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Fatal H5N1Tamiflu-Resistant Infections in Vietnam

Recombinomics Commentary

December 21, 2005

Although sequencing traces also revealed the presence of a minor wild-type 274H population in viral RNA from the swab, only 274Y variants were observed in the isolate, possibly reflecting overgrowth of the predominant mutant population during culture.

…..influenza A (H5N1) virus was isolated only from the last specimen from Patient 4, obtained three days after the completion of treatment (Figure 3). Sequence analysis of this isolate revealed the H274Y substitution in N1. Although sequencing traces of the isolate revealed only mutant 274Y variants, direct sequencing of viral RNA from the same swab revealed evidence of a minor subpopulation of wild-type 274H viruses similar to that in specimens from Patient 1. Patient 4 died of respiratory failure six days after the isolation of resistant virus.

The above comments from the New England Journal of Medicine report indicate that oseltamivir (Tamiflu) resistance developed in two patients with fatal H5N1 infections.  The resistant H5N1 became the dominant species, in contrast to a report on another patient who was started on a prophylactic dose of Tamiflu, but received after treatment levels were increased.

The latest data on patients extends prior in vitro and in vivo experiments which suggested that the FDA proved treatment and prophylactic doses of Tamiflu may be sub-optimal in the treatment of H5N1 infections.

Experiments with H3N2 suggested that Tamiflu resistant flu may not be as fit as wild type.  However, the latest data suggests that Tamiflu resistant H5N1 is quite fit.  In the patient it became the dominant species, but even when the virus was grown in culture in the absence of Tamiflu it maintained its dominance over wild type.

In addition, the resistant mutant from patient 1 may have been transmitted human-to-human since the patients mother died of H5N1 juts as the patient was developing symptoms.  Consequently, the patient was treated with a full treatment dose shortly after symptoms developed, but still died with resistant H5N1 circulating.

The two patients above bring the total reported cases of H274Y to three, suggesting resistance develops in H5N1 fairly easily.  The above 3 cases were from Vietnam, where isolates are resistant to amantadines.

However, all human cases of H5N1 in Indonesia and China are sensitive to amantadines ands the first reported case in mainland China survived after antiviral treatment with amantadine alone.

The latest data on Tamiflu suggests combination therapy with amantadines and neuraminidase inhibitors such as Tamiflu or Relenza may be appropriate in cases that do not involve isolates that are resistant to the two classes of antivirals.


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