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During the 18 months prior to the emergence of the 2009 H1N1 pandemic virus, the old seasonal H1N1 virus developed nearly complete resistance to the antiviral drug oseltamivir (Tamiflu ®).
The novel swine H1N1 virus – while resistant to the older amantadines – has fortunately remained sensitive to oseltamivir. The concern is, that over time, this newer strain might one day develop resistance as well.
So testing influenza samples for resistance-producing mutations, and epidemiological tracking of resistant isolates, is a big part of global influenza surveillance.
During the first two years, only 1%-2% of samples tested have shown the most common mutation known to convey oseltamivir resistance; H275Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275.
(Note: some scientists use 'N2 numbering' (H274Y) and some use 'N1 numbering' (H275Y))
Most of the cases we’ve seen reported are isolated and sporadic, with no apparent epidemiological links.
Most occurred in patients under therapeutic or prophylactic treatment with oseltamivir, or were among immunocompromised patients; factors commonly associated with the development of spontaneous resistance.
In a few instances, we’ve see small clusters of resistant influenza, suggestive of person-to-person transmission of a resistant virus.
- In August of this year, in Australia Reports Cluster Of Antiviral Resistant H1N1, I wrote of a large clustering of oseltamivir (Tamiflu) resistant H1N1 cases in New South Wales. More than 2 dozen patients – roughly 14% of the isolates tested from that region since May – have shown a genetic mutation that confers resistance.
- In December of 2009, in NEJM: Community Cluster Of Tamiflu Resistant H1N1, we saw a report on 7 healthy people who contracted a resistant H1N1 flu while on a train ride from Ho Chi Minh City to Hanoi.
- Also in December of 2009 we saw a report on a small cluster of resistant H1N1 influenza among cancer patients (see Duke Hospital Reports No Further Spread Of Resistant Strain).
But these have really been the exception, not the rule.
For the most part, the 2009 H1N1 virus, seasonal H3N2, and influenza B remain overwhelmingly sensitive to oseltamivir.
Today, the World Health Organization’s WER (Weekly Epidemiological Record) updates us on the detection of antiviral resistance in currently circulating influenza viruses.
4 November 2011, No. 45, 2011, 86, 497–508
Introduction
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.
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.
This report notes that a variant of the H1N1 virus I wrote about earlier this summer (see Eurosurveillance: A `Mildly’ Resistant Strain of H1N1 Emerges) has appeared in a small percentage of flu cases in Singapore and Northern Australia, but that no new cases have been reported since April of 2011.
This variant carries a S247N neuraminidase mutation, instead of the H275Y mutation mentioned above. At least one case of a patient with both (S247N & H275Y) mutations has been detected, and that patient exhibited high levels of oseltamivir resistance.
This report concludes by stating:
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.
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.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.
While surveillance for antiviral resistance continues to be reassuring, scientists remember the remarkable speed by which seasonal influenza went from being almost 100% sensitive to being nearly 100% resistant.
So, as the report says, continued vigilance is required.
