18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

EMERGENCE OF MUTATIONS AND PHENOTYPIC RESISTANCE WITH TIPRANAVIR TREATMENT IN PROTEASE INHIBITOR-EXPERIENCED PATIENTS

Antivir Ther 2009; 14 Suppl 1:A53 (abstract no. 49)

D Hall¹, J Schapiro², J Baxter³, C Boucher⁴, J Scherer⁵, M Witvrouw⁶, C Tilke⁵ and R Bethell^6
1Boehringer Ingelheim, CT, USA; ²National Hemophilia Center, Tel-Hashomer, Israel; ³Cooper University Hospital/UMDNJ-Robert Wood Johnson Medial School, New Jersey, USA; ⁴Erasmus Medical Center, Rotterdam, the Netherlands; ⁵Boehringer Ingelheim, Ingelheim, Germany; ⁶Boehringer Ingelheim (Canada) Ltd., Laval, Québec, Canada

OBJECTIVES: Virologic failure associated with the emergence of resistance to tipranavir (TPV) in patients receiving TPV-based therapy has been evaluated and reported in a small number of early failures. An investigation of all virologic failures in the RESIST trials provides a critical mass of new data for characterizing the effects of TPV selection for mutations in vivo.

METHODS: TPV-treated patients who failed virologically in RESIST were identified. Baseline specimens, initial failure specimens and later specimens when patients continued to take TPV were submitted for genotypic and phenotypic testing at Monogram Biosciences. Baseline and first failure results were compared to evaluate the selected mutation patterns and the patterns of protease inhibitor (PI) resistance.

RESULTS: Initial failure on TPV was associated with a 3.8-fold increase in IC₅₀ FC from baseline, and continued treatment was associated with an additional 2.7-fold increase from initial to last failure observation. By contrast IC₅₀ FC for DRV, FPV, LPV and SQV at initial TPV failure decreased by 10%, 20%, 30% and 10%, respectively. At last failure FC for DRV had returned to above baseline, whereas the others were unchanged. The most common emergent mutations at first failure were V82T, which emerged primarily in patients with the PI mutation V82A at baseline (n=45), I84V, which emerged in patients with virus without a substitution at codon 84 at baseline (n=28), and L24L or M, which emerged in patients with the PI mutation L24I at baseline (n=23).

CONCLUSIONS: Virologic failure while on a tipranavirbased regimen does not lead to a change in phenotypic susceptibility to DRV, FPV, LPV or SQV, even in patients who continued on the failing regimen. The most commonly selected mutations in patients who failed on a TPV-based regimen were A82T, I84V and I24L/M. L24M has not been reported previously as selected by PI-based therapy.

ACKNOWLEDGEMENTS: Supported by Boehringer Ingelheim.

2009-06-09
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