Influenza Antiviral Drug Resistance

Questions & Answers

What are reduced susceptibility and antiviral resistance?

When an antiviral drug is fully effective against a virus, that virus is said to be susceptible to that antiviral drug. Flu viruses are constantly changing, and some changes can make antiviral drugs work less well or not work at all against these viruses. Antivirals drugs work by targeting a specific location or site found on a flu virus. When a flu virus develops changes to the site antiviral drugs use to work, that virus may show reduced or no susceptibility to that antiviral drug. Antiviral drugs may not work as well against viruses with reduced susceptibility. Flu viruses can show reduced susceptibility to one or more flu antiviral drugs. Reduced susceptibility detected using laboratory tests can be a sign of potential antiviral drug resistance in clinical settings. Typically, flu virus is called resistant after sufficient evidence was gathered to prove a lack of antiviral effect of a particular antiviral medication in patients infected with such virus.

In the United States, there are four FDA-approved antiviral drugs recommended by CDC this season. Three are neuraminidase inhibitor antiviral drugs: oseltamivir (available as a generic version or under the trade name Tamiflu®) for oral administration, zanamivir (trade name Relenza®) for oral inhalation using an inhaler device, and peramivir (trade name Rapivab®) for intravenous administration. The fourth is a cap-dependent endonuclease (CEN) inhibitor, baloxavir marboxil (trade name Xofluza®) for oral administration. Baloxavir marboxil was approved for use in the United States by FDA in October of 2018.

There is another class of FDA-approved antiviral drugs, M2 inhibitors amantadine and rimantadine, also called the adamantanes, that have activity against flu A viruses. They are not recommended for use in the United States for many years because of widespread antiviral resistance to this class of antivirals among circulating flu A viruses.

How widespread are reduced susceptibility and antiviral resistance in the United States?

In the United States, the majority of the recently circulating flu viruses have been fully susceptible to the neuraminidase inhibitors and to CEN inhibitor baloxavir. However, near all flu A viruses are resistant to the M2 inhibitors, which is why they are not recommended for use at this time.

How does reduced susceptibility and antiviral resistance happen?

Flu viruses are constantly changing; they can change in significant way 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 less susceptible to one or more of the antiviral drugs used to treat or prevent flu. Flu viruses can become less susceptible to antiviral drugs during the course of antiviral treatment or emerge spontaneously. Antiviral resistant flu viruses vary in their ability to infect people and are not necessarily more or less transmissible than susceptible flu viruses.

How are reduced susceptibility and antiviral resistance detected?

CDC routinely tests flu viruses collected through domestic and global surveillance to see if they have indications of reduced susceptibility to any of the FDA-approved flu antiviral drugs, as this can suggest the potential for antiviral resistance. In addition, numerous state public health laboratories participate in screening of additional viruses for genetic changes indicative of potential resistance to neuraminidase inhibitors. CDC also is collaborating with the Association of Public Health Laboratories (APHL) and the Wadsworth Center NYSDOH, a National flu Reference Center (NIRC), to establish additional laboratory-testing capacity for monitoring baloxavir susceptibility. This combined data informs public health policy recommendations about the use of flu antiviral medications.

CDC is continuously improving testing algorithms and methods used for monitoring antiviral susceptibility in circulating viruses. Detection of reduced susceptibility and antiviral resistance involves several laboratory tests, including phenotypic assays (testing in the presence of an antiviral) and molecular techniques (sequencing and pyrosequencing) to look for genetic changes that have been associated with reduced antiviral susceptibility.

How has CDC prepared to test for reduced susceptibility and antiviral resistance to the new flu antiviral baloxavir?

CDC’s Influenza Division took specific laboratory actions to incorporate the antiviral drug baloxavir into routine virologic surveillance. This included the creation and validation of new assays to determine baloxavir susceptibility, and training of laboratorians to conduct baloxavir susceptibility testing.

Seasonal flu A and B viruses in humans as well as several flu A viruses that circulate in animals were tested to established baseline susceptibility to baloxavir. In addition, the susceptibility of other distantly related flu viruses to baloxavir was tested. CDC also collaborated with the Association of Public Health Laboratories (APHL) and the Wadsworth Center NYSDOH, a National flu Reference Center (NIRC), to establish laboratory-testing capacity for baloxavir susceptibility. CDC has trained staff within these partner organizations to use CDC’s method for assessing baloxavir susceptibility.

What is oseltamivir resistance and what causes it?

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: hemagglutinin (HA) and neuraminidase (NA) (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 the most commonly prescribed antiviral drug of those recommended in the United States to treat flu illness. Oseltamivir is known as a “NA inhibitor” because this antiviral drug binds to NA proteins of a flu virus and inhibits the enzymatic activity of these proteins. By inhibiting NA activity, oseltamivir prevents flu viruses from spreading from infected cells to other healthy cells.

Changes in the NA proteins of a flu virus can reduce oseltamivir’s binding to them. As a result, oseltamivir’s ability to inhibit the enzyme activity of NA proteins can be diminished and this may cause “oseltamivir resistance” (non-susceptibility). A particular genetic change known as the “H275Y” mutation in the NA is the mutation that is known to confer oseltamivir resistance in A(H1N1) pdm09 flu viruses. Flu viruses that have H275Y mutation show highly reduced inhibition by oseltamivir in laboratory assays. The “H275Y’ mutation makes oseltamivir ineffective in treating illnesses with that flu virus by preventing oseltamivir from inhibiting NA activity, which then allows the virus to infect healthy cells. The H275Y mutation also reduces the effectiveness of peramivir to treat infections caused by a flu virus with this mutation. Some other mutations in the NA proteins of circulating viruses have been shown to affect the oseltamivir’s ability to inhibit the enzyme activity of their NA proteins. Such viruses can show ‘reduced’ or even ‘highly reduced’ inhibition by oseltamivir and other NA inhibitors in laboratory tests, however, not all are considered “resistant” due to insufficient data to support their drug resistance from clinical settings.

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

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

How did influenza antiviral susceptibility patterns change during the previous (2019-2020) influenza season?

Antiviral susceptibility patterns changed very little in 2020-2021 compared with the previous season (2019-2020). During the 2020-2021 and 2019-2020 seasons, only a small number of viruses were resistant to oseltamivir. Most of the flu viruses tested during 2020-2021 continued to be susceptible to the antiviral drugs recommended for flu by the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) (oseltamivir, zanamivir, peramivir and baloxavir). Resistance to the adamantane class of antiviral drugs among A(H3N2) and A(H1N1) pdm09 viruses remained widespread (flu B viruses are not susceptible to adamantane drugs).

CDC conducts ongoing surveillance and testing of flu viruses for antiviral reduced susceptibility and resistance among seasonal and novel flu viruses, and guidance is updated as needed.

Because there were no dramatic changes in antiviral susceptibility patterns during the 2020-2021 flu season, the guidance for the 2021-2022 flu season on the use of flu antiviral drugs remains unchanged. The latest guidance for clinicians on the use of antiviral drugs for flu is available on the CDC web site at Antiviral Drugs: Information for Health Professionals.

What can people do to protect themselves against flu viruses with reduced susceptibility and antiviral resistance?

Getting a yearly seasonal flu vaccination is best way to reduce the risk of flu and its potentially serious complications. Flu vaccines protect against influenza A viruses of two subtypes, A(H1N1) pdm09 and A(H3N2), and type B viruses from two lineages. CDC recommends that everyone 6 months of age and older get vaccinated each year. If you are in a group at higher risk of serious flu-related complications and become ill with flu symptoms, call your doctor right away, you may benefit from early treatment with a flu antiviral drug. If you are not at higher 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. See Important Information For People Sick With Flu for more information.

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

NAI medications can be used in the event that a novel flu A virus, such as avian flu A(H7N9) virus, gains the ability to spread easily among people in a sustained manner, and is susceptible to NAI antiviral drugs. During the 2009 H1N1 pandemic, antiviral drugs were released from the SNS and used to treat infection with the pandemic virus, now referred to as flu A(H1N1) pdm09 virus. Information about how antiviral drugs from the SNS were used during the 2009 H1N1 pandemic is available in The 2009 H1N1 Pandemic: Summary Highlights, April 2009-April 2010. Antivirals in the SNS are for use during public health emergencies in the United States, such as a flu pandemic, but not for seasonal flu epidemics. CDC no longer oversees the SNS. More information is available at Strategic National Stockpileexternal icon.