Drug Resistance, Person-to-Person Transmission Increasing Among Flu Strains

Laurie Barclay, MD

December 07, 2010

December 7, 2010 — Drug resistance and transmissibility appear to be increasing among certain influenza virus strains, according to the results of 2 studies published online December 7 and in the January 1 print issue of the Journal of Infectious Diseases.

The first study described person-to-person transmission of oseltamivir-resistant influenza strains in a UK hematology unit, and the second looked at 28 seasonal H1N1 viruses with dual drug resistance from 2008 to 2010 in 5 countries. Both studies raise public health concerns and highlight the need for new antiviral treatment options and strategies.

Person To Person Transmission

"By October 2009, the sporadic emergence of oseltamivir-resistant (OR) (H1N1) 2009 virus was reported in immunocompromised patients who were receiving oseltamivir therapy and in some individuals who had received oseltamivir prophylaxis," write Catherine Moore, from Public Health Wales Microbiology, Public Health Wales National Health Service Trust, in Cardiff, United Kingdom, and colleagues. "Fewer than 60 isolates of OR-(H1N1) 2009 had been reported to the World Health Organization by the end of October 2009, and, of these, only 3 isolates had been identified in the United Kingdom. There were no confirmed reports of person-to-person transmission of OR-(H1N1) 2009 virus except for 1 incident involving 2 cases of resistant virus in adolescents at a summer camp in the United States, where evidence of spread was inconclusive. "

Although the 2009 pandemic H1N1 virus was adamantine-resistant, it was initially susceptible to oseltamivir. Between October and November 2009, however, Dr. Moore's group identified the emergence of OR-H1N1 2009 virus during a nosocomial outbreak on a hematology unit, with molecular as well as epidemiological evidence of person-to-person transmission.

Among 11 cases of H1N1 2009 virus infection, sequence analysis of the hemagglutinin and neuraminidase genes showed that 10 were related. OR virus was present in 8 of 10 case patients, of whom 4 were infected by direct transmission of resistant virus, based on H275Y analysis. This study is the first to confirm person-to-person transmission of this dually resistant OR-H1N1 2009 virus strain, using molecular epidemiologic methods.

The risk for emergence of OR-H1N1 virus during treatment was greatest in immunocompromised patients, as was the risk for person-to-person transmission. Because OR-H1N1 transmission could occur even from immunocompromised patients who had no influenza symptoms or who had completed antiviral therapy, screening of high-risk patients for OR-H1N1 viruses is particularly important.

"Zanamivir should be considered as first-line therapy for influenza in patients with lymphopenic hematological conditions and uptake of influenza vaccination encouraged to further reduce the number of susceptible individuals," the study authors write. "Guidelines may need to be changed to include active screening for the [OR] mutation in hematology patients diagnosed with H1N1 and other patients who are immunocompromised when oseltamivir is used," they explain in a news release.

More Evidence of Dual Resistance Emerging

The second study, from senior author Larisa Gubareva, MD, PhD, and colleagues from the Centers for Disease Control and Prevention in Atlanta, Georgia, as well as health agencies in West Virginia, Texas, and Canada, offers additional evidence regarding increased emergence of dual resistance during the past 3 years, often through varying mechanisms.

"Because only two classes of antiviral agents are approved, the detection of viruses with resistance to drugs in both classes is concerning," Dr. Gubareva said in a news release. "If circulation of viruses with dual resistance becomes more widespread among any of the predominant circulating influenza A viruses, treatment options will be extremely limited. New antiviral agents and strategies for antiviral therapy are likely to be necessary in the future."

In recent flu seasons, 2 distinct genetic clades of seasonal influenza A(H1N1) viruses have cocirculated: clade 2B OR and adamantane-susceptible viruses, and clade 2C viruses that are resistant to adamantanes and susceptible to oseltamivir. An analysis of 28 seasonal dually resistant H1N1 viruses from 2008 to 2010 in 5 countries showed that further antiviral resistance could develop rapidly in a previously single-resistant strain because of genetic mutation, drug response, or gene exchange with another virus.

The dually resistant H1N1 viruses belonged to 4 distinct genotypes. Among the viruses tested, those with dual resistance increased from 0.06% in the 2007 to 2008 flu season, to 1.5% in 2008 to 2009, to 28% in 2009 to 2010. The findings should be regarded with caution in that the number of circulating seasonal H1N1 viruses was low during the 2009 to 2010 season, and only 25 viruses were tested.

Rapid Detection of Resistance Limited

In an accompanying editorial, Frederick G. Hayden, MD, from the University of Virginia School of Medicine, in Charlottesville, and Menno D. de Jong, MD, from the University of Amsterdam in the Netherlands, note that options for rapidly detecting resistance are currently limited, and that most available assays target only the H275Y mutation. Failure to recognize resistance emergence may lead to prolonged use of suboptimal or ineffective therapy, thereby selecting highly resistant viral populations, and potentially other mutations.

"There is also a need for developing new influenza antivirals with novel mechanisms of action," Dr. Hayden and Dr. de Jong write. "The design of future clinical trials needs to be guided by a better understanding of the relationships between viral-replication measures at different sites in the respiratory tract, disease pathogenesis biomarkers such as plasma cytokines and chemokines, and clinical outcomes. Such information will ensure more rapid development and testing of alternative antiviral regimens for use in immunocompromised hosts and seriously ill hospitalized patients to address their unmet medical needs and the associated public health concerns, particularly the continuing threat of antiviral resistance."

Dr. Moore and colleagues have disclosed no relevant financial relationships. Two of this study's authors have received funding from the Wellcome Trust or from Roche. The US Centers for Disease Control and Prevention supported Dr. Gubareva's study. She and her colleagues have disclosed no relevant financial relationships. Dr. Hayden is a member of the Neuraminidase Inhibitor Susceptibility Network with honoraria to University of Virginia since 2008 (funding of the network from GlaxoSmithKline and Roche) and has served as an uncompensated advisor to multiple companies involved in the development of influenza antivirals since 2008.

J Infect Dis. 2011;203:6-10, 13-17, 18-24.


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