|2006 CDC HAN On Amantadine|
Twelve years ago Amantadine was the preferred influenza antiviral. It was cheap, plentiful, and worked reasonably well as both a treatment, and a preventative.
But by late 2005 Amantadine began to lose its effectiveness against the H3N2 seasonal flu virus and some strains of the H5N1 bird flu. In January of 2006 the CDC issued a warning (see above) to doctors not to rely on Amantadine or Rimantadine to treat influenza.
Tamiflu (Oseltamivir), while far more expensive, became the new treatment standard.But within a couple of years seasonal H1N1 began to show growing resistance to Tamiflu as well (although H3N2 remained sensitive). By the spring of 2009, - in the space of just about a year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant.
It seemed as if antiviral crisis was inevitable, when in a Deus Ex Machina moment a new swine-origin H1N1 virus - that happened to be sensitive to Tamiflu - swooped in as a pandemic strain in the spring of 2009, supplanting the older resistant H1N1 virus.Both incidents showed that antivirals - much like antibiotics - can lose effectiveness over time, as pathogens evolve and resistant strains emerge.
While Amantadine resistance has appeared permanently `fixed' in both seasonal and most novel flu viruses tested over the past decade, there may be a glimmer of hope in a report published yesterday in the Eurosurveillance Journal that finds an unexpected jump in amantadine sensitive H3N2 viruses in Australia during their recent flu season.
The number of Australian amantadine sensitive samples was small (n=15), but exceeded the combined number reported globally between 2011-2016.Amantadine sensitive isolates were detected during July, August and September in four states in Australia (Victoria: n = 10; New South Wales: n = 2; Queensland: n = 2; Northern Territory: n = 1) along with one reported from New Zealand. At its peak, in August, 8.7% of samples tested (10 of 115) showed sensitivity to Amantadine.
So far surveillance has not picked up any similar changes in H1N1 viruses.While none of this is enough to make Amantadine useful for treating influenza again, it is a remarkable turn of events, and we'll be keen to see if this trend continues during during this winter's Northern Hemisphere flu season.
Follow the link to read the full report in its entirety.
Rapid communication Open Access
Detection of adamantae-sensitive influenza A(H3N2) viruses in Australia, 2017: a cause for hope?
Aeron Hurt1,2, Naomi Komadina1, Yi-Mo Deng1, Matthew Kaye1, Sheena Sullivan1,3, Kanta Subbarao1,2, Ian Barr1,2
Amantadine and rimantadine are compounds of the adamantane class of antivirals which act on influenza A viruses by binding to the M2 ion channel, preventing uncoating of the virus during replication. Treatment of influenza A virus infection with these drugs within 48 hours of symptom onset reduces illness by ca 24 hours, and when given prophylactically, the drugs can prevent ca 60% of influenza cases .
However, effectiveness of both drugs is lost when viruses acquire an amino acid substitution at one of five critical residues of the M2 protein i.e. positions 26, 27, 30, 31 and 34 . The occurrence of adamantane-resistant influenza A viruses was rare among circulating influenza viruses  until 2000, when an increasing proportion of viruses from Asia, particularly China, contained the serine (S) to asparagine (N) substitution at residue 31 (S31N) of the M2 protein .
By the end of the 2005/06 influenza season, over 90% of circulating A(H3N2) viruses in North America and other parts of the northern hemisphere, such as Asia, contained the S31N substitution even though the vast majority of resistant viruses were from patients who had not been treated with adamantanes . After more than 7 years of almost complete dominance of adamantane-resistant A(H3N2) influenza viruses globally, we describe the detection in Australia of increased numbers of adamantane-sensitive viruses during the 2017 influenza season.
The Australian 2017 influenza season was dominated by high levels of A(H3N2) influenza virus activity. During this season, 15 adamantane-sensitive A(H3N2) viruses encoding M2 S31 were detected in Australia (Table 2), which exceeded the cumulative total of 11 adamantane-sensitive influenza A viruses detected globally between 2011 and 2016 (Table 1). In contrast, the frequency of adamantane-resistance in circulating A(H1N1)pdm09 viruses has remained unchanged at > 99.9% both in Australia and worldwide.
Discussion and conclusion
Adamantane-resistance was first detected in persons infected with influenza virus who were treated with adamantanes in the late 1980s, in closed settings, such as nursing homes [10,11], as well as community settings . In the latter, there was apparent transmission of drug-resistant strains, when rimantadine was used for treatment or post-exposure prophylaxis in families . Adamantane-resistant viruses were also detected in nursing home patients without exposure to these drugs , demonstrating that adamantane-resistant variants may be able to spread in the community. Up to 45% of children treated with rimantadine have been reported to shed resistant viruses .
In addition to widespread adamantane-resistance among A(H3N2) influenza viruses circulating globally, seasonal influenza A(H1N1) viruses also developed adamantane-resistance between 2005 and 2008 [15,16], and the A(H1N1)pdm09 virus that emerged and caused the influenza pandemic in 2009 was also adamantane-resistant. As consequence of these developments, adamantanes are no longer recommended for treatment of influenza .
The spread of M2 N31 viruses in the early 2000s was thought to be due to linkage to advantageous substitutions elsewhere in the virus, in a process referred to as genetic ‘hitch-hiking’, and not related to adamantane-induced selection pressure . Even though the A(H3N2) virus has continued to undergo substantial antigenic and genetic evolution over the last decade, the M2 N31 residue has remained almost completely fixed, suggesting that during that time it contributed to viral fitness.
However, the recent detection of M2 S31 and D31 viruses in Australia suggests that the importance of the M2 N31 residue in viral fitness may no longer be as strong as it was. We encourage surveillance laboratories, where possible, to conduct M2 sequencing of A(H3N2) viruses during the upcoming 2017/18 northern hemisphere influenza season to see if the M2 S31 or D31 viruses begin to circulate in greater numbers globally.
In the seminal publication by Bright et al. on the emergence of the S31N variant in the early 2000s , the authors stated that ‘further genetic and antigenic evolution of influenza A(H3N2) viruses resulting in the disappearance of the S31N mutation and reversion back to the drug sensitive phenotype should not be excluded’.
It may be that the M2 S31 viruses detected in Australasia in 2017 could be the progenitors for a reversion back to more widely circulating adamantane-sensitive A(H3N2) viruses, some 12 years after the resistant strain emerged and then dominated globally. If this were the case, it would revive the option of using adamantanes to treat A(H3N2) virus infections and improve the opportunities for using these drugs in combination with other antivirals .(Continue . . . )