• Tipranavir/Ritonavir (TPV/r) Demonstrates Potent Efficacy in Multiple Protease Inhibitor (PI)-Experienced Patients: BI 1182.52 (Oral 179)
  Authored by J. Gathe, V.M. Kohlbrenner, G. Pierone, K. Arasteh, R. Rubio, R. LaLonde, P. Piliero, S. McCallister, S. Garfinkel, R. Chaves, G.M. Mukwaya, C. Dohnanyi, S. Shaw, U. Drees, D. Mayers
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Tipranavir, a protease inhibitor (PI) entering the final stages of clinical testing, was evaluated in a dose ranging study that enrolled patients with wide antiretroviral experience.

This PI is billed as having activity against a range of PI-resistant strains of HIV-1 in vitro. In addition, tipranavir has been shown to have activity against HIV-2. Unfortunately, the drug is poorly bioavailable, requiring 12 pills TID. However, when taken with a lower dose of ritonavir (RTV, Norvir), dosing frequency and pill burden drop into the range of feasibility. Various concoctions of tipranavir and RTV have been studied in preliminary studies but the optimal dosing strategy had not been determined. To obtain safety, pharmacological and efficacy data on candidate doses of tipranavir/RTV, the maker of this drug, Boehringer Ingelheim Pharmaceuticals, conducted the BI 1182.52 study. This is a multi-centered, international, randomized and blinded study of three dosing strategies of tipranavir/RTV: 500 mg/100 mg BID, 500 mg/200 mg BID and 750 mg/200 mg BID. Eligible subjects had to have experience with agents of all three classes of approved antiretroviral therapy -- including two or more PIs. They also had to be failing their current PI-based regimen with an HIV RNA PCR level above 1,000 copies/mL and finally have at least one of a specified list of primary PI mutations (30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V and 90M) but not have more than one of the following: 82L/T, 84V, 90M.

After entering the study, subjects discontinued their PIs and initiated one of the three study doses of tipranavir/RTV while maintaining their pre-study NRTIs. After 14 days, subjects were assessed for changes in viral load and, at that point, were permitted to have their regimens optimized by modifying their pre-entry antiretrovirals. Subjects then continued on tipranavir/RTV and their optimized regimens for continued safety and efficacy data collection.

A total of 216 subjects were enrolled in the trial and randomized to the three dosage arms. Subjects were generally male (84 percent) and white (76 percent) and had a median entry viral load and CD4 cell count of 4.53 log10 copies/mL and 153 cells/mm³, respectively. About a third of the subjects had prior exposure to lopinavir/RTV (LPV+RTV, Kaletra) and more than three quarters prior indinavir (IDV, Crixivan) therapy.

At entry there was significant evidence of PI resistance despite the inclusion criteria. Over 90 percent of the subjects had 10 or more mutations associated with resistance to all available antiretroviral drugs, and 41 of the isolates from the cohort had genotypic resistance patterns that indicated reduced susceptibility to all current PIs.

After 14 days there was a decline from baseline HIV viral load of 0.9 log10 in the 500/100 arm, a 1.0 log10 drop in the 500/200 arm and a 1.2 log10 fall in the 750/200 arm (p=NS). Response was truncated when multiple PI resistance mutations were present at baseline, but, according to the presentation, it was only after 16 or more such mutations were detected that the efficacy of tipranavir/RTV waned significantly. Tipranavir/RTV also continued to demonstrate an ability to reduce viral load, at least at 14 days after initiation, even when one to two of the so-called universal PI-associated mutations or UPAMs (l33I/V/F, V82A/F/L/T, I84V and L90M) were present baseline.

After 28 days, toxicity was assessed. Grade 3 or 4 increases in ALT, AST and total bilirubin were seen across all arms and were dose dependent as were adverse event related treatment discontinuations. Tipranavir combined with RTV also clearly can increase lipid levels. Elevations of triglycerides to greater than grade 2 was seen in 9.5 percent of the 500/100 subjects, 15.5 percent of those receiving 500/200 and 11.3 percent of participants assigned to 750/200 after a month of therapy.

Based on these results and pharmacokinetic data presented at this conference, the company has decided to pursue further clinical development of the 500/200 BID dosing strategy. The demonstration that this PI combination can provide durable viral load suppression beyond two weeks, particularly in PI-experienced patients, is the next hurdle that must be cleared. Further, more information needs to be collected on longer-term lipid elevations and hepatic safety if this agent is to be considered as part of a first or second treatment regimen. Additionally, data presented earlier at this conference suggest that as many as 20 percent of subjects in a pharmacokinetics substudy receiving the 500/200 dose achieved a trough concentration of the drug below 20 µM -- a level that is 10 times the protein adjusted IC90 for PI-resistant HIV and a concentration target. Examination of the factors that may influence tipranavir levels needs to also be included in the next phase of study.

In summary, these are encouraging early data regarding this important PI. Continued study of this drug will help determine where it may best fit as an addition to our growing armamentarium of antiretrovirals.