have to think about the side effects and warn people about them.”

However, where the experts disagree is on the value of the drugs for those outpatients specifically targeted for treatment by the guidelines, including the elderly and those with chronic illness. “When used in patients at high risk, the drugs can prevent severe outcomes like hospitalization, transfer to the ICU, and death,” said Dr. Pavia. “We now have approaching 30 high-quality, observational studies that have looked at treatment of high-risk or hospitalized patients.”

Ecologic studies also support the use of the drugs, according to Dr. Hayden. “It's noteworthy that in Japan, which has had the highest per capita use of neuraminidase inhibitors, they had the lowest overall mortality of any country during the first year of the [2009] pandemic, and they had no deaths due to influenza in pregnant women,” he said.

The IDSA and CDC reaffirmed their recommendations on use of antivirals in response to publication of the Cochrane reviews. “We've obviously looked at those very carefully. CDC still recommends the use of antivirals in patients that are at high risk of complications from influenza,” said Dr. Havers.

Because complications and deaths from influenza are relatively rare, a randomized trial to provide the gold standard of evidence specifically for high-risk outpatients would have to be enormous and is unlikely to occur, the experts agreed.

It's reasonable to consider the debate among researchers when deciding whether to use the drugs in healthy patients, but physicians shouldn't hold them back from the high-risk groups, according to Dr. Hayden. “The failure to use these drugs—not uncomplicated flu in low-risk patients, but in those who have underlying risk conditions, or those who are hospitalized—that's a huge lost opportunity to provide benefit to the patient,” he said.

To further help high-risk patients, educate them in advance, added Dr. Havers. “The drugs do work best if started within the first 48 hours of illness,” she said. “Have a conversation, particularly for patients in these high-risk groups: ‘Flu season is coming up. If you develop symptoms, don't wait 3 or 4 days to call us.’”

Before flu season starts is also a good time to educate people about proper use of antibiotics and why they shouldn't be prescribed for a viral illness. “When a person is sitting in front of you who is miserable who has just spent their time to come into the office and has an expectation of antibiotics, that's not the best time to educate them,” said Dr. Pavia. “It works quite well when people do it in the waiting room with pamphlets or with e-mails to patients or messages on their answering machine.”