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Low Rates of Darunavir Mutations After Failure of Other PIs
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5th European HIV Drug Resistance Workshop
Cascais, Portugal
March 29, 2007
Mark Mascolini
Almost two thirds of 92,000 HIV isolates resistant to protease inhibitors (PIs) did not harbor a single darunavir-related resistance mutation in a Virco database analysis [1]. A smaller study from Carlos III Hospital in Madrid confirmed low rates of darunavir mutations in virus isolated from people in whom other PIs had failed [2]. In the Virco study fewer than 7% of isolates had 3 or more darunavir mutations, even though the isolates came from people in whom other PIs failed.
Virco researchers analyzed almost 208,000 isolates submitted for resistance testing between July 1998 and June 2006. Defining reduced individual PI susceptibility as a fold change in 50% inhibitory concentration above Virco's lower clinical cutoff for that PI, the Virco team determined that 91,932 isolates (44%) were resistant to one or more PIs other than darunavir. The phase 3 POWER trials of darunavir defined 5 major darunavir-related mutations: (I50V, I54L/M, L76V, and I84V) and 6 minor mutations (V11I, V32I, L33F, I47V, G73S, and L89V). People with 0, 1, or 2 of these mutations had the best chance of responding to 600/100 mg of darunavir/ritonavir twice daily in POWER.
Only 4 of 11 darunavir mutations turned up in 5% or more of the PI failure samples analyzed--I84V in 17.8%, G73S in 11.1%, L33F in 11.2%, and V32I in 5.4%. Almost two thirds of the isolates analyzed, 62.4%, had no darunavir mutations despite evidence of resistance to other PIs. Only 6.7% of viral samples contained 3 or more darunavir mutations, 9.9% harbored 2 darunavir mutations, and 21% had 1 darunavir mutation.
The most frequent double darunavir mutations were G73S + I84V in 2.6% of samples and L33F + I84V in 1.5%. Three triple mutations appeared in 0.4% of isolates: L33F + G73S + I84V, L33F + I54 + I84V, and V11L + G73S + I84V . The most frequent major PI mutations not on the darunavir list were L90M in 46.2% of isolates, V82A in 23.2%, and M46I in 22.3%.
Eva Poveda and Carlos III Hospital colleagues also tabulated low rates of major darunavir resistance mutations in 1021 viral samples collected from people in whom another PI had failed [2]. The most common failed PIs in this 1999-2006 survey were lopinavir/ritonavir in 38.6%, nelfinavir in 27.4%, saquinavir/ritonavir in 17.1%, indinavir/ritonavir in 16%, atazanavir/ritonavir in 9.5%, fosamprenavir/ritonavir in 1.8%, and tipranavir/ritonavir in 1.3%. The Carlos III cohort included 14.1% in whom a double PI failed.
As in the Virco analysis, I84V proved the most common major darunavir mutation after another PI failed, occurring in 14.5% of samples, followed by L76V in 2.6%, I50V in 2%, and I54M in 1.2%. The most frequent minor darunavir mutations were G73S in 12.9%, L33F in 11%, and V32I in 4%. Certain darunavir mutations appeared significantly more often after failure of tipranavir/ritonavir (V32I, L33F, I47V, G73S, and I84V), fosamprenavir/ritonavir (L33F, I54L, and I84V), atazanavir/ritonavir (I54M, G73S, and I84V), lopinavir/ritonavir (V32I, L33F, I47V and L76V), and saquinavir/ritonavir (I84V).
In this cohort total PI mutations in the IAS-USA list correlated with the number of darunavir-linked mutations: 4 IAS-USA mutations correlated with 0 to 1 darunavir mutations, 10 IAS-USA mutations with 2 darunavir mutations, and 12 IAS-USA mutations with 3 or more darunavir mutations. Both number IAS-USA mutations and number of PIs taken independently predicted detection of darunavir-related mutations (P < 0.001).
Earlier failure of tipranavir/ritonavir or fosamprenavir/ritonavir, compared with other PIs, correlated with a higher number of darunavir mutations--2 versus 0 for tipranavir/ritonavir (P < 0.001) and 2 versus 0 for fosamprenavir/ritonavir (P < 0.001). Risk of cross-resistance to darunavir was lower after failure of atazanavir/ritonavir, indinavir/ritonavir, nelfinavir, lopinavir/ritonavir, or saquinavir/ritonavir in this population.
References
1. Rinehart A, Picchio G, de Bethune M, et al. Prevalence of Darunavir resistance associated mutations in samples received for routine clinical resistance testing. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 44.
2. Poveda E, de Mendoza C, Corrall A, et al. Prediction of the impact of protease resistance mutations on response to darunavir/ritonavir in patients who have failed other protease inhibitors. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 45.
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