Effects of Tipranavir, Darunavir, and Ritonavir on Platelet Function, Coagulation, and Fibrinolysis in Healthy Volunteers

Jens J Kort,Joseph Scherer,Patrick Robinson,Veronika Kohlbrenner,John P Sabo,Stella Aslanyan

doi:10.2174/157016211796320306

Abstract

The use of HIV protease inhibitors (PIs) as part of antiretroviral therapy in the treatment of HIV-1 infection may be associated with an increased risk of bleeding. This prospective, randomized, open-label trial in healthy volunteers compared the effects of tipranavir/ritonavir (TPV/r), darunavir/ritonavir (DRV/r), and ritonavir (RTV) alone on platelet aggregation after a single dose and at steady-state concentrations. Subjects were selected on the basis of normal platelet aggregation and arachidonic acid (AA)-induced platelet aggregation inhibition after administration of a single 325-mg dose of aspirin. All 3 PI therapies were administered twice daily for 10 days.In some but not all subjects, TPV/r inhibited AA-induced platelet aggregation and prolonged PFA-100® closure time with collagen-epinephrine cartridge, which was of lesser magnitude and consistency compared with aspirin, but greater when compared to DRV/r and RTV. At least 2 subjects in each treatment arm showed complete inhibition of AA-induced platelet aggregation on treatment, and the magnitude of change in all platelet-function tests did not correlate with PI plasma concentrations. Effects of TPV/r on platelet aggregation were reversed 24 hours after the last TPV/r dose. None of the PI treatments tested were associated with increases in bleeding time, decreases in plasma coagulation factors, or increase in fibrinolysis. There was large inter-patient variability in antiplatelet effect for all PI treatments, ranging from no effect to complete inhibition of AA-induced platelet aggregation.

Highlights

Long-term combination antiretroviral therapy is associated with various complications, including cardiovascular events [1], lipodystrophy [2], and non-AIDSdefining cancers [3].Tipranavir (TPV), coadministered with low-dose ritonavir (TPV/r), is indicated for cART of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than 1 protease inhibitor (PI) [4]
Subjects were screened at visit 1, baseline platelet-function tests were obtained for each eligible subject at visit 2, and at visit 3, each subject received a single dose of aspirin 325 mg followed by determination of platelet function after 4 hours
Our results demonstrate that TPV/r inhibits the pathway of arachidonic acid (AA)-induced platelet aggregation in some, but not all subjects while single-dose aspirin completely inhibited AAinduced platelet aggregation in all subjects not allowing for correlation analysis between aspirin and TPV/r effects

Summary

Introduction

Tipranavir (TPV), coadministered with low-dose ritonavir (TPV/r), is indicated for cART of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than 1 protease inhibitor (PI) [4]. The incidence of ICH events in TPV/rtreated patients is low, 0.26/100 person-years of exposure, or 13 cases of ICH in 6,840 patients in TPV/r pre-approval trials [6], and this incidence for ICH is similar to that of HIV-infected patients who received a non-TPV/r-containing cART based on retrospective analyses of 2 large patient cohorts (N > 78,000 HIV-infected patients combined) from the California state Medicaid program (Medi-Cal) and the U.S Veterans Healthcare System (VA) [9,10]. In a recent study with platelet-rich plasma (PRP) taken from 5 HIV-infected patients receiving TPV/r-containing cART, inhibition of collagen- (p

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