Survey of brecanavir (BCV) and other protease inhibitor (PI) susceptibility to HIV-1 variants containing PI resistance-associated amino acid substitutions (RAS)
Background: Brecanavir, a PI with high-affinity binding, shows >100-fold improved binding over currently approved PIs and 10-fold over TMC-114. BCV exhibits picomolar antiviral activity and a resilient resistance profile due to an adaptive thiazolylmethyl moiety. The cross-resistance profile of BCV, in Phase II development, was studied.
Methods: 94 HIV-1 clinical isolates selected according to the presence of known PI RAS (defined by IAS USA, Fall, 2005) were analysed for IC50 and fold change (FC) versus all approved PI except NFV using PhenoSenseä.
Results: The mean number of major PI RAS per isolate was 2.6 (range: 0 – 6; median 3). The median IC50s for the other PI were significantly above that for BCV (geometric mean IC50 nM: BCV:0.4; APV:97, IDV:99, LPV:56, ATV:20, TPV:110). The median fold change (FC) for BCV was lower than for all PIs apart from TPV (median FC: BCV:2.1, APV:8.6, IDV:15, LPV:19, ATV:15, TPV:1.3). At the clinically derived cut-offs for IDV/r and LPV/r (10-FC), ATV/r (5.2-FC) and TPV/r (4-FC), 59%, 57%, 70% and 15% of isolates were resistant to these PI respectively. For BCV, the ‘resistant’ proportions were 10% at 10-FC, 20% at 5.2-FC and 28% at 4-FC. The mean number of major PI RAS for isolates with FCs ³ and < cut off were, 3.24/1.82, 3.17/1.95, 3.03/1.75 and 3.71/2.46 for IDV, LPV, ATV and TPV respectively; and 4.33/2.47, 3.53/2.42 and 3.27/2.41 for BCV at the same FCs (10, 5.2 and 4 respectively). The TPV/r mean major PI RAS ratio at 4-FC was reproduced by BCV at FC 6.5-7.0.
Conclusions: BCV shows greater potency than APV, IDV, LPV, ATV and TPV and lower FC than all PIs except TPV/r, which shows relatively low intrinsic potency and low clinical cut-off. The BCV virologic profile along with early signs of good tolerability and efficacy in subjects with PI-resistant isolates further supports its on-going development.
AIDS 2006 - XVI International AIDS Conference
"C.Craig, et al.
Survey of brecanavir (BCV) and other protease inhibitor (PI) susceptibility to HIV-1 variants containing PI resistance-associated amino acid substitutions (RAS).
Oral abstract session:
AIDS 2006 - XVI International AIDS Conference: