• Frequently Asked Questions on antiviral resistance

Q. What are the anti-influenza drugs?

There are two classes of drug active against influenza viruses; neuraminidase inhibitors and M2 blockers. Two neuraminidase inhibitors are licensed for use; oseltamivir ((Tamiflu) Roche, Switzerland) and zanamivir ((Relenza) GSK, UK). The NIs function by blocking neuraminidase enzyme activity thus causing budding virus to aggregate at the cell surface. They are active against all influenza A subtypes as well as influenza B. A further neuraminidase inhibitor drug, Peramivir, is currently in the experimental stages of testing.

There are two M2 blockers, otherwise known as adamantanes; rimantadine (Flumadine) and amantadine (Symmetrel). These drugs block the M2 ion channel, preventing acidification of the endosome during entry of the viral particle into the cell. This block prevents fusion of the viral and endosomal membranes, meaning the viral genome is not released into the cell and viral replication is halted. These drugs are active only against Influenza A viruses and not influenza B viruses.

Q. What is antiviral resistance and how does it arise?

Antiviral resistance can be defined as a change in a virus which means that it is no longer susceptibility to a drug usually used to treat or prevent illness caused by the virus.

Antiviral resistance arises from random changes in the virus genetic material (genome) during replication. This ability to constantly change is a characteristic of influenza viruses. Influenza viruses often change from one season to the next or they can even change within the course of one flu season.

Q. How does antiviral resistance arise?

Antiviral resistance arises from random changes in the virus genetic material (genome) during replication. This ability to constantly change is a characteristic of influenza viruses. Influenza viruses often change from one season to the next or they can even change within the course of one flu season.

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

On 25th January 2008, the Norwegian authorities officially notified the World Health Organisation (WHO) and their EU partners about a high rate of resistance to the antiviral drug, oseltamivir, in seasonal influenza A(H1N1) viruses. Of 12 viruses tested, 16 (75%) were resistant to oseltamivir. Oseltamivir resistant viruses were subsequently identified in a large number of other countries with widely varying prevalence (0% - >60%). Previous surveillance studies undertaken by NISN have found much lower levels of resistant viruses (typically 0% to <0.5%) circulating in the community. The highest rate of resistant isolates previously reported, again by NISN, was in Japan during 2005-06 when 2.2% of 178 H1N1 isolates were found to be resistant. This suggests that the recent high rate of oseltamivir resistance is a new problem.

Q. Is there an explanation for the emergence of this high level of oseltamivir resistance?

The reason for such a high level of resistance is currently unknown. There is no evidence to suggest that resistance has emerged due to selective drug pressure, as few of the patients are known to have taken oseltamivir. It is believed that a resistant strain emerged spontaneously or has continued to spread after initially arising from someone being treated with oseltamivir. Further virological and epidemiological analysis is being undertaken to try and answer this question.

Q. How is oseltamivir resistance being monitored?

Testing was initially undertaken by National Institute of Public Health, Norway, the European Surveillance Network for Vigilance Against Viral Resistance (VirGiL), the WHO Collaborating Center (CC) at the MRC National Institute for Medical Research in London and the European Influenza Surveillance Scheme (EISS). The WHO has subsequently sought information from participants in its Global Influenza Surveillance Network (GISN) to assess the extent of circulation of oseltamivir resistant viruses globally and continues to monitor the situation.

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

There is no evidence to suggest that the oseltamivir resistant virus has caused illness any more or less severe than other influenza viruses. Influenza A(H1N1) is characteristically associated with less severe illness and lower mortality overall than infection caused by influenza A(H3N2) or influenza B.

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

The resistant H1N1 viruses contain a specific mutation which makes them highly resistant to the drug oseltamivir. This means that oseltamivir will be ineffective in treating or preventing infection caused by these viruses, although it is likely to be effective against other influenza virus infections. To date, the oseltamivir resistant viruses remain fully susceptible to the other antiviral drugs, zanamivir and the adamantanes (amantadine and rimantadine).

Q. Are the oseltamivir resistant viruses likely to cause a pandemic?

No, human seasonal influenza A(H1N1) viruses, including those with the resistance mutation, do not have the potential to cause a pandemic. The human H1N1 influenza viruses have been circulating widely in the population for many years.

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

The antiviral drug stockpile of many countries contains both neuraminidase inhibitor drugs: zanamivir and oseltamivir. These drugs will be used in the event that a novel influenza A virus subtype, such as influenza A(H5N1), emerges and develops the ability to transmit efficiently between humans. The stockpiles are for use in the event of a pandemic, rather than seasonal influenza activity. Resistance among seasonal influenza isolates does not predict resistance among pandemic influenza virus strains. 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.