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Predictors of New Darunavir Resistance Mutations Upon Darunavir Failure
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11th European AIDS Conference
October 24-27, 2007
Madrid
Mark Mascolini
A higher viral load before starting a darunavir salvage regimen and fewer nucleosides in that regimen predicted emergence of darunavir-associated mutations in a 54-person study at three Paris clinics [1]. Pre-darunavir detection of L76V, a darunavir-specific mutation, lowered the risk of further darunavir mutations during virologic failure, perhaps because L76V alone engenders such high-level resistance to darunavir.
The study involved 48 men and 6 women starting a darunavir-based rescue regimen after trying multiple other protease inhibitors (PIs). Forty-five people (83%) had used indinavir, 44 (81%) saquinavir, 43 (80%) amprenavir, 38 (70%) lopinavir, and 20 (37%) tipranavir. Several people had also tried atazanavir, amprenavir, and/or nelfinavir. They began darunavir with a median viral load of 4.9 log copies, or about 79,500 copies/mL (range 2.8 to 6.0 log copies) and a median CD4 count of 87 (range 0 to 812).
Eight people took the investigational nonnucleoside etravirine (TMC125) with darunavir, but no one took nevirapine or efavirenz. One person took one nucleoside with the darunavir regimen, 9 took two, 28 took three, and 16 took four. The most frequently prescribed nucleosides were 3TC in 50 people, abacavir in 39, tenofovir in 35, and AZT in 26.
Through months 1 to 3 of darunavir salvage, the median load fell to 4.2 log or about 16,000 copies (range 1.5 to 5.9 log), but there was no further improvement during months 3 to 6 (median 4.4 log or about 25,000 copies, range 1.6 to 5.9). The median CD4 count climbed to 161 cells (range 2 to 943) during treatment months 1 to 3 but improved no further in months 3 to 6 (median 125, range 1 to 845).
When darunavir salvage began, the most frequent PI mutations were M46I/L, I84V (a darunavir mutation), L90M, L33F, V82A/F/T, and I54M/L (a darunavir mutation). Ten people had the darunavir-associated mutation L76V when they started salvage. Patients had a median of three darunavir mutations when they began darunavir, four major PI mutations, and 10 minor PI mutations. The most common new mutations upon darunavir failure were V32I in 44%, L33F in 25%, I54M/L in 24%, I84V in 21%, and L89V in 12%. All these mutations appear on the list of darunavir-linked mutations, while I54M/L and I84V rank as major darunavir mutations [2].
Multivariate analysis determined that every 10-fold (1-log) higher pre-darunavir viral load raised the risk of new darunavir mutations upon failure 5.59 times (P = 0.005). Each additional nucleoside in the salvage regimen lowered the risk of new darunavir mutations 74%. And L76V before starting darunavir lowered that risk almost 98%.
Variables that did not affect emergence of darunavir mutations were individual prior PIs or number of prior PIs, detection of pre-darunavir mutations other than L76V, pre-darunavir viral load or CD4 count, HIV-1 subtype, gender, darunavir minimum concentration, number of major pre-darunavir resistance mutations, number of pre-darunavir resistance mutations, use of etravirine, or use of enfuvirtide.
Analyzing the mutation profile after darunavir failure, Sidonie Lambert-Niclot and colleagues figured that emergence of new mutations did not further imperil prospects of responding to tipranavir. They suggested that the link between pre-darunavir L76V and low risk of further darunavir mutations implies that "selection of other mutations is not required for failure of darunavir-containing regimens" if L76V has already evolved.
References
1. Lambert-Niclot S, Flandre P, Canestri A, et al. Factors associated with the selection of protease inhibitor mutations in PI experienced patients failing to darunavir. 11th European AIDS Conference. October 24-27, 2007. Madrid. Abstract P3.5/01.
2. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: fall 2006. Topics HIV Med. 2006;14:125-130.
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