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

NCT ID: NCT02383355

Last Updated: 2019-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-01
• Study Completion Date: 2017-07-01

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.

Conditions

HIV

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Switch group

Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks

Group Type: EXPERIMENTAL

Raltegravir

Intervention Type: DRUG

Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy

Continuation group

Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria

Group Type: ACTIVE_COMPARATOR

Continuation of own regimen

Intervention Type: DRUG

Continuation of own antiretroviral medication during the 10 weeks follow-up

Interventions

Raltegravir

Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy

Intervention Type: DRUG

Continuation of own regimen

Continuation of own antiretroviral medication during the 10 weeks follow-up

Intervention Type: DRUG

Other Intervention Names

Isentress

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Quirijn de Mast, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University (Radboudumc)

References

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.

Reference Type: RESULT

PMID: 25265076 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30134289 (View on PubMed)

Other Identifiers

2014-1320

Identifier Type: OTHER

Identifier Source: secondary_id

NL50681.091.14

Identifier Type: -

Identifier Source: org_study_id