Background: Tipranavir (TPV), the first non-peptidic protease inhibitor (NPPI), has a uniquely robust resistance profile, demonstrating viral load responses against multiple protease inhibitor (PI)-resistant HIV-1 both in vitro and in clinical studies. Phase IIA studies have identified a range of doses of tipranavir/ritonavir (TPV/r) which are expected to have efficacy and tolerability in both single and multiple PI-experienced patients (pts). The present study was designed to determine the optimal dose for use in Phase III trials.

Methods: BI 1182.52 is a multicenter, 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. Any CD4⁺ cell count was allowed, and viral load > 1000 copies/mL. Background therapy was optimized after 2 weeks of functional monotherapy with TPV/r. The primary endpoints were viral load reduction at 2 wks and specific adverse events (AEs) at 4 wks.

Results: A total of 216 pts were randomized and evenly distributed between arms with regard to baseline viral load, CD4⁺ cell count, demographics and prior treatment experience; 84.5% were male, 76.4% were white, and 7.9% were HCV co-infected. Prior use of individual PIs ranged from 37.5% for lopinavir to 79.6% for indinavir. The median baseline viral load was 4.5 log copies/mL and CD4⁺ cell count was 153 cells/mm³. After 2 wks, the median change in viral load was -0.9 log, -1.0 log, and -1.2 log in the 500/100, 500/200, and 750/200 arms, respectively (intent-to-treat; last observation carried forward [ITT;LOCF]); these values did not show a statistically significantly difference. Overall, 15.3% of pts experienced ≥ Grade 2 diarrhea and 11.6% experienced vomiting; however, no clear dose response relationship was observed. A dose-dependent trend was observed for Grade 3/4 AEs, laboratory abnormalities, and AE related treatment discontinuations. Eleven (11) pts (5.1%) experienced serious AEs of any causality during the first 4 wks, and 2/11 were regarded as treatment related.

Conclusions: All 3 doses of TPV/r tested demonstrated potent antiviral efficacy with an acceptable safety profile. The final dose to be taken forward into Phase III trials will be determined and reviewed with regulatory authorities.