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Frequently Asked Questions - Resistance

Q. What are the anti-influenza drugs?

A. There are two principal classes of antivirals active against influenza viruses: inhibitors of the virus neuraminidase enzyme and inhibitors of the virus M2 proton channel.

Two neuraminidase inhibitors (NAIs), oseltamivir (Tamiflu) and zanamivir (Relenza) are licensed for use in many countries, while peramivir and laninamivir have been developed more recently and have been licensed in Japan.  The NAIs function by blocking neuraminidase enzyme activity, preventing release and spread of progeny virus.  They are active against all influenza A subtypes and type B influenza viruses.

There are two licensed inhibitors of the M2 proton channel, amantadine (Symmetrel) and rimantadine (Flumadine).  They act by preventing acidification of the virus particle during its entry of into the cell via endocytosis.  As a consequence, the virus genome is not uncoated and is prevented from entering the nucleus to initiate replication.  These drugs are active only against Influenza A viruses and not influenza B viruses.

Q. What is antiviral resistance?

A. Antiviral resistance can be defined as a change in a virus such that it is no longer susceptible to a drug used to treat or prevent illness caused by the virus.

Q. How does antiviral resistance arise?

A. Antiviral resistance arises from random changes in the virus genetic material (genome) during replication and their selection during drug treatment (usually).  This ability to constantly change is a characteristic of influenza viruses, which often change from one flu season to the next.

Q. What is the significance of oseltamivir resistance that has been reported in influenza viruses?

A. In late 2007, seasonal A(H1N1) viruses acquired a change in their neuraminidase (NA), designated by the abbreviation H275Y, which caused resistance to oseltamivir.  The subsequent spread of these viruses around the world meant that oseltamivir was no longer effective against infection by these viruses.  However, the other NAI zanamivir was still effective.  These viruses no longer circulate following the pandemic of 2009 and have been replaced by the viruses designated A(H1N1)pdm09.  Oseltamivir is effective against these viruses and was widely used during the pandemic.  The detection of a few clusters of oseltamivir-resistant A(H1N1)pdm09 viruses has, however, caused concern that they might also spread widely such that oseltamivir might no longer be effective against this influenza A subtype.

Oseltamivir resistance among the H3N2 subtype of influenza A and influenza B viruses has remained very low.

Q. How is drug resistance being monitored?

A. The emergence of resistant virus is monitored in association with drug treatment in hospital and in the community by national and international (World Health Organisation) organisations and networks who conduct surveillance of the incidence of circulating influenza viruses and changes in the viruses.

Q. Was infection with oseltamivir-resistant virus associated with severe illness?

A. There is no evidence to suggest that the oseltamivir-resistant viruses have caused illness any more or less severe than the sensitive viruses.

Q. Which antiviral drugs can be used to treat infection with oseltamivir-resistant viruses?

A. The specific mutation, designated H275Y, which makes H1N1 viruses highly resistant to oseltamivir does not cause resistance to zanamivir, the other widely available anti-NA drug, or the anti-M2 drugs (amantadine and rimantadine).  This means that these drugs may be effective in treating oseltamivir-resistant influenza infections.

Q. What are the implications of oseltamivir resistance for the antiviral stockpiles that some countries have created for pandemic planning purposes?

A. The antiviral drug stockpile of many countries contains both anti-NA drugs, zanamivir and oseltamivir.  These drugs were used effectively in some countries to reduce the impact of the 2009 pandemic during the initial phases.  They will again be used in the event of another novel influenza A virus subtype, such as influenza A(H5N1), emerging and developing the ability to transmit efficiently between humans and cause a pandemic.  The World Health Organization continues to recommend oseltamivir as the first-line influenza antiviral drug for the treatment of patients infected with influenza A(H5N1).  To date, oseltamivir-resistant viruses have been isolated from a very small number of patients infected with avian influenza A(H5N1), and these viruses did not spread to other people.  Further information on the role of antiviral drugs in the event of a pandemic can be found on the WHO website.

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