Seemingly from one influenza season to the next, we have lost the use of our leading antiviral influenza drug because of resistance. This winter, the circulating strain of seasonal influenza A virus (H1N1) is resistant to the neuraminidase inhibitor oseltamivir. Moreover, rather than emerging under selective pressure of drug use, as many antibiotic-resistant bacteria do and as has been the concern for influenza, this resistant strain seems to be a natural, spontaneously arising variant. Nevertheless, science has given us the tools with which to anticipate these events — and should allow us to develop new clinical solutions that build on our knowledge of the biology of RNA viruses.
Neuraminidase cleaves sialic acid residues on the cellular receptor that bind the newly formed virions to the cell and to one another, enabling infection to spread to new host cells and ongoing infection to be established. The neuraminidase inhibitors mimic neuraminidase's natural substrate and bind to the active site, preventing the enzyme from cleaving host-cell receptors, thereby preventing infection of new host cells and halting the spread of infection. The two licensed neuraminidase inhibitors, zanamivir (Relenza) and oseltamivir (Tamiflu), have very little toxicity and are effective against all neuraminidase subtypes and, therefore, against all strains of influenza virus.
But the possibility of widespread oseltamivir resistance has been a concern for several years. Structural analysis of the influenza neuraminidase predicted that resistance to oseltamivir would be feasible — and more likely to arise than resistance to zanamivir.1 Although the concern was focused on the emergence of resistance under the selective pressure of drug treatment, the same principles apply to natural variants: mutations could arise that would inhibit oseltamivir's action while leaving viral fitness and zanamivir activity unaffected. These predictions were borne out by clinical data during the past several years, as resistance to oseltamivir in influenza A isolates from treated patients, especially children, has grown more common. However, some complacency about the clinical significance of neuraminidase-inhibitor–resistant influenza was based on the belief that such viruses would be less infectious and less transmissible in humans. Clearly, this complacency was not warranted. H1N1 influenza viruses containing a mutation conferring resistance to oseltamivir — one of the most common resistance mutations seen in treated patients since 2004 — have now circled the globe.
A Multidrug Strategy for the Future
Over time, influenza viruses will probably develop resistance to any single antiviral agent. Treatment with several compounds that act at different stages of the viral life cycle would be more effective and make it less likely that any single mutation could confer resistance. This strategy may become feasible as new agents, such as the following, become available1:
Intravenous zanamivir: A therapy for patients hospitalized with severe influenza and for those in whom neither oral nor inhaled routes are an option
Peramivir: An as-yet-unlicensed neuraminidase inhibitor that is being developed in intravenous and intramuscular formulations
Long-acting inhaled neuraminidase inhibitors: A therapy based on the enhanced potency of dimeric derivatives of zanamivir that will probably be available in the next few years; administration may be possible in a single dose for treatment or once a week for prophylaxis
Fludase (DAS181): A sialidase fusion construct that cleaves the sialic acid receptors that influenza viruses use for attachment, removing influenza receptors from the airway epithelium and preventing infection of lung cells
Cyanovirin-N: A hemagglutinin inhibitor that may block viral entry
Short interfering RNAs: A therapy that may hold promise for influenza
T-705: A substituted pyrazine compound that is active against neuraminidase-inhibitor–resistant and amantadine-resistant viruses and that probably inhibits the RNA polymerase
The recent discovery of the active site of a key endonuclease activity in the PA subunit of the influenza polymerase molecule could lead to a new class of drugs targeting the essential polymerase function of "cap-snatching."5 Other promising antiviral avenues under investigation include signal transduction inhibitors, interferon inducers, and molecules targeting the interaction between the influenza NS1A protein and the 30-kD subunit of cleavage and polyadenylation specificity factor.
sumber : new england journal of medicine
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