Oseltamivir-resistant H5N1 virus isolated from Vietnamese girl

Oct 14, 2005 (CIDRAP News) – A report published today by scientists who isolated an H5N1 virus resistant to oseltamivir from a infected Vietnamese girl further fuels concern over preparedness for a potential and widely anticipated pandemic caused by the strain.

Numerous countries are stockpiling oseltamivir as a tool against infection with H5N1. The drug has proved to be effective against a wide range of flu viruses; its effectiveness against H5N1 has not been tested extensively because of the small number of human cases to date.

Writing in Nature, a group headed by Yoshihiro Kawaoka, a virologist from the University of Tokyo and the University of Wisconsin, report on testing done in a 14-year-old Vietnamese girl hospitalized last spring with H5N1.

The girl, who recovered from the disease, had been treated with oseltamivir prophylactically (75 mg once daily for 4 days) and then therapeutically (75 mg twice daily for 7 days). The agent blocks neuraminidase, an enzyme that enables the virus to escape from an infected cell and spread to other cells.

The authors amplified a viral specimen collected at the end of the prophylactic treatment period by polymerase chain reaction. On direct sequencing, it was found that tyrosine was substituted for histidine at position 274 of the neuraminidase protein. This mutation is considered indicative of oseltamivir resistance, according to the researchers.

The authors then tested the sensitivity of the virus to oseltamivir and found that the dose required for 50% inhibition of neuraminidase activity (IC50) was higher than for oseltamivir-sensitive viruses (90 nM versus 0.1-10 nM).

Next the authors examined the likelihood of possible human transmission in the case. The girl had had no known contact with poultry. However, she had cared for her 21-year-old brother during the time that he had been infected with confirmed H5N1.

The researchers cloned the sample from the girl through plaque purification; randomly picked a number of clones, classifying them according to oseltamivir sensitivity; and then compared genes from the various clones with genes from the virus isolated from her brother during his illness.

Specific neuraminidase and hemagglutinin genes from the brother were identical or very similar to those from the cloned viruses from the girl. This finding, plus the timing of infection in the siblings and the fact that the girl had had no known contact with poultry, led the authors to conclude that it is possible the virus was transmitted from brother to sister.

In further testing, the researchers evaluated growth of the oseltamivir-sensitive and oseltamivir-resistant clones in ferrets. Viral titres were found to be higher in the animals infected with the drug-sensitive virus. When given oseltamivir treatment, animals with drug-sensitive virus showed reduced viral titres, but animals with the resistant virus did not. The drug-resistant animals did, however, show sensitivity to zanamivir, another neuraminidase inhibitor.

According to the authors, even though their study involved a single patient, the findings "raise the possibility that it might be useful to stockpile zanamivir as well as oseltamivir in the event of an H5N1 influenza pandemic."

The authors further point out that their findings "highlight the importance of monitoring the emergence of drug resistance in H5N1 isolates from patients treated with neuraminidase inhibitors."

When asked to comment on the implications of this study, infectious disease expert Michael T. Osterholm, PhD, MPH, said the new study is important in that it confirms what we have known—that strains of H5N1 resistant to oseltamivir are emerging as the disease spreads and treatment expands. However, "What remains to be seen is how this will play out if a population is blanketed with treatment, as would be the case early in a pandemic. It would support emergence of resistant strains and even give those strains selective advantage."

Osterholm, director of CIDRAP, publisher of this Web site, added that while the stockpiling of zanamivir is a scientifically sound recommendation based on the current findings and others, limitations in the supply chain remain the roadblock. "Neither oseltamivir nor zanamivir can now be manufactured in quantities that would be meaningful once efficient human transmission started."

The H5N1 strain of avian influenza has caused mammoth numbers of poultry deaths across Asia and is spreading west in the bird population, reaching Turkey and possibly Romania in the past few days. It has caused 117 human infections in Southeast Asia, including 60 human deaths, according to official WHO numbers.

Le QM, Kiso M, Someya K, et al. Isolation of drug-resistant H5N1 virus. Nature 2005 Oct 20;437:1108 [Abstract]

See also:

Reports of oseltamivir resistance in H3N2 influenza A:
   Bright et al, Lancet, Oct 2005 [Abstract with link to text]
   Kiso et al, Lancet, Aug 2004 [Abstract with link to text]

Report on zanamivir for H5N1:
   Tsang et al, Lancet, Aug 2005 [Listing with link to text]

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