The risk of developing at least three TMC125 resistance-associated mutations (RAMs) [7,8] was assessed by means of binary logistic regressions models. Univariate and multivariate analyses were performed to estimate crude and adjusted relative risks (odds ratios, 95% confidence intervals and Wald statistic) for gender, age, HIV RNA, CD4 cell count; and NVP, EFV, protease inhibitor (PI) and enfuvirtide (T20) exposure. Moreover, we considered the number of NNRTIs received and the duration

of NNRTI therapy. The level of statistical significance was set at P=0.05. spss 15 for Windows was the statistical software package used for the analyses (SPSS, Chicago, IL, USA). Moreover, we conducted our analysis with the endpoint of having a TBT WGS>2, which has been reported to predict poor virological response to TMC125 in treatment-experienced patients [16]. A total of 5011 sequences obtained from 2955 patients were evaluated. Of these, 1241 subjects (42.0%) were exposed

GSK2118436 chemical structure only to NVP, 1053 (35.6%) only to EFV, and 613 (20.7%) to both NVP and EFV. Of these 2955 patients, 2153 (72.9%) presented with at least one TMC125 RAM. Among the sequences in ARCA, 68% had at least one and 9.8% at least three TMC125 RAMs, whereas 31% showed a WGS>2. Among the samples with at least one RAM for TMC125 (n=3407), the mutations most frequently represented were Y181C (27%), G190A (22.8%), K101E (11.7%) and A98G (9.3%). K103N was present in 53.9% of sequences. V179F, Y181V and G190S were present in 0.3%, 1.0% Decitabine order and 4.9% of sequences, respectively. When at least three TMC125-related mutations were found (n=495), the mutations most frequently represented were G190A Cyclopamine nmr (62%), Y181C (57.6%) and K101E (44%). K103N was present in 44.8% of sequences. V179F, Y181V and G190S were present in 1.4%, 1.0% and 13.5% of sequences, respectively (Fig. 1). Among the samples with TBT WGS>2 (n=1553), the most frequent mutations were Y181C (59.3%), G190A (26.7%) and K101E (17.8%); K103N was found in 40.1% of sequences. We also analysed the association between TMC125 RAMs and exposure to NVP and EFV: these mutations appeared more frequently in NVP- than EFV-treated patients:

90.2% of sequences from patients exposed to NVP vs. 35.2% of sequences from patients exposed to EFV had mutation Y181C, and these percentages were, respectively, 84.7%vs. 43.1% for G190A, 72.7%vs. 49.8% for K101E, 100%vs. 23.5% for Y181V, and 66.7%vs. 33.3% for V179F. G190S appeared more frequently with exposure to EFV (81.4% of sequences) than NVP (43.3% of sequences). Multivariate analysis revealed that male gender and being EFV- or NVP-experienced were associated with statistically significant increases in the risk of developing three or more TMC125 RAMs. CD4 values ≥200 cells/μL and older age (for each additional 10 years) were statistically protective factors, whereas PI and T20 experience and HIV RNA values did not show any statistically significant associations.