Resistant flu cases underline need for new antivirals

Dec 8, 2010 (CIDRAP News) – A package of studies and commentary published this week by the Journal of Infectious Diseases points up the ability of influenza viruses to become drug-resistant and continue to spread, highlighting the need for new antivirals.

In one report, US and Canadian researchers identified 28 seasonal H1N1 viruses from 2008 to 2010 that were resistant to the adamantane class of antiviral drugs and to oseltamivir (Tamiflu), one of the two neuraminidase inhibitors licensed in the United States. They found that the dual-resistant viruses became more common during that time.

A second report describes the spread of an oseltamivir-resistant 2009 H1N1 virus in the hematology unit of a British hospital in the fall of 2009, which the authors call the first confirmed episode of its kind. Four of eight patients were found to have contracted the resistant virus from others.

"Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs," say two leading flu experts, Frederick G. Hayden and Menno D. de Jong, in an accompanying commentary. Hayden works at the University of Virginia and for the Wellcome Trust in London; de Jong is at the University of Amsterdam.

The reports note that zanamivir (Relenza)—the other US-licensed neuraminidase inhibitor—can be used to treat US patients sick with influenza A viruses resistant to the adamantanes and oseltamivir, but other options are very limited. The adamantanes—older drugs—are amantadine and rimantadine.

Dual-resistant H1N1 viruses
The report on dual-resistant viruses comes from researchers with the US Centers for Disease Control and Prevention (CDC), several state health departments, and the Public Health Agency of Canada, with Tiffany G. Sheu of the CDC as first author.

About 1,500 seasonal (prepandemic) H1N1 isolates, most of them collected in the United States in the 2008-09 season and a few in the 2009-10 season, were analyzed. The researchers found 28 isolates that were resistant to both the adamantanes and oseltamivir, including 4 from the United States, 13 from mainland China, 8 from Hong Kong, and 1 each from Canada, Kenya, and Vietnam.

Twenty-one of the dual-resistant isolates were from the 2008-09 season (in which all H1N1 isolates in many countries were oseltamivir-resistant), seven were collected in the 2009-10 season, and one was from the 2007-08 season, the report says. The isolates were susceptible only to zanamivir.

The authors say their findings and earlier reports indicate that dual-resistant seasonal H1N1 viruses became more common over the last three flu seasons: .06% (1 of 1,753 tested) in 2007-08, 1.5% (21 of 1,426) in 2008-09, and 28% (7 of 25) in 2009-10.

The seasonal H1N1 virus was largely replaced in 2009-10 by the 2009 pandemic H1N1 strain. Though it is uncertain if seasonal and pandemic H1N1 viruses will co-circulate in the future, the authors write, "the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries warrants concern because of the limited treatment options currently available for dual-resistant influenza A viruses."

The report says flu viruses can gain antiviral resistance either through pressure from drug treatment, spontaneous mutation, or reassortment with another drug-resistant virus. Some of the dual-resistant isolates were probably the product of reassortments that occurred when patients were infected with adamantane-resistant and oseltamivir-resistant viruses at the same time, the authors suggest.

Outbreak in hospital ward
The British researchers report an outbreak of oseltamivir-resistant 2009 H1N1 flu that occurred in an adult hematology unit at the University Hospital of Wales in Cardiff in October and November 2009, which marked the peak of the pandemic's second wave.

They identified 11 H1N1 cases, 10 of which were related, as shown by genetic analysis. At the start of the outbreak, all the patients received standard oseltamivir treatment for 5 days, and afterward they were put on a double-dose regimen for 10 days, with zanamivir added if resistance was suspected. The patients' symptoms were generally mild, and all of them recovered.

Eight of the 10 related cases had the H275Y mutation that confers oseltamivir resistance, the report says. By analyzing patient samples before and after oseltamivir treatment, the authors determined that 4 of the 8 patients contracted the resistant strain from others.

The virus first spread into the ward from the community, "with oseltamivir resistance being driven by treatment in 2 lymphopenic patients with onward transmission of . . . virus to other patients on the unit," the report says.

The outbreak prompted the hospital to revise its treatment guidelines for hematology patients with 2009 H1N1 infections. Although all the patients recovered with a combination of oseltamivir and zanamivir treatment, another recent study suggests that this combination offers no advantage, the authors write. "Zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups," they state.

Agile viruses
Commenting on the reports, Hayden and de Jong write, "Antiviral resistance in influenza may not only develop during treatment but also sometimes transmit widely to replace susceptible strains in the absence of drug pressure." This has been shown by the spread of adamantane-resistant H3N2 viruses since 2003 and adamantane-resistant pandemic H1N1 viruses in 2009, as well as the spread of oseltamivir-resistant seasonal H1N1 viruses starting in 2007, they add.

While oseltamivir-resistant 2009 H1N1 cases have been uncommon, Hayden and de Jong note that transmission of such viruses has been suspected in a few other cases besides the Cardiff outbreak. One of those was an outbreak in a hematology-oncology ward at Duke University Hospital in Durham, N.C., in the fall of 2009.

Although zanamivir remains effective for oseltamivir-resistant 2009 H1N1, its safety and effectiveness in seriously ill patients are unclear, and the inhaled or nebulized form can interfere with ventilator filters, Hayden and de Jong write. Thus they suggest intravenous zanamivir, an investigational drug, as the most reasonable choice when oseltamivir resistance occurs in seriously ill pandemic H1N1 patients.

They comment that the effectiveness of peramivir, an intravenous neuraminidase inhibitor that has not been approved in the United States but was used on an emergency basis during the pandemic, in treating oseltamivir-resistant H1N1 cases is not clear.

Hayden and de Jong suggest that future research should focus on the effectiveness of zanamivir and combination antiviral therapy and on antivirals with new mechanisms of action.

Sheu TG, Fry AM, Garten RJ, et al. Dual resistance to adamantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008-2010. J Infect Dis 2010 Jan 1;203(1):13-7 [Full text]

Moore C, Galiano M, Lackenby A, et al. Evidence of person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus in a hematology unit. J Infect Dis 2010 Jan 1;203(1):18-24 [Full text]

Hayden FG, de Jong MD. Emerging influenza antiviral resistance threats. (Editorial) J Infect Dis 2010 Jan 1;203(1):6-10 [Full text]

See also:

February WHO Weekly Epidemiological Record report describing oseltamivir-resistant H1N1 case clusters

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