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      Absence of peripapillary retinal nerve-fiber–layer thinning in combined antiretroviral therapy-treated, well-sustained aviremic persons living with HIV

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          Abstract

          Purpose

          To compare peripapillary retinal nerve-fiber–layer (pRNFL) thickness, total retina macular volume, and ganglion-cell-layer (GCL) macular volume and thickness between persons living with HIV (PLHIVs) with well-controlled infections and good immune recovery, and sex- and age-matched HIV-uninfected controls (HUCs).

          Methods

          This prospective cross-sectional study ( www.clinicaltrials.gov identifier: NCT02003989) included 56 PLHIVs, infected for ≥10 [median 20.2] years and with sustained plasma HIV-load suppression on combined antiretroviral therapy (cART) for ≥5 years, and 56 matched HUCs. Participants underwent spectral-domain optical coherence tomography (SD-OCT) with thorough ophthalmological examinations and brain magnetic resonance imaging (MRI). Their overall and quadrant pRNFL thicknesses, total macular volumes, and GCL macular volumes and thicknesses were compared. Cerebral small-vessel diseases (CSVD) complied with STRIVE criteria.

          Results

          Median [interquartile range, IQR] ages of PLHIVs and HUCs, respectively, were 52 [46–60] and 52 [44–60] years. Median [IQR] PLHIVs’ nadir CD4+ T-cell count and current CD4/CD8 T-cell ratio were 249/μL [158–350] and 0.95 [0.67–1.10], respectively; HIV-seropositivity duration was 20.2 [15.9–24.5] years; cART duration was 16.8 [12.6–18.6] years; and aviremia duration was 11.4 [7.8–13.6] years. No significant between-group pRNFL thickness, total macular volume, macular GCL-volume and -thickness differences were found. MRI-detected CSVD in 21 (38%) PLHIVs and 14 (25%) HUCs was associated with overall thinner pRNFLs, and smaller total retina and GCL macular volumes, independently of HIV status.

          Conclusions

          SD-OCT could not detect pRNFL thinning or macular GCL-volume reduction in well-sustained, aviremic, cART-treated PLHIVs who achieved good immune recovery. However, CSVD was associated with thinner pRNFLs and GCLs, independently of HIV status.

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          Most cited references52

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          Retinal imaging and image analysis.

          Many important eye diseases as well as systemic diseases manifest themselves in the retina. While a number of other anatomical structures contribute to the process of vision, this review focuses on retinal imaging and image analysis. Following a brief overview of the most prevalent causes of blindness in the industrialized world that includes age-related macular degeneration, diabetic retinopathy, and glaucoma, the review is devoted to retinal imaging and image analysis methods and their clinical implications. Methods for 2-D fundus imaging and techniques for 3-D optical coherence tomography (OCT) imaging are reviewed. Special attention is given to quantitative techniques for analysis of fundus photographs with a focus on clinically relevant assessment of retinal vasculature, identification of retinal lesions, assessment of optic nerve head (ONH) shape, building retinal atlases, and to automated methods for population screening for retinal diseases. A separate section is devoted to 3-D analysis of OCT images, describing methods for segmentation and analysis of retinal layers, retinal vasculature, and 2-D/3-D detection of symptomatic exudate-associated derangements, as well as to OCT-based analysis of ONH morphology and shape. Throughout the paper, aspects of image acquisition, image analysis, and clinical relevance are treated together considering their mutually interlinked relationships.
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            Automated 3-D intraretinal layer segmentation of macular spectral-domain optical coherence tomography images.

            With the introduction of spectral-domain optical coherence tomography (OCT), much larger image datasets are routinely acquired compared to what was possible using the previous generation of time-domain OCT. Thus, the need for 3-D segmentation methods for processing such data is becoming increasingly important. We report a graph-theoretic segmentation method for the simultaneous segmentation of multiple 3-D surfaces that is guaranteed to be optimal with respect to the cost function and that is directly applicable to the segmentation of 3-D spectral OCT image data. We present two extensions to the general layered graph segmentation method: the ability to incorporate varying feasibility constraints and the ability to incorporate true regional information. Appropriate feasibility constraints and cost functions were learned from a training set of 13 spectral-domain OCT images from 13 subjects. After training, our approach was tested on a test set of 28 images from 14 subjects. An overall mean unsigned border positioning error of 5.69+/-2.41 microm was achieved when segmenting seven surfaces (six layers) and using the average of the manual tracings of two ophthalmologists as the reference standard. This result is very comparable to the measured interobserver variability of 5.71+/-1.98 microm.
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              CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy.

              Despite immune recovery in individuals on combination antiretroviral therapy (CART), the frequency of HIV-associated neurocognitive disorders (HANDs) remains high. Immune recovery is typically achieved after initiation of ART from the nadir, or the lowest historical CD4. The present study evaluated the probability of neuropsychological impairment (NPI) and HAND as a function of CD4 nadir in an HIV-positive cohort. One thousand five hundred and twenty-five HIV-positive participants enrolled in CNS HIV Antiretroviral Therapy Effects Research, a multisite, observational study that completed comprehensive neurobehavioral and neuromedical evaluations, including a neurocognitive test battery covering seven cognitive domains. Among impaired individuals, HAND was diagnosed if NPI could not be attributed to comorbidities. CD4 nadir was obtained by self-report or observation. Potential modifiers of the relationship between CD4 nadir and HAND, including demographic and HIV disease characteristics, were assessed in univariate and multivariate analyses. The median CD4 nadir (cells/μl) was 172, and 52% had NPI. Among impaired participants, 603 (75%) had HAND. Higher CD4 nadirs were associated with lower odds of NPI such that for every 5-unit increase in square-root CD4 nadir, the odds of NPI were reduced by 10%. In 589 virally suppressed participants on ART, higher CD4 nadir was associated with lower odds of NPI after adjusting for demographic and clinical factors. As the risk of NPI was lowest in patients whose CD4 cell count was never allowed to fall to low levels before CART initiation, our findings suggest that initiation of CART as early as possible might reduce the risk of developing HAND, the most common source of NPI among HIV-infected individuals.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 March 2020
                2020
                : 15
                : 3
                : e0229977
                Affiliations
                [1 ] Département d’Ophtalmologie, Fondation Adolphe de Rothschild, Paris, France
                [2 ] Service d’Ophtalmologie, APHP, Hôpital Bichat–Claude-Bernard, Paris, France
                [3 ] Service des Maladies Infectieuses et Tropicales, APHP, Hôpital Saint-Antoine, Paris, France
                [4 ] Service d’Imagerie Médicale, Fondation Adolphe de Rothschild, Paris, France
                [5 ] Service des Maladies Infectieuses et Tropicales, APHP, Hôpital Bichat–Claude-Bernard Paris, Paris, France
                [6 ] Unité de Recherche Clinique, Fondation Adolphe de Rothschild, Paris, France
                [7 ] Service de Pneumologie, Institut Mutualiste Montsouris, Paris, France
                [8 ] Sorbonne Paris Cité, Université Paris Diderot, Paris, France
                [9 ] Service de Neurologie, Fondation Adolphe de Rothschild, Paris, France
                University of Florida, UNITED STATES
                Author notes

                Competing Interests: C. Lamirel, N. Valin, J. Savatosky, A.-S. Alonso, J.-P. Vincensini, L. Salomon and I. Cochereau have no disclosures to report. F.-X. Lescure has received funding for board membership from Gilead Sciences and MSD France; for lectures from BioMérieux, Gilead Sciences and MSD France; and to travel to meetings from Gilead Sciences, MSD France, Astellas and Eumedica. P. Girard has received support to travel to meetings and accommodations from Bayer and Leo Pharma. P.-M. Girard has received honoraria for participation on international advisory boards from Gilead, ViiV Healthcare and Abbvie, and honoraria for speaking engagements from Janssen and BMS. A. Moulignier has received research support from the Association Nationale de Recherche sur le SIDA (ANRS); funding for lectures from Biogen Idec and Norvartis, and to travel to meetings from Biogen Idec and Teva Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-6732-1779
                http://orcid.org/0000-0001-7566-0175
                Article
                PONE-D-19-30049
                10.1371/journal.pone.0229977
                7064175
                32155200
                e66d5314-3829-4918-b146-0b9b83b2c8bc
                © 2020 Lamirel et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 October 2019
                : 18 February 2020
                Page count
                Figures: 3, Tables: 4, Pages: 18
                Funding
                Funded by: french ministry of health
                Award ID: CRC3F
                Award Recipient :
                This research was supported by a budgetary grant from the French Ministry of Health/DGOS/CRC3F. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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