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New Report of Oseltamivir Resistance in Vietnam

By Eric Toner, December 22, 2005

In an article published today in The New England Journal of Medicine (N Engl J Med 2005;353:2667-72) de Jong and colleagues from the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam report on 8 patients treated with oseltamivir for H5N1 influenza. While 4 of the 8 patients died, only one had received oseltamivir within the first 2 days of illness. The other 7 had been sick for an average of 6 days before starting treatment.

All 8 of the patients received the standard therapeutic doses of 75 mg bid. Viral load decreased immediately in all but the 2 patients who presented in respiratory failure. Each of the 4 survivors had declines in viral load to undetectable levels, whereas the 4 who died did not. Two of the 4 patients who died were clearly in the late stage of disease on presentation. It appears that drug resistant strains of the virus evolved during treatment of the other 2, which resulted in therapeutic failure and ultimately death.

One of the patients with resistant virus was a 13 year old girl who presented on the second day of illness. While no viral specimen was obtained prior to treatment, her mother died the day before of infection with an H5N1 virus known to be sensitive to oseltamivir. The child was immediately treated with oseltamivir and was continued on standard doses. She did well clinically for 3 days. On day 4, her condition took a turn for the worse, which was associated with a rising viral load. She died on day 8. Viral specimens obtained on day 4 and day 8 revealed a tyrosine for histidine substitution at amino acid position 274 (H274Y) in the N1 neuraminidase, which is known to confer high level resistance to oseltamivir.

The other patient with resistant virus was an 18 year old girl who presented on the 6th day of illness. A throat swab obtained two days after the initiation of oseltamivir, when her viral load was decreasing, revealed wild type, oseltamivir sensitive H5N1. On day 4, she required endotracheal intubation coincident with a rise in viral load. A subsequent specimen revealed the H274Y mutation.

This is the first report of deaths among patients who developed oseltamivir resistant virus while receiving the standard twice-per-day regimen. A previous report from Vietnam (Nature 2005;437: 1108) of partial oseltamivir resistance in a patient receiving a prophylactic dose of oseltamivir (75 mg qd) indicated that the patient survived once the dose was increased.

This new report underscores several key points:

  • Oseltamivir therapy may be beneficial in the setting of ongoing viral replication since it may reduce viral loads even when started well past the usual 48 hour therapeutic window.

  • Clinical outcome of H5N1 infection appears to be associated with viral load.

  • Clinically significant oseltamivir resistance in H5N1 infection may occur frequently at the currently recommended standard dose of 75 mg bid. As pointed out by the authors, higher doses of oseltamivir may be a reasonable approach to combat this problem and deserves further evaluation. Multi-drug regimens also need to be investigated.