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Abstract & Commentary
Synopsis: Oseltamivir treatment of children with influenza A virus infection was associated with the selection of resistant mutants in 18%.
Source: Kiso M, et al. Lancet. 2004;364:759-765.
Kiso and colleagues in Japan collected serial upper respiratory tract samples from children receiving oseltamivir for treatment of influenza A (H3N2), for isolation of the virus.
Mutations in neuraminidase were identified in virus obtained from from 9 of 50 (18%) immunocompetent children treated with oseltamivir. Eight of the 9 contained mutations previously identified as conferring resistance to oseltamivir, while the ninth had a novel mutation. In vitro susceptibility testing demonstrated that all 9 were resistant to this neuraminidase inhibitor.
Drug resistant mutants were detected as early as 4 days after the start of treatment.
Comment by Stan Deresinski, MD, FACP
Treatment of influenza virus infections with M2 ion channel inhibitors, such as rimantidine, have at least 2 drawbacks: this class of drugs is only active against influenza A, and resistant virus is often rapidly selected during treatment. The neuraminidase inhibitors are active against all influenza virus types. For instance, the H5N1 avian influenza strains that emerged in 2004, while resistant to the M2 inhibitors, are susceptible to neuraminidase inhibitors. While emergence of resistance has not been reported during treatment with the topically applied neuraminidase inhibitor zanamivir, it has previously been reported with oseltamivir, but at a frequency of less than 1% in adults and 4% in children. Thus, the detection of resistance, occurring in 18% of children in this study, is disturbing.
Influenza hemagglutinin initiates infection by binding to the sialooligosaccharide receptors on the cell surface. Viral neuraminidase sialidase promotes the release of replicated virus from infected cell by removing sialic acid from the receptor. Blockade of neuraminidase thus prevents viral spread from infected to noninfected cells.
Of note, is that the doses of oseltamivir used to treat the children in this study were lower than is recommended in most countries, a factor which might explain the high rate of selection of resistant mutants.
We may, unfortunately, be heading toward a perfect storm. For the upcoming influenza season, we have the problem of an inadequate supply of vaccine. Furthermore, the reemergence of H5N1 avian influenza in poultry, and its spread to humans (and recently, possible human-to-human transmission of the virus) in the absence of a vaccine suitable for humans, raises the specter of a new influenza pandemic. In such a circumstance, the only available tool would be antiviral drugs. These, however, are produced in insufficient supply. In addition, this report of a high rate of resistance to oseltamivir only increases the concern.
Dr. Deresinski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, Palo Alta, Calif.