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Prevalence of Darunavir-Linked Mutations Stays Low After Licensing
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
Rates of darunavir-associated resistance mutations did not change substantially after the protease inhibitor (PI) got approved in the United States in June 2006--at least not in people who had other PI mutations [1]. In the 18 months after darunavir's US approval date, three quarters of PI-resistant viral samples submitted to Virco had no darunavir resistance mutations and 6% had three or more, a predictor of poor virologic response to darunavir/ritonavir in the POWER trials.
From June 2006 to December 2007, darunavir's maker estimates that 30,000 people started the PI in the US and Europe, where darunavir got licensed in February 2007. To see if rates of darunavir mutations and viral susceptibility (fold-change in 50% inhibitory concentration or IC50) rose after darunavir entered the clinic, Tibotec and Virco researchers analyzed 98,326 routine clinical samples submitted to Virco from November 2004 to November 2007, including 50,727 sent after May 2006. All samples had genotypic or phenotypic evidence of resistance to other PIs. The latest list of darunavir-specific mutations includes V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, and L89V.
Working from the FDA PI mutation list (any change at protease sites 30, 32, 36, 46, 47, 48, 50, 53, 54, 73, 82, 84, 88, or 90), the researchers found that overall PI mutation prevalence varied hardly at all from before May 2006 (47.9%) to after that cutoff (46.5%). Defining resistance as a predicted IC50 fold-change below the VircoTYPE lower clinical cutoff (the point at which virus begins to lose susceptibility to a drug), the investigators measured pre- and post-May 2006 PI resistance rates of 37.8% and 35.5%.
Among viral isolates with one or more FDA-defined PI mutations, proportions of isolates with 0, 1, 2, or 3 or more darunavir-linked mutations also stayed flat in the 18 months before and after May 2006:
· 0 darunavir mutations: 73.2% versus 74.6%
· 1 darunavir mutation: 13.3% versus 11.9%
· 2 darunavir mutations: 7.2% versus 7.0%
· 3 or more darunavir mutations: 6.3% versus 6.5%
Results were similar when the Tibotec and Virco researchers looked at samples with evidence of PI resistance according to the VircoTYPE lower clinical cutoff.
Prevalence of 11 darunavir-specific mutations in the 18 months before and after May 2006 stood at 3.0% and 2.7% for V11I, 5.1% and 5.4% for V32I, 11.7% and 11.6% for L33F, 4.2% and 4.4% for I47V, 1.5% and 1.5% for I50V, 3.3% and 3.4% for I54L, 2.5% and 2.5% for I54M, 1.6% and 1.8% for T74P (which replaced G73S in an older darunavir list), 2.2% and 2.2% for L76V, 12.6% and 11.8% for I84V, and 3.1% and 3.0% for L89V.
The most prevalent double darunavir mutation among people with at least one FDA PI mutation, L33F plus I84V, appeared in 21.6% of samples before May 2006 and in 20.5% of later samples. The most common triple darunavir mutation before the cutoff date (L33F plus I54L plus I84V) turned up in 8.5% of samples before that date and in 8.1% of later samples. The second most prevalent triple darunavir mutation before darunavir approval (L33F plus T74P plus I84V) appeared in 7.9% of samples before May 2006 and 9.3% of later samples.
Reference
1. Lathouwers E, De Meyer S, Dierynck I, et al. Update on the prevalence of 2007 darunavir resistance-associated mutations in samples received for routine clinical resistance testing. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 68.
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