Clinical trial NCT02383355: Effects of Raltegravir Based Regimen on Platelet Reactivity, Platelet-monocyte Aggregation and Immune 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Keywords: Persistent immune activation
Platelet hyperreactivity
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-03-09
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding
timeFrame: Baseline and week 10
Secondary outcomes:
measure: Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry)
timeFrame: Baseline and week 10
measure: T-cell Dysfunction (CD4-cells)
timeFrame: Baseline and Week 10
measure: Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP)
timeFrame: Baseline and week 10
measure: Persistent Immune Activation - Monocyte Subsets
timeFrame: Baseline and week 10
Other outcomes:
Locations:
Study officials:
affiliation: Radboud University (Radboudumc)
name: Quirijn de Mast, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tunjungputri RN, Van Der Ven AJ, Schonsberg A, Mathan TS, Koopmans P, Roest M, Fijnheer R, Groot PG, de Mast Q. Reduced platelet hyperreactivity and platelet-monocyte aggregation in HIV-infected individuals receiving a raltegravir-based regimen. AIDS. 2014 Sep 10;28(14):2091-6. doi: 10.1097/QAD.0000000000000415.
citation: van der Heijden WA, van Crevel R, de Groot PG, Urbanus RT, Koenen HJPM, Bosch M, Keuter M, van der Ven AJ, de Mast Q. A switch to a raltegravir containing regimen does not lower platelet reactivity in HIV-infected individuals. AIDS. 2018 Nov 13;32(17):2469-2475. doi: 10.1097/QAD.0000000000001993.