Background:  TMC125 is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), designed to have a high genetic barrier to the development of resistance and activity against existing NNRTI mutations. In study TMC125-C223, TMC125 showed substantial and sustained efficacy at 24 weeks. This analysis investigated baseline resistance parameters that influenced virologic response.

Methods:  TMC125-C223 is a randomized dose-finding study of TMC125 in heavily pretreated patients with documented NNRTI resistance and ³3 primary protease inhibitor (PI) mutations at baseline. Patients were randomized to receive 1 of 2 different doses of TMC125 with an investigator-selected optimized background regimen or a standard-of-care control regimen. Intent-to-treat analyses of the TMC125 800 mg twice daily group are presented, as a new formulation with comparable exposure has been selected for further clinical development.

Results:  All 79 patients included in this analysis had prior PI exposure (median = 4 PI); 94% had used NNRTI and 30% enfuvirtide. At baseline patients had a median of 4 primary PI and 2 NNRTI mutations; 19% of patients had no NNRTI mutation at baseline but had NNRTI mutations documented in historical genotypes, and 40% of these patients were on a treatment interruption at screening. The median baseline fold change in EC₅₀ (FC) for EFV, nevirapine (NVP), and TMC125 was 41, 61, and 1.7, respectively. Mutations associated with an increased baseline FC for TMC125 were uncommon (prevalence 0.6 to 2.9%).At baseline 83% of the patients showed no phenotypic susceptibility to any PI. Virologic response associated with different baseline factors is shown below.

                  *mean change in viral load at week 24 (log₁₀ copies/mL)

Conclusions:  In this study of patients with extensive NNRTI and PI resistance, a viral load reduction of ≥1 log was observed at 24 weeks in patients using TMC125 with £2 NNRTI mutations. Patients with ³3 mutations achieved a mean 0.66 log reduction, which while lower than the overall response to TMC125 (–1.18), was substantially higher than in the active control group (–0.19). This analysis shows that TMC125 retains activity in the presence of multiple NNRTI mutations where current NNRTI are not expected to be effective.