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Viral Resistance to Indinavir
Abstract 145
In Vivo Evolution of Resistance to the HIV-1 Protease Inhibitor Indinavir
Authors: J Condra, W Schleif, O Blahy, R Danovich, L Gabryelski, D Graham,
J Quintero, A Rhodes, H Robbins, E Roth, M Shivaprakash, D Titus, Y Yang,
J Chodakewitz, P Deutsch, D Holder, and E Emini.
This study reported the detection of indinavir resistant viruses in patients who had received suboptimal doses of the inhibitor during early clinical trials. Reduced viral sensitivity to indinavir was a consequence of highly variable and overlapping combinations of mutations in at least 11 codons of the protease gene (see also Appendix C).
Higher levels of resistance was associated with greater numbers of codon changes. Stepwise accumulations of these mutations resulted in progressive increases in the extent of viral resistance. Selection with certain protease inhibitors, such as indinavir, saquinavir, ritonavir and 141W94, has led to the emergence of cross-resistant viruses in cell culture experiments.
Based on these observations, Dr. Condra concluded that initial therapy with any one of the protease inhibitors stated above may select for mutations that will facilitate the emergence of resistance to a second inhibitor given later, due to the existence of their overlapping cross-resistance patterns. He also concluded that therapy should begin with the highest safe dose of the most potent protease inhibitor in order to provide both a greater barrier to resistance selection and to suppress the viral replication required for such selection.
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