Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.
Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.
For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).
Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.
"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."
In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.
Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).
Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."
In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. "Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks," they wrote (J. Infect. Dis. 2011;203[1]6-10).
The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.
Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.