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Tibotec Refines List of Darunavir-Specific Mutations
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
Pooling data from the three POWER trials and the two DUET studies, Tibotec investigators fine-tuned their list of 11 mutations that make HIV resistant to the protease inhibitor darunavir [1]. As with the older (2006) list, three or more mutations from the new set dim chances of responding to a darunavir/ritonavir regimen.
The Tibotec team merged data from everyone taking 600/100 mg of darunavir/ritonavir twice daily in the POWER trials and from people taking darunavir/ritonavir without etravirine or enfuvirtide in the DUET trials. They used three touchstones to select critical darunavir mutations in these 1071 people:
· Protease mutations leading to a rising fold-change in darunavir 50% effective concentration
· Pretreatment protease mutations associated with a virologic response below 75% of the entire study group's response in that trial, excluding people taking enfuvirtide for the first time
· Protease mutations that evolved in 10% or more people with virologic rebound
Any mutation that met two of these three criteria got designated a darunavir mutation. The researchers defined virologic response as a viral load below 50 copies at week 24 in a time-to-loss-of-virologic-response analysis; they defined rebounders as people still in the trial at week 16 who had at least two consecutive 1-log (10-fold) drops in viral load from baseline and then either (1) two consecutive viral load readings less than 1-log below baseline or (2) discontinuation of darunavir with the last viral load less than 1-log below baseline. Tibotec investigators counted 188 rebounders (18% of 1071), 185 of whom had baseline and endpoint genotypes.
This protocol identified 11 protease mutations, only one of which changed from the 2006 list: The new list added T74P and tossed out G73S. The resulting catalog includes V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V and L89V. Next the Tibotec team compared the new list with the old list to see which predicted failure better in the combined POWER and DUET study groups. The newer list proved marginally more accurate. Week-24 sub-50-copy response rates dwindled with each added 2007 darunavir resistance mutation:
· Overall 24-week sub-50-copy response: 39%
· 24-week sub-50 response with 0 darunavir mutations: 72%
· 24-week sub-50 response with 1 darunavir mutation: 53%
· 24-week sub-50 response with 2 darunavir mutations: 37%
· 24-week sub-50 response with 3 darunavir mutations: 29%
· 24-week sub-50 response with 4 or more darunavir mutations: 7%
The median fold-change in susceptibility to darunavir exceeded 10 in people with 3 or more of the 2007 list of darunavir mutations.
Whenever virus harbored 1 of the 11 new darunavir mutations, it also carried 13 to 15 other protease mutations from the 2006 IAS-USA inventory [2]. Having three or more mutations from the new list predicted a blunted response to darunavir/ritonavir in people not taking enfuvirtide.
References
1. De Meyer S, Dierynck I, Lathouwers E, et al. Identification of mutations predictive of a diminished response to darunavir/ritonavir: Analysis of data from treatment-experienced patients in POWER 1, 2, 3 and DUET-1 and 2. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 54.
2. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2006. Topics HIV Med. 2006;14:125-130.
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