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Etravirine limits the emergence of darunavir and other protease inhibitor resistance-associated mutations in the DUET trials
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AIDS:
27 March 2010 - Volume 24 - Issue 6 - p 921-924
doi: 10.1097/QAD.0b013e328336ac2a
Research Letters
Peeters, Monika; Vingerhoets, Johan; Tambuyzer, Lotke; Azijn, Hilde; Hill, Andrew; De Meyer, Sandra; Picchio, Gaston
aTibotec BVBA, Mechelen, Belgium
bUniversity of Liverpool, Liverpool, UK
cTibotec Inc, Yardley, Pennsylvania, USA.
Abstract
Etravirine is a recently approved nonnucleoside reverse transcriptase inhibitor. The ability of etravirine to limit the emergence of resistance to protease inhibitors, and specifically to darunavir, was investigated in the subset of treatment-experienced patients with virologic rebound in the phase III DUET trials. Of those experiencing rebound, fewer etravirine-treated than placebo-treated patients developed mutations associated with resistance to protease inhibitors in general and to darunavir in particular, and more patients in the etravirine than the placebo-group maintained baseline darunavir susceptibility at endpoint.
The potential for new agents to limit the development of resistance to other antiretrovirals is important in maintaining patients' future treatment options, particularly for treatment-experienced patients with antiretroviral resistance who need an active regimen to effectively suppress viral replication [1-3].
The recently approved nonnucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC125) has demonstrated superior antiviral efficacy and comparable safety versus placebo in treatment-experienced patients in the phase III DUET trials [4]. HIV-1-infected, NNRTI-resistant patients with at least three IAS-USA primary protease inhibitor resistance-associated mutations (RAMs) and viral load more than 5000 copies/ml were randomized to receive etravirine 200 mg (n = 599) or placebo (n = 604), each twice-daily with a background regimen of darunavir/ritonavir, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and optional enfuvirtide. After 48 weeks, 61% of patients in the etravirine group reached a viral load of less than 50 copies/ml, versus 40% in the placebo group (P < 0.0001) [4] and, at 96 weeks, 57% of patients in the etravirine group had a viral load of less than 50 copies/ml, versus 36% in the placebo group (P < 0.0001) [5].
The objective of the current analysis was to assess whether treatment with etravirine could limit the emergence of protease inhibitor RAMs, and specifically darunavir RAMs (since darunavir was the only protease inhibitor that patients were permitted to receive [4]), in patients with virologic rebound in the DUET trials.
On the basis of the subset of 1081 patients who were included in the DUET week 48 analysis and did not discontinue for reasons other than virologic failure (n = 540 in the etravirine group, n = 541 in the placebo group), resistance to protease inhibitors in general and to darunavir in particular was examined in patients experiencing virologic rebound (demonstrating a confirmed virologic response of a viral load less than 50 copies/ml at earlier time points but subsequently rebounding to viral load more than 50 copies/ml on at least two consecutive time points). Emerging mutations were defined as those present at endpoint (the last available time point during the treatment period), but not at baseline. Phenotyping and genotyping were performed with the Antivirogram and vircoTYPE HIV-1 assays (Virco BVBA, Mechelen, Belgium), respectively, if the viral load was at least 1000 copies/ml. Darunavir RAMs were defined as V11I, V32I, L33F, I47 V, I50 V, I54L, I54 M, T74P, L76 V, I84 V and L89 V [6]; primary protease inhibitor RAMs were classified according to the 2007 IAS-USA list [7]. Statistical significance between treatment groups was determined using the chi-square test; Fisher's exact test was used for the comparison of the proportions of patients-maintaining darunavir susceptibility [fold-change in 50% effective concentration (FC) ≤10]. The emergence of NNRTI and NRTI resistance in patients with virologic failure by rebound will be reported in detail elsewhere.
Virologic rebound occurred in 57 of 540 patients (11%) in the etravirine group and 119 of 541 patients (22%) in the placebo group (P < 0.0001). Patients experiencing rebound in the etravirine group had previously used a median of 13 antiretrovirals compared with 12 for rebounders in the placebo group and nonrebounders in both treatment groups. The rebounders in the etravirine group had previously used a median of two NNRTIs and five protease inhibitors, versus one NNRTI and five protease inhibitors for rebounders in the placebo group and nonrebounders in both groups. The proportions of rebounders who received no active agents in their background regimen (based on phenotypic sensitivity score) were 30% in the etravirine group and 17% in the placebo group, compared with 15% of nonrebounders in both groups.
Among the rebounders, the baseline median number of darunavir RAMs was three in the etravirine group and two in the placebo group, versus two in the nonrebounders in both treatment groups. The baseline median number of primary protease inhibitor RAMs was five in the etravirine group and four in the placebo group in patients experiencing rebound, versus four in the nonrebounders in both groups. Baseline median etravirine FC was 3.9 for rebounders in the etravirine group versus 1.8 for rebounders in the placebo group and 1.6 and 1.3, respectively, for nonrebounders. Rebounders in the etravirine group had a baseline median darunavir FC of 21.7, versus 7.6 for rebounders in the placebo group and 6.2 for nonrebounders in both groups; 30% of etravirine-treated rebounders were susceptible to darunavir at baseline (FC ≤ 10), versus 62% of placebo-treated rebounders and 66-68% of nonrebounders.
Lower proportions of rebounders in the etravirine than the placebo group developed additional darunavir RAMs (regardless of baseline darunavir FC; Fig. 1a) or primary protease inhibitor RAMs (65% versus 92%, respectively; P < 0.0001). In the analyzed population of 1081 patients (rebounders plus nonrebounders) the proportion of patients developing at least one additional darunavir RAM was 12% (64 of 540 patients) in the etravirine group and 38% (207/541 patients) in the placebo group.
Among the rebounders in both treatment groups, the median numbers of emerging darunavir RAMs and primary protease inhibitor RAMs were one and two, respectively. The most frequently emerging darunavir and primary protease inhibitor RAMs were V32I (in 32% of rebounders in the etravirine group versus 60% in the placebo group) and I54L (in 16% versus 34% of rebounders, respectively; Fig. 1b).
Darunavir susceptibility (FC ≤ 10) was maintained from baseline to endpoint by a higher proportion of rebounders in the etravirine group than the placebo group (47% versus 7%, P = 0.0003). Relative to baseline, the mean increase in darunavir FC at rebound was 2.8-fold in the etravirine group and 10.1-fold in the placebo group (P < 0.0001). In patients with baseline darunavir FC 10 or less, mean increases in darunavir FC at rebound were 4.0-fold and 15.6-fold in the etravirine and placebo groups, respectively; in patients with baseline darunavir FC greater than 10, increases were 2.3-fold and 5.0-fold, respectively.
This subanalysis of data from the DUET trials demonstrates that in treatment-experienced patients with existing protease inhibitor resistance, adding etravirine to a darunavir/ritonavir-containing regimen not only resulted in a lower incidence of virologic rebound compared with adding placebo to the same regimen, but also limited the development of resistance to protease inhibitors, and specifically to darunavir, in patients with virologic rebound. Fewer etravirine-treated patients developed darunavir and primary protease inhibitor RAMs compared with placebo-treated patients. In addition, more patients in the etravirine than the placebo group maintained susceptibility to darunavir and smaller increases in darunavir FC were observed with etravirine than placebo.
The ability of antiretrovirals to limit the development of resistance to other agents has been observed in other studies, particularly with protease inhibitors. Treatment with protease inhibitor/NRTI-based regimens has been found to limit the development of NRTI resistance more effectively than treatment with NRTIs alone in patients with first-line virologic failure [8,9]. Darunavir has also been shown to be more effective at protecting the background regimen than lopinavir by limiting the emergence of protease inhibitor and NRTI mutations following virologic failure in treatment-experienced patients [10]. However, our results represent the first time this effect has been observed with an NNRTI, indicating that etravirine may play an important role in preserving future therapy options for treatment-experienced patients.
The main limitations of this post-hoc analysis are that the trials were not powered to show a difference between subgroups of rebounders and nonrebounders and that the sizes of these subgroups (particularly the etravirine-treated rebounders) were small relative to the overall trial population. Nevertheless, although in this trial darunavir was the only protease inhibitor combined with etravirine, the findings of this analysis suggest there may be value in future evaluation of the potential for etravirine to limit the development of resistance to protease inhibitors other than darunavir in treatment-experienced patients.
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