PREVALENCE OF ETRAVIRINE (ETR)-RESISTANCE ASSOCIATED MUTATIONS AT NNRTI FAILURE AND PREDICTORS OF RESISTANCE TO ETR IN A LARGE ITALIAN RESISTANCE DATABASE (ARCA)

Background: Etravirine (TMC125, ETR) is the newest nonnucleoside reverse transcriptase inhibitor (NNRTI) designed to be active against both wild-type and NNRTI-resistant HIV. Three algorithms have been developed to interpret ETR resistance: Monogram (MGR), Tibotec (TBT), and enhanced MGR (ENH). We investigated the prevalence of drug resistance mutations associated to NNRTI-based regimens failure and the predictors of resistance to ETR among subjects included in a large Italian resistance database. Material and methods: From the Italian database ARCA ( http://www.hivarca.net), we selected 5,547 sequences from 3,047 subjects up to 29 December 2010. Among these individuals, 39 had\18 (P) years and 2,815 were C18 (A) years-old. These subjects failed their current NNRTI treatment, were three-class experienced and had been exposed toNNRTIC3 months. Complete treatment history,HIV-1 RNA [1,000 cp/mL at failure, CD4 counts within 30 days before the genotypic resistance test were available. Binomial logistic regression analysis was carried out and odds ratio (AORorOR[CI 95%])were expressed.All data were adjusted for CD4 counts and HIV-1 RNA levels. Results: 1,827 A subjects (64.9%) and 32 P subjects (82.1%) harboured virus with at least one ETR mutation included in at least one score. Among the A subjects with at least one ETR mutation, mutations more frequently detected were Y181C (18.5%), G190A (15.1%), and V179I (11.2%). Among P subjects, V179I, Y181C, and G190A were present in 30.8, 28.2 and 23.1%, respectively. Univariate analysis revealed an increased risk in the pediatric population (vs. adult population) for exceeding cut-off values of ETR resistance with all three algorithms: MGR[3 OR 2.10 (1.11-3.94) p = .022, TBT[2 OR 2.56 (1.36-4.82) p = .004, and ENH C4 OR 2.44 (1.28-4.64) p = .007. Multivariate analysis revealed an increased risk of developing TBT[2 for NNRTI exposure, ENH C4 for NNRTI and EFV exposure in P subjects; NVP exposure and higher (C3.5 log10) HIV-RNA values for all three algorithms in A subjects, whereas CD4 C200/lL appeared to be protective. Conclusions: The DUET studies showed that C3 ETR-associated mutations were required to impair the efficacy of the drug and Y181C/V, V179F and G190S had the most pronounced effect on response. The prevalence of Y181C mutation was higher in P versus A subjects (28.2 vs. 18.5%) together with G190A and V179I. The risk to be ETR resistant, according to all algorithms, was more than double for P versus A subjects, probably due to a more extensive use of NNRTI and an incomplete virological control. Determinants of genotypic resistance to ETR were higher HIV-1 RNA values and greater NVP exposure in A subjects; a detrimental effect of NNRTI and EFV exposure was shown in P subjects. Higher levels of immune competence were protective for future development of ETR genotypic resistance.