February 1, 2008


Europe Reports High Percentage of Oseltamivir-resistant Influenza Virus


European health officials have reported finding oseltamivir resistance in a surprisingly high percentage of H1N1 influenza virus isolates tested so far this season. The highest percentage came from a country where oseltamivir usage is low, suggesting the emergence of fit and transmissible oseltamivir-resistant viruses.

As of Feb. 14, 20 percent of H1N1 isolates (202 out of 987) had a mutation -- H274Y -- that confers resistance to oseltamivir. Norway reported the highest percentage of resistant H1N1 isolates -- 66 percent -- despite the fact that oseltamivir is infrequently used in Norway. France had the second-highest percentage, with 40 percent.

Last season, oseltamivir resistance was not detected in Europe; nor was it found in Japan, where the neuraminidase inhibitor is used more frequently. One percent of isolates tested in the United States last season were resistant.

“These viruses appear to have arisen without drug pressure,” said Arnold S. Monto, MD, FIDSA, founding director of the University of Michigan Bioterrorism Preparedness Initiative and a member of the IDSA Pandemic Influenza Task Force. “It is a surpriseand it is something that needs to be watched.”

Neuraminidase inhibitors, such as oseltamivir and zanamivir, have  become the primary influenza antivirals as resistance to adamantane inhibitors has grown in recent years. Dr. Monto said experts were aware that adamantane-inhibitor resistance could develop relatively easily. “But we didn’t know that about the neuraminidase-inhibitor resistant strains. As a matter of fact, we thought that these resistant strains had some competitive disadvantage. One of the things that need to be done with these new resistant viruses is see how they have changed and whether this will persist,” said Dr. Monto. He also noted the oseltamivir-resistant strains are sensitive to zanamivir.

Dr. Monto observed the overall number of samples tested so far is small and the rates of resistance varied widely from country to country. These geographic variations may be real, he said, or, “It also may mean that we don’t have enough specimens that have been examined. We need more data.”

Resistance has not appeared in H3N2 or B strains of virus circulating this year, Dr. Monto said. And although H1N1 and the highly pathogenic H5N1 share the neuraminidase gene where the resistance-conferring H274Y mutation is located, there is no evidence that similar resistant, transmissible strains of H5N1 strains have emerged.  

IDSA and other organizations have been recommending stockpiling of oseltamivir to prepare for an influenza pandemic. No changes in treatment recommendations have been made and Dr. Monto said it’s too soon to say whether any will be necessary. “It’s early days,” he said. “We need to better understand what’s going on here.” The U.S. national stockpile includes zanamivir as well.

His advice for now: stay tuned.

The latest information on H1N1 oseltamivir resistance is available online from WHO.

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