Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).

OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 µg/l vs. 8.6 ± 2.8 µg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 µg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 µmol/l vs. 9 ± 21.8 µmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Imaging correlates of the blood-brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications.

OBJECTIVE: HIV-associated neurocognitive disorders (HANDs) in the context of suppressive combination antiretroviral therapy (cART) still occur. We explored the role of blood-brain barrier (BBB) disruption in the pathogenesis of HAND in the context of fully suppressive cART using dynamic contrast enhanced perfusion (DCE-P) MRI. DCE-P is a new MRI technique that measures capillary permeability as an indicator for BBB integrity. We hypothesized that virally suppressed incident HAND would be associated with an impaired BBB as determined by DCE-P. DESIGN: A cross sectional study. METHODS: K-trans, a metric derivative of DCE-P, was obtained from different regions of the brain in a cohort of 20 patients with HAND who were virally suppressed in both cerebrospinal fluid (CSF) and blood compared with CSF and blood markers of neuroinflammation as well as with neurometabolites derived from magnetic resonance (MR) spectroscopy. RESULTS: The K-trans data showed significantly impaired BBB in HAND patients when compared with the controls in the regions of the basal ganglia and anterior frontal white matter (both P < 0.0001). CSF neopterin and CSF/serum albumin ratio correlated positively with K-trans but not with blood levels. CONCLUSION: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region-specific BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that HIV and not systemic inflammation is driving the BBB disturbance and that the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease.

Atrophic brain signatures of mild forms of neurocognitive impairment in virally suppressed HIV infection.

OBJECTIVE: There is a lack of evidence for the neurobiological underpinning of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MNDs) in virally suppressed HIV-positive persons. We hypothesized that such mild impairment would be associated with focal brain atrophy. DESIGN: A cross-sectional observational study. METHODS: Eighty-five virally suppressed HIV-positive and 44 geographically, demographically and lifestyle comparable HIV-negative men underwent anatomical MRI, neuropsychological evaluation and HIV laboratory tests. Volumes of interest (VOI) from magnetic resonance (MR) images were extracted using FreeSurfer to yield grey and white matter volumes in regions associated with HIV-related brain injury. HIV-associated neurocognitive disorder (HAND) [ANI = 38%, MND = 13%, HIV-associated dementia (HAD) = 3% vs. neuropsychologically-normal] was classified using Global Deficit Score (GDS ≥0.5) and functional decline. Effects of HIV status on VOI were assessed with multivariate analyses controlling for family-wise error. HAND categories and HIV biomarker effects on VOI were assessed with multiple regression. RESULTS: Relative to the HIV-negative group, the HIV-positive group demonstrated subcortical grey (d = 0.50-0.60) and white matter (d = 0.43-0.69) atrophy, with relative cortical sparing (d = 0.23). ANI showed reduced medial-orbitofrontal white matter compared with NP-normal cases (P = 0.04). MND showed enlarged lateral ventricles (P = 0.02) and reduced caudal-middle-frontal white matter (P = 0.04), caudal-anterior-cingulate white matter (P = 0.006) and inferior-parietal white matter (P = 0.04) compared with neuropsychologically normal. Across the HIV-positive group, lower CD4+/CD8 ratio was the strongest predictor of atrophy in subcortical regions. Across HAND categories, HIV disease duration uniquely predicted greater medial-orbitofrontal white matter atrophy only in ANI (P = 0.002). CONCLUSION: ANI shows specific frontal white matter atrophy to which HIV disease duration is a unique contributor. MND is characterized by more widespread subcortical atrophy.

Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder.

OBJECTIVE: To investigate whether intensification of combined antiretroviral therapy (cART) with the CC chemokine receptor type 5 (CCR5) entry inhibitor maraviroc leads to improvement in global neurocognitive functioning in virally suppressed men with HIV-associated neurocognitive disorder (HAND). DESIGN: Prospective, double observer-blinded, open-label pilot randomized-controlled trial. Participants were randomized to remain on their existing cART regimen (control arm; n = 8) or receive maraviroc-intensification (maraviroc arm; n = 9). METHODS: Participants completed a five-domain neuropsychological battery at baseline, 6- and 12-month visits. Raw scores were transformed into age-corrected z-scores and averaged into a global z-score. Single voxel (H)-magnetic resonance spectroscopy (MRS) major cerebral metabolite concentrations were collected at baseline and 12 months in the basal ganglia and frontal white matter and quantified using jMRUI. Neuroinflammatory biomarkers cerebrospinal fluid neopterin and ß2-microglobulin were also measured. RESULTS: Fourteen of the 17 participants completed the study: nine maraviroc arm and five control. We found medium to large effect sizes in favour of improved global neurocognitive performance in the maraviroc arm over time {arm*time interaction: P < 0.05; 6 month: [ß=-0.10, standard error (SE)= 0.04, 90% confidence interval (90%CI)= -0.18,.03; P < 0.03] yielding a large effect-size d = 0.77 (90%CI = -0.19,1.71); 12 month: [ß=-0.01; SE = 0.05; 90%CI = -0.09, 0.06; P < 0.77] yielding a moderate effect-size d = 0.55 (90%CI = -0.47,1.55)}. No treatment-related changes were detected for H-MRS metabolites or cerebrospinal fluid biomarkers. CONCLUSION: This pilot study provides feasibility, tolerability, proof-of-concept and preliminary evidence for clinically relevant neurocognitive improvement in cART enhancement with maraviroc in virally suppressed HAND patients. Lack of concomitant brain metabolite and biomarker change may be related to complex dynamics of brain repair.