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Classic Nonnucleoside Mutations Emerge Upon Etravirine Failure
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
Two hallmark nonnucleoside mutations and two etravirine-specific mutations arose upon failure of an etravirine/darunavir regimen in the DUET trials [1]. But patients with two of these mutations before starting etravirine (TMC125) did not run a higher risk of failure than people without these mutations at study entry.
DUET-1 and DUET-2 enrolled people taking a failing regimen with evidence of resistance to the nonnucleosides nevirapine and efavirenz and to PIs [2,3]. Everyone in the study took darunavir/ritonavir and other antiretrovirals with etravirine or placebo. A combined 48-week intent-to-treat analysis of 1203 people found that 61% taking etravirine versus 40% taking placebo had a viral load below 50 copies (P < 0.0001). The new analysis focused on people with virologic failure by 48 weeks, defined as at least a half-log viral load rebound from the lowest viral load achieved after at least a 1-log (10-fold) drop.
At week 48 the investigators counted almost twice as many failures with placebo as with etravirine. Of 599 people taking etravirine, 91 (15%) had a virologic failure. Among 75 people with etravirine failure and genotypic and phenotypic resistance data, the analysis found trends to higher median etravirine and darunavir fold-change in 50% effective concentration at study entry (3.3-fold versus 1.6-fold for etravirine failure versus nonfailure; 14.0-fold versus 5.3-fold for darunavir), more darunavir-associated mutations (3 versus 2), more primary protease inhibitor mutations (5 versus 4), and more nonnucleoside mutations (3 versus 2). Both people in whom etravirine failed and those in whom it did not had a median of 1 etravirine mutation when the study began (range 0 to 5).
Mutations conferring resistance to both etravirine and darunavir arose in 73% of patients in whom etravirine failed. Four nonnucleoside mutations emerged in at least 10% of people with virologic failure of an etravirine regimen: V108I in 11%, V179I in 17%, V179F in 17%, and Y181C in 12%. Researchers had already identified V179F and Y181C as etravirine-associated mutations. The IAS-USA rates V108I and Y181C as mutations that make HIV resistant to nevirapine and efavirenz [4]. In site-directed mutagenesis studies, these four mutations resulted in the following fold changes in susceptibility to etravirine:
· V108I: 0.5-fold
· V179F: 0.1-fold, but 187-fold with Y181C
· V179I: 0.8-fold, but 9.1-fold with Y181C
· Y181C: 3.9-fold
V108I always arose with other emergent or pretreatment nonnucleoside mutations, including mutations at positions 179 and 181. V179F evolved during failure only along with Y181C. V179I also arose in 6% of people with virologic failure in the placebo group, none of whom was taking a nonnucleoside. Although V108I and V179I emerged during etravirine failure, if a person already had one of those mutations when they started etravirine, V108I and V179I did not appear to affect virologic response.
Defining the study endpoint as the last visit during etravirine treatment with both genotypic and phenotypic testing, the investigators tracked a jump in median number of etravirine mutations from 1 to 2 and a surge in fold-change in susceptibility from 3.3-fold to 34.2-fold. Median number of darunavir mutations climbed from 3 to 4, and median fold-change in susceptibility to darunavir rose from 14.0-fold to 70.6-fold.
References
1. Tambuyzer L, Vingerhoets J, Azijn H, et al. Emerging mutations in patients with virological failure on TMC125 in the DUET-1 and DUET-2 clinical trials. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 47.
2. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.
3. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.
4. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2007. Topics HIV Med. 2007;15:119-125.
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