Methods
A panel of 245 clinical samples was retrospectively evaluated, which were derived from 226 HIV-infected patients treated at more than 20 outpatient centres and private practices in Germany between 1/1998-7/2002. Samples were selected for availability of treatment histories; all patients were naïve for Amprenavir, Lopinavir, and Atazanavir. Resistance testing was performed by a recombinant virus assay.

Results
Reduced susceptibilities of more than 3.5-fold were observed for Indinavir (46.1%), Saquinavir (43.3%), Ritonavir (43.7%), Nelfinavir (51.0%), Amprenavir (33.1%), Lopinavir (36.7%), and Atazanavir (43.3%). 24.8% of the Lopinavir resistant samples ranged between 3.5- and 9.5-fold reduced susceptibility. If 9.5-fold reduced susceptibility was applied as cut-off, the number of Lopinavir resistant samples was reduced to 26.5%. Samples resistant against at least one of the previously approved PI frequently displayed cross-resistance to Atazanavir (78.3-85.5%), whereas cross-resistance to Lopinavir (62.0-75.0%) and in particular to Amprenavir (58.7-67.1%) was considerably lower. If 9.5-fold was used as cut-off for Lopinavir, cross-resistance was reduced to 44.6-53.9%. Similar results were obtained if cross-resistance to the new PI was evaluated with respect to the number of previously approved PI showing more than 3.5-fold reduced susceptibility and the number of PI in the pre-treatment. These data indicate a higher cross-resistance of Atazanavir compared to Lopinavir and Amprenavir. Furthermore, these data suggest that PI cross-resistance is considerably influenced by drug levels.

Discussion
The enhanced drug exposure by boosted PI may have three consequences: (i) clinically relevant cut-offs may be increased, (ii) low-level resistance may be overcome by boosted PI, and (iii) boosted PI may successfully be applied for salvage therapy.