Influenza B partially resistant to neuraminidase inhibitors

May 2007

Influenza B viruses have become partially resistant to two front-line antiviral influenza drugs, according to a report published in The Journal of the American Medical Association.

Researchers from the University of Tokyo conducted two series of analyses including two groups of patients who had influenza B and were treated at hospitals in Japan during the 2004-2005 influenza season. The first analysis consisted of 74 patients aged 15 and younger who were treated with oseltamivir (Tamiflu, Roche) for five days. Eighteen children received 2 mg of oseltamivir per kg of body weight twice daily and 56 children received unit doses of oseltamivir based on their weight twice daily. Dosing was distributed by the following weight: 30 mg twice daily if body weight was 15 kg (30 lb), 45 mg twice daily if body weight was between 15 kg and 23 kg (51 lb), 60 mg twice daily if body weight was between 23 kg and 40 kg (88 lb) and 75 mg twice daily if body weight was more than 40 kg. The second analysis included 442 patients aged 61 years and younger who contracted influenza B during the 2004-2005 influenza season and were studied prior to treatment; this group also included the previous group of 74 children with influenza B.

Both oseltamivir, which was approved in 2001, and zanamivir (Relenza, GlaxoSmithKline), which was approved in 2000 and was the other neuraminidase inhibitor studied in this series, are used more in Japan than anywhere else worldwide. Due to the influenza B epidemic in 2004-2005 in Japan, prevalence and transmission of influenza B were analyzed as well as the emergence rate of influenza B with reduced sensitivity to neuraminidase inhibitors.

Resistant mutations

According to the researchers, oseltamivir-resistance was found in 5.5% of children aged 1 to 12 years infected with influenza A and no children with influenza B. However, in children who had influenza A and were treated with oseltamivir, 18% of children with H3N2 and 16% of children with H1N1 retained resistant variants with neuraminidase mutations after treatment.

Using pretreatment and posttreatment influenza B isolates, the concentrated neuraminidase inhibitor required to inhibit 50% of the sialidase activity of influenza B virus (IC₅₀) was determined in a 7-year-old patient. The patient received oseltamivir immediately after diagnoses. The IC₅₀ value of the posttreatment isolate tested for resistance to zanamivir increased 7.1-fold (46.9 nmol/L vs. 6.6 nmol/L); and for oseltamivir, it increased 3.9-fold (280.6 nmol/L vs. 72.3 nmol/L).

Seven of the 422 patients had reduced sensitivity to zanamivir, oseltamivir or both. Each of the seven isolates that had reduced sensitivity contained the amino acid substitute in the neuraminidase. Three isolates had Asp198Asn mutations, three isolates had Ile222Thr mutations and one isolate had a Ser250Gly mutation. The Ile222Thr mutation was found in all of the cDNA clones collected. The IC₅₀ values for viruses containing the Ile222Thr mutation were between 443 nmol/L and 514 nmol/L regarding oseltamivir.

The mean peak plasma concentration of oseltamivir carboxylate was assessed after healthy children were given oseltamivir at 2 mg/kg of their body weight. The concentration was 630 nmol/L among children aged between 3 and 5 years, and 426 nmol/L among children aged between 1 and 2 years. These concentrations of IC₅₀ values tested against oseltamivir suggest that oseltamivir may not be as effective against influenza B as it is with influenza A.

In Japan, oseltamivir was prescribed about 90 times more than zanamivir during the 2004-2005 influenza season. During that time, about 11 million people were treated with oseltamivir, which is about 9% of Japan’s total population, said researcher Norio Sugaya, MD, of the department of pediatrics at Keiyu Hospital in Japan. The researchers suggested that mutants with reduced sensitivity were possibly generated due to widespread use of oseltamivir.

For more information:

• Hatakeyama S, Sugaya N, Ito M, et al. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA. 2007;297:1435-1442.