AEGiS-10CROI: First Clinical Results on Antiretroviral Activity, Pharmacokinetics, and Safety of TMC114, an HIV-1 Protease Inhibitor, in Multiple PI-experienced Patients.

10th Conference on Retroviruses and Opportunistic Infections

Boston, MA USA - February 10 -14, 2003

First Clinical Results on Antiretroviral Activity, Pharmacokinetics, and Safety of TMC114, an HIV-1 Protease Inhibitor, in Multiple PI-experienced Patients.

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 8
K. Arasteh¹, N. Clumeck², A. Pozniak³, H. Jaeger⁴, M. De Pauw⁵, H. Muller⁵, M. Peeters⁵, R. Hoetelmans⁵, S. De Meyer⁵, I. van der Sandt⁶, S. Comhaire⁷, R. van der Geest⁵
¹Epimed c/o Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany; ²CHU-UMC Saint-Pierre, Brussels, Belgium; ³Chelsea and Westminster Hosp, London, UK; ⁴MUC Res, Munich, Germany; ⁵Tibotec, Mechelen, Belgium; ⁶Kinesis, Breda, The Netherlands; and ⁷Medisearch Intl, Mechelen, Belgium

BACKGROUND: TMC114 is a Protease Inhibitor (PI) with potent in vitro antiviral activity against wild-type and PI-resistant HIV-1. The study objective was to evaluate the activity, safety, and pharmacokinetics of TMC114 with low dose ritonavir (TMC114/r) in multiple PI-experienced patients (pts) currently failing a PI-containing regimen at study entry.

METHODS: Open, randomized Phase IIa study in 50 multiple PI-experienced pts. TMC114/r was substituted for the failing PI(s); all other ARVs were not changed. Pts received TMC114/r at doses of 300/100 mg bid (A: n = 13), 600/100 mg bid (B: n = 12), 900/100 mg qd (C: n = 13) or continued the failing regimen (D: n = 12). Pts received TMC114/r for 14 days after which it was discontinued and changes in ART were permitted.

RESULTS: Median baseline plasma HIV-1 RNA for the study group was 4.3 log₁₀ and median baseline CD4 cell count was 297/µL. Median number of previously used PIs was: A:3, B:3, C:4, D:3. Median number of PIs within the range of drug susceptibility (Antivirogram) was A:1, B:1, C:0, and D:1. The median number of primary PI mutations was A:7, B:6, C:7, and D:8. In the ITT analysis, the median change in plasma HIV-1 RNA (log₁₀) from baseline to day 14 in arms A, B, C and D was -1.24, -1.50, -1.13 and +0.02 (p < 0.001). The range of HIV-1 RNA reduction in the treatment arms was -0.47 to -2.5 log₁₀ (median -1.35). In arms A, B, C, and D, 69%, 92%, 69%, and 17% had at least a 1.0 log₁₀ reduction in HIV-1 RNA, respectively, and in the TMC114/r groups, 97% had at least a 0.50 log₁₀ reduction from baseline. Median TMC114 C_min and AUC_24h at day 14 in Arms A, B, and C were 1.2 µg/ml and 53.3 µg.h/ml, 1.4 µg/ml and 60.4 µg.h/ml, and 1.6 µg/ml and 67.9 µg.h/ml, respectively. Treatment with TMC114/r was generally well tolerated. The most commonly reported AEs were GI events. One (1) pt in arm C discontinued treatment due to GI discomfort and 1 pt in arm B had an SAE (hepatitis). Overall, in the TMC114/r arms, 2, 2, and 1 pts had a grade 3/4 ALT, AST or GGT elevations, respectively. One (1) pt in the control group had a grade 3 AST.

CONCLUSIONS: TMC114/r exhibited potent antiretroviral activity and favorable pharmacokinetics when given for 14 days to multiple PI-experienced pts currently failing a PI-containing regimen. For the TMC114/r arms, maximum and median changes in HIV-1 RNA (log₁₀) were -2.49 and -1.35 copies/ml, respectively. TMC114/r was generally well tolerated.

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