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Abstract
Analysis of cleavage site evolution following virological rebound on a tipranavir-based regimen
Tremblay S.1, Bourgon L.1, Hall D.2, Elston R.1, Bethell R.1
Objectives: Tipranavir (TPV, Aptivus®), a novel non-peptidic HIV-1 protease inhibitor (PI), has proven efficacy in PI-experienced patients. Following virological rebound (V-RBD) during TPV-based therapy: if present at baseline, the V82A mutation is deselected in favour of V82T; baseline I50V mutations are deselected; in other isolates the TPV-associated V82L mutation may emerge. Development of PI mutations V82A and I50V has been associated with co-development of p7/p1 and p1/p6 cleavage site (CS) mutations respectively. In view of TPV’s unique resistance profile, changes in gag CSs following V-RBD during TPV-based therapy were investigated.
Methods: Virus was isolated, at baseline and following V-RBD, from 20 PI-experienced patients participating in the RESIST 1 & 2 clinical studies who experienced V-RBD while receiving a TPV-based regimen. The MA/CA, CA/p2, p2/p7(NC), p7(NC)/p1 and p1/p6 CSs were sequenced.
Results: Ten isolates harbored the V82A mutation at baseline. In 8/10 cases 82T replaced 82A upon V-RBD. 6 of these 8 viruses harbored PI-associated p7/p1 CS mutations at baseline. No further evolution was observed at this CS following V-RBD. Of the five isolates that harbored the I50V mutation at baseline, all five isolates had p1/p6 CS mutations at baseline (L449F/V n=2, P453L n=3). Upon V-RBD, all five lost the I50V, and two isolates also lost the P453L CS mutation. Six isolates developed the TPV-associated V82L mutation upon V-RBD. 5/6 isolates harbored the p7/p1 CS mutation A431V at baseline and it developed in the remaining patient. Additional p1/p6 CS mutations were selected in 3/6 viruses in which the V82L mutation developed (L449F, P453L or R452S, P453L).
Conclusions: Upon V-RBD during TPV-based therapy: 1. Replacement of V82A by V82T was not associated with CS evolution. 2. I50V de-selection was accompanied by CS de-selection in 2/5 patients. 3. New CS mutations were observed in 3/6 patients in whom the V82L was selected.
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
Abstract no.
MOPEA054
Suggested Citation
"TremblayS., et al.
Analysis of cleavage site evolution following virological rebound on a tipranavir-based regimen.
Poster exhibition:
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention:
Abstract no.
MOPEA054"
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