August 15, 2006
Tipranavir (TPV, Aptivus) is a novel protease inhibitor (PI) with potent activity against HIV that is resistant to multiple PIs. Its efficacy has been evaluated in two large phase 3 trials called RESIST (Randomized Evaluation of Strategic Intervention in Multidrug Resistant Patients With Tipranavir) 1 and RESIST 2. In these studies, patients were randomized to receive an optimized regimen to include tipranavir or another PI boosted with ritonavir (RTV, Norvir). Patients enrolled in these studies had at least three months exposure to three classes of antiretroviral agents, including two or more PI-based regimens, and had evidence of PI resistance (two or more primary mutations, but no more than two mutations at codons 33, 82, 84 and 90). All patients received 500 mg of tipranavir boosted with 200 mg of ritonavir twice daily or comparator boosted PIs at approved doses. The current analysis reports on efficacy in the two arms of the studies as a function of prior PI experience.1
In RESIST 1 and RESIST 2 combined, there were 746 patients enrolled in the tipranavir arm and 737 patients in the control arm. The mean baseline HIV plasma viral load and CD4+ cell count were 4.73 log10 copies/mL and 196 cells/mm3, respectively, in the tipranavir arm and were 4.73 log10 copies/mL and 195 cells/mm3, respectively, in the control arm. Patients had prior exposure to a median of 12 agents, including four PIs. Overall, suppression of viral load was more common in the tipranavir-treated patients (30.4% versus 13.8% less than 400 copies/mL; 22.8% vs. 10.2% less than 50 copies/mL at week 48).
In patients previously exposed to four or more PIs, the advantage of tipranavir was still greater (27.0% versus 7.5% less than 400 copies/mL; 18.8% versus 4.3% less than 50 copies/mL at week 48). Even in patients with more modest PI exposure (two to three agents), tipranavir still had an advantage (37.7% versus 27.2% less than 400 copies/mL; 30.7% versus 22.6% less than 50 copies/mL at week 48).
It thus appears that if one were to use tipranavir in clinical practice, it has a substantial benefit over older PIs in patients who have been exposed to most of the available agents in this class. However, this benefit seems to extend to patients who have had prior use of as few as two PIs. In such cases, we would be tempted to use older agents, thinking they retain some efficacy. These data clearly demonstrate that tipranavir is a better option, perhaps defining its role more precisely in our clinical armamentarium.
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