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

Phase 4

Completed

Conditions: HIV

Interventions: Drug: Continuation of own regimen
Drug: Raltegravir

Registration Number: NCT02383355

Lead Sponsor: Radboud University Medical Center

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:

1. Platelet-leukocyte aggregates (eg. PMA).

2. Activation markers on T cells and monocytes.

3. Soluble (plasma) markers of platelet and monocyte activation.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Continuation group	Continuation of own regimen	Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria
Switch group	Raltegravir	Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks

Primary Outcome Measures

Name	Time	Method
Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding	Baseline and week 10	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.

Secondary Outcome Measures

Name	Time	Method
Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry)	Baseline and week 10	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.
T-cell Dysfunction (CD4-cells)	Baseline and Week 10	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.
Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP)	Baseline and week 10	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.
Persistent Immune Activation - Monocyte Subsets	Baseline and week 10	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.