Background:  In patients with 3-class HIV resistance, combinations of investigational ART may represent the only therapeutic option. TMC114 and TMC125 are potent investigational ART with activity in naïve and experienced patients. However, the drug interaction between these agents has not been characterized in HIV-patients.

Methods:  Multi-class experienced HIV-patients with documented 3 class resistance were enrolled into a study to investigate the pharmacokinetics, safety, and efficacy of TMC114/r 600/100 mg twice daily and TMC125 200 mg twice daily (new formulation) plus nucleoside reverse transcriptase inhibitors (NRTI) with or without enfuvirtide (ENV). TMC114/r/TMC125 pharmacokinetics was assessed over 12 hours on days 7 and 28. HIV resistance, safety, and efficacy parameters were assessed over the study period. Non-compartmental analysis was used to measure the TMC114 and TMC125 area under the curve (AUC); pharmacokinetic parameters were compared to historical data; associations with virologic response were assessed by linear regression analysis.

Results:  Of 11 patients, 10 completed both pharmacokinetic phases; median (range) baseline characteristics included age 43 (38 to 56) years; CD4 75 (3 to 490) copies/mm³; log₁₀ viral load 4.6 (3.9 to 5.5); number of mutations (IAS, October 2005) for protease inhibitors, primary 4 (0 to 5), and resistance associated 11 (2 to 13), for NRTI 7 (2 to 9), and for NNRTI 2 (0 to 6). Of 10 patients, 6 had prior exposure to tipranavir and to ENV; only 2 used ENV for the first time. On day 28, TMC114 and TMC125 mean (SD) AUC_0-12, C_max, C_0h were 72321ng/h/mL (21687), 9109ng/ml (2482), 5175ng/ml (2011) and 4921ng.h/ml (2982), 569ng/ml (381), 340 ng/mL (213), respectively. As compared to historical controls, these reflect unchanged exposure to TMC114 and modestly reduced (30%) exposure to TMC125. Coefficient of variation in TMC114 and TMC125 pharmacokinetic parameters ranged from 27 to 70%. At week 6, all patients had achieved at least a 2 log₁₀ decrease in HIV RNA with a median of –2.55; 5 and 8/10 had viral load <40 and 400 copies/mL, respectively. Median CD4 increase was 83 copies/mm³. No serious adverse events or changes in laboratory safety were reported. No statistically significant associations were observed between log₁₀ change in viral load and TMC114/TMC125 pharmacokinetic parameters, TMC114 inhibitory quotient (IQ) or use of ENF.

Conclusions:  No significant pharmacokinetic interaction between TMC114 and TMC125 was observed. The combination was well tolerated and showed impressive short-term efficacy against 3-class resistant HIV. Further studies of this combination are warranted.