Dominance of H5N1 Tamiflu Resistance in Egypt
Recombinomics Commentary 21:58
January 3, 2008
The WHO has said some of those who died having contracted the H5N1 virus strain showed moderate resistance to Tamiflu, the antiviral drug.
The above comments on moderate resistance to Tamiflu in some of the fatal cases are cause for concern. Since there are only four confirmed fatalities, at least half are Tamiflu resistant. The “moderate” resistance is almost certainly due to N294S, the genetic change found in the Gharbiya cluster a year ago. N294S was present in samples collected prior to treatment, indicating it was circulating in Egypt.
WHO and the Eastern Mediterranean branch of WHO, have issued situation updates on all five confirmed cases. The updates from the Mediterranean branch were most detailed, with dates for the start of Tamiflu treatment for four of the five cases. The date of sample collection matched the start date for Tamiflu, indicating the resistance found in the H5N1 sequences was present prior to treatment. This conclusion is further supported by the dates of death, which were shortly after the treatment date, limiting the time for resistance to develop.
Thus, like the cases from last year, the sequence data indicates N294S is circulating in Egypt. However, unlike last year, when reported N294S was limited to a single cluster, it appears to be present in multiple patients. The exact number is unclear. Tamiflu resistance is not mentioned in any of the updates on the five patients.
Last season WHO issued a comprehensive report that was somewhat delayed because samples were sent for biological confirmation of the sequence data. The biological results matched data generated with H5N1 from Asia that also had N294S. The resistance was in the range of 15-20 fold, which was markedly less than H294Y, but high enough to raise serious treatment concerns. N294S has been seen previously in H5N1 in ducks from China, but it was only detected in one case in Vietnam.
In contrast, N294S was in a cluster in Gharbiya last season, and now is in “some” of the recent four fatal cases. Since WHO has acknowledged that the resistance is “moderate”, the number of confirmed cases with N294S should be delineated in an update, and sequences should be released.
The five confirmed cases were widely dispersed in Egypt, and only two of the five came from the same governorate, Menoufia, which also has the largest number of hospitalized suspect cases (see satellite map). All four fatal cases were from seperate governorates.
Recently, Egypt announced a Tamiflu dispersal plan in Gharbiya and possibly additional governorates in the Nile Delta. The frequency of H5N1 in patients in Egypt is not well understood. Although Egypt has the highest number of confirmed H5N1 outside of Asia, the number of suspect cases is markedly higher than confirmed cases. False negatives are always a possibility, but the failure to get sequence data from the third Gharbya cluster member, and 9 of the 10 H5N1 infected patients in Pakistan tested negative on confirmatory testing. These data indicate that false negatives are easily generated, so the number of human H5N1 cases may be markedly higher than the number of confirmed cases.
Tamiflu is used liberally in Egypt, which raises the possibility of selection of N294S. Selection may explain why multiple patients with N294S were found in a small number of confirmed fatal cases, raising concerns that N294S is becoming dominant in Egypt.
Last season N294S was not reported in any of the poultry isolates and was limited to the one cluster. The comments above suggest that N294S is widespread in Egypt, and cause for concern.
Release of human and poultry sequences would be useful. N294S is well defined, both with regard to biological resistance and coding, as seen in sequences from last season in (A/Egypt/14724-NAMRU3/2006 and A/Egypt/14725-NAMRU3/2006).
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