Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus Infections, United States, 2010–11

During October 2010–July 2011, 1.0% of pandemic (H1N1) 2009 viruses in the United States were oseltamivir resistant, compared with 0.5% during the 2009–10 influenza season. Of resistant viruses from 2010–11 and 2009–10, 26% and 89%, respectively, were from persons exposed to oseltamivir before specimen collection. Findings suggest limited community transmission of oseltamivir-resistant virus.


The Study
During October 1, 2010-July 31, 2011, the Centers for Disease Control and Prevention (CDC; Atlanta, Georgia, USA) asked all state public health laboratories to submit pandemic (H1N1) 2009 virus-positive respiratory specimens and virus isolates for antiviral susceptibility testing. Laboratories were asked to provide the fi rst 5 specimens of any type/subtype collected during each 2-week period for virus isolation. Comprehensive antiviral testing, including neuraminidase inhibition (NI) assay, was performed on all isolates, and sequencing was performed on all isolates with elevated 50% inhibitory concentration values. CDC also requested that laboratories provide 5 additional specimens every 2 weeks for pyrosequencing to identify the H275Y substitution in the neuraminidase, a change associated with oseltamivir resistance (3). In addition to (or instead of) participating in the national surveillance, state laboratories in California, Maine, Maryland, Minnesota, New York, Texas, and Washington performed pyrosequencing on state surveillance specimens to detect the H275Y substitution. We included those statespecifi c data in the national surveillance data for this report. State health departments used a standard case form to collect demographic and clinical information for patients with oseltamivir-resistant pandemic (H1N1) 2009 virus infection and their ill close contacts.
Oseltamivir resistance was determined by use of an NI assay or pyrosequencing for the H275Y substitution. For NI testing on isolates, we used the NA-Fluor kit (Applied Biosystems, Foster City, CA, USA) as described (4). We performed pyrosequencing, as described (5), on all oseltamivir-resistant pandemic (H1N1) 2009 isolates identifi ed by NI assay to confi rm the presence of the H275Y substitution. We performed pyrosequencing for H275Y, without the NI assay, to screen pandemic (H1N1) 2009 clinical specimens (5). For the national surveillance, NI testing was performed at CDC and pyrosequencing was performed at CDC and at state laboratories in Wisconsin, New York, and California. State laboratories followed pyrosequencing protocols provided by CDC; when possible, CDC confi rmed results for resistant viruses by use of pyrosequencing and NI assay. Most oseltamivir-resistant viruses in this report were included in the weekly FluView report prepared by CDC (6).
We tested a total of 3,652 pandemic (H1N1) 2009 virus isolates and specimens from every state and the District of Columbia; 35 (1.0%) isolates/specimens from a total of 18 states were oseltamivir-resistant ( Figure). Overall, 8 (1.3%) of 609 isolates tested by NI assay and 27 (1.0%) of 3,043 specimens tested by pyrosequencing were resistant to oseltamivir. The state-specifi c prevalence of oseltamivir-resistant pandemic (H1N1) 2009 viruses varied; however, the number of viruses and specimens tested also varied markedly between states, and several states submitted only a few specimens. Forty-four states submitted >20 specimens for antiviral resistance surveillance. The prevalence of oseltamivir resistance among these specimens ranged from 0% to 5.6%. None of the 609 pandemic (H1N1) 2009 isolates tested by NI assay were resistant to zanamivir. The ranges of 50% inhibitory concentration values for oseltamivir-resistant and -susceptible isolates were 166.17-230.37 nmol/L and 0.10-0.80 nmol/L, respectively.
The median age of the 35 patients with oseltamivirresistant pandemic (H1N1) 2009 virus infections was 33 years. Of 34 patients with available information, 26% reported receiving oseltamivir before providing a specimen for antiviral susceptibility testing (Table 1). Among 33 patients with a completed case form, 67% had at least 1 preexisting chronic medical condition, 24% had an immunocompromising medical condition, 42% required hospitalization, and 9% died. Most patients with oseltamivirresistant virus infection for whom housing information was available lived in a single-family household. Two siblings from 1 household had oseltamivir-resistant virus infection; neither child had received oseltamivir.
All oseltamivir-resistant pandemic (H1N1) 2009 viruses were identifi ed from specimens collected during December 2010-April 2011; the prevalence of resistance did not change signifi cantly over time (test for trend, p = 0.18) ( Table 2). In addition, the proportion of patients with oseltamivir-resistant virus infections who did not have exposure to oseltamivir before specimen collection did not change signifi cantly over time (test for trend, p = 0.48); however, the number of specimens tested each month was small.
The number of oseltamivir-resistant pandemic (H1N1) 2009 virus-infected patients was small during the 2009-10

Conclusions
During the 2010-11 US infl uenza season, the prevalence of oseltamivir-resistant pandemic (H1N1) 2009 viruses remained low, and most persons with oseltamivir-resistant virus infection had no prior oseltamivir exposure. This is a notable difference from surveillance fi ndings both globally and in the United States during the 2009-10 season, when most patients with oseltamivir-resistant pandemic (H1N1) 2009 virus infection had a history of oseltamivir exposure, and many were severely immunocompromised, a condition that may increase the risk for resistance developing during oseltamivir therapy (2,7). These data suggest a low level of community transmission of oseltamivir-resistant pandemic (H1N1) 2009 virus in the United States during the 2010-11 infl uenza season. The United Kingdom also reported that the proportion of oseltamivir-resistant pandemic (H1N1) 2009 virus-infected patients without prior oseltamivir exposure was higher during 2010 -11 than 2009-10 (8).
The increase during the 2010-11 infl uenza season in the proportion of patients with oseltamivir-resistant pandemic (H1N1) 2009 virus infections without prior oseltamivir exposure causes concern in light of the recent history of oseltamivir resistance among seasonal infl uenza A (H1N1) viruses that circulated before pandemic (H1N1) 2009 virus emerged. In the United States before the 2007-08 infl uenza season, the prevalence of oseltamivir resistance among seasonal infl uenza A (H1N1) viruses was <1% (9,10). However, during the 2007-08 season, the prevalence of oseltamivir resistance among seasonal infl uenza A (H1N1) viruses increased to 12%, and by the 2008-09 season, resistance dramatically increased to >99% (9,11,12). No association was found between this increase in oseltamivir resistance and prior oseltamivir use (11,13). Oseltamivir resistance in pandemic (H1N1) 2009 and seasonal infl uenza A (H1N1) viruses was conferred by the H275Y substitution in the neuraminidase. However, unlike seasonal infl uenza A (H1N1) viruses, which retained susceptibility to the M2-blocking adamantanes (amantadine and rimantadine), >99% of circulating pandemic (H1N1) 2009 viruses are inherently resistant to adamantanes (14). Thus, inhaled zanamivir or investigational drugs, such as intravenous zanamivir, are the only treatment options for patients with oseltamivir-resistant pandemic (H1N1) 2009 virus infection.
Our conclusions are limited by the small number of patients with oseltamivir-resistant pandemic (H1N1) 2009 virus infection. Variability in state surveillance and the number of specimens tested from each state may also have limited the representativeness of our data. Despite these shortcomings, our fi ndings emphasize the importance of ongoing surveillance for oseltamivir-resistant pandemic (H1N1) 2009 viruses in the United States and globally and of close monitoring for changes in the epidemiology of oseltamivir resistance among pandemic (H1N1) 2009 viruses. Updated information about antiviral resistance in infl uenza viruses in the United States is available at www. cdc.gov/fl u/professionals/.