Researchers observe zanamivir advantages in kids' flu

Jan 20, 2011 (CIDRAP News) – Zanamivir might be a better flu treatment for children than oseltamivir, according to a research group from Japan who observed the two drugs over four flu seasons, finding that zanamivir produced shorter virus-shedding times with fewer links to resistance.

The group based its findings on 144 pediatric patients who were seen as outpatients at four hospitals in Japan over four flu seasons between 2005 and 2009. Their findings appeared yesterday in an early online edition of Clinical Infectious Diseases. The group was led by Yoshihiro Kawaoka, DVM, PhD, a virologist from Japan who is also with the University of Wisconsin, Madison's Department of Pathological Sciences.

Though zanamivir (Relenza) and oseltamivir (Tamiflu) are both neuraminidase inhibitors that are useful therapies for flu, Kawaoka's group noted that flu virus resistance to zanamivir, an inhaled drug, is reported less frequently than with oseltamivir, which is taken orally. They therefore wanted to compare the drugs to see if their drug-resistance and virus-shedding profiles were different. They questioned whether resistance was less likely to be reported with zanamivir because of its less frequent use or because of its unique properties.

Oseltamivir-resistant seasonal H1N1 flu viruses emerged in 2006, with and without selective pressure from antiviral use. However, during the 2009 H1N1 pandemic few cases of resistance in the new strain were confirmed. According to the World Health Organization's (WHO's) Jan 14 update, only 319 oseltamivir-resistant 2009 H1N1 cases have been reported.

The children in the study received either oseltamivir or zanamivir based on their clinical symptoms, such as vomiting or wheezing. Illnesses were relatively mild, and none of the patients required hospitalization. They were treated within 48 hours of symptom onset. None of them were immunocompromised or receiving corticosteroids or immunosuppressive therapy.

Researchers collected clinical specimens from patients two or three times: during their initial visit, on day 3 to 4 and/or on day 5 to 7 after drug treatment. Half were treated with oseltamivir and half received zanamivir. Using the follow-up testing to gauge the drugs' effects on viral shedding, they collected 60 and 50 "second" specimens from the oseltamivir and zanamivir patients, respectively. The group obtained 33 "second or third" specimens from each group.

They used neuraminidase inhibition assay to test the sensitivity of the viruses to the two drugs.

A comparison of the two drugs' effects on virus shedding were based on 41 oseltamivir and 25 zanamivir samples collected on days 3 to 4 after treatment and on 23 oseltamivir and 13 zanamivir samples collected on days 5 to 7 post treatment.

The group didn't find a statistically significant difference between the two treatment groups among the earlier specimens, but they found that the viral isolation rate in the later specimens was significantly higher in the kids who were treated with oseltamivir. Researchers concluded that zanamivir was more efficient than oseltamivir at reducing the virus-shedding period.

To detect drug resistance, they sequenced the viral neuraminidase (NA) gene for all specimens they collected. They detected NA substitutions in specimens collected from six (8.3%) patients who were treated with oseltamivir, but none were found in specimens from those who received zanamivir. All of the resistant mutations were detected on or after day 4 of drug treatment, and the oseltamivir-resistant viruses didn't appear to be linked to prolonged virus shedding or increased illness severity, according to the researchers.

"These results reveal that the frequency of viruses resistant to zanamivir is significantly lower than the frequency of those resistant to oseltamivir," Kawaoka and his colleagues wrote.

They suggested that young children's relatively immature immune system, compared with adults', could lead to more persistent viral replication, which has been reflected in increased and sustained infections in this group in influenza pandemics. "Taken together, oseltamivir-resistant variants may emerge more frequently in a pandemic situation in which the majority of patients are immunologically naive to the virus," the group wrote.

Zanamivir's comparable efficacy to oseltamivir and its efficacy against oseltamivir-resistant strains shows that is may play a key role in flu treatment, they concluded.

Dr Raphael Dolin, a virologist at Beth Israel Deaconess Medical Center-Harvard Medical School in Boston, wrote in an accompanying commentary that the Kawaoka study provides important information about the frequency of resistant viruses after treatment with both drugs.

He noted that zanamivir-resistant virus infections are rare but have mainly been described in immunosuppressed patients.

The observational nature of the study and its relatively small sample size limit some of the study's interpretations, Dolin wrote. The children's illnesses were relatively mild, which limited the researchers' ability to compare the clinical treatment effects and complication rates.

Studies such as the Kawaoka one highlight the importance of strategies to reduce antiviral resistance against flu, which should be based on the latest molecular, pharmacokinetic, and physiologic findings and on data from rigorous clinical trials, he added.

Though one traditional approach to block resistance has been combination therapies that have synergistic or additive effects, Dolin wrote that a recent randomized trial combining oseltamivir and zanamivir was less effective than oseltamivir alone for treating influenza A (H3N2) infections in adults.

He said comparative antiviral studies should be confirmed and extended to other patient populations and flu subtypes, and surveillance for resistance plays a key role in guiding appropriate antiviral use and future clinical studies.

Tamura T, Sugaya N, Ozawa M, et al. Frequency of drug-resistant viruses and virus shedding in pediatric influenza patients treated with neuraminidase inhibitors. Clin Infect Dis 2011 (published online Jan 19) [Abstract]

Dolin R. Resistance to neuraminidase inhibitors. (Commentary) Clin Infect Dis 2011 (published online Jan 19) [Extract]

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