Evaluation of Platelet Activation by HIV Protease Inhibitors – The HIV-PLA II Study

Abstract

Background

In the past, protease inhibitors (PIs) and the reverse transcriptase inhibitor abacavir were identified increasing the risk for thromboembolic complications and cardiovascular events (CVE) of HIV infected patients taking a combination antiretroviral therapy (cART). Results of the previous HIV-PLA I-study lead to the assumption that platelet activation could play a substantial role in increasing CVE risks.

Methods

The open label, monocentric HIV-PLA II-study investigated HIV-1-infected, therapy-naïve adults (n=45) starting with cART, consisting either of boosted PI (atazanavir, n= 6, darunavir, n=11), NNRTI (efavirenz, n=14) or integrase inhibitor (raltegravir, n=14), each plus tenofovir/emtricitabine co-medication. Main exclusion criteria were tobacco smoking, the intake of NSAIDs or abacavir or past CVE. Platelet adhesive molecule p-selectin (CD62P) and FITC anti-human Integrin α-IIb/Integrin β-3 (CD41/CD61) antibody (PAC-1) binding, monocyte CD11b/monocyte-associated CD41 expression and the endogenous thrombin potential (ETP) were assessed ex vivo-in vitro at baseline, weeks 4, 12 and 24. Therapy regimens were blinded to the investigators for laboratory and statistical analyses.

Results

CD11b and ETP showed no significant changes or differences between all study groups. In contrast, the mean + SD mean fluorescence units (MFI) of CD62P and PAC-1 increased significantly in patients taking PI, indicating an enhanced potential for thrombocyte activation and aggregation.

Conclusion

CD62P expression, detecting the ɑ-platelet degranulation of pro-inflammatory and pro-thrombotic factors and adhesive proteins, and PAC-1 expression, representing a marker for conformation changes of the GIIb/IIIa receptor, increased significantly in patients taking HIV protease inhibitors. The findings of this study revealed a yet unknown pathway of platelet activation, possibly contributing to the increased risk for CVE under HIV protease inhibitor containing cART.

Clinical Trial Registration No.

DRKS00000288.

Keywords:

• HIV protease inhibitors
• platelets
• leucocytes
• PAC-1
• GIIb/IIIa-receptor

Data Sharing Statement

Data, ie anonymized patient´s characteristics and laboratory raw data, can be accessed by an official request (c. Person, Institution, Direction, Contact Data) via email to the corresponding author until 30.06.2021. Deidentified participant data or any other study documents will not be shared due to the European and German data safety regulations (General Data Protection Regulation, GDPR, Art. No.3).

Disclosure

Dr Karina Kuczka reports grants from Heinrich- und Fritz Riese-Stiftung (Foundation) during the conduct of the study. Dr Timo Wolf reports personal fees from Gilead, during the conduct of the study; personal fees from Gilead, Merck Sharp Dome, outside the submitted work. Dr Pavel Khaykin reports personal fees from Gilead, AbbVie, Sanofi, ViiV, outside the submitted work. The authors report no other conflicts of interest in this work.

Additional information

Funding

The authors are grateful for the support of this study provided by the Fritz- und Heinrich Riese Foundation.