Background: Tipranavir (TPV)-based therapy, has demonstrated sustained viral load response up to 48 wks of treatment in single and multiple PI-experienced patients (pts) with up to 20 protease gene mutations. Studies to date have identified very few individuals with reduced baseline or treatment emergent reduced phenotypic susceptibility to TPV (IC₅₀ > 4-fold wild-type [WT]). This study in highly treatment-experienced pts allows for further characterization of this novel non-peptidic protease inhibitor (NPPI).

Methods: BI 1182.52 is a multi-center, international, randomized, blinded trial of 3 doses of TPV/r (500 mg/100 mg; 500 mg/200 mg; and 750 mg/200 mg). Entry criteria included experience of all 3 available classes of antiretroviral, including at least 2 PIs and at least one primary PI mutation from 30N, 46I/L,48V, 50V, 82A/F/L/T, 84V or 90M (≤1 from 82L/T, 84V or 90M). Background therapy was optimized after 2 wks of functional TPV/r monotherapy. Phenotypic analysis was conducted using the Virco Antivirogram assay.

Results: A total 216 pts with a median baseline viral load of 4.5 log₁₀ copies/mL and CD4⁺ cell count of 153 cells/mm³ were randomized. The median baseline fold WT IC₅₀ in 157 isolates was 1.1 (range 0.3–100.2) for TPV, 76.5 (0.5–165.3) for lopinavir, 8.7 (0.3–150.7) for amprenavir, 7.0 (0.1–108.9) for saquinavir, 12.2 (0.4–197.4) for indinavir, 36.8 (0.3–96.4) for nelfinavir, and 94.2 (0.2–808.5) for ritonavir. The distribution of TPV susceptibility in these isolates was 42% ≤1-fold WT, 27% > 1 to 2-fold WT, 18% > 2 to 4-fold WT, and 12% > 4-fold WT. The overall median viral load changes across these strata after 2 wks of functional monotherapy were -1.23 log₁₀, -1.24 log₁₀, -0.21 log₁₀, and -0.19 log₁₀, respectively. This indicates a robust antiviral response for TPV IC₅₀ β 2-fold WT, and a lesser response for TPV IC₅₀ >2-fold WT.

Conclusions: These results indicate that baseline phenotypic susceptibility to TPV was maintained in the majority of isolates that were highly resistant to available PIs. There was an apparent breakpoint in TPV susceptibility at an IC₅₀ approximately 2-fold WT; however, a TPV IC₅₀ 2-fold WT required the accumulation of a large number of protease gene mutations.