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Safety and Efficacy of Tipranavir (TPV), a Novel Non-Peptide Protease Inhibitor in PI-Failure Patients
(study 1182.4)
written by Jules Levin
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Charles Farthing presented preliminary results from studying Tipranavir compared to the double PI regimen of ritonavir/saquinavir in patients with previous PI experience. The problem with this study is that many patients did not have PI resistance although they had prior PI experience. Farthing said 40%-50% of patients entering the study had no PI mutations. Also, Farthing did not report PI resistance mutations for patients that had any. The potential appeal for Tipranavir is for patients with resistance to protease inhibitors and perhaps for patients with extensive PI resistance. This study does not examine Tipranavir use in these types of patients. This study does show the antiviral activity of Tipranavir but it is not expected that Tipranavir is any more potent or has any more antiviral activity than other Pis. In fact its antiviral activity may or may not be equal to other Pis. The potential usefulness for this PI is in patients with extensive PI resistance, and this study does not examinine its use for these patients. In addition, the manufactuter, Boerhinger-Ingleheim, is still unsure of the dose to be used. Three twice daily doses will be explored in future studies: 500/100, 500/200, and 750/200 (TPV/RTV). Studies in patients with extensive resistance are expected to be conducted. Dosing for TPV may eventually be different than thae dosing explored in this study.
Farthing said as others have reported that TPV is the first in a new class of non-peptidic Pis. It has a flexible structure that allows it to bind to the protease enzyme despite the presence of PI resistance mutations. Previous studies reported TPV retains in vitro activity against >90% of virsuses resistant to protease inhibitors currently available. It also has shown potent activity against wild-type HIV.
Farthing said the target plasma levels for wild-type are: EC90 0.5-1.0 um; for PI resistant virus: >20-25 um. TPV blood levels (trough and AUC) are markedly enhanced by ritonavir and will be used in combination.
This study was an open-label, randomized, parallel group trial of patients with single PI failure and 2 or more NRTI options. Patients could have any CD4 count and viral load >1000 copies/ml.
Patients were randomized to one of three arms:
--TPV SEDDS (self-emulsifying drug delivery) formulation 500 mg with100 mg ritonavir (RTV) twice daily and 2 NRTIs (n=21)
--TPV SEDDS formulation 1250 mg plus 100 mg RTV twice daily with 2 NRTIs (n=21)
--saquinavir 400 mg +ritonavir 400 mg twice daily with 2 NRTIs (n=21)
All 3 groups were fairly evenly matched for baseline demographic characertistics:
--15 men, 6 females
--age: 37-40
--race: white 43%-67%; black 28-57%
--median HIV-RNA: 4.44 log (27,000 copies/ml) in 500/100 arm; 4.63 log (42,000 copies/ml) in 1250/100 arm; 4.2 log (16,000 c/ml) in RTV/SQV arm
--median CD4 count: 293-370
RESULTS
Viral Load Reduction at week 16 (ITT-LOCF, last observation carried forward)
-1.40 log for the TPV 1250/100 arm
-1.40 log for the 500/100 TPV arm
-1.36 for the RTV/SQV arm
So, the viral load reduction was about the same or better for both TPV arms compared to the RTV/SQV arm. However, company researchers said many patients in this study did not have PI resistance, therefore this study would not be a true test of TPV's performance in patients with extensive PI resistance. Farthing reported patients with no PI mutations (n=17) in the 2 TPV arms combined had a viral load reduction of -1.41 compared to -0.87 for patients in the RTV/SQV arm who had no PI mutations (n=11) but this difference was not statistically significant (p=1.0).
Percent of Patients with >1 log reduction in HIV-RNA (ITT-MCF)
About 55% in the 2 TPV arms and 40% in the RTV/SQV arms
Boerhinger-Ingleheim that reported at week 16 (ITT, but I'm not sure if analysis was LOCF or M=F), 55% in the TPV 1250, 39% in the TPV 500 group, and 40% in the RTV/SQV group had <400 copies/ml. The percent of patients with <50 copies/ml was reported at 35% in TPV 1250, 22% in TPV 500, and 30% in SQV/RTV.
Discontinuations
There were a total of 5 discontinuations in the TPV 500 arm (1 due to adverse event), 4 in 1250 TPV (2 due to adverse event), and 11 in RTV/SQV (5 due to adverse event). In sum, there were 3/42 (7%) AE-related discontinuations in the 2 TPV arms and 5/21 (24%) in the RTV/SQV arms.
Most Common Adverse Events (grade 2 or more)
Reportedly the most common drug related adverse events were gastrointestinal (GI): diarrhea, nausea, vomiting. The amount of GI side effects does appear to be related to the dose of TPV with higher dosing showing more GI side effects. Diarrhea: 14% in RTV/SQV; 19% in TPV 1250, 5% in TPV 500. Nausea: RTV/SQV 14%, TPV 1250 33%, TPV 500 14%. Vomiting: 10% RTV/SQV, 24% 1250 TPV, 0% 500 TPV. Fatigue: 14% RTV/SQV, 19% 1250 TPV, 0% 500 TPV.
Lab Abnormalities
-- ALT („ grade 3): 1 patients (5%) in TPV arm and 1 in RTV/SQV arm
-- Triglycerides („ grade 3) 3 patients (14%) in TPV 500 , 4 patients (19%) in TPV 1250, 1 patient (5%) in RTV/SQV.
-- Total cholesterol („2x ULN): 2 patients (10%) in TPV 500, 0% in TPV 1250, 1 patient (5%) in RTV/SQV
--CPK („ grade 3): 2 patients (10% in TPV 500, 0% in TPV 1250, and 2 patients (10%) in RTV/SQV.
Farthing reported that the GI side effects were self-limiting, meaning that they tended to occur with the first 28 days of treatment & resolved spontaneously or with the use of over-the-counter remedies. It does appear as though elevations in triglycerides and cholesterol will acompany TPV use.
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