Adamantane resistance in influenza A(H1) viruses increased in 2007 in South East Asia but decreased in Australia and some other countries
Introduction
Since the mid-2000s the level of resistance to the adamantanes, a class of antivirals active against influenza A viruses, has been increasing for both the A(H3N2) and A(H1N1) influenza viruses in most countries. This has been especially evident for the A(H3) viruses which have reached almost 100% resistance in several countries (Bright et al., 2005, Deyde et al., 2007, Barr et al., 2007) and resistance in A(H1) viruses has also been rising in recent years (Bright et al., 2006, Deyde et al., 2007, Barr et al., 2007). This class of drugs, which includes the licensed products amantadine (Symmetrel™) and rimantadine (Flumadine™), has been widely used in many countries to combat seasonal influenza and in some countries has been stockpiled by for use in future pandemics (Aoki, 1998, Tsiodras et al., 2007). Due to the persistence of high rates of adamantane-resistant viruses, the use of the newer group of influenza antivirals known as neuraminidase inhibitors (NIs) (Reece, 2007), oseltamivir (Tamiflu™) and zanamivir (Relenza™), was recommended for the treatment or prevention of influenza for the last two influenza seasons by the US CDC (Centers for Disease Control and Prevention) and ACIP (Advisory Committee on Immunization Practices) (CDC, 2006, Fiore et al., 2007). Recently however there has been an increase in the proportion of A(H1N1) viruses with resistance to oseltamivir found in Europe, North America, Australia, Hong Kong, Japan, and especially in Norway where resistance was reported to be as high as 66% (155/234 viruses tested) of the 2007–2008 A(H1) viruses (last quarter 2007–April 4 2008, WHO, 2008a). There have also been reports of increased levels of resistance to zanamivir in circulating viruses in Australia and South East Asia (Hurt and Barr, 2007).
With the increasing levels of resistance to both licensed NI it is important to monitor the rates of resistance to the adamantanes in both circulating seasonal and potentially pandemic strains of influenza. The adamantanes work by blocking the ion channel formed by the M2 protein of influenza A viruses and inhibiting the early stages of virus replication (Hay, 1992, Pinto et al., 1992, Aoki, 1998). The mechanism of resistance is well understood and revolves around mutations in the M2 protein that lead to the loss of binding or action of these drugs (Hay et al., 1985, Aoki, 1998,). Several amino acid substitutions (at positions 26, 27, 30, 31 and 34) in the M2 protein and prevent binding of the adamantanes or change the structure of the ion channel to allow it to operate even in the presence of bound drug, with both types of change resulting in the generation of resistant viruses (Hay et al., 1986, Astrahan et al., 2004). This occurs when patients with influenza are treated with these drugs where there is a rapid generation of adamantane-resistant viruses and these resistant viruses are fully capable of transmission to other humans (Shiraishi et al., 2003). Abed et al. (2005) used reverse genetics to generate recombinant influenza A A(H1N1) viruses with the commonly observed adamantane resistance mutations in the M2 gene (L26F, V27A, A30T, S31N, G34E, and V27A/S31N). They showed not only did all of these mutations cause amantadine resistance but also the M2 mutants had no impairment in their replicative capacities in vitro and were at least as virulent as the wild-type virus in experimentally infected mice.
The recent proliferation of adamantane-resistant A(H3) viruses appears to have occurred by a chance reassortant event between influenza A(H3) viruses, which has made these viruses fully fit, possibly even more fit than other circulating A(H3) viruses, resulting in their current predominance (Simonsen et al., 2007). It is unclear at this stage what events have occurred to increase the A(H1) resistance levels although recombination with adamantane-resistant A(H3) viruses or increased use of the drug appear unlikely causes. Resistance among A(H1) viruses has generally not increased as quickly as it has among A(H3) viruses, with only a few regions having high levels of resistance in 2006 (e.g. Taiwan, Province of China with 82% (9/11) resistant strains) and most having low levels of resistance. For example in Malaysia and the Philippines in 2006, no A(H1) adamantane-resistant viruses were detected among 26 viruses tested. In Australia levels of resistance in A(H1) viruses grew from 0% in 2005 to 40% in 2006 (Barr et al., 2006a, Barr et al., 2007) compared to the global levels of 4.1% in 2004–2005 rising to 15.5% in 2005–2006 (Deyde et al., 2007). In the present study we examined influenza A viruses isolated in 2007 from patients with influenza in Africa, Australia, France, New Zealand, South East Asia, Macau (SAR of China), Pacific Islands and Taiwan (Province of China) and compared these results to adamantane resistance levels seen in these regions in previous years.
Section snippets
Viruses
Influenza A(H3) and A(H1) viruses were received from WHO National Influenza Centres, WHO Influenza Collaborating Centres and other regional laboratories and hospitals from Australia, New Zealand, and the Asia/Pacific region. Viruses were received as isolates passaged in cell culture (MDCK cells) or as original clinical samples in which influenza A had been detected by immunofluorescence or by RT-PCR. Once received at the Centre, the isolates were cultured in MDCK cells and monitored for growth
Results
An increased proportion (34.2%) of influenza A(H1) viruses (from the total number of influenza A(H1), A(H3) and B viruses) was received at the WHO Collaborating Centre for Reference and Research on Influenza, Melbourne in 2007 compared to recent years (2006 16.8%; 2005 12.8%; 2004 8.4%; 2003 0.9%). This increase was particularly high for some countries such as New Zealand, Australia and Sri Lanka compared to 2006. A total of 127 A(H1) viruses and 154 A(H3) viruses sent to the Centre during
Discussion
Adamantane resistance in A(H3) strains has continued to increase in many countries from 2005 to 2007 (e.g. Australia, Japan, Malaysia, New Caledonia, New Zealand, Philippines, and Singapore) while remaining very high in other places (e.g. Macau, Taiwan, and South Africa) (Barr et al., 2007, Saito et al., 2008) including the USA (A(H3) were 99.4% resistant in 2007–2008, CDC, 2008). Resistance in A(H1) strains however has been quite variable during this period. For example in Australia there was
Acknowledgements
The authors would like to thank the National Influenza Centres and laboratories in Australia, Cambodia, France, New Caledonia, New Zealand, South Africa, Malaysia, Philippines, Macau (SAR), Singapore, the Solomon Islands, South Africa, Taiwan (POC) and Thailand, for providing influenza isolates that were used for analysis in this paper. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health and Ageing.
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