Signs of Tamiflu-resistant 2009 H1N1 flu transmission cited

Dec 19, 2011 (CIDRAP News) – An analysis of 2009 H1N1 influenza virus isolates from the 2010-11 flu season suggests that low-level community transmission of an oseltamivir-resistant strain took place, a development that bears close watching, researchers reported today.

Though the conclusion was based on a small number of patients, the authors said a higher prevalence of the resistant strain last year in people who weren't exposed to oseltamivir (Tamiflu) compared to the pandemic months is a notable difference. Researchers from the US Centers for Disease Control and Prevention (CDC) and their state partners reported their findings in an early online release from Emerging Infectious Diseases.

Resistance found in 1% of isolates
During surveillance last season, federal and state health officials conducted oseltamivir-resistance testing on 3,652 isolates of the 2009 H1N1 virus, which yielded 35 (1.0%) positive findings, according to the report. As part of the CDC's antiviral resistance surveillance activities, researchers test isolates that state health laboratories send in and collect sequencing information from seven states that do their own testing for the H275Y mutation that has been linked to oseltamivir resistance.

The median age of the patients who were sick with resistant strains was 33 years. Further information was available for all but one of the patients. Nine (26%) had been exposed to oseltamivir before susceptibility testing. Of 33 patients who completed a case form, 67% (22) had at least one preexisting medical condition, 24% (8) were immunocompromised, 42% (14) were hospitalized, and 9% (3) died.

Most patients who were sick with oseltamivir-resistant infections lived in single-family homes. Two siblings from the same household were infected with the strain, though neither had received osteltamivir.

During the pandemic months the number of oseltamivir-resistant isolates was also small, 37 (0.5%) of 6,740 specimens tested. However, the researchers said those patients were more likely to report exposure to oseltamivir, by a margin of 89% for 2009-10 to 26% for 2010-11.

The group noted that the United Kingdom also found a higher percentage of patients with oseltamivir-resistant strains during the 2010-11 flu season. They said the pattern is worrisome, considering the dramatic rise in oseltamivir-resistant seasonal flu strains seen during the two seasons that preceded the pandemic. The oseltamivir-resistant seasonal H1N1 strain involved the same H275Y substitution in the neuraminidase of the virus.

Unlike the resistant seasonal H1N1 virus, the 2009 H1N1 virus has not retained susceptibility to adamantanes, which the authors said limits the treatment options to inhaled zanamivir (Relenza) or an investigational intravenous version of zanamivir.

The authors cautioned that their conclusions are based on a small number of patients with oseltamivir-resistant cases and that differences in state surveillance may limit how representative the data are. However, the findings underscore the importance of ongoing surveillance for oseltamivir resistance in the 2009 H1N1 virus.

Recommendations proposed
In a separate report today, experts who advise the World Health Organization on antiviral-resistance issues relating to the 2009 H1N1 virus echoed concerns about community spread of oseltamivir-resistant strain and proposed a set of recommendations for testing, reporting cases, and managing infected patients. The group published its report in an early online issue of The Lancet Infectious Diseases.

Since April 2009 the WHO has received data on more than 27,000 samples that were tested for neuraminidase resistance, from which 447 oseltamivir-resistant viruses were detected. The group credited pandemic planning efforts and upgrades at the Global Influenza Surveillance and Response System for allowing such large-scale testing.

Most cases were detected in patients undergoing oseltamivir treatment, including those who were immunocompromised. The report says that a small number (14%) were detected in patients who weren't treated with oseltamivir and had no known contact with patients who were.

The article notes that more studies are under way to explore the fitness and transmissibility of oseltamivir-resistant H1N1. So far, studies have not reported any differences in clinical symptoms or disease severity among 2009 H1N1 patients with and without the oseltamivir-resistant strain.

Early detection of changes depends on surveillance, and the authors recommended that countries that routinely use antiviral medications establish a baseline of susceptibility monitoring. Patients hospitalized for 2009 H1N1 infections should be tested before, during, and after antiviral therapy, they added.

Experts should form a consensus on thresholds for changing first-line drug recommendations, which could be modified depending on the patient population and history of drug treatment, the authors said.

The group also called for a global database that would allow researchers to rapidly share information about current and newly discovered neuraminidase mutations linked to reduced osteltamivir susceptibility.

For clinical management, they urged doctors to consider a low threshold for resistance testing, especially among patients in risk groups, such as those with immune compromise and those with severe or worsening infections who don't respond to neuraminidase inhibitors.

Though combination antiviral treatment has been used for some severely ill patients, a lack of large randomized controlled trials limits the interpretation of its efficacy, leaving intravenous zanamivir as the next treatment of choice in patients who have suspected or confirmed oseltamivir-resistant 2009 H1N1 infections.

Storms AD, Gubareva V, Su S, et al. Oseltamivir-resistant pandemic (H1N1) 2009 virus infections, United States, 2010-11. Emerg Infect Dis 2011 Dec 19 [Full text]

Hurt AC, Chotpitayasunondh T, Cox N, et al. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspective. Lancet Infect Dis 2011 Dec 19 [Abstract]

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