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Global monitoring of antiviral resistance in currently circulating human influenza viruses, November 2011 (WHO, edited)

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  • Global monitoring of antiviral resistance in currently circulating human influenza viruses, November 2011 (WHO, edited)

    [Source: World Health Organization, Weekly Epidemiologiocal Record, full PDF document: (LINK). Extract, edited.]

    Weekly epidemiological record / Relevé épidémiologique hebdomadaire
    4 november 2011, 86th year / 4 novembre 2011, 86e année - No. 45, 2011, 86, 497–508 -

    Global monitoring of antiviral resistance in currently circulating human influenza viruses, November 2011


    Antiviral treatment is an important tool in the clinical management of severe or complicated influenza, and treatment recommendations need to take account of information on the prevalence of resistance to antiviral medicines among the circulating viruses.

    This article provides a brief update on global incidence of resistance in currently circulating human influenza viruses since the last published report on oseltamivir resistance in influenza A(H1N1) 2009 viruses, now termed influenza A(H1N1) pdm09 viruses.(1)

    It also highlights the need to monitor and report resistance during the post-pandemic period.

    All influenza viruses currently circulating in the community are resistant to adamantanes (amantadine and rimantadine), but most are sensitive to neuraminidase inhibitors, although a limited number of sporadic cases involving resistant viruses have been reported.

    However, a recently reported cluster of cases involving oseltamivir-resistant influenza A(H1N1)pdm09 virus suggests that such viruses may have been transmitted locally, and reinforces the need for continual surveillance.

    Resistance among circulating influenza viruses

    Information is routinely received from participants in the WHO Global Influenza Surveillance and Response System,(2) including data from National Influenza Centres and WHO Collaborating Centres for Reference and Research on Influenza, and from Member States reporting under the International Health Regulations 2005 (IHR (2005)).(3)

    Additional information has been retrieved from national governments’ web sites, reports from public health agencies, and publications in medical journals.

    The currently circulating human influenza viruses are influenza A(H1N1)pdm09, influenza A(H3N2), and influenza type B.(4)

    The influenza A(H1N1) viruses that were circulating prior to the 2009 pandemic – the majority of which have become resistant to oseltamivir – are no longer circulating.(5)

    Influenza A(H1N1)pdm09

    Influenza A(H1N1)pdm09 viruses circulating now are known to be resistant to adamantanes(6) but in general remain sensitive to neuraminidase inhibitors, although sporadic cases of resistance have been reported since April 2009.

    As of 5 October 2011, a total of 605 cases of oseltamivir-resistant infections with influenza A(H1N1) pdm09 virus have been reported; they occurred in 32 countries across 5 WHO regions. These oseltamivir-resistant viruses carry the H275Y substitution in the neuraminidase glycoprotein, which is known to confer resistance to oseltamivir.

    Information on the clinical background of cases with oseltamivir resistance is available for 468/605 (77%) cases. A total of 133 (28%) occurred in patients who were severely immunocompromised, and 335 (72%) occurred in patients who were not immunocompromised.

    Of the patients who were not immunocompromised, 211 cases (63%) were associated with the therapeutic and prophylactic use of antiviral medicines. These cases include those that occurred during or after treatment with oseltamivir or peramivir, or both, and also cases that were associated with post-exposure prophylaxis.

    A total of 124/335 cases (37%) occurred in patients who had not been given antiviral medicines prior to detection of the resistant viruses; these included cases of known or suspected person-to-person transmission.

    In addition to the 2 clusters of oseltamivir-resistant viruses which occurred in severely immunocompromised patients as described previously,(1) and the cluster of oseltamivir-resistant viruses which occurred in healthy adults, also described previously,(1) an additional community cluster of 31 cases was reported in August 2011.(7)

    The viruses in this cluster have been shown to be sensitive to zanamivir, but resistant to amantadine and rimantadine. Cases in this cluster had no underlying health conditions, and only 1 individual had received oseltamivir prior to an influenza specimen being collected.

    These resistant viruses did not differ antigenically from other circulating influenza A(H1N1)pdm09 viruses that were sensitive to oseltamivir, and they are similar to WHO’s recommended vaccine component.

    With the exception of these clusters, there are few epidemiological links among the reported cases. The majority of cases have been sporadic and isolated, and linked to the use of antiviral medicines; few cases have been reported from community-based sampling conducted for surveillance.

    The results of 1 study suggested that there may have been a higher prevalence of oseltamivir-resistant viruses in community-based samples from the United Kingdom during 2010–2011 compared with the previous year, but the prevalence was still low, with 99% of viruses found to be susceptible to oseltamivir.(8)

    Also, countries including Japan and the United States have reported increased proportions of resistant cases that had no known exposure to oseltamivir.(9)

    This trend demonstrates the need to maintain timely community-based monitoring for antiviral susceptibility.

    While most viruses carrying the H275Y substitution remain sensitive to zanamivir, 1 virus variant with an I223R NA substitution has been reported from an immunocompromised patient; this virus showed reduced levels of susceptibility to oseltamivir and zanamivir.(10)

    Further reports indicate that a virus variant has emerged with an S247N neuraminidase mutation: this was found in >10% of community specimens in Singapore and >30% of samples from northern Australia.

    This mutation resulted in a slightly reduced sensitivity to oseltamivir and zanamivir, with no significant reduction in sensitivity to peramivir. In 1 patient who was treated with oseltamivir, dual H275Y+ S247N substitutions were detected, resulting in high levels of oseltamivir resistance.(11)

    The WHO Collaborating Centre in Melbourne has not detected viruses with the S247N substitution since April 2011.

    Japan reported 1 case of resistance to peramivir and oseltamivir associated with the H275Y substitution in a patient being treated with peramivir.(12)

    Other circulating human influenza viruses

    Resistance to neuraminidase inhibitors in the other circulating influenza viruses, influenza A(H3N2) and influenza type-B, has been reported rarely, and has usually been associated with prolonged treatment in immunocompromised patients.

    A cluster of influenza type B viruses with reduced susceptibility to oseltamivir and peramivir has been reported from routine surveillance of antiviral susceptibility in the United States.(13)

    The viruses, which have an I221V substitution in the neuraminidase, were detected in 14 samples, but the clinical significance of this observation is not known. There have been no other recent reports of resistance to neuraminidase inhibitors from community-based samples of either influenza A(H3N2) or type B viruses.

    Implications for clinical management

    The prevalence of resistance to neuraminidase inhibitors in circulating human influenza viruses remains low, and WHO guidelines for treatment of patients and use of antiviral medicines remain as previously published.(14, 15)

    Oseltamivir is recommended for treatment of patients with severe or progressive influenza disease; oseltamivir or zanamivir is recommended for treatment of patients with uncomplicated illness who are at a high risk of developing severe disease. WHO recommends that a specific antiviral medicine should not be used in cases where the virus is known to be resistant to it or is highly likely to be resistant. Therefore, local virological and epidemiological knowledge about the presence and circulation of resistant viruses is necessary to ensure appropriate case management.
    Zanamivir remains a therapeutic alternative for all patients with serious illness caused by infection with an influenza virus that is known to be resistant to oseltamivir.

    Recommendations for post-pandemic surveillance

    WHO has collated and reported data on all known cases of infection with influenza A(H1N1)pdm09 virus since the start of the 2009 pandemic.(16) Such data support the conclusion that resistance to neuraminidase inhibitors does not currently constitute a significant risk to public health.

    However recent characterization of case clusters, and an increased prevalence of resistant viruses in community-based cases, are causes for concern, and suggest that continued vigilance is required.

    Consequently, WHO urges all countries to maintain an appropriate level of surveillance for antiviral resistance as previously described,(1) and to notify WHO of events or data that may indicate a change in the situation.

    Such events include:
    1. any indication of person-to-person transmission of viruses known to be resistant to antiviral medicines, including the occurrence of clusters of cases;
    2. changes in the results of routine virological surveillance, such as detecting a higher than normal incidence of antiviral resistance;
    3. detection of novel substitutions and related genetic markers for antiviral resistance.
    In any of these events, it is important to document complementary clinical information, such as the clinical background of the cases in which resistance has been detected. Such information is necessary to assess the public health risk and potential changes in virulence.

    Such events should be notified to WHO through National Influenza Centres or WHO Collaborating Centres which are part of the Global Influenza Surveillance and Response System, or if appropriate under the IHR (2005) through national focal points. WHO will ensure that these events and changes are communicated to national authorities and agencies as appropriate, including through the Global Influenza Surveillance and Response System and the WHO website.

    WHO will discontinue routine reporting of the cumulative number of cases of antiviral resistance.


    The prevalence of resistance to neuraminidase inhibitors in circulating human influenza viruses remains low; therefore clinical recommendations are unchanged. Given current trends, however, continued vigilance is required.

    1. See No. 6, 2010, pp. 37–40.
    2. Information on the Global Influenza Surveillance and Response System is available at (LINK).
    3. International Health Regulations (2005). Geneva, World Health Organization, 2005. (Also available from LINK.)
    4. See No. 43, 2011, pp. 469–480.
    5. Influenza virus activity in the world, 23 September 2011. Geneva, World Health Organization, 2011 (LINK, accessed October 2011).
    6. Update: drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009. MMWR Morbidity and Mortality Weekly Report, 2009, 58:433–435.
    7. Australian influenza surveillance report No. 13, 2011: reporting period: 3 September to 16 September 2011. Woden, Australia, Australian Government, Department of Health and Ageing, 2011 (LINK, accessed October 2011).
    8. Lackenby A et al. Continued emergence and changing epidemiology of oseltamivirresistant influenza A(H1N1)2009 virus, United Kingdom, winter 2010/11. Eurosurveillance, 2011, 16(5):pii=19784 (LINK, accessed October 2011).
    9. See No. 42, 2011, pp. 457–468.
    10. van der Vries E, Stelma FF, Boucher CAB. Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. New England Journal of Medicine, 2010, 363:1381¬–1382 (also available at LINK).
    11. Hurt AC et al. Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation. Eurosurveillance, 2011, 16(23):pii=19884 (LINK, accessed October2011).
    12. [Case study detects resistant viruses from patients treated with peramivir H275Y]. Infectious Agents Surveillance Report (LINK, accessed October 2011). In Japanese
    13. Sleeman K et al. Influenza B viruses with mutation in the neuraminidase active site, North Carolina, USA, 2010−11. Emerging Infectious Diseases [serial on the Internet], 2011 LINK , accessed October 2011).
    14. WHO guidelines for pharmacological management of pandemic influenza A(H1N1) 2009 and other influenza viruses. Geneva, World Health Organization, 2010 (LINK, accessed October 2011).
    15. See No. 8, 2011, 86, pp. 61–66.
    16. Update on oseltamivir resistance in influenza A(H1N1)2009. Geneva, World Health Organization, 2011 (LINK, accessed October 2011).