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1st International Workshop on HIV Drug Resistance & Treatment Strategies25-28 June 1997, St. Petersburg, Florida, USA |
BIOLOGICAL CROSS-RESISTANCE TO HIV-1 PROTEASE INHIBITORS
Antiviral Therapy 1997;2 (Suppl 5):10 (abstract no. 15)
Terri Smith and Ronald Swanstrom
Department of Biochemistry and Biophysics, and Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Understanding the potential for cross-resistance between HIV-1 protease inhibitors has important implications for the possible sequential use of these inhibitors. We have passaged HIV-1 in the presence of escalating inhibitor concentrations using the HIV-1 protease inhibitors saquinavir, ritonavir and indinavir. Based on the number of mutations seen within the protease coding domain, we estimate that the selective pressure that was applied surpassed that attained in vivo for each of the inhibitors.
These inhibitors were very similar in their capacity to select for multiple mutations, and there was significant overlap in the mutations that appeared during each of the selections. At the highest level of selection used, resistance to the selecting inhibitor was of the order of 100- to 1000-fold. In all cases, cross-resistance to the other two inhibitors was at a similar level. Initial results with viruses selected to intermediate levels of resistance to indinavir and saquinavir showed intermediate levels of cross-resistance to the other inhibitors. Similar analyses are in progress with viruses selected to intermediate levels of resistance to ritonavir, and these virus pools are also being tested for cross-resistance to other protease inhibitors. These virus pools represent viruses with varying degrees of resistance to the inhibitors and as such are useful reagents for exploring the issue of cross-resistance. The overlap in sequence changes that are selected and the demonstrated cross-resistance both suggest that sequential use of these inhibitors after an initial therapy failure with a protease inhibitor will be under conditions where the efficacy of the second inhibitor has been compromised.
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1997-06-25
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