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Worldwide Spread of H1N1 Multi-Drug Resistance - XDR
Recombinomics Commentary 17:17
October 2, 2010

Two recent publications describe pandemic H1N1 multi-drug (Tamiflu, Relenza, Peramivir) resistance (XDR).  One case (5M) was a patient in the Netherlands who had acute lymphoblastic leukemia (see New England Journal of Medicine report).  He was treated with Tamiflu (oseltamivir) and recovered, but the H1N1 sequence had H274Y (H275Y with N1 numbering).  When the patient relapsed he was treated with Relenza (zinamivir), but that treatment failed and the patient died.  H1N1 from the later collection (A/Netherlands/2631b/2009) had I222R (I223R in N1 numbering) and in vitro testing demonstrated resistance to Relenza (H274Y produces resistance to Tamiflu and Peramivir).  Similar results were seen in a teenager (14F) from Pennsylvania. She had lupus (see Clinical Infectious Disease letter) and was initially treated with Tamiflu, followed by treatment with Relenza, which also failed.  She also died and the NA sequence (A/Pennsylvania/30/2009) had H274Y and I222R.  In vitro testing also demonstrated resistance to Tamiflu, Relenza, and Peramivir.

Both of these fatal infections developed in late 2009.  A search of NA sequences at GISAID identified two additional sequences from patients in Japan (A/HIROSHIMA/490/2009) and Canada (A/Ontario/313762/2009).  These samples were also collected in late 2009 and the NA is likely to be Relenza resistant.

In addition, NA sequences from Chile (A/Santiago/21579/2009 and A/Chile/1579/2009) and Italy (A/Italy/181/2009) had I222K which are also likely to be Relenza resistant since the isoleucine at position 222 was replaced with another basic amino acid (lysine instead or arginine).  The two sequence from Chile were from a patient (44F) who was also treated with Tamiflu, but died three days after admission.  She was obese and had diabetes, but the characterization sheet associated with the sequence did not indicate that she was immunosupressed or treated with Relenza.

The sudden appearance of I222R and associated resistance to Relenza are causes for concern.  Relenza use increased in late 2009 because of the explosion of H1N1 cases in the northern hemisphere.  Reports of H274Y and associated resistance to Tamiflu and Peramivir and reports of I222R in four patients (and death in at least two) along with I222K in two additional patients and death in at least one, raise concerns that emerging pandemic H1N1 strains will be resistant to the three most widely used neuraminidase inhibitors.

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