Dec 19, 2008 (CIDRAP News) – Increased resistance to oseltamivir (Tamiflu), the leading influenza drug, has prompted federal health officials to change their advice about flu treatment, saying clinicians for now should consider using zanamivir (Relenza) or a combination of two drugs for patients suspected of having influenza A.
The Centers for Disease Control and Prevention (CDC) today said 49 of 50 influenza A/H1N1 viruses tested so far this season have shown resistance to oseltamivir. But all the isolates remained sensitive to zanamivir and to the two older flu drugs, amantadine and rimantadine.
H1N1 is one of the three viral types and subtypes included in season flu vaccine; the others are A/H3N2 and B.
"When influenza A (H1N1) virus infection or exposure is suspected, zanamivir or a combination of oseltamivir and rimantadine are more appropriate options than oseltamivir," the CDC said in today's advisory. "Local influenza surveillance data and laboratory testing can help with physician decision-making regarding the choice of antiviral agents for their patients."
But Dr. Anthony Fiore, a medical epidemiologist in the CDC's Influenza Division, said rapid flu tests don't identify the viral subtype, and many areas don't have good flu surveillance data. "This problem really does complicate deciding what kind of antiviral to use," he told CIDRAP News.
At the same time, he said US flu activity remains low so far this season, and the resistant H1N1 viruses seem no more virulent than susceptible ones. In its weekly surveillance update today, the CDC said 3 states have reported local flu activity, while 36 states have reported only sporadic cases. Another 11 states have reported no flu cases yet.
The CDC said vaccination should continue as the primary method for preventing the flu, as the oseltamivir-resistant H1N1 viruses are antigenically similar to the H1N1 strain in this year's vaccine.
Resistance emerged last season
Since January 2006, oseltamivir and zanamivir have been the only antivirals recommended for flu in the United States. At that point the CDC advised clinicians to stop using amantadine and rimantadine, known as the adamantanes, because H3N2 viruses had become highly resistant to them. Today's interim guidance puts the adamantanes back in the recommendations.
Significant H1N1 resistance to oseltamivir emerged in the United States and a number of other northern hemisphere countries during the 2007-08 flu season. Overall, 10.9% of tested H1N1 viruses in this country showed resistance, according to the CDC.
But resistance rose to nearly 100% in some southern hemisphere countries, particularly Australia and South Africa, in their 2008 season, said Fiore.
The CDC's new interim recommendations for healthcare providers include the following:
- Review local or state flu virus surveillance data weekly to determine which types and subtypes are circulating.
- Consider using rapid tests that can distinguish types A and B. Fiore said some rapid tests can do this, but others can't.
- Patients who test positive for type B can be given either oseltamivir or zanamivir if treatment is indicated.
- If a patient tests positive for type A, zanamivir should be considered if treatment is indicated. Oseltamivir should be used alone only if local surveillance data suggest that circulating viruses are likely to be A/H3N2 or B. A combination of oseltamivir and rimantadine is an acceptable alternative, and may be necessary for patients who can't take zanamivir, which is taken by inhalation and is not licensed for children younger than 7 years. Amantadine can replace rimantadine if the latter is not available.
- If a patient tests negative on a rapid flu test, clinicians should still consider treatment, depending on local flu activity and clinical signs and symptoms. (Fiore said rapid tests are not very sensitive and work better in children than adults.) If treatment is indicated, zanamivir or a combination of oseltamivir and rimantadine should be considered.
- Where available, testing for viral subtypes can guide treatment. For patients with an H3N2 or B virus, either oseltamivir or zanamivir can be used; for an H1N1 infection, zanamivir or the combination of oseltamivir and rimantadine can be used.
What pushed the CDC to make the new recommendations, said Fiore, was the high level of resistance in the H1N1 viruses tested, plus the fact that most of the viruses tested so far this season have been H1N1.
The latter factor could easily change, he said. "Last season at this time, H1N1 was the most common [subtype], but a month later they were a distant third place. That could happen again. So these are interim guidelines, and one hope we have is that clinicians will recognize that things are a little complicated this year and keep track of the recommendations that come out."
Fiore said polymerase chain reaction (PCR) tests that can identify flu subtypes are now available, but their use is mostly limited to specialty labs, such as state health departments. Once samples arrive at the lab, the tests take a couple of hours. "So if you were going to wait to decide therapy, you're going to end up with a pretty substantial delay," he said.
Also, he said many areas don't have good local flu surveillance data. "That advice to look at local data is probably not going to be useful in a lot of areas," he commented.
On the other hand, he noted, "We don't have much flu activity of any kind right now. . . . And things could continue to evolve and change."
He added, "The fact is that most people don't get antiviral treatment in the first place. And the resistant viruses are not any more dangerous or virulent, so the person is not going to know if they have resistant flu."
Experts air practical concerns
Kristine Moore, MD, MPH, medical director of the University of Minnesota Center for Infectious Disease Research and Policy, which publishes CIDRAP News, said she's not surprised by the sudden spike in antiviral resistance in this year's circulating H1N1 strain. She said influenza A viruses have a strong tendency to mutate rapidly, and that increasing use of oseltamivir has placed more selective pressure on the virus.
The quick emergence of antiviral resistance and the CDC's revised treatment recommendation have important implications for pandemic flu planning, Moore said. A rapid change affecting treatment could happen in a pandemic influenza strain. "This teaches us not to rely on any one strategy," she said.
William Schaffner, MD, chairman the Department of Preventive Medicine at the Vanderbilt University School of Medicine, told CIDRAP News that healthcare providers expect a little disconcerting news each flu season. "But we got the prize in the Cracker Jack box early this year," he said.
If physicians need to prescribe treatment for some of their patients who have influenza, they're going to have to get a sense of what strains are circulating in their area, which will be a change for many practitioners.
Schaffner advises physicians to use the rapid test to guide treatment. Patients who have the B strain will still benefit from oseltamivir treatment.
Though the CDC recommends zanamivir as an option for treating patients who have A strains, Schaffner said many physicians aren't as familiar with teaching patients how to use the inhaler. "Pharmacists are going to be very helpful," he said.
Some experts questioned if physicians will have enough information about what influenza subtypes are circulating in their area. Kristen Ehresmann, RN, MPH, manager of immunization, tuberculosis, and international health at the Minnesota Department of Health (MDH) in St. Paul, told CIDRAP News that many state public health laboratories have the reagents used to distinguish influenza subtypes.
However, she said getting a timely picture of the circulating strains will be a challenge. Though most public health labs easily handle sentinel surveillance samples, they have a more limited ability to process randomly submitted samples.
"Every state's resources are different," Ehresmann said, adding that the MDH uses a weekly e-mail listserv to update clinicians on the status of circulating influenza strains.
Schaffner said he contacted Vanderbilt's virus lab today and asked if they could start subtyping the influenza A strains and communicating the results to Tennessee's health department and the general medical community.
"This is new for the labs, but there is an urgency for this information," he said. "Doctors will have to learn how to keep up with information about the circulating strains."
The experts who spoke with CIDRAP News said they were concerned about the nation's supply of zanamivir, given the CDC's revised antiviral recommendations. Moore said even if the supply seems adequate, some regions of the country may still experience shortages.
However, GlaxoSmithKline, the maker of zanamivir, said today in a press release that it has sufficient supplies to meet the needs of the 2008-09 influenza season and that pharmacies can get the medicine from their wholesalers.
Moore and Schaffner both expressed concerns about the combination (oseltamivir and rimantadine) therapy alternative recommended for patients who can't take zanamivir. "It's a reasonable recommendation, but its efficacy and safety have never been demonstrated in humans," Moore said.
Added impetus to vaccinate
A silver lining in the CDC's antiviral resistance warnings and treatment recommendations is that they strengthen the rationale for seasonal flu vaccination, the experts said. "These events speak to the value of vaccination and not counting on being able to treat influenza after the fact," Ehresmann said.
Schaffner, who is also president-elect of the National Foundation for Infectious Diseases, said vaccine supplies are abundant this year, and an examination of early viral isolates suggests that the vaccine is a good match with the circulating strains.
This year so far looks like a typical flu season, and activity usually peaks in February, he said, "so there's still time to be protected by getting the vaccine through December and into January."
CDC interim antiviral guidance for 2008-2009