Background:  TMC114 with low-dose ritonavir (TMC114/r) showed significant efficacy benefits over investigator-selected control protease inhibitors (CPI) in the POWER 1 (TMC114-C213) and 2 (TMC114-C202) trials. This sub-analysis examines pooled baseline and on-treatment resistance data from both trials.

Methods:  Patients with non-nucleoside reverse transcriptase inhibitors (NNRTI), NRTI, and PI experience, at least 1 primary PI mutation and HIV RNA >1000 copies/mL were randomized to receive an optimized NRTI background regimen, with or without enfuvirtide (EFV), and either TMC114/r or a CPI of choice. Pheno/genotypes of plasma viruses and site-directed mutants were determined by Virco. At week 24, efficacy was analyzed by baseline genotype and sensitivity to the CPI using phenotypic cut-offs of 10 for lopinavir/ritonavir (LPV/r), 2.5 for saquinavir (SQV), 2.5 for aprenavir (APV), and 2.4 for atazanavir (ATV); HIV RNA data were analyzed by the intent-to-treat non-completer = failure method.

Results:  Mean baseline HIV RNA was 4.6 log₁₀ copies/mL, with median 8 PI-resistance-associated mutations. Week-24 HIV RNA data are shown in the table. Multivariate analysis showed that HIV RNA log₁₀ reduction for TMC114/r was significantly greater than for either a sensitive or resistant CPI (p <0.0001). Mutations were identified as being associated with decreased susceptibility to TMC114 by a stepwise regression model performed on 1405 screening samples from various trials in highly experienced patients. Among those mutations, the presence of V32I, I47V, or I54M at baseline, was associated with a lower mean decrease in viral load at week 24 (<1 log₁₀ but >0.5 log₁₀) but still higher than control. Presence of V32I, I47V, or I54M at baseline was associated with a higher number of PI-resistance-associated mutations compared with isolates without those mutations. Site-directed mutants with these mutations in different combinations did not show a TMC114 fold change >4. Analysis of patients receiving TMC114/r who responded and then lost their antiviral response showed development of mutations V32I, L33F, I47V, or I54L.

Conclusions:  TMC114/r 600/100 mg twice daily showed significant efficacy benefits over CPI, independent of baseline CPI susceptibility. In a background of a substantial number of PI-resistance mutations, particular additional mutations may be associated with reduced TMC114 susceptibility.