HIV
Conditions
Keywords
Persistent immune activation, Platelet hyperreactivity
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.
Interventions
DRUGRaltegravir
Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy
DRUGContinuation of own regimen
Continuation of own antiretroviral medication during the 10 weeks follow-up
Sponsors
Merck Sharp & Dohme LLC
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Switch Group Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy for 10 weeks
Raltegravir: Raltegravir 400mg tablets administered twice daily together with continuation of their own backbone therapy | 19 |
| Continuation Group Individuals in the continuation group will continue the regimen, which consists of antiretroviral therapy as indicated in the inclusion criteria
Continuation of own regimen: Continuation of own antiretroviral medication during the 10 weeks follow-up | 21 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | Switch Group | Continuation Group | Total |
|---|---|---|---|
| Age, Continuous | 48 years | 49 years | 48 years |
| Region of Enrollment Netherlands | 19 participants | 21 participants | 40 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 18 Participants | 21 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 21 |
| other Total, other adverse events | 2 / 19 | 0 / 21 |
| serious Total, serious adverse events | 0 / 19 | 0 / 21 |
Outcome results
Primary
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.
Time frame: Baseline and week 10
Population: Intention to treat, if week 10 is not available, week 4 was used for these individuals (n=2)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 125uM CD62p expression | 0.9 Ratio |
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 125uM Fibrinogen binding | 1 Ratio |
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 7.8uM CD62p expression | 0.88 Ratio |
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 7.8uM fibrinogen binding | 0.85 Ratio |
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 655ng/ml CD62p expression | 0.95 Ratio |
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 655ng/ml fibrinogen binding | 0.8 Ratio |
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 27.33ng/ml CD62p expression | 0.87 Ratio |
| Switch Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 27.33 ng/ml fibrinogen binding | 0.88 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 27.33 ng/ml fibrinogen binding | 1.04 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 125uM CD62p expression | 0.96 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 655ng/ml CD62p expression | 0.94 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 125uM Fibrinogen binding | 0.99 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 27.33ng/ml CD62p expression | 0.84 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 7.8uM CD62p expression | 0.99 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | CRP (collagen) XL 655ng/ml fibrinogen binding | 0.8 Ratio |
| Continuation Group | Platelet Reactivity Measured by Expression of P-selectin (CD62p) and Fibrinogen Binding | ADP 7.8uM fibrinogen binding | 1.02 Ratio |
Secondary
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.
Time frame: Baseline and week 10
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Switch Group | Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP) | 1.208 ratio | Standard Deviation 0.895 |
| Continuation Group | Circulating Levels of High Sensitive C-reactive Protein (Hs-CRP) | 1.103 ratio | Standard Deviation 1.007 |
Secondary
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.
Time frame: Baseline and week 10
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Switch Group | Persistent Immune Activation - Monocyte Subsets | classical monocytes as % of total monocytes | 0.98 ratio |
| Switch Group | Persistent Immune Activation - Monocyte Subsets | intermediate monocytes as % of total monocytes | 1.042 ratio |
| Switch Group | Persistent Immune Activation - Monocyte Subsets | non-classical monocytes as % of total monocytes | 1 ratio |
| Continuation Group | Persistent Immune Activation - Monocyte Subsets | classical monocytes as % of total monocytes | 0.998 ratio |
| Continuation Group | Persistent Immune Activation - Monocyte Subsets | intermediate monocytes as % of total monocytes | 0.979 ratio |
| Continuation Group | Persistent Immune Activation - Monocyte Subsets | non-classical monocytes as % of total monocytes | 1.089 ratio |
Secondary
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.
Time frame: Baseline and week 10
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Switch Group | Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry) | 0.95 ratio |
| Continuation Group | Platelet-leukocyte Aggregates (Platelet Monocyte Complex Measured by Flow-cytometry) | 0.932 ratio |
Secondary
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.
Time frame: Baseline and Week 10
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Switch Group | T-cell Dysfunction (CD4-cells) | 1.314 ratio |
| Continuation Group | T-cell Dysfunction (CD4-cells) | 1.016 ratio |