CDC warns of variances in influenza strains

Centers for Disease Control and Prevention surveillance data for the week ending March 14 indicate that U.S. flu activity slightly decreased, with 30 states reporting widespread activity -- five fewer than in the previous report, and 18 more with regional activity.

Every year the CDC monitors the influenza virus, focusing on type A strains, H1N1 and H3N2, and type B strains. Since the beginning of the 2008-09 flu season, type A (H1N1) viruses have been dominant. But in recent reporting periods, several regions noted a higher relative proportion of influenza B viruses than at the national level or in other regions.

During the current season, the CDC also detected a significant increase in resistance to flu antivirals in one of the circulating strains.

The flu types and subtypes on this watch list are the viruses that circulate every year, though the proportion of strains is different, explained Nila Dharan, MD, an epidemic intelligence service officer in the CDC's Influenza Division. In addition, the prevalence and proportion can vary during the course of a flu season among communities and even within a specific community, according to CDC materials. These changes in type and subtype affect which antiviral drug will be most useful.

For physicians, this reality can be problematic when it comes to selecting flu antivirals. In an office setting, doctors can be limited as to what information tests will provide about a patient's influenza, Dr. Dharan said. A quick test can confirm the presence of the flu virus and sometimes will be sensitive enough to tell if it is a type A or B. "But that's it," she added.

Dr. Dharan also noted, though, that a physician can make a more effective choice by being aware of what strains are circulating in his or her region or even more locally. But still, influenza treatment and chemoprophylaxis with antivirals is no easy proposition.

Two drug classes exist. The newer drugs are the neuraminidase inhibitors -- oseltamivir or Tamiflu and zanamivir or Relenza. The second category, the adamantanes, is made up of amantadine and rimantidine, which is marketed as Flumadine.

To date, 100% of H3N2 viruses have tested resistant to adamantanes. Though all flu strains remain susceptible to zanamivir, this drug has limitations that make it unsuitable for certain categories of patients at very high risk for flu complications. Meanwhile, the adamantanes are not active against type B strains. Emerging resistance to oseltamivir has added to this complexity.

"Before last year, there was very little resistance to oseltamivir among routinely tested viruses -- less than 1%," Dr. Dharan said. But during the 2007-08 flu season, this circumstance changed as resistance to this antiviral reached 12%. During that period, though, H1N1 viruses made up only about 19% of circulating strains. Therefore, the proportion of overall resistance among all influenza viruses tested was not high.

The figures for the 2008-09 season thus far reveal a different picture. Seventy-five percent of circulating strains have been type A and 24% have been type B. Unfortunately, the vast majority of type A viruses are H1N1, and about 98% of H1N1 viruses tested are resistant to oseltamivir.

Experts highlight specific messages from this situation.

The current resistance situation makes the flu vaccine more important than ever, especially because the vaccine for the 2008-09 season and for that of 2009-10 protects against the strain of H1N1 that is resistant to oseltamivir.

Also, resistance to these antivirals functions differently than that of the usual understanding of antibacterial resistance. Because flu virus is constantly mutating and changing, it is "not necessarily the case that the resistance will persist next year," Dr. Dharan said.

In response to the growing resistance, though, the CDC updated the public health recommendations regarding the selection of antiviral drugs in December 2008. This document directs physicians to use a combination of oseltamivir and rimantadine. Zanamivir also remains an option when appropriate.

Antivirals and the national stockpile

Meanwhile, the current resistance profile warrants attention for reasons far from the day-in, day-out concerns of the exam room. These reasons are related to pandemic preparedness.

"We are watching this very carefully," said Robin Robinson, PhD, director of the Biomedical Advanced Research and Development Authority, which is part of the Dept. of Health and Human Services Office of the Asst. Secretary for Preparedness and Response.

Influenza antivirals have been considered by public health experts to be an important medical countermeasure in the event of a pandemic influenza epidemic. The U.S. Strategic National Stockpile, for instance, houses 50 million treatment courses of the neuraminidase inhibitors. Of this amount, the ratio is 80 to 20, oseltamivir to zanamivir. The stockpile also holds 2.8 million courses of rimantidine.

Officials have been monitoring the resistance situation for at least 18 months, Robinson said, and active deliberation continues. Compared with other countries, the U.S. oseltamivir-zanimivir ratio falls in the middle -- some nations have more oseltimivir, some less. "But no country has made a drastic change yet," he said. A decision about whether to take steps to adjust the stockpile's makeup could occur later this spring.

Robinson also noted that historical data show influenza viruses, even within the H1N1 subtype, can "burn out." In this case, the emergence of the resistant strains has not been driven by exposure to the drugs or, therefore, selective pressure. Instead, it is a natural mutation.