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Influenza Antiviral Drug Resistance

Questions & Answers

What is antiviral resistance?

Antiviral resistance means that a virus has changed in such a way that the antiviral drug is less effective in treating or preventing illnesses. In the United States, four antiviral drugs are FDA-approved for use against influenza: amantadine, rimantadine, zanamivir (Relenza®) and oseltamivir (Tamiflu®). The adamantane drugs (amantadine and rimantadine) are approved for influenza A, while the neuraminidase inhibitor drugs (zanamivir and oseltamivir) are approved for both influenza A and influenza B. CDC issues guidance for health care providers on which antiviral drugs to use each flu season. Note: currently circulating flu viruses have high levels of resistance to the adamantane class of antiviral drugs (which includes amantadine and rimantadine), and therefore, these drugs are not recommended for use in the United States at this time.

How does antiviral resistance happen?

The ability to change is a hallmark of flu viruses. Flu viruses often change from one season to the next and can even change within the course of one flu season. As a flu virus replicates (i.e., make copies of itself), the genetic makeup may change in a way that results in the virus becoming resistant to one or more of the antiviral drugs used to treat or prevent influenza. Resistance of influenza A viruses to antiviral drugs can occur spontaneously or emerge during the course of antiviral treatment or antiviral exposure.

How is antiviral resistance detected?

CDC routinely collects viruses through a domestic and global surveillance system to monitor for changes in flu viruses. Samples of viruses collected from around the United States and worldwide are studied to determine if they are resistant to any of the four FDA-approved flu antiviral drugs. The information collected is used in making informed public health policy recommendations about the use of flu antiviral medications. Antiviral resistance testing involves several laboratory tests, including a specific functional assay, the neuraminidase inhibition (NI) assay, and molecular techniques (sequencing and pyrosequencing) to look for genetic changes associated with antiviral resistance in circulating flu viruses.

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What is oseltamivir resistance?

Oseltamivir (trade name Tamiflu®) is an antiviral drug that is used to treat flu illness. Antiviral resistance means that a virus has changed in such a way that an antiviral drug is less effective in treating or preventing illness. Oseltamivir resistance is a term that refers to antiviral resistance against the drug oseltamivir.

What causes oseltamivir resistance?

Flu viruses are constantly changing (for more information, see How the Flu Virus Can Change). Changes that occur in circulating flu viruses typically involve the structures of the viruses’ two primary surface proteins: neuraminidase (NA) and hemagglutinin (HA). (See image below for a visualization of a flu virus and its HA and NA surface proteins.)

 3D graphical representation of the biology and structure of a generic influenza virus, and are not specific to the 2009 H1N1 virus.

Oseltamivir is known as a “neuraminidase inhibitor” because this antiviral drug binds to a flu virus’ neuraminidase and inhibits the activity of this protein. By inhibiting NA activity, oseltamivir prevents flu viruses from spreading from infected cells to other healthy cells. However, as the NA proteins of circulating flu viruses change, oseltamivir can lose its ability to bind to and inhibit the function of these viruses’ NA proteins. This results in oseltamivir resistance. A particular genetic change known as the “H275Y” mutation is known to confer oseltamivir resistance in 2009 H1N1 flu viruses. (Technically speaking, the H275Y mutation is a substitution of histidine for tyrosine at position 275 in the NA.) This substitution prevents oseltamivir from inhibiting NA activity, which results in the drug not working and flu viruses being able to infect healthy cells as they normally would.

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How does CDC improve monitoring of influenza viruses for antiviral resistance?

CDC continually improves the ability to rapidly detect and monitor antiviral resistance through improvements in laboratory methods and by increasing the number of surveillance sites domestically and globally and increasing the number of laboratories that can test for antiviral resistance. Enhanced surveillance efforts have provided CDC with the capability to detect resistant strains more quickly, and enabled CDC to monitor for changing trends over time.

How is this surveillance information used?

Enhanced surveillance efforts have provided CDC with the capability to detect resistant influenza strains more quickly, and enabled CDC to monitor for changing trends overtime. Virus surveillance information is helpful in making recommendations on which antiviral drugs should be used for treating or preventing flu.

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How did influenza antiviral resistance patterns change during the 2012-2013 influenza season?

Antiviral resistance patterns did not change significantly from the previous season. Most of the influenza viruses tested during 2012-2013 continued to be susceptible to the antiviral drugs recommended for influenza by the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) (oseltamivir and zanamivir) and H1N1 and H3N2 resistance to the adamantanes class of antiviral drugs remains widespread.

Specifically, for the 2012-2013 season:

  • 99.6% of the tested 2009 H1N1 viruses were susceptible to oseltamivir (Tamiflu®), and 100% of the 2009 H1N1 viruses tested were susceptible to zanamivir (Relenza®).
  • 100% of influenza A (H3N2) tested were susceptible to both oseltamivir and zanamivir, and;
  • 100% of influenza B viruses tested were susceptible to both oseltamivir and zanamivir.
  • High levels of resistance to the adamantanes (amantadine and rimantadine) persist among the influenza A viruses currently circulating. The adamantanes are not effective against influenza B viruses.

Because there were no dramatic changes in antiviral resistance patterns during 2012-2013 flu season, the 2013-2014 guidance on the use of influenza antiviral drugs remains the same.

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What antiviral drugs are recommended for use during the 2013-2014 flu season?

Antiviral medications currently recommended include oseltamivir (Tamiflu®) and zanamivir (Relenza®). The vast majority of currently circulating influenza virus strains are sensitive to these medications. Rare exceptions have been detected. Note: currently circulating flu viruses have high levels of resistance to the adamantane class of antiviral drugs (which includes amantadine and rimantadine), and therefore, these drugs are not recommended for use in the United States at this time.

What can people do to protect themselves against antiviral resistant flu viruses?

Getting a yearly seasonal flu vaccination is the first and most important step in preventing the flu. The vaccine protects against an influenza A (H1N1) virus, an influenza A (H3N2) virus, and one or two influenza B viruses (depending on the vaccine). CDC recommends that everyone 6 months of age and older get vaccinated each year. If you are in a group at high risk of serious flu-related complications and become ill with flu symptoms, call your doctor right away, you may benefit from early treatment. If you are not at high risk, if possible, stay home from work, school and errands when you are sick. This will help prevent you from spreading your illness to others.

What implications does antiviral resistance have for the U.S. antiviral stockpile that was created as part of the United States pandemic plan?

Antiviral drugs are one component of a multifaceted approach to pandemic preparedness planning and response. Oseltamivir is the drug recommended by the World Health Organization (WHO) as the primary influenza antiviral drug for the treatment of patients infected with influenza A (H5N1). The U.S. influenza antiviral drug stockpile includes supplies of both of the neuraminidase inhibitor agents, oseltamivir and zanamivir. These medications are to be used in the event that a novel influenza A subtype virus, such as the avian influenza A (H5N1) virus, emerges and begins to spread easily among humans. During the 2009 H1N1 pandemic, antiviral drugs were released from the Strategic National Stockpile (SNS) and used to treat infection with the 2009 influenza A (H1N1) virus. Information about how antiviral drugs from the stockpile were used during the 2009 H1N1 pandemic is available in The 2009 H1N1 Pandemic: Summary Highlights, April 2009-April 2010. The stockpile is for public health emergencies in the United States, such as an influenza pandemic, not to provide medication for the treatment of seasonal influenza. Antiviral resistance among seasonal viruses does not predict resistance among pandemic influenza viruses.

CDC will continue ongoing surveillance and testing of influenza viruses for antiviral resistance among seasonal and novel influenza viruses, such as H5N1 viruses.

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