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Infections With Oseltamivir-Resistant Influenza A(H1N1) Virus in the United States

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HenryN

Retired
Infections With Oseltamivir-Resistant Influenza A(H1N1) Virus in the United States

[FONT=verdana, arial, helvetica, sans-serif]<NOBR>Nila J. Dharan, MD</NOBR>; <NOBR>Larisa V. Gubareva, PhD</NOBR>; <NOBR>John J. Meyer, MPH</NOBR>; <NOBR>Margaret Okomo-Adhiambo, PhD</NOBR>; <NOBR>Reginald C. McClinton, MPH</NOBR>; <NOBR>Steven A. Marshall, MS</NOBR>; <NOBR>Kirsten St. George, MAppSc, PhD</NOBR>; <NOBR>Scott Epperson, MPH</NOBR>; <NOBR>Lynnette Brammer, MPH</NOBR>; <NOBR>Alexander I. Klimov, PhD</NOBR>; <NOBR>Joseph S. Bresee, MD</NOBR>; <NOBR>Alicia M. Fry, MD, MPH</NOBR>; for the Oseltamivir-Resistance Working Group</NOBR> [/FONT]

[FONT=verdana, arial, helvetica, sans-serif]JAMA. 2009;301(10):1034-1041. Published online March 2, 2009 (doi:10.1001/jama.2009.294). [/FONT]
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<!--startindex-->[FONT=verdana, arial, helvetica, sans-serif]Context During the 2007-2008 influenza season, oseltamivir<SUP> </SUP>resistance among influenza A(H1N1) viruses increased significantly<SUP> </SUP>for the first time worldwide. Early surveillance data suggest<SUP> </SUP>that the prevalence of oseltamivir resistance among A(H1N1)<SUP> </SUP>viruses will most likely be higher during the 2008-2009 season.<SUP> </SUP>
Objectives To describe patients infected with oseltamivir-resistant<SUP> </SUP>influenza A(H1N1) virus and to determine whether there were<SUP> </SUP>any differences between these patients and patients infected<SUP> </SUP>with oseltamivir-susceptible A(H1N1) virus in demographic or<SUP> </SUP>epidemiological characteristics, clinical symptoms, severity<SUP> </SUP>of illness, or clinical outcomes.<SUP> </SUP>
Design, Setting, and Patients Influenza A(H1N1) viruses<SUP> </SUP>that were identified and submitted to the Centers for Disease<SUP> </SUP>Control and Prevention by US public health laboratories between<SUP> </SUP>September 30, 2007, and May 17, 2008, and between September<SUP> </SUP>28, 2008, and February 19, 2009, were tested as part of ongoing<SUP> </SUP>surveillance. Oseltamivir resistance was determined by neuraminidase<SUP> </SUP>inhibition assay and pyrosequencing analysis. Information was<SUP> </SUP>collected using a standardized case form from patients with<SUP> </SUP>oseltamivir-resistant A(H1N1) infections and a comparison group<SUP> </SUP>of patients with oseltamivir-susceptible A(H1N1) infections<SUP> </SUP>during 2007-2008.<SUP> </SUP>
Main Outcome Measures Demographic and epidemiological<SUP> </SUP>information as well as clinical information, including symptoms,<SUP> </SUP>severity of illness, and clinical outcomes.<SUP> </SUP>
Results During the 2007-2008 season, influenza A(H1N1)<SUP> </SUP>accounted for an estimated 19% of circulating influenza viruses<SUP> </SUP>in the United States. Among 1155 influenza A(H1N1) viruses tested<SUP> </SUP>from 45 states, 142 (12.3%) from 24 states were resistant to<SUP> </SUP>oseltamivir. Data were available for 99 oseltamivir-resistant<SUP> </SUP>cases and 182 oseltamivir-susceptible cases from this period.<SUP> </SUP>Among resistant cases, median age was 19 years (range, 1 month<SUP> </SUP>to 62 years), 5 patients (5%) were hospitalized, and 4 patients<SUP> </SUP>(4%) died. None reported oseltamivir exposure before influenza<SUP> </SUP>diagnostic sample collection. No significant differences were<SUP> </SUP>found between cases of oseltamivir-resistant and oseltamivir-susceptible<SUP> </SUP>influenza in demographic characteristics, underlying medical<SUP> </SUP>illness, or clinical symptoms. Preliminary data from the 2008-2009<SUP> </SUP>influenza season identified resistance to oseltamivir among<SUP> </SUP>264 of 268 influenza A(H1N1) viruses (98.5%) tested.<SUP> </SUP>
Conclusions Oseltamivir-resistant A(H1N1) viruses circulated<SUP> </SUP>widely in the United States during the 2007-2008 influenza season,<SUP> </SUP>appeared to be unrelated to oseltamivir use, and appeared to<SUP> </SUP>cause illness similar to oseltamivir-susceptible A(H1N1) viruses.<SUP> </SUP>Circulation of oseltamivir-resistant A(H1N1) viruses will continue,<SUP> </SUP>with a higher prevalence of resistance, during the 2008-2009<SUP> </SUP>season.<SUP> </SUP>
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In January 2006, the US Centers for Disease Control and Prevention<SUP> </SUP>(CDC) recommended against the use of adamantanes due to a significant<SUP> </SUP>increase in resistance among circulating influenza A(H3N2) viruses.<SUP>1</SUP><SUP> </SUP>As a result, neuraminidase inhibitors (NAIs) became the only<SUP> </SUP>class of antiviral agents recommended for the treatment and<SUP> </SUP>prophylaxis of influenza virus infections in the United States.<SUP>1-2</SUP><SUP> </SUP>Since their introduction in 1999, the proportion of influenza<SUP> </SUP>viruses resistant to NAIs among circulating influenza viruses<SUP> </SUP>has been low, generally less than 1% of isolates tested worldwide.<SUP>3-5</SUP><SUP> </SUP>
However, during the 2007-2008 influenza season, increased levels<SUP> </SUP>of resistance to oseltamivir, 1 of the 2 licensed NAIs, were<SUP> </SUP>detected for the first time in the United States and worldwide.<SUP>4,<SUP> </SUP>6-7</SUP> In addition, early 2008-2009 influenza season surveillance<SUP> </SUP>data suggest that oseltamivir resistance among influenza A(H1N1)<SUP> </SUP>viruses will most likely be higher during the upcoming season.<SUP>8</SUP><SUP> </SUP>Resistance to oseltamivir was identified in only 1 influenza<SUP> </SUP>A virus subtype, influenza A(H1N1), and all of the identified<SUP> </SUP>resistant viruses have had the same mutation known to confer<SUP> </SUP>resistance, H274Y (N2 NA numbering) in the viral neuraminidase.<SUP>6</SUP><SUP> </SUP>Before the 2007-2008 influenza season, detection of oseltamivir-resistant<SUP> </SUP>viruses in humans had typically been reported only among persons<SUP> </SUP>treated with oseltamivir,<SUP>9-13</SUP> and human-to-human transmission<SUP> </SUP>of an NAI-resistant virus had never been documented.<SUP>14-15</SUP> In<SUP> </SUP>addition, clinical case reports and in vitro and animal studies<SUP> </SUP>suggested that the infectivity and replicative ability of NAI-resistant<SUP> </SUP>viruses were compromised.<SUP>16-18</SUP> As a result, it was unknown whether<SUP> </SUP>resistant viruses would cause clinical illness similar to other<SUP> </SUP>influenza viruses.<SUP> </SUP>
In this study, we described patients infected with oseltamivir-resistant<SUP> </SUP>influenza A(H1N1) identified from influenza surveillance in<SUP> </SUP>the United States during the 2007-2008 influenza season and<SUP> </SUP>described risk factors for infection with oseltamivir-resistant<SUP> </SUP>viruses. In addition, we compared characteristics of patients<SUP> </SUP>with oseltamivir-resistant and oseltamivir-susceptible influenza<SUP> </SUP>A(H1N1) infection to determine whether there were any differences<SUP> </SUP>in demographic or epidemiological characteristics, clinical<SUP> </SUP>symptoms, severity of illness, or clinical outcomes.<SUP> </SUP>
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[FONT=verdana, arial, helvetica, sans-serif]METHODS [/FONT]<TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa>
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Each year, US public health laboratories submit a sample of<SUP> </SUP>influenza isolates to the CDC for virus stain and antiviral<SUP> </SUP>resistance surveillance. During the 2007-2008 influenza season<SUP> </SUP>(September 30, 2007-May 17, 2008), the US public health laboratories<SUP> </SUP>were asked to submit all A(H1N1) virus isolates, clinical specimens,<SUP> </SUP>or both, in addition to a sample of other virus types and subtypes.<SUP> </SUP>Early during the 2008-2009 season (September 28, 2008-February<SUP> </SUP>19, 2009), the number of isolates sent to the CDC was standardized,<SUP> </SUP>the first 10 or 20 (depending on state population) isolates<SUP> </SUP>were sent to the CDC. After the early season aliquot was sent,<SUP> </SUP>each laboratory was asked to send a random sample of isolates<SUP> </SUP>selected each week (the number selected depended on state population).<SUP> </SUP>
Testing for NAI resistance was performed by the neuraminidase<SUP> </SUP>inhibition assay with chemiluminescent substrate as previously<SUP> </SUP>described.<SUP>4</SUP> All oseltamivir-resistant viruses exhibited IC<SUB>50</SUB><SUP> </SUP>values of more than 80 nM. IC<SUB>50</SUB> is a concentration of drug (oseltamivir<SUP> </SUP>carboxylate) needed to inhibit enzyme activity by 50%. The presence<SUP> </SUP>of the oseltamivir-resistance conferring mutation (H274Y) in<SUP> </SUP>the neuraminidase of virus isolates with elevated IC<SUB>50</SUB> values<SUP> </SUP>was determined by sequencing, pyrosequencing, or both, as previously<SUP> </SUP>described.<SUP>4, 19</SUP> Testing for adamantane resistance was performed<SUP> </SUP>by a pyrosequencing assay for detection of markers of adamantane<SUP> </SUP>resistance in the M2 gene as previously described.<SUP>20</SUP> When only<SUP> </SUP>an unsubtyped clinical specimen (without a matching virus isolate)<SUP> </SUP>was provided for NAI-resistance testing, the viral RNA was isolated<SUP> </SUP>directly from the clinical specimen and used in both pyrosequencing<SUP> </SUP>assays targeting N1 and M2 genes.<SUP> </SUP>
Clinical specimens from patients from Wisconsin with A(H1N1)<SUP> </SUP>infections were tested by the Wisconsin State Laboratory of<SUP> </SUP>Hygiene (WSLH) by using the pyrosequencing assays for N1 NA<SUP> </SUP>and M2 mutations. Clinical specimens from patients from New<SUP> </SUP>York with A(H1N1) infections were tested at the Wadsworth Center,<SUP> </SUP>New York State Department of Health (NYSDOH), by the pyrosequencing<SUP> </SUP>assay for M2 mutations and by dideoxysequencing of the NA gene<SUP>21</SUP>;<SUP> </SUP>sequencing was performed in the Molecular Genetics Core facility.<SUP> </SUP>A subset of New York and Wisconsin specimens was also tested<SUP> </SUP>at the CDC.<SUP> </SUP>
Because a majority of A(H1N1) viruses but only a sample of reported<SUP> </SUP>A(H3N2) and B viruses were submitted to the CDC for antiviral<SUP> </SUP>resistance testing during the 2007-2008 influenza season, we<SUP> </SUP>estimated an adjusted overall proportion of influenza viruses<SUP> </SUP>resistant to oseltamivir in the United States. We assumed that<SUP> </SUP>the proportion of A(H1N1) and A(H3N2) viruses among subtyped<SUP> </SUP>influenza A viruses was equal to the proportion among those<SUP> </SUP>influenza A viruses that were not subtyped. The proportions<SUP> </SUP>of subtyped A viruses reported to the CDC by the US World Health<SUP> </SUP>Organization (WHO) Collaborating Laboratories and the National<SUP> </SUP>Respiratory and Enteric Virus Surveillance System<SUP>7</SUP> that were<SUP> </SUP>A(H1N1) and A(H3N2) were applied to the number of reported influenza<SUP> </SUP>A viruses without subtype data to estimate the total number<SUP> </SUP>of viruses of each subtype. The adjusted proportion of overall<SUP> </SUP>oseltamivir resistance was estimated by the following equation<SUP> </SUP>(the percentage of oseltamivir resistance detected among A[H1N1]<SUP> </SUP>viruses by CDC, WSLH, and NYSDOH [FONT=arial,helvetica]x[/FONT] the total estimated number<SUP> </SUP>of A[H1N1] viruses)/(the total estimated number of A[H3N2] and<SUP> </SUP>A[H1N1] viruses and the total number of B viruses reported by<SUP> </SUP>the WHO and the National Respiratory and Enteric Virus Surveillance<SUP> </SUP>System).<SUP> </SUP>
As infections with oseltamivir-resistant A(H1N1) viruses were<SUP> </SUP>identified during the 2007-2008 season, each case-patient was<SUP> </SUP>contacted by telephone and information on demographic characteristics,<SUP> </SUP>medical history, whether the patient received the 2007-2008<SUP> </SUP>influenza vaccine, influenza illness, and illness in household<SUP> </SUP>members was collected by using a standardized questionnaire.<SUP> </SUP>Race and ethnicity were collected for demographic characterization<SUP> </SUP>and were determined by the patients from options read to them<SUP> </SUP>by the interviewer. In addition, the health care professional<SUP> </SUP>for each patient was contacted by telephone and information<SUP> </SUP>was obtained regarding medications prescribed to the patient,<SUP> </SUP>temperature documented at the visit, and whether the patient<SUP> </SUP>had received the 2007-2008 influenza vaccine. Data on vaccination<SUP> </SUP>status were obtained from the patient interview. Data on prescribed<SUP> </SUP>antiviral medications and length of illness before seeking care<SUP> </SUP>were obtained from the patient's health care clinician interview<SUP> </SUP>when available. The clinician confirmed that an antiviral agent<SUP> </SUP>was taken for 93% of those patients who reported taking an antiviral<SUP> </SUP>agent for their influenza illness; 7% of clinicians were unable<SUP> </SUP>to be interviewed.<SUP> </SUP>
In states in which oseltamivir-resistant A(H1N1) cases had been<SUP> </SUP>identified, the state health department identified a comparison<SUP> </SUP>group of persons who had oseltamivir-susceptible A(H1N1) infections<SUP> </SUP>by randomly selecting from the list of oseltamivir-susceptible<SUP> </SUP>A(H1N1) viruses from each state's laboratory log. There were<SUP> </SUP>no matching criteria. Each state chose 1 to 4 comparison cases<SUP> </SUP>for each person infected with an oseltamivir-resistant A(H1N1)<SUP> </SUP>virus depending on the number of identified A(H1N1) viruses<SUP> </SUP>isolated within the state and state resources. The patients<SUP> </SUP>with oseltamivir-susceptible A(H1N1) infections were called<SUP> </SUP>and interviewed using the same standardized questionnaire as<SUP> </SUP>patients with oseltamivir-resistant A(H1N1) infections. Health<SUP> </SUP>care clinicians of patients with oseltamivir-susceptible A(H1N1)<SUP> </SUP>infections were not contacted.<SUP> </SUP>
To compare demographic and clinical characteristics between<SUP> </SUP>patients with oseltamivir-resistant and oseltamivir-susceptible<SUP> </SUP>A(H1N1) infections, we conducted univariate analyses by using<SUP> </SUP>2-sided
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<SUP>2</SUP> and Fisher exact tests for categorical variables and<SUP> </SUP>Wilcoxon rank sum tests for continuous variables. Because univariate<SUP> </SUP>analysis did not identify variables that significantly differed<SUP> </SUP>between the 2 groups, multivariable analysis was not performed.<SUP> </SUP>However, we did control for age and state. Underlying illness<SUP> </SUP>and symptoms vary between age groups and state surveillance<SUP> </SUP>and laboratory practices vary.<SUP> </SUP>
We determined an adjusted odds ratio for each variable, controlling<SUP> </SUP>for age group (0-4 years, 5-18 years, 19-50 years, or >50 years)<SUP> </SUP>and state as a clustered variable, with logistic regression<SUP> </SUP>analysis using generalized estimating equations. In the comparison<SUP> </SUP>of age groups, we only controlled for state. Two-sided P
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.05<SUP> </SUP>was considered statistically significant. Statistical analysis<SUP> </SUP>was conducted by using SAS version 9.1 (SAS Institute Inc, Cary,<SUP> </SUP>North Carolina). We excluded 7 oseltamivir-resistant A(H1N1)<SUP> </SUP>cases from 1 state that was unable to interview a comparison<SUP> </SUP>group of oseltamivir-susceptible A(H1N1) cases.<SUP> </SUP>
We compared the proportion of A(H1N1) viruses tested for antiviral<SUP> </SUP>resistance that were resistant to oseltamivir during the 2007-2008<SUP> </SUP>season and the proportion of total filled anti-infective prescriptions<SUP> </SUP>(including antibiotics, antifungals, antiparasitic, and antiviral<SUP> </SUP>drugs except for antiretroviral medications) that were prescriptions<SUP> </SUP>for oseltamivir during 2007.<SUP> </SUP>
The annual number of total filled anti-infective prescriptions<SUP> </SUP>and filled oseltamivir prescriptions from 2007 was supplied<SUP> </SUP>by BioSense.<SUP>22</SUP> The prescription data were provided to BioSense<SUP> </SUP>by RelayHealth, a national electronic pharmacy claims management<SUP> </SUP>services provider that collects data from 20 000 to 30 000<SUP> </SUP>pharmacies in the United States, Virgin Islands, Puerto Rico,<SUP> </SUP>and Guam.<SUP>23</SUP> We chose states that had more than 18 A(H1N1) viruses<SUP> </SUP>tested for antiviral resistance. We could detect 5% prevalence<SUP> </SUP>with a 10% error with 18 specimens. A correlation coefficient<SUP> </SUP>between the proportion of state A(H1N1) viruses from the 2007-2008<SUP> </SUP>influenza season resistant to oseltamivir and the 2007 proportion<SUP> </SUP>of filled total anti-infective prescriptions that were for oseltamivir<SUP> </SUP>was calculated by using SAS version 9.1.<SUP> </SUP>
The investigation of oseltamivir-resistant influenza A(H1N1)<SUP> </SUP>cases during the 2007-2008 influenza season was deemed public<SUP> </SUP>health practice (surveillance, not human subjects research)<SUP> </SUP>and therefore did not require institutional review board review.<SUP> </SUP>Before we asked any state to contact A(H1N1) cases identified<SUP> </SUP>through routine surveillance, we submitted a summary of the<SUP> </SUP>current situation, reasons additional information needed to<SUP> </SUP>be collected, and the data forms and telephone scripts for determination<SUP> </SUP>of applicability of human subjects regulations. All documents<SUP> </SUP>were submitted to the Influenza Division for approval and clearance<SUP> </SUP>and then to the National Center for Immunization and Respiratory<SUP> </SUP>Diseases (NCIRD) Human Subjects Contact. The final determination<SUP> </SUP>that this was public health practice (surveillance and not human<SUP> </SUP>subjects research) was made by the NCIRD Human Subjects Contact<SUP> </SUP>in consultation with the NCIRD Associate Director of Science.<SUP> </SUP>After the final determination that this was public health practice<SUP> </SUP>(surveillance), we asked the state influenza coordinators to<SUP> </SUP>collect additional information from the surveillance A(H1N1)<SUP> </SUP>cases by telephone interview. All A(H1N1) cases were contacted<SUP> </SUP>by telephone and gave oral consent before answering questions.<SUP> </SUP>
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Resistance to oseltamivir was identified among 142 of 1155 US<SUP> </SUP>influenza A(H1N1) viruses (12.3%) tested during the 2007-2008<SUP> </SUP>influenza season. Of the 142 oseltamivir-resistant A(H1N1) viruses<SUP> </SUP>identified, 134 were identified at the CDC, 5 at the WSLH and<SUP> </SUP>3 at the Wadsworth Center, NYSDOH. All oseltamivir-resistant<SUP> </SUP>A(H1N1) viruses were sensitive to zanamivir, the other licensed<SUP> </SUP>NAI, and the adamantanes.<SUP> </SUP>
Of the 45 states that submitted A(H1N1) viruses for antiviral<SUP> </SUP>resistance testing, oseltamivir-resistant viruses were identified<SUP> </SUP>in 24 states (53%) (Figure 1). Eighteen states (75%) collected<SUP> </SUP>data on patients with oseltamivir-resistant infections and 17<SUP> </SUP>states (94%) collected data on a comparison group of patients<SUP> </SUP>with oseltamivir-susceptible A(H1N1) infections.<SUP> </SUP>
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The map illustrates the number of oseltamivir-resistant influenza A(H1N1) viruses that were identified as of September 5, 2008. An interactive eFigure is available here. [/FONT]
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The proportion of influenza A(H1N1) among all influenza viruses<SUP> </SUP>identified in the United States, including type A and B, was<SUP> </SUP>greatest early in the season, between September 30, 2007, and<SUP> </SUP>February 2, 2008.<SUP>24-25</SUP> For the entire 2007-2008 season, between<SUP> </SUP>September 30, 2007, and May 17, 2008, 39 827 influenza<SUP> </SUP>viruses were reported to the CDC, 2175 (5%) were reported as<SUP> </SUP>A(H1N1), 6115 (15%) were reported as A(H3N2), 19 973 (50%)<SUP> </SUP>were reported as type A, no subtype specified, and 11 564<SUP> </SUP>(29%) were reported as type B. Applying our assumption to the<SUP> </SUP>unsubtyped A viruses, we estimated a total of 7415 A(H1N1) viruses<SUP> </SUP>(19%). Overall, 2% of all influenza viruses (A[H1N1], A[H3N2]<SUP> </SUP>and B) were resistant to oseltamivir.<SUP> </SUP>
Preliminary data from the early 2008-2009 influenza season demonstrate<SUP> </SUP>that oseltamivir resistance among A(H1N1) viruses continues<SUP> </SUP>to be detected. As of February 19, 2009, resistance to oseltamivir<SUP> </SUP>had been identified among 264 of 268 US influenza A(H1N1) viruses<SUP> </SUP>(98.5%) tested.<SUP>26</SUP><SUP> </SUP>
Among 142 oseltamivir-resistant A(H1N1) viruses identified,<SUP> </SUP>99 patients (70%) were contacted and agreed to participate.<SUP> </SUP>Among the 99 cases, the median age was 19 years (range, 1 month<SUP> </SUP>to 62 years), 41 cases (41%) were male, and 70 cases (71%) were<SUP> </SUP>white. Twenty-four cases (24%) reported having 1 or more chronic<SUP> </SUP>underlying medical conditions. Thirty cases (30%) received the<SUP> </SUP>2007-2008 influenza vaccine. None of the oseltamivir-resistant<SUP> </SUP>A(H1N1) cases reported taking oseltamivir before testing for<SUP> </SUP>influenza, and none of the cases had household contacts that<SUP> </SUP>took oseltamivir before the case's onset of illness. Of the<SUP> </SUP>11 cases who reported travel in the 5 days before their onset<SUP> </SUP>of illness, 3 reported international travel (2 to Europe and<SUP> </SUP>1 to the Bahamas and Central America).<SUP> </SUP>
A total of 47 oseltamivir-resistant cases (47%) received a prescription<SUP> </SUP>for an antiviral agent, all of whom reported taking the antiviral<SUP> </SUP>agent after a specimen was collected for influenza testing.<SUP> </SUP>Of these 47 cases, 44 (94%) received oseltamivir alone and 3<SUP> </SUP>(6%) received both oseltamivir and rimantadine. Of the 47 patients<SUP> </SUP>who took oseltamivir, 36 (77%) took the medication within 2<SUP> </SUP>days after the onset of illness. Five cases were hospitalized;<SUP> </SUP>3 of these recovered and 2 died.<SUP> </SUP>
Four patients with oseltamivir-resistant influenza A(H1N1) infection<SUP> </SUP>died. Two patients died on the way to the hospital or in the<SUP> </SUP>emergency department, 1 patient was 4 years old and previously<SUP> </SUP>healthy, and 1 patient was 4 years old with neurological problems.<SUP> </SUP>Both were thought to die from complications of their influenza<SUP> </SUP>infection. Two deaths were among hospitalized patients, 1 patient<SUP> </SUP>was a 1-year-old with multiple medical problems (admitted in<SUP> </SUP>respiratory failure and subsequently was deemed do not resuscitate)<SUP> </SUP>and 1 patient, hospitalized for a stem cell transplant, was<SUP> </SUP>22 years old and diagnosed with influenza infection on the fifth<SUP> </SUP>day of hospitalization. Influenza vaccination status was available<SUP> </SUP>for 2 of the patients, both with underlying medical conditions;<SUP> </SUP>1 had been vaccinated and 1 had not.<SUP> </SUP>
In our comparison of patients with oseltamivir-resistant and<SUP> </SUP>oseltamivir-susceptible influenza A(H1N1) infections, we excluded<SUP> </SUP>7 cases from 1 state. As a result, we compared 92 cases of oseltamivir-resistant<SUP> </SUP>A(H1N1) infection with 182 cases of oseltamivir-susceptible<SUP> </SUP>A(H1N1) infection (Table 1). We found no significant differences<SUP> </SUP>in sex, age group, race/ethnicity, or underlying medical conditions.<SUP> </SUP>Also, there were no differences in whether cases received the<SUP> </SUP>2007-2008 influenza vaccine, whether they had traveled in the<SUP> </SUP>5 days before they sought care for their influenza illness,<SUP> </SUP>or whether they presented first for care to an emergency department<SUP> </SUP>or hospital vs a clinic. Of those patients who were prescribed<SUP> </SUP>antiviral agents, 47 of 47 oseltamivir-resistant cases (100%)<SUP> </SUP>received oseltamivir and 62 of 66 oseltamivir-susceptible cases<SUP> </SUP>(94%) reported receiving oseltamivir. One of the 66 oseltamivir-susceptible<SUP> </SUP>cases (2%) reported receiving zanamivir and 3 (5%) reported<SUP> </SUP>receiving adamantanes (2 received amantadine and 1 received<SUP> </SUP>rimantadine).<SUP> </SUP>
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<TABLE cellSpacing=0 cellPadding=1 width="100%" bgColor=#6a90aa border=0><TBODY><TR><TD align=middle><TABLE cellSpacing=0 cellPadding=0 width="100%" align=center bgColor=#6a90aa border=0><TBODY><TR><TD vAlign=top align=left bgColor=#dce4ee><TABLE cellSpacing=0 cellPadding=10 width=140 border=0 marginheight="0" marginwidth="0" topmargin="0" leftmargin="0"><TBODY><TR><TD vAlign=center align=middle bgColor=#dce4ee>[FONT=verdana, arial, helvetica, sans-serif]View this table:
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We found no significant difference in our comparison of the<SUP> </SUP>clinical symptoms and outcomes of untreated patients with oseltamivir-resistant<SUP> </SUP>and oseltamivir-susceptible influenza A(H1N1) infections, excluding<SUP> </SUP>patients who were treated with antiviral agents (Table 2). Patients<SUP> </SUP>with oseltamivir-susceptible A(H1N1) infections were statistically<SUP> </SUP>more likely to report myalgias or arthralgias and to be hospitalized.<SUP> </SUP>However, 1 of the untreated patients with oseltamivir-resistant<SUP> </SUP>influenza A(H1N1) infection died on the way to the hospital<SUP> </SUP>and a second patient died in the emergency department before<SUP> </SUP>admission. If these 2 cases had been included as hospital admissions<SUP> </SUP>in the analysis, the difference would be no longer significant.<SUP> </SUP>
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We found no correlation between the prevalence of oseltamivir<SUP> </SUP>resistance and the proportion of total filled anti-infective<SUP> </SUP>prescriptions that were prescriptions for oseltamivir during<SUP> </SUP>2007 in 22 states (r = 0.00007, P = .99)<SUP> </SUP>(Figure 2).<SUP> </SUP>
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Scatterplot of proportion of total filled anti-infective prescriptions that were prescriptions for oseltamivir during 2007 by 2007-2008 state prevalence of oseltamivir-resistant influenza A(H1N1) and the line of best fit (determined using least squares regression). Total anti-infective prescriptions include antibiotics, antifungals, antiparasitic, and antiviral medications except for antiretroviral drugs. [/FONT]
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[FONT=verdana, arial, helvetica, sans-serif]COMMENT [/FONT]<TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD width="100%" bgColor=#6a90aa>
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We report the first, to our knowledge, detailed description<SUP> </SUP>of persons infected with oseltamivir-resistant influenza A(H1N1)<SUP> </SUP>viruses identified during the 2007-2008 influenza season in<SUP> </SUP>the United States. Although oseltamivir-resistant A(H1N1) viruses<SUP> </SUP>circulated widely in the United States, during the 2007-2008<SUP> </SUP>influenza season, the national adjusted overall proportion of<SUP> </SUP>oseltamivir-resistance among all influenza viruses was low (2%),<SUP> </SUP>and national recommendations for use of antiviral agents were<SUP> </SUP>not changed during 2007-2008.<SUP>7</SUP> However, early surveillance data<SUP> </SUP>from 2008-2009 suggest that the prevalence of oseltamivir resistance<SUP> </SUP>among A(H1N1) viruses will most likely be higher (>90%) during<SUP> </SUP>the 2008-2009 season.<SUP>8, 26</SUP> The findings of this investigation<SUP> </SUP>informed interim guidelines released by the CDC on the use of<SUP> </SUP>antiviral agents for the 2008-2009 influenza season.<SUP>27</SUP><SUP> </SUP>
We did not find an association between use of oseltamivir and<SUP> </SUP>cases of illness due to infection with oseltamivir-resistant<SUP> </SUP>A(H1N1) viruses in the United States. Similar findings were<SUP> </SUP>reported to the WHO and by investigators in Norway.<SUP>6, 28-31</SUP><SUP> </SUP>Before the 2007-2008 influenza season, resistance to oseltamivir<SUP> </SUP>had only been described in association with oseltamivir exposure.<SUP>9-13</SUP><SUP> </SUP>At the present time, it is unclear why oseltamivir-resistant<SUP> </SUP>influenza A(H1N1) viruses emerged during the 2007-2008 season<SUP> </SUP>and appear to continue circulating during the 2008-2009 season.<SUP> </SUP>
The prevalence of underlying medical conditions, the age distribution,<SUP> </SUP>and the clinical symptoms of patients with oseltamivir-resistant<SUP> </SUP>and oseltamivir-susceptible A(H1N1) infections were similar.<SUP> </SUP>Although oseltamivir-resistant cases reported fewer hospitalizations<SUP> </SUP>compared with oseltamivir-susceptible cases, 2 oseltamivir-resistant<SUP> </SUP>cases died on the way to the hospital and were not included<SUP> </SUP>as hospital admissions. Thus, it is likely that there were no<SUP> </SUP>significant clinical differences between patients with oseltamivir-resistant<SUP> </SUP>and oseltamivir-susceptible A(H1N1) infections. A study<SUP>28</SUP> from<SUP> </SUP>2007-2008 in Norway found similar results.<SUP> </SUP>
We identified 4 deaths among cases with oseltamivir-resistant<SUP> </SUP>influenza A(H1N1) infections. Three of these deaths were among<SUP> </SUP>patients with severe underlying medical conditions that put<SUP> </SUP>them at high risk for complications associated with influenza<SUP> </SUP>virus infection, similar conditions as the 1 previously reported<SUP> </SUP>death in a patient with oseltamivir-resistant A(H1N1) infection.<SUP>32</SUP><SUP> </SUP>We were not able to compare the risk of death between oseltamivir-resistant<SUP> </SUP>and oseltamivir-susceptible A(H1N1) cases because death from<SUP> </SUP>influenza A(H1N1) infection is a rare outcome and oseltamivir-resistant<SUP> </SUP>A(H1N1) cases were identified from all states, whereas oseltamivir-susceptible<SUP> </SUP>cases were identified from states in which resistant viruses<SUP> </SUP>were identified.<SUP> </SUP>
Before the 2007-2008 season, the level of resistance to oseltamivir<SUP> </SUP>among circulating influenza viruses was less than 1%.<SUP>3-5</SUP> Transmission<SUP> </SUP>of 1 virus with the H274Y mutation, originally recovered from<SUP> </SUP>a patient treated with oseltamivir, was demonstrated in a ferret<SUP> </SUP>model,<SUP>18</SUP> but transmission of oseltamivir-resistant viruses among<SUP> </SUP>humans had never been documented previously.<SUP>14-15</SUP> Worldwide,<SUP> </SUP>from the last quarter of 2007 to March 31, 2008, 1182 of 7530<SUP> </SUP>influenza A(H1N1) viruses (16%) tested and reported to the WHO<SUP> </SUP>were resistant to oseltamivir.<SUP>6</SUP> It is unclear how oseltamivir-resistant<SUP> </SUP>A(H1N1) viruses became able to maintain the ability to circulate<SUP> </SUP>among humans as widely as oseltamivir-susceptible viruses. Mutations<SUP> </SUP>that confer resistance to NAI occur in or nearby the active<SUP> </SUP>site of the neuraminidase, an enzyme that plays an important<SUP> </SUP>role in the ability of the virus to infect host cells, and it<SUP> </SUP>was expected previously that NAI-resistant viruses would be<SUP> </SUP>less viable than sensitive ones.<SUP>16-17</SUP> It is possible that the<SUP> </SUP>resistant viruses may have acquired other mutations that compensate<SUP> </SUP>for these changes to the neuraminidase and allow for continued<SUP> </SUP>efficient transmission of virus and continued pathogenicity.<SUP> </SUP>Further studies are needed to better understand the mechanisms<SUP> </SUP>of emergence of NAI-resistant mutants in influenza viruses.<SUP> </SUP>
Our study had the following limitations. The number of A(H1N1)<SUP> </SUP>cases identified from surveillance was small and the confidence<SUP> </SUP>intervals in our comparison analysis were large. We could not<SUP> </SUP>detect small or moderate differences (<50%) between oseltamivir-resistant<SUP> </SUP>and oseltamivir-susceptible cases for most categorical outcomes;<SUP> </SUP>however, we had sufficient power to detect a 1 day difference<SUP> </SUP>in continuous outcomes. Viral strain surveillance was passive;<SUP> </SUP>states received varying numbers of influenza specimens and submitted<SUP> </SUP>varying proportions of influenza viruses for oseltamivir-resistance<SUP> </SUP>testing at the CDC. Therefore, these results may not be representative<SUP> </SUP>of all A(H1N1) infections during the 2007-2008 season in the<SUP> </SUP>United States.<SUP> </SUP>
The emergence of oseltamivir resistance has highlighted the<SUP> </SUP>need for the development of new antiviral drugs and rapid diagnostic<SUP> </SUP>tests that determine viral subtype or resistance, as well as<SUP> </SUP>improved representativeness and timeliness of national influenza<SUP> </SUP>surveillance for antiviral resistance. Timely monitoring and<SUP> </SUP>weekly reporting of resistance during the 2008-2009 influenza<SUP> </SUP>season will be conducted to help inform policy for antiviral<SUP> </SUP>use in the United States and inform clinical antiviral treatment<SUP> </SUP>decision making.<SUP> </SUP>
Early surveillance data from the 2008-2009 influenza season<SUP> </SUP>has demonstrated that although influenza activity was still<SUP> </SUP>low, the majority of subtyped influenza A viruses were A(H1N1)<SUP> </SUP>and more than 90% of tested A(H1N1) viruses were resistant to<SUP> </SUP>oseltamivir and sensitive to zanamivir.<SUP>8, 26</SUP> As a result, the<SUP> </SUP>CDC released interim recommendations for the use of influenza<SUP> </SUP>antiviral medications.<SUP>27</SUP> The guidelines recommend that clinicians<SUP> </SUP>consider the results of patient testing and local influenza<SUP> </SUP>surveillance data on circulating types and subtypes of influenza<SUP> </SUP>viruses in deciding whether oseltamivir alone could be used.<SUP> </SUP>These guidelines provide options, including preferential use<SUP> </SUP>of zanamivir or a combination of oseltamivir and rimantadine,<SUP> </SUP>which might be more appropriate in treating patients who might<SUP> </SUP>have influenza caused by an oseltamivir-resistant virus.<SUP> </SUP>
Updated CDC influenza antiviral recommendations can be monitored<SUP> </SUP>at http://www.cdc.gov/flu/professionals/antivirals. Additional<SUP> </SUP>options for the treatment and prophylaxis of influenza virus<SUP> </SUP>infection are critically needed.<SUP> </SUP>
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Corresponding Author: Nila J. Dharan, MD, Influenza Division,<SUP> </SUP>Centers for Disease Control and Prevention, 1600 Clifton Rd,<SUP> </SUP>MS A-32, Atlanta, GA 30333 (nfd6@cdc.gov<SCRIPT type=text/javascript><!-- var u = "nfd6", d = "cdc.gov"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></SCRIPT> ).<SUP> </SUP>
Published Online: March 2, 2009 (doi:10.1001/jama.2009.294).<SUP> </SUP>
Author Contributions: Dr Dharan had full access to all of the<SUP> </SUP>data in the study and takes responsibility for the integrity<SUP> </SUP>of the data and the accuracy of the data analysis.<SUP> </SUP>
Study concept and design: Dharan, Epperson, Klimov, Bresee,<SUP> </SUP>Fry.<SUP> </SUP>
Acquisition of data: Dharan, Gubareva, Meyer, Okomo-Adhiambo,<SUP> </SUP>McClinton, Marshall, St. George, Epperson, Fry.<SUP> </SUP>
Analysis and interpretation of data: Dharan, Gubareva, St. George,<SUP> </SUP>Epperson, Brammer, Klimov, Fry.<SUP> </SUP>
Drafting of the manuscript: Dharan, Epperson, Bresee, Fry.<SUP> </SUP>
Critical revision of the manuscript for important intellectual<SUP> </SUP>content: Dharan, Gubareva, Meyer, Okomo-Adhiambo, McClinton,<SUP> </SUP>Marshall, St. George, Epperson, Brammer, Klimov, Bresee, Fry.<SUP> </SUP>
Statistical analysis: Dharan, Epperson, Fry.<SUP> </SUP>
Obtained funding: Klimov, Bresee.<SUP> </SUP>
Administrative, technical, or material support: Dharan, Gubareva,<SUP> </SUP>McClinton, St. George, Epperson, Bresee.<SUP> </SUP>
Study supervision: St. George, Klimov, Fry.<SUP> </SUP>
Financial Disclosures: None reported.<SUP> </SUP>
Funding/Support: No additional funds were required for enhanced<SUP> </SUP>surveillance.<SUP> </SUP>
Role of the Sponsor: Members of the Epidemiology and Prevention<SUP> </SUP>Branch of the Influenza Division of the Centers for Disease<SUP> </SUP>Control and Prevention are responsible for the design and conduct<SUP> </SUP>of the study, for the collection, management, analysis, and<SUP> </SUP>interpretation of the data, and for the preparation, review,<SUP> </SUP>and approval of the manuscript.<SUP> </SUP>
Oseltamivir-Resistance Working Group Members: Farhad Ahmed,<SUP> </SUP>MBBS, MPH, Kumar Nalluswami, MD, MPH, Pennsylvania Department<SUP> </SUP>of Health, Harrisburg; Susan D. Bascom, BSN, Communicable Disease<SUP> </SUP>Surveillance Section, New Hampshire Department of Health and<SUP> </SUP>Human Services, Concord; Vjollca Berisha, MD, MPH, Office of<SUP> </SUP>Epidemiology, Maricopa County Department of Public Health, Phoenix,<SUP> </SUP>Arizona; Rachelle B. Boulton, MSPH, Utah Department of Health,<SUP> </SUP>Salt Lake City; Joyce Cohen, MPH, Edward Corkren, MPH, Molly<SUP> </SUP>Crockett, MPH, Massachusetts Department of Public Health, Boston;<SUP> </SUP>Christine Dao, Varough M. Deyde, MSc, PhD, Henrietta Hall, Monica<SUP> </SUP>Patton, Tiffany G. Sheu, Teresa R. Wallis (Influenza Division),<SUP> </SUP>Craig Hales, MD, MPH (National Center for Public Health Informatics),<SUP> </SUP>Rebecca Sunenshine, MD (Coordinating Office for Terrorism and<SUP> </SUP>Emergency Response), Centers for Disease Control and Prevention,<SUP> </SUP>Atlanta, Georgia; Laura M. Erhart, MPH, Ken Komatsu, MPH (state<SUP> </SUP>epidemiologist), Rebecca Sunenshine, MD, Arizona Department<SUP> </SUP>of Health Services, Phoenix; Kate Goodin, MPH, Florida Department<SUP> </SUP>of Health, Tallahassee; Matt Hanson, MD, DTM&H (Epidemic<SUP> </SUP>Intelligence Service Officer), Jenny Koepsell, MS, Krista Rietberg,<SUP> </SUP>MPH, Communicable Disease Epidemiology and Immunization Section,<SUP> </SUP>Public Health?Seattle & King County, Washington; Thomas<SUP> </SUP>Haupt, MS, Wisconsin Division of Public Health, Madison; Jennifer<SUP> </SUP>M. Laplante, Lisa Mingle, PhD (Laboratory of Viral Diseases),<SUP> </SUP>Wadsworth Center, New York State Department of Health, Albany;<SUP> </SUP>Purisima Linchangco, MPH, Vaccine Preventable Disease Unit,<SUP> </SUP>Cook County Department of Public Health, Chicago, Illinois;<SUP> </SUP>Janice Louie, MD, MPH, Anthony Moore, California Department<SUP> </SUP>of Public Health, Viral and Rickettsial Disease Laboratory,<SUP> </SUP>Richmond; Lisa McHugh, MPH, New Jersey Department of Health<SUP> </SUP>and Senior Services, Trenton; Zach Moore, MD, MPH, North Carolina<SUP> </SUP>Department of Health and Human Services, Raleigh; Rene Najera,<SUP> </SUP>MT, MPH, Division of Communicable Disease Surveillance, Office<SUP> </SUP>of Epidemiology and Disease Control Programs, Maryland Department<SUP> </SUP>of Health and Mental Hygiene, Baltimore; Sarah Park, MD, Ranjani<SUP> </SUP>Rajan, MPH, Hawaii State Department of Health, Honolulu; Cara<SUP> </SUP>J. Person, MPH, Kimberly Yousey-Hindes, MPH, CDC/CSTE Applied<SUP> </SUP>Epidemiology Fellow, New York State Department of Health, Albany;<SUP> </SUP>Rene J. Powell, MPH (epidemiologist), Oklahoma State Department<SUP> </SUP>of Health, Acute Disease Service, Communicable Disease Division,<SUP> </SUP>Oklahoma City; Erik Reisdorf, BS, CLS M (NCA), Communicable<SUP> </SUP>Disease Division, Peter A. Shult, PhD, Tam T. Van, PhD (Emerging<SUP> </SUP>Infectious Disease Research Fellow), Wisconsin State Laboratory<SUP> </SUP>of Hygiene, Madison; Shawn M. Richards, Indiana State Department<SUP> </SUP>of Health, Indianapolis; Alicia Siston, PhD, MPH, MS, Chicago<SUP> </SUP>Department of Public Health, Chicago, Illinois; Alaina Stoute,<SUP> </SUP>MPH, New York City Department of Health and Mental Hygiene,<SUP> </SUP>New York City, New York; Clayton Van Houten Jr, MS, Wyoming<SUP> </SUP>Department of Health, Cheyenne. The members of the Oseltamivir-Resistance<SUP> </SUP>Working Group helped with the acquisition of data but did not<SUP> </SUP>receive any extra compensation for their contribution.<SUP> </SUP>
Disclaimer: The findings and conclusions in this article are<SUP> </SUP>those of the authors and do not necessarily represent the views<SUP> </SUP>of the Centers for Disease Control and Prevention.<SUP> </SUP>
Previous Presentation: Presented in part at the 48th Annual<SUP> </SUP>Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious<SUP> </SUP>Diseases Society of America (ICAAC/IDSA) 46th Annual Meeting;<SUP> </SUP>October 24, 2008; Washington, DC.<SUP> </SUP>
Additional Information: Online eFigure is available here.<SUP> </SUP>
[/FONT]<!--stopindex--><!--null-->[FONT=verdana, arial, helvetica, sans-serif]Author Affiliations: Epidemic Intelligence Service, Office of Workforce and Career Development Assigned to Influenza Division (Dr Dharan), and Influenza Division (Drs Gubareva, Okomo-Adhiambo, Klimov, Bresee, and Fry and Ms Brammer and Mr Epperson), Centers for Disease Control and Prevention, Atlanta, Georgia; Arizona Department of Health Services, Phoenix (Mr Meyer); Wyoming Department of Health, Cheyenne (Mr McClinton); Wisconsin State Laboratory of Hygiene, Madison (Mr Marshall); and Wadsworth Center, New York State Department of Health, Albany (Dr St. George). [/FONT]
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</TD></TR></TBODY></TABLE><!-- null -->30. World Health Organization. Influenza A (H1N1) virus resistance to oseltamivir; 20 August, 2008. http://www.who.int/csr/disease/influenza/H1N1webupdate20082008_kf.pdf. Accessed January 2, 2009.<!-- HIGHWIRE ID="301:10:1034:30" --><!-- /HIGHWIRE --> <TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD>
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</TD></TR></TBODY></TABLE><!-- null -->31. Lackenby A, Thompson CI, Democratis J. The potential impact of neuraminidase inhibitor resistant influenza. Curr Opin Infect Dis. 2008;21(6):626-638.<!-- HIGHWIRE ID="301:10:1034:31" --> [FONT=verdana, arial, helvetica, sans-serif]FULL TEXT[/FONT] | [FONT=verdana, arial, helvetica, sans-serif]ISI[/FONT] | [FONT=verdana, arial, helvetica, sans-serif]PUBMED[/FONT] <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD>
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</TD></TR></TBODY></TABLE><!-- null -->32. van der Vries E, van den Berg B, Schutten M. Fatal oseltamivir-resistant influenza virus infection. N Engl J Med. 2008;359(10):1074-1076.<!-- HIGHWIRE ID="301:10:1034:32" --> [FONT=verdana, arial, helvetica, sans-serif]FREE FULL TEXT[/FONT] <!-- /HIGHWIRE --><TABLE cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD>
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