Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development

Objectives: To assess the in-vitro drug susceptibility of a panel of five w ell-characterized drug-resistant HIV variants to recently developed anti-HI V compounds including seven reverse transcriptase (RT) inhibitors and seven protease inhibitors. Methods: Drug-resistant viral strains were selected on the basis of the pre valence of these mutants in patient samples from local area HIV clinics. Th e isolates included one multinucleoside-resistant virus containing the Q151 M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against th ese isolates was determined using drug susceptibility assays and measuring the viral antigen p24 end-point. Results: These clinically relevant highly drug-resistant viruses were resis tant to many of the new compounds in clinical development. In most cases th e resistance mutations of the clinical isolate were different from those se lected in vitro for the particular experimental compound. Conclusions: it is critical to expand the preclinical development of new dr ugs to include the assessment of their activity against currently circulati ng highly drug resistant clinical strains, in order to develop appropriate salvage therapies For patients harboring resistant strains. (C) 1999 Lippin cott Williams & Wilkins.