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To assess the in-vitro drug susceptibility of a panel of five well-characterized drug-resistant HIV variants to recently developed anti-HIV compounds including seven reverse transcriptase (RT) inhibitors and seven protease inhibitors.Drug-resistant viral strains were selected on the basis of the prevalence of these mutants in patient samples from local area HIV clinics. The isolates included one multinucleoside-resistant virus containing the Q151M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 end-point.These clinically relevant highly drug-resistant viruses were resistant to many of the new compounds in clinical development. In most cases the resistance mutations of the clinical isolate were different from those selected in vitro for the particular experimental compound.It is critical to expand the preclinical development of new drugs to include the assessment of their activity against currently circulating highly drug-resistant clinical strains, in order to develop appropriate salvage therapies for patients harboring resistant strains.