Effects of Raltegravir Based Regimen on Platelet Reactivity, Platelet-monocyte Aggregation and Immune Activation

Study Overview
=================
Brief Summary
-----------------
Cardiovascular disease (CVD) has emerged as a leading cause of morbidity and mortality in HIVinfected individuals. The precise mechanisms underlying this increased cardiovascular risk remain to be elucidated. Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are found in HIVinfectedpatients and may contribute to the excess cardiovascular risk as platelets play a key role in the onset and progression of atherosclerosis and in acute cardiovascular events. In addition, HIV-infected individuals frequently suffer from persistent immune activation and inflammation. In a crosssectional study the investigators recently showed that individuals using a regimen containing the integrase inhibitor raltegravir have reduced platelet hyperreactivity and PMA compared to other antiretroviral regimens. Other recent studies showed that raltegravir is associated with decreased immune activation. Due to the inherent limitations of cross sectional studies, the investigators aim to expand our findings in an intervention study. The investigators will conduct a randomized control trial where the investigators switch patients to a integrase containing treatment regimen to assay possible changes in platelet function and persistent immune activation. Knowledge gathered in the proposed study can help understand and prevent cardiovascular disease in patients treated for a HIV infection by reducing platelet hyperreactivity and persistent immune activation.

Detailed Description
-----------------
Rationale: Cardiovascular disease (CVD) has emerged as a leading cause of morbidity and mortality in HIV-infected individuals. The precise mechanisms underlying this increased cardiovascular risk remain to be elucidated . Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are found in HIV-infected patients and may contribute to the excess cardiovascular risk as platelets play a key role in the onset and progression of atherosclerosis and in acute cardiovascular events. In addition, HIV-infected individuals frequently suffer from persistent immune activation and inflammation. In a cross-sectional study the investigators recently showed that individuals using a regimen containing the integrase inhibitor raltegravir have reduced platelet hyperreactivity and PMA compared to other antiretroviral regimens. Other recent studies showed that raltegravir is associated with decreased immune activation. Due to the inherent limitations of cross sectional studies, the investigators aim to expand our findings in an intervention study. Objective: Investigate whether switch from a non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based regimen to a raltegravir-based regimen results in reduced platelet reactivity, reduced platelet-leukocyte aggregate formation and pro-inflammatory status of monocytes. Study design: Investigator initiated, single-center, open-label, randomized controlled trial in HIV-infected patients using a NNRTI- or PI-based regimen. Study population: Adult HIV-infected study participants with undetectable (<40 copies/mL) viral load receiving a standard backbone of two NRTI's (either tenofovir (TDF)/emtricitabine (FTC) or abacavir (ABC)/lamivudine (3TC)) with either a NNRTI (efavirenz (EFV) or rilpivirine (RPV)) or a boosted PI (Darunavir (DRV/r), atazanavir (ATZ/r) or Lopinavir (LPV/r)). After Sample size calculation two groups of 20 subjects will be enrolled. Intervention: Participants will be randomized (1:1) to continue the same ART regimen (Continuation group) or to switch their NNRTI or PI to raltegravir (Switch group) during 10 weeks. Main study parameters/endpoints: Primary parameter: 1. Platelet reactivity: platelet expression of the platelet activation marker CD62P (P-selectin) and activated fibrinogen receptor (αIIbβ3) upon stimulation with different platelet agonists. Secondary parameters: Platelet-leukocyte aggregates (eg. PMA). Activation markers on T cells and monocytes. Soluble (plasma) markers of platelet and monocyte activation.

Official Title
-----------------
Switch From an NNRTI or PI-based Regimen to a RAltegravir-based Regimen in Virologically Suppressed HIV-infected Patients: Effects on Platelet Reactivity, Platelet-monocyte Aggregation and the Inflammatory anD Thrombotic State of Monocytes

Conditions
-----------------
HIV

Intervention / Treatment
-----------------
* Drug: Raltegravir
* Drug: Continuation of own regimen


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female Documented HIV-infection Age ≥ 18 years Willing to comply with the protocol requirements On stable antiretroviral therapy (ART) for ≥ 6 months at screening Undetectable plasma HIV viral load (<50 copies/mL) for at least 6 months CD4 cell count > 300 cells/mm3 at last measurement Current ART regimen at screening consisting of a backbone of two NRTI's (either TDF/FTC or ABC/3TC) with either a NNRTI (EFV or RPV) or a boosted PI (DRV/r, ATZ/r or LPV/r) and on this regimen for > 3 months If female and of childbearing potential using effective birth control methods Exclusion Criteria: Use of platelet function inhibitors, such as aspirin and adenosine diphosphate (ADP) receptor antagonists Known hypersensitivity to raltegravir or any other component of the formulation Using any concomitant therapy disallowed as per summary of product characteristics (SPC) for the study drug Signs of symptoms of an active (opportunistic) infection other than HIV Active hepatitis B or C Estimated glomerular filtration rate (by MDRD) <50 ml/min Clinical or laboratory evidence of significantly decreased hepatic function, defined as alanine aminotransferase (ALAT) level > 2 upper limit of normal (ULN) History of suspected or proven virologic failure since ART initiation (HIV-1 RNA blips less than 500 copies per milliliter with subsequent suppression are allowed) Known genotypic resistance to any current ART component Prior use of single or dual NRTI-only regimens, or history of any ART not considered highly active by current standards. In females, pregnancy or breast feeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Switch group<br>Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks | Drug: Raltegravir<br>* Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy<br>* Other names: Isentress;|
| Active Comparator: Continuation group<br>Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria | Drug: Continuation of own regimen<br>* Continuation of own antiretroviral medication during the 10 weeks follow-up<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | Platelet expression of the platelet activation marker CD62P (P-selectin) and of the activated fibrinogen receptor (αIIbβ3) through fibrinogen binding following stimulation with two concentrations of the platelet agonists ADP (adenosine diphosphate) and CRP-XL (crosslinked collagen related peptide). Difference between week 0 and week 10. Primary outcome is CD62p expression upon stimulation with ADP (power calculation based on this measure). Expression of both markers are expressed as MFI (Median fluorescence intensity) and measured by flowcytometry. Change after 10 weeks was calculated as a ratio between baseline and week 10. | Baseline and week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry) | Platelet monocyte complex (PMCs) measured by flow-cytometry. % of CD61+ (platelet-marker) monocytes. Change after 10 weeks was calculated as a ratio between baseline and week 10. | Baseline and week 10 | 
| T-cell Dysfunction (CD4-cells) | Markers of persistent immune activation measured by flow cytometry (% of CD4-cells positive for CD38HLA-DR cells). Change after 10 weeks was calculated as a ratio between baseline and week 10. | Baseline and Week 10 | 
| Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP) | Plasma levels of hs-CRP (ng/mL) measured by ELISA . Change in concentration was calculated as a ratio between baseline (week 0) and week 10. | Baseline and week 10 | 
| Persistent Immune Activation - Monocyte Subsets | Monocyte subsets measured by flowcytometry. Classical monocytes (CD14+,CD16-), intermediate (CD14+CD16+), Non-classical (CD14dimCD16+). Reported values are change between baseline and week 10 and reported as ratio. | Baseline and week 10 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Persistent immune activation, Platelet hyperreactivity