tamiflu resistance update, page-3

More Tamiflu Resistant Pandemic H1N1 in Hong Kong
Recombinomics Commentary 17:07
August 14, 2009


Centre Controller Dr Thomas Tsang said today she started taking Tamiflu on July 15 after 21 people at the home fell ill the day before. She came down with a fever, cough and sore throat on July 21 and was sent to Eastern District Hospital. She was confirmed to be infected with swine flu and later recovered.

Laboratory tests available today showed her virus sample was resistant to Tamiflu - the only one among the 21 cases at the home.

The above description describes another patient who developed symptoms while of prophylactic Tamiflu. New reports of cases are now happening almost daily. The Hong Kong patient developed symptoms on day 6 of treatment, which is similar to cases in Denmark and Japan, who developed symptoms on day 5. These incubation periods are slightly longer than the typical 2-4 days, suggesting that the detected H274Y is not due to de novo synthesis, but represents and minor H1N1 population, which is below detection levels in untreated patients, as seen in sequences of contacts.

However, these frequent reports on detection of H274Y in patients of prophylactic Tamiflu, as well as reports of H274Y in patients who are not taking Tamiflu, like the first H274Y positive patient in Hong Kong, who arrived from San Francisco, raise concerns that H1N1 with H274Y is evolutionarily fit and circulating as a major or minor species. Thus, far there have been no reports of resistance at any position other than H274Y and no reports of resistance in patients being treated with Tamiflu. All cases have been on prophylactic or no Tamiflu.

The true extent of this spread is unclear. Although the forst Hong Kong patient did not take Tamiflu and arrived in Hong Kong on a direct flight from San Francisco, there have been no reports of resistance in California. Similarly, another American was identified in Singapore in May (the 3rd confirmed case in Singapore) and she developed symptoms in flight from Honolulu, again signaling H274Y in the United States, but no H274Y has been confirmed in the US.

However, last week there were reports of resistance in Texas, along the border with Mexico and although these reports were denied, the description of two patients said to resistant was quite specific suggesting that these were resistant cases where resistance had not been biologically confirmed. However, H1N1 isolates with H274Y are very resistant Tamiflu, requiring 300-1000 fold more Tamiflu to achieve the inhibitory levels for wild type H1N1.

Moreover, after H274Y was reported in Singapore and Hunan, China, which was clear from sequences made public last week, WHO conceded that there were additional cases, but refused to give locations or the number of such cases. Media reports of a least one confirmed case in Thailand, and this cases in Hong Kong may have been among the undisclosed cases, but the frequency of reports, with three new examples last week and another this week, suggest that H274Y is widespread and circulating in evolutionarily fir H1N1.

These data parallel results from seasonal flu, which involved H274Y jumping from one genetic background to another, but in the 2007/2008 it began hitchhiking with a dominant sub-clade that produced high frequencies of H274Y in northern Europe, which was followed by another sub-clade in the southern hemisphere, which had acquired HA A193T, which led to the fixing of H274Y in Brisbane/59 clade 2B, which is currently co-circulating with pandemic swine H1N1.

Disclosure of the additional instances of H274Y and associated sequences and use of Tamiflu in these patients prior to the collection of H274Y positive samples would be useful.