15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

PHENOTYPIC SUSCEPTIBILITY TO TMC-114 AND TIPRANAVIR BEFORE AND AFTER LOPINAVIR/RITONAVIR-BASED TREATMENT IN SUBJECTS DEMONSTRATING EVOLUTION OF LOPINAVIR RESISTANCE

Antivir Ther. 2006, 11:S34 (abstract no. 29)

M King¹, TP Young¹, B Bernstein¹, L Klein¹, DK Tokimoto¹, MJ Fath¹, N Parkin², GJ Hanna¹ and DJ Kempf^1
1Abbott, Abbott Park, IL., USA; ²Monogram Biosciences, South San Francisco, CA, USA

BACKGROUND: TMC-114/ritonavir and tipranavir/ritonavir have demonstrated antiviral activity in multiple protease inhibitor–experienced subjects. We assessed the change in susceptibility to TMC-114 and tipranavir in subjects developing lopinavir resistance while receiving a lopinavir/ritonavir-based regimen.

METHODS: In 4 studies of protease inhibitor–experienced subjects (n=311) treated with lopinavir/ritonavir-based regimens, 24 subjects demonstrated incremental evolution of lopinavir resistance. Fold change (FC) in IC₅₀ of lopinavir, TMC-114 and tipranavir and replication capacity (RC) were analysed with archived plasma samples available at both baseline and rebound. TMC-114 powder was provided in a blinded fashion by Abbott.

RESULTS: Resistance testing was successful at both baseline and rebound for 18 subjects. Median (IQR) FC values at baseline and rebound were 6.9 (4.4–18) and 63 (34–120) for lopinavir, 1.4 (1.0–1.9) and 2.7 (1.2–9.2) for TMC-114, and 1.9 (1.1–3.2) and 1.8 (1.1–5.1) for tipranavir. Log-transformed FC values at rebound for lopinavir were significantly correlated with those of TMC-114 (R²=0.48, P=0.001) but not tipranavir (R²=0.05, P=0.34). Pre-lopinavir/ritonavir treatment, four subjects had TMC-114 FC>2 and one had FC>4 (TMC-114 clinical cut-off undefined), compared to twelve and eight subjects after rebound, respectively. Eight subjects had tipranavir FC>2 (tipranavir lower clinical cut–off) prior to lopinavir/ritonavir treatment, compared to seven subjects after rebound. Two-fold or greater FC increase between baseline and rebound to TMC-114 and tipranavir was observed in seven and five subjects, respectively. Isolates from two of the three subjects with greatest incremental FC increase to both tipranavir and TMC-114 demonstrated emergence of the L33F protease mutation at rebound in conjunction with the presence or emergence of L10F, M46I, I54V, I84V or V82A, and L90M. Isolates from the other subject had L10I, K20M/R, I84I/V, and L90M at baseline and added M36I, M46I, I47V, and I54V mutations at rebound. Median (IQR) RC (n=15) declined by 64 (40–86) percent between baseline and rebound.

CONCLUSIONS: Evolution of high-level resistance to lopinavir/ritonavir generally resulted in lower RC with relatively little change in susceptibility to tipranavir and modest changes in susceptibility to TMC-114 in some subjects. Boosted tipranavir or TMC-114, guided by resistance testing, may be useful for salvage therapy following incremental evolution of resistance on a lopinavir/ritonavir-based regimen.

2006-06-13
29

Copyright © 2006 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.