New Mechanisms of Protease Inhibitors Resistance

Stanford University, Stanford CA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): The proposed study is a pilot which brings innovative sequencing approaches to a current clinical problem in the treatment of patients who have failed the recommended sequence of regimens in developing countries. We are addressing hypotheses about the mechanism(s) of virologic failure of a boosted Lopinavir/ritonavir (LPV/r) regimen. In an international clinical trial ACTG A5230, and in multiple recent studies of ritonavir boosted protease inhibitors (PI) there are very few consensus mutations to guide the choice of subsequent treatment. In ACTG 5230 where LPV/r monotherapy with Truvada (TDV) intensification was offered upon failure, only a minority of virologic failure subjects developed P resistance mutations and these were not sufficient to impart high level resistance. Further investigation of minority quasispecies through ultra-deep sequencing is a new approach to understanding virologic failure. In addition, gag cleavage sites (where protease cleaves the polyprotein products of HIV replication) may adapt and mutate to compete effectively with PI. Finally a recent, in vitro study has demonstrated a role for protease in viral entry and reverse transcription mediated by the env gene. Thus we are proposing exploratory studies to obtain robust, preliminary data on the mechanism(s) which may explain virologic failure following a boosted PI regimen. By determining the mechanism(s) of virologic failure it will be possible to design diagnostic sequencing to identify the optimal sequential regimen(s) for continued treatment.