The effectiveness of cinacalcet: a randomized, open label study in chronic hemodialysis patients with severe secondary hyperparathyroidism

Background: Secondary hyperparathyroidism (SHPT) is associated with high incidences of cardiovascular disease, bone fracture, and mortality. This study was conducted to demonstrate the effectiveness of cinacalcet treatment on chronic kidney disease-mineral bone disorder (CKD-MBD) markers in chronic hemodialysis patients with severe SHPT. Methods: In phase 1, 30 adult HD patients were randomized to cinacalcet or control groups for 12 weeks to explore the achievement of >30% reduction of iPTH. In phase 2, 45 patients were participated to further explore the effect of cinacalcet on CKD-MBD parameters for 24-week follow up and 12 additional weeks after cinacalcet discontinuation. Results: In phase 1, the baseline serum iPTH levels were not different [1374 (955, 1639) pg/mL in the control group vs. 1191 (1005, 1884) pg/mL in the cinacalcet group], the percentage of patients achieving iPTH target were significantly higher in the treatment group [80% vs. 13%, p = .001]. In phase 2, the significant reductions of iPTH, FGF-23, tartrate-resistant acid phosphatase 5b, and slightly decreased size of parathyroid gland and stabilized vascular calcification were observed at 24-week follow up and markedly rebounded after discontinuation of cinacalcet. Conclusions: The effectiveness of cinacalcet were still obviously demonstrated even in chronic HD patients with severe SHPT. In addition, the improvements of bone markers and FGF-23, and stabilization of vascular calcification were observed. Therefore, cinacalcet can provide salutary effects on CKD-MBD in severe SHPT and might be an initially effective PTH-lowering therapy prior to surgical parathyroidectomy as well as an alternative treatment in the patients unsuitable for surgery. Clinical trial registration: ClinicalTrials.gov: NCT02056730. Date of registration: February 4, 2014

Structural and Functional Brain Imaging in Acute HIV

Background:HIV RNA is identified in cerebrospinalfluid (CSF) within eightdays of estimated viral exposure. Neurological findings and impaired neuropsychological testing performance are documented in a subset of individuals with acuteHIV infection (AHI). The purpose of this study was to determine whether microstructural white matter and resting-state functional connectivity (rsFC) are disruptedin AHI.Methods:We examined 49 AHI (100% male; mean age = 30 ± SD 9.9) and 23 HIV-uninfected Thai participants (78% male; age = 30 ± 5.5) with diffusion tensor imaging (DTI) and rsFC acquired at 3 Tesla, and four neuropsychological tests (summarized as NPZ-4). MRI for the AHI group was performed prior to combination antiretroviral treatment (ART) in 26 participants and on average two days (range:1–5) after ART in 23 participants. Fractional anisotropy (FA), mean (MD), axial(AD), and radial diffusivity (RD) were quantified for DTI. Seed-based voxelwise rsFC analyses were completed for the default mode (DMN), fronto-parietal, and salience and 6 subcortical networks. rsFC and DTI analyses were corrected for family-wise error, with voxelwise comparisons completed using t-tests. Group-specific voxelwise regressions were conducted to examine relationships between imaging indices, HIV disease variables, and treatment status.Results:The AHI group had a mean (SD) CD4 count of 421(234) cells/mm3 plasma HIV RNA of 6.07(1.1) log10copies/mL and estimated duration of infection of20(5.5) days. Differences between AHI and CO groups did not meet statistical significance for DTI metrics. Within the AHI group, voxelwise analyses revealed associations between brief exposure to ART and higher FA and lower RD and MD bilaterally in the corpus callosum, corona radiata, and superior longitudinal fasciculus (p \u3c 0.05). Diffusion indices were unrelated to clinical variables or NPZ-4. The AHI group had reduced rsFC between left parahippocampal cortex (PHC)of the DMN and left middle frontal gyrus compared to CO (p \u3c 0.002). Within AHI, ART status was unrelated to rsFC. However, higher CD4 cell count associated with increased rsFC for the right lateral parietal and PHC seeds in the DMN. Direct associations were noted between NPZ-4 correspond to higher rsFC of the bilateral caudate seed (p \u3c 0.002).Conclusions: Study findings reveal minimal disruption to structural and functional brain integrity in the earliest stages of HIV. Longitudinal studies are needed to determine if treatment with ART initiated in AHI is sufficient to prevent the evolution of brain dysfunction identified in chronically infected individuals

Regional brain volumetric changes despite 2 years of treatment initiated during acute HIV infection

Objective:To assess changes in regional brain volumes after 24 months among individuals who initiated combination antiretroviral therapy (cART) within weeks of HIV exposure.Design:Prospective cohort study of Thai participants in the earliest stages of HIV-1infection.Methods:Thirty-four acutely HIV-infected individuals (AHI; Fiebig I-V) underwent brain magnetic resonance (MR) imaging and MR spectroscopy at 1.5T and immediately initiated cART. Imaging was repeated at 24 months. Regional brain volumes were quantified using FreeSurfer's longitudinal pipeline. Voxel-wise analyses using tensor-based morphometry (TBM) were conducted to verify regional assessments. Baseline brain metabolite levels, blood and cerebrospinal fluid biomarkers assessed by ELISA, and peripheral blood monocyte phenotypes measured by flow cytometry were examined as predictors of significant volumetric change.Results:Participants were 31±8 years old. The estimated mean duration of infection at cART initiation was 15 days. Longitudinal analyses revealed reductions in volumes of putamen (P<0.001) and caudate (P=0.006). TBM confirmed significant atrophy in the putamen and caudate, and also in thalamic and hippocampal regions. In exploratory post-hoc analyses, higher baseline frequency of P-selectin glycoprotein ligand-1 (PSGL-1)-expressing total monocytes correlated with greater caudate volumetric decrease (ρ=0.67, P=0.017), whereas the baseline density of PSGL-1-expressing inflammatory (CD14 +CD16 +) monocytes correlated with putamen atrophy (ρ=0.65, P=0.022).Conclusion:Suppressive cART initiated during AHI may not prevent brain atrophy. Volumetric decrease appears greater than expected age-related decline, although examination of longitudinal change in demographically similar HIV-uninfected Thai individuals is needed. Mechanisms underlying progressive HIV-related atrophy may include early activation and enhanced adhesive and migratory capacity of circulating monocyte populations