Increasing Prevalence of Influenza A Resistance to Drug Oseltamivir, JAMA Study Finds

March 3, 2009 - Influenza A viruses (H1N1 subtype) that are resistant to the drug oseltamivir circulated widely in the U.S. during the 2007-2008 influenza season, with an even higher prevalence of drug resistance during the current 2008-2009 influenza season, according to a study to be published in the March 11 issue of the Journal of the American Medical Association (JAMA), and released early online yesterday, along with two other related studies below, because of their public health importance.

During the 2007-2008 influenza season, increased levels of resistance to the influenza drug oseltamivir (marketed as Tamiflu) were detected for the first time in the United States and worldwide.

In addition, early 2008-2009 influenza season surveillance data suggest that oseltamivir resistance among influenza A(H1N1) viruses will most likely be higher, according to background information in the article. It was unknown whether some resistant viruses would cause clinical illness similar to other influenza viruses.

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Nila J. Dharan, M.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues examined the trends and characteristics of patients infected with oseltamivir-resistant and -susceptible influenza A(H1N1) virus. These viruses, identified and submitted to the CDC by U.S. public health laboratories between September 2007 and May 2008 and between September 28, 2008, and February 19, 2009, were tested as part of ongoing surveillance.

During the 2007-2008 season, influenza A(H1N1) accounted for an estimated 19 percent of circulating influenza viruses in the United States. Resistance to oseltamivir was identified among 142 of 1,155 U.S. influenza A(H1N1) viruses (12 percent) tested during the 2007-2008 influenza season.

Data were available for 99 persons infected with oseltamivir-resistant influenza and 182 persons infected with oseltamivir-susceptible influenza from this period.

Among resistant cases, median (midpoint) age was 19 years, 5 patients (5 percent) were hospitalized, and 4 patients (4 percent) died. No significant differences were found between cases of oseltamivir-resistant and oseltamivir-susceptible influenza in demographic characteristics, underlying medical illness, or clinical symptoms.

The researchers did not find an association between use of oseltamivir and cases of illness due to infection with oseltamivir-resistant A(H1N1) viruses in the United States.

Preliminary data from the early 2008-2009 influenza season indicates that oseltamivir resistance among A(H1N1) viruses continues at high levels.

As of February 19, 2009, resistance to oseltamivir had been identified among 264 of 268 (98.5 percent) U.S. influenza A(H1N1) viruses tested.

"The emergence of oseltamivir resistance has highlighted the need for the development of new antiviral drugs and rapid diagnostic tests that determine viral subtype or resistance, as well as improved representativeness and timeliness of national influenza surveillance for antiviral resistance," the authors write.

They add that on December 19th, 2008, the CDC released interim recommendations for the use of influenza antiviral medications based on the early surveillance data from the 2008-2009 influenza season. "The guidelines recommend that clinicians consider the results of patient testing and local influenza surveillance data on circulating types and subtypes of influenza viruses in deciding whether oseltamivir alone could be used. These guidelines provide options, including preferential use of [the anti-viral drug] zanamivir or a combination of oseltamivir and [the anti-viral drug] rimantadine, which might be more appropriate in treating patients who might have influenza caused by an oseltamivir-resistant virus."

"Additional options for the treatment and prophylaxis of influenza virus infection are critically needed."

Editorial: The Evolution of Influenza Resistance and Treatment

In an accompanying editorial, David M. Weinstock, M.D., of the Dana-Farber Cancer Institute, Boston, and Gianna Zuccotti, M.D., of Brigham and Women's Hospital, Boston, and Contributing Editor, JAMA, Chicago, comment on the findings regarding influenza.

"The understanding of influenza biology and epidemiology has advanced markedly; however, the global dissemination of oseltamivir-resistant influenza came as a great surprise. Undoubtedly, new surprises await in the perpetual struggle with influenza as one thing is certain—the organism will continue to evolve. Anticipating the rapid and endless changes in influenza biology and dynamics will require faster diagnostics to molecularly characterize specimens, extensive surveillance among humans and animals, and more rapid and [flexible] systems for translating basic and epidemiological discoveries into clinically applicable interventions. For now, the best tools to mitigate influenza infection are tried-and-true—vaccination, social distancing, hand washing, and common sense."

Drug Resistant Influenza A Virus Potentially Serious to High-Risk Patients

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A mutation of the influenza A(H1N1) virus that is resistant to the drug oseltamivir may pose a serious health threat to hospitalized patients who have a weakened immune system, according to a study to be published in the March 11 issue of the Journal of the American Medical Association (JAMA), and released early because of its public health importance.

A global emergence and rapid spread of oseltamivir-resistant influenza A(H1N1) viruses carrying a neuraminidase (NA; an enzyme) gene H274Y mutation has been observed since January 2008. Viruses carrying this mutation have been presumed to be of lower risk and less likely to be transmitted. "However, current widespread circulation of oseltamivir-resistant influenza A(H1N1) viruses associated with typical influenza illnesses and viral pneumonia suggest that these viruses retain significant transmissibility and pathogenicity [ability to cause disease]," the authors write.

Jairo Gooskens, M.D., of Leiden University Medical Center, Leiden, the Netherlands, and colleagues analyzed the transmission of the oseltamivir-resistant influenza A(H1N1) virus with NA gene H274Y mutation to two hematopoietic (the formation of blood or blood cells) stem cell transplant recipients and an elderly patient in a Dutch university hospital in February 2008. The investigation included a review of the medical records and various influenza and genetic tests.

The analysis confirmed that four patients in the hospital had the virus mutation, and that the virus was most likely transmitted while these patients were in the hospital. Influenza virus pneumonia (3 patients) and attributable death (2 patients) during active infection was observed in patients with lymphocytopenia (having an abnormally low level of white blood cells, important to the immune system) at onset.

Five health care workers developed influenza-like illness during admission of the presumed index patient. However, samples for influenza testing were not obtained from any of these health care workers, so their role in possibly contributing to this transmission could not be confirmed.

"Early identification and prolonged isolation precautions appear prudent in the care for infected immunocompromised patients to prevent [hospital] influenza virus outbreaks. This study confirmed that circulating H274Y-mutated A(H1N1) viruses can retain significant pathogenicity and lethality, as shown in these elderly or immunocompromised patients with lymphocytopenia, underlining the urgency for the introduction of new effective antiviral agents and therapeutic strategies," the authors write.

They add that because the study consisted of a small number of patients, the findings require careful interpretation and do not allow conclusions on the frequency of this complication in hospital settings.

Inactivated Flu Vaccine Associated with Fewer Medical Visits for Respiratory Illness than Intranasal Vaccine

A study among U.S. military personnel finds that those who received a flu shot with the trivalent inactivated vaccine had fewer subsequent health care visits related to pneumonia and influenza than those who received an intranasal live attenuated influenza vaccine, according to a study appearing in the March 4 issue of the Journal of the American Medical Assocation (JAMA).

Military personnel are prone to outbreaks of respiratory illness such as influenza for a variety of reasons, including crowding and stressful conditions. Trivalent inactivated vaccine (TIV), administered intramuscularly, was first developed and tested in the military in the 1940s and has been used annually since the 1950s to prevent influenza and its complications.

In 2003, a live attenuated influenza vaccine (LAIV) was formulated for intranasal application and approved for use among healthy adults, according to background information in the article. Service members were immediately targeted for LAIV use by the U.S. Department of Defense because of the ease of vaccine administration and availability early in the season.

Since 2004, increasing numbers of military personnel have been immunized with LAIV while most others received TIV. However, data about live virus vaccine effectiveness among healthy adults are limited.

Zhong Wang, Ph.D., M.P.H., of the Armed Forces Health Surveillance Center, Silver Spring, Md., and colleagues investigated the incidence of health care encounters for pneumonia and influenza illness among active-duty service members, age 17 to 49 years, eligible for influenza vaccination who were stationed in the United States during the 2004-2005 (n = 1,061,728), 2005-2006 (n = 1,041,264), and 2006-2007 (n = 1,067,959) influenza seasons. Immunization rates ranged from 51.9 percent in the 2004-2005 to 78.4 percent in the 2006-2007 influenza season. The proportion of immunized persons receiving LAIV increased from 33.5 percent in the 2004-2005 influenza season to 47.9 percent in the 2006-2007 season.

The researchers found that the incidence rate of health care encounters for pneumonia and influenza was highest in the unimmunized group each season, with the LAIV immunized group having the next highest incidence rates, and the TIV immunized group with the lowest incidence.

The incidence rates of hospitalizations for pneumonia and influenza were highest in the LAIV immunized group for each of the 3 seasons, and the incidence rate in this group was significantly higher than that in the unimmunized group during the 2004-2005 season but not during 2005-2006 or 2006-2007.

Live attenuated influenza vaccine was found to have an effect similar to TIV in those who had not received a flu vaccine before. "This suggests that pre-existing vaccine-induced immunity may play a role in determining the effectiveness of LAIV," the authors write.

"These results suggest that in a highly immunized adult population, TIV may be more effective than LAIV for the prevention of pneumonia- and influenza-related morbidity. Live attenuated influenza vaccine may be more appropriate for those with no prior immunization, such as military recruits," the researchers write.

"Because our population is highly immunized against influenza on an annual basis, results from this report may not be generalizable to the entire U.S. adult population but could be useful for nonmilitary adult populations where vaccinations rates are high. Additional efficacy trials in this population or effectiveness studies using laboratory-confirmed influenza infections may be warranted."

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