TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial.

Objective: To evaluate antiviral activity, tolerability, and safety of the protease inhibitor (PI) TMC114 boosted with low-dose ritonavir (RTV).

Design: A randomized, open-label, controlled, phase IIA clinical trial in 15 sites in Europe with 50 HIV-1-infected patients who had taken multiple PIs.

Methods: At entry, PIs in non-suppressive regimens were replaced with TMC114/RTV (300/100 or 600/100 mg twice daily, or 900/100 mg once daily) or left unchanged for 14 days. The time-averaged difference (DAVG) in HIV-1 RNA from baseline, change in HIV-1 RNA from baseline, proportions achieving plasma HIV-1 RNA < 400 copies/ml and > or = 0.5 and > or = 1.0 log10 copies/ml reductions in HIV-1 RNA, and safety were assessed.

Results: DAVG responses in all TMC114/RTV groups (range, -0.56 to -0.81 log10 copies/ml) were significantly greater (P < 0.001) than in the controls (-0.03 log10 copies/ml). Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively. A reduction of > or = 0.5 and > or = 1.0 log10 copies/ml was attained by 97% and 76% of patients, respectively, in all TMC114/RTV groups and by 25% and 17%, respectively, in the control group. HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group. Most common reported adverse events were gastrointestinal and central nervous system disorders (mild to moderate severity). No dose relationship was observed. Biochemical, haematological and electrocardiographic parameters showed no significant changes.

Conclusions: TMC114/RTV demonstrated a potent antiretroviral effect over 14 days in multiple-PI-experienced patients and was generally well tolerated.