Resistance to newly approved and investigational protease inhibitors

The aim of this paper was to review recent literature on the HIV-1 genotypic and phenotypic resistance determinants of therapeutic response to newly approved protease inhibitors and the viral resistance pathways to these and to investigational protease inhibitors.

Published papers and conference abstracts highlighting HIV drug resistance selection and response to tipranavir and darunavir, as well as to investigational protease inhibitors brecanavir, PL-100 and SP-256, were reviewed. Tipranavir and darunavir exhibit a high genetic barrier to resistance, and demonstrate significant antiviral efficacy in patients carrying multidrug-resistant HIV. Drugs activities are affected by partly distinct patterns of resistance mutations. Investigational agents show promising in-vitro activity against viral strains resistant to other protease inhibitors. The in-vitro selection of viruses resistant to these inhibitors is slow and results in limited cross-resistance to other agents.

Recently approved protease inhibitors can be usefully employed for salvage therapy in a significant proportion of patients failing previous protease inhibitors. Genotypic resistance patterns or phenotypic susceptibility together with the activity of the accompanying antiretroviral agents will determine the probability of therapeutic response. Ongoing clinical studies will determine whether the newly approved agents could be employed earlier in therapeutic sequencing.