The CDC has issued a health advisory which indicates that a high number of currently circulating H1N1 influenza viruses are resistant to the antiviral drug oseltamivir. Fifty H1N1 isolates obtained in the U.S. since October 2008 were examined for drug sensitivity; 98% of these isolates are resistant to oseltamivir. Influenza H3N2 isolates, however, are still susceptible to the drug. The H1N1 isolates remain sensitive to zanamivir and amantadine. As a result of this finding, the CDC suggests that for treatment of influenza, “zanamivir or a combination of oseltamivir and rimantadine are more appropriate options than oseltamivir alone.”
Oseltamivir and zanamivir are recently developed influenza antiviral drugs that inhibit the viral neuraminidase. This enzyme is required for infection and spread, and consequently its inhibition reduces viral production and disease. Both inhibitors were designed to mimic the natural ligand of neuraminidase, sialic acid. In theory, the more an inhibitor resembles the natural compound, the less likely the target can change to avoid drug binding while maintaining viable function. The results with oseltamivir do not support this theory. During the 2007-08 influenza season, 10.9% of H1N1 viruses tested in the U.S. were resistant to the drug. Although it is not known what percentage of the 2008-09 isolates will be resistant to oseltamivir, it is clear that resistance to this drug is rising.
It is not surprising to observe increasing resistance to oseltamivir, given the high mutation rates of RNA viruses. What is somewhat surprising is the absence of resistance to zanamivir. This difference may be in part due to structural differences between the two compounds – perhaps it is more difficult for the neuraminidase to be resistant to zanamivir and still have enzymatic function. The ways that the drugs are administered may also play a role – oseltamivir is taken orally, a route that is more widely accepted, while zanamivir is given by inhaler. Consequently, it is probably used less than oseltamivir.
One consequence is probably certain: the CDC recommendation that the two neuraminidase inhibitors be used in combination this year is likely to increase resistance to both neuraminidase inhibitors. This will be a difficult problem because there is widespread resistance among H3N2 strains against the only other licensed anti-influenza virus drug, the amantadines.
The more an inhibitor resembles the natural compound, the less likely the target can change to avoid drug binding while maintaining viable function. The results with oseltamivir do not support this theory.
The more an inhibitor resembles the natural compound, the less likely the target can change to avoid drug binding while maintaining viable function. The results with oseltamivir do not support this theory.