Some 2009 H1N1 viruses have reduced sensitivity to 2 drugs

Jun 11, 2011 (CIDRAP News) – Some 2009 H1N1 influenza virus strains in Singapore and Australia have been showing "mildly reduced" sensitivity to both of the main flu drugs, which is not a clinical problem now but could become one if the viruses pick up further mutations, according to a report in Eurosurveillance.

In the first few months of this year, more than 10% of community specimens collected in Singapore and 30% of those in the Darwin, Australia, area had a novel mutation that mildly lowers sensitivity to the two neuraminidase inhibitors—oseltamivir (Tamiflu) and zanamivir (Relenza), according to the report, published yesterday. The mutation is known as S247N.

One patient was infected with a virus that had both the S247N mutation and another one, H275Y, that confers resistance to oseltamivir and has been seen in a few hundred 2009 H1N1 cases globally since that virus emerged. The virus with both mutations was extremely resistant to oseltamivir, and the patient died despite receiving intravenous zanamivir, the report says. The patient, from Perth, Australia, had a compromised immune system.

The article, by a team of Australian and Singaporean investigators, says 22 2009 H1N1 viruses containing the S247N mutation have been detected in the Asia-Pacific region since December 2010. Nine of 28 isolates from the Darwin region in the first 3 months of this year had the mutation, as did 10 of 80 isolates collected in Singapore since last December. The variant has also been detected in Western Australia and Brunei and, on the basis of genetic sequence data, has been seen rarely in a few other places since 2009.

Nine of the 22 S247N viruses were cultured and were found to have a sixfold reduction in oseltamivir sensitivity and a threefold reduction in zanamivir sensitivity, compared with typical 2009 H1N1 isolates, the report says. The viruses showed no reduction in sensitivity to peramivir, a newer neuraminidase inhibitor that is not yet licensed in the United States.

Patients who receive the recommended dosages of oseltamivir and zanamivir would easily have high enough systemic levels of the drugs to still be effective against the S247N variant, "and therefore the variant is unlikely to be clinically resistant," the report states.

However, the investigators voice concern that the combination of S247N with other known resistance-conferring mutations, such as H275Y and I223L, could produce clinically resistant viruses, as was seen in the patient in Perth. They note that the S247N variant appears to be able to circulate widely.

"If the S247N variant spreads globally, the greatest concern is that other NA [neuraminidase] mutations which may have previously caused only mild reductions in NAI [neuraminidase inhibitor] susceptibility . . . could instead cumulatively decrease NAI sensitivity to levels that may be clinically significant and affect treatment efficacy," the report concludes.

"Laboratories should consider screening currently circulating specimens and isolates for the S247N NA mutation to determine whether the variant is spreading into other regions."

Hurt AC, Lee RT, Leang SK, et al. Increased detection in Australia and Singapore of a novel influenza A(H1N1) variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation. Eurosurveillance 2011 Jun;16(23) [Full text]

See also:

Feb 3 CIDRAP News story "UK findings hint at spread of resistant H1N1 strain"

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