Oseltamivir-resistant influenza A(H1N1)pdm09 patterns across the globe: findings in Australia (season 2011) and United States (season 2010-11)Archived

ECDC comment

Review and comments of two articles: Community Transmission of Oseltamivir-Resistant A(H1N1)pdm09 Influenza and Oseltamivir-resistant pandemic (H1N1) 2009 virus infections, United States, 2010–11.

Community Transmission of Oseltamivir-Resistant A(H1N1)pdm09 Influenza Hurt AC, Hardie K, Wilson NJ, et al. N Engl J Med 2011; 365:2541-2542December 29, 2011

In this letter the authors describe being able to identified a sustained community transmission of oseltamivir-resistant influenza A(H1N1)pdm09 viruses in Australia. They looked at reverse-transcriptase-polymerase-chain-reaction-positive influenza A(H1N1)pdm09 viruses obtained from 182 patients in emergency departments, intensive care units and general practitioners' offices in the Hunter New England region of New South Wales, Australia, between May and August 2011. These viruses were analyzed for oseltamivir susceptibility. A total of 29 viruses (16%) were resistant due to the H275Y neuraminidase substitution; all were resistant to adamantanes. Virus culture was attempted for all specimens and yielded 90 isolates, of which 15 contained the H275Y substitution linked to the resistance pattern observed. However, these isolates remained fully sensitive to zanamivir. The frequency of H275Y variants was 4 in 50 (8%) viruses in June 2011, 20 in 85 (24%) viruses in July 2011, and 4 in 45 (9%) viruses in August 2011.

Further haemagglutinin and neuraminidase sequence analysis showed that the resistant strains were closely related, suggesting the spread of a single variant. Hospital records and interviews with patients and general practitioners revealed that only 1 of the 29 patients with resistant influenza had received oseltamivir before the influenza specimen collection. The ages were similar among the 29 patients with oseltamivir-resistant influenza (median, 31 years; range, 4 months to 62 years) and the 153 patients with sensitivity to oseltamivir (median, 29 years; range, 1 month to 74 years). Five patients with oseltamivir-resistant influenza were children younger than 5 years of age. The resistant viruses remained antigenically similar to the vaccine strain, including those from 3 patients who received the 2011 influenza vaccine. The authors also looked for epidemiological links. Four households had 2 affected patients each and 2 other patients shared a short car journey. The remaining patients had no known epidemiological link with the other patients with oseltamivir-resistant influenza.Oseltamivir-resistant pandemic (H1N1) 2009 virus infections, United States, 2010–11 Storms AD, Gubareva LV, Su S, et al.Emerging Infectious Diseases, Volume 18, Number 2—February 2012

This article describes the patterns of oseltamivir-resistant influenza A(H1N1)pdm09 virus infections during the influenza season 2010-2011 in the United States. The paper describe how during the period October 2010 to July 2011, only 1% of influenza A(H1N1)pdm09 viruses in the US were oseltamivir resistant, little different from the 0.5% during the influenza season 2009-10. In addition, during the season 2009-2010, 89% of resistant viruses were from people exposed to oseltamivir before specimen collection, whereas this proportion felt to 26% during the influenza season 2010-11. In addition, the authors note that many patients with oseltamivir-resistant influenza A(H1N1) virus infection during the season 2009-2010 were severely immunocompromised, which could have increased the risk of developing resistance during therapy with oseltamivir.

These data suggest a low level of community transmission of oseltamivir-resistant influenza A(H1N1)pdm09 virus in the United States during the influenza season 2010–2011, but there was an observed increase in the proportion of patients with oseltamivir-resistant influenza A(H1N1) virus infections without prior oseltamivir exposure during the influenza season 2010-11. For comparison purposes, the authors also described the oseltamivir-resistant findings in the United States prior to the 2009 pandemic. Before the influenza season 2007-2008 the prevalence of oseltamivir resistance among the old seasonal influenza A(H1N1) viruses was <1%; during the influenza season 2007-08, the prevalence of oseltamivir resistance among the old seasonal influenza A(H1N1) viruses increased to 12%; and during the influenza season 2008-09 this resistance dramatically increased to >99%. No association was found between this increase in oseltamivir resistance and prior oseltamivir use. In addition, oseltamivir resistance in influenza A(H1N1)pdm09 and the old seasonal influenza A(H1N1) viruses was conferred by the H275Y substitution in the neuraminidase. However, unlike the old seasonal influenza A(H1N1) viruses, >99% of circulating influenza A(H1N1)pdm09 viruses were resistant to adamantanes.

ECDC comment, 20 February 2012:

Antiviral susceptibility is a key area for influenza surveillance. The susceptibility results can affect patient management and prevention of outbreaks as well as pandemic preparedness. Active surveillance in the area of antiviral resistance may assist restriction of resistance outbreaks in health care settings and can affect also vaccination policy, especially of the risk groups in a season where antiviral susceptibility resistance is substantial.  Therefore the gathering surveillance data across the globe is very valuable and needs to be followed carefully.(1)  Europe arguably has a special role having been the first region to detect the rapid emergence and then pre-dominance of the H275Y related oseltamivir resistance in the seasonal A(H1N1) viruses that were present before the 2009 pandemic.(2)  In a way it is fortunate that those viruses have now been entirely displaced by the A(H1N1)pdm09 which is now the ‘new’ seasonal A(H1N1).

The information gathered and collated in this way in the northern or southern hemisphere can serve to inform expectations of the more likely occurrence of resistance patterns during the following influenza season in the other part of the world. ECDC has summarised the southern hemisphere season recently (3).  However flu has the ability to surprise and the 2007-8 rise in resistance was despite there being no warning in the previous seasons (2).  The Australian results are unusual in that it seems to show detection of community transmission of an oseltamivir-resistant A(H1N1)pdm09 influenza strain between May and August , the southern hemisphere 2011 influenza season. Despite the high proportion of positive specimens from the affected area in July 2011 (24%), the cluster remained limited and did not spread widely in Australia, which fits with the general.

In the second paper, during the 2010-2011 northern hemisphere influenza season, a low level of oseltamivir-resistant viruses were detected across the US (1% total).In Europe, antiviral resistance to oseltamivir in influenza A(H1N1)pdm09 remained at a low level throughout the influenza (northern hemisphere) season 2010-2011. Most reports of resistance were from people with severe conditions on antiviral therapy. However, there were some cases of resistance associated with the H275Y substitution in the virus neuraminidase where there was no history of exposure to antiviral medications, indicating low-level community transmission of resistant viruses (3). One hundred and eleven (3.2%) of 3 431 influenza A(H1N1)2009 viruses tested were resistant to oseltamivir, but all viruses tested remained sensitive to zanamivir. All resistant viruses carried the NA H275Y substitution. Of 58 patients infected with resistant viruses and for whom information about possible exposure to antivirals was available, 17 (29.3%) had not been treated with oseltamivir (4).

All these reports, both from southern and northern hemisphere, indicate the importance to continue and strengthen antiviral susceptibility surveillance. These results and others indicate that a low level of oseltamivir resistance in the A(H1N1)pdm09 viruses seems to be normal at present, with even lower levels of transmission of such viruses.  In Australia, as the community transmission was detected early on, when the cluster might theoretically be limited. However more commonly the limitation of the antiviral resistance has been impossible and the resistant viruses have spread across Europe and then globe, as in 2007-2009 seasons (2).   

Comments should be sent to influenza@ecdc.europa.eu.