ABSTRACT: Objectives: To investigate viral susceptibility for tipranavir of HIV-1 isolates with reduced susceptibility to other protease inhibitors, in particular ritonavir, indinavir or saquinavir.
Materials and Methods: Recombinant viruses with documented reduced susceptibility to saquinavir and indinavir were used. They were created using the amplified pool of protease genes of patients extensively treated with saquinavir (week 0) or 8 weeks after switching from saquinavir (hard capsule formation) to saquinavir (oral formulation) or indinavir (week 8). The viral protease had been completely sequenced and drug susceptibility to indinavir and saquinavir of the recombinant viruses had been determined. Recombinant viruses with documented reduced susceptibility to ritonavir were also used. Recombinant viruses were created using the amplified and cloned protease genes of longitudinal samples obtained from a patient treated with ritonavir (patient 129). The viral protease genes had been completely sequenced and the ritonavir susceptibility of the recombinant viruses had been determined. All drug susceptibility determinations were performed by the recombinant virus approach using the MTT assay. However, for this study we used a protease deletion clone. Changes in drug susceptibility are defined by an at least threefold change in drug susceptibility relative to the patient's pretreatment isolate.
Results: Tipranavir susceptibility was determined for each of the selected viral isolates. All 1C50 concentrations indicated reflect the geometric mean of a drug susceptibility assay performed in duplicate. Recombinant viruses with documented reduced susceptibility to ritonavir did not result in reduced susceptibility. One of the isolates (460-2) demonstrated a 33-fold reduced susceptibility to ritonavir which corresponded to only a threefold change for tipranavir.
Conclusions: In this study we did not observe cross resistance to tipranavir for the isolates with reduced susceptibility to other protease inhibitors.
