4 Jun 2020: Lamirel C, Valin N, Savatovsky J, Lescure FX, Alonso AS, et al. (2020) Correction: Absence of peripapillary retinal nerve-fiber–layer thinning in combined antiretroviral therapy-treated, well-sustained aviremic persons living with HIV. PLOS ONE 15(6): e0234497. https://doi.org/10.1371/journal.pone.0234497 View correction
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).
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.
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.
Citation: Lamirel C, Valin N, Savatovsky J, Lescure F-X, Alonso A-S, Girard P, et al. (2020) Absence of peripapillary retinal nerve-fiber–layer thinning in combined antiretroviral therapy-treated, well-sustained aviremic persons living with HIV. PLoS ONE 15(3): e0229977. https://doi.org/10.1371/journal.pone.0229977
Editor: Alfred S. Lewin, University of Florida, UNITED STATES
Received: October 28, 2019; Accepted: February 18, 2020; Published: March 10, 2020
Copyright: © 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.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: 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.
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.
Combined antiretroviral therapy (cART) ensures human immunodeficiency virus (HIV) suppression and immunological recovery in a majority of persons living with HIV (PLHIVs), dramatically improving life expectancy [1,2]. As a consequence, cART-treated PLHIVs are exposed to chronic HIV-infection that may be deleterious to neural tissues [3,4]. Hence, despite well-sustained immunovirological control on cART, subtle structural and functional retinal abnormalities, described as HIV-associated neuroretinal disorder (HIV–NRD) and milder forms of HIV-associated neurocognitive disorders (HAND) are still frequent in PLHIVs [5,6]. In addition, aging PLHIVs’ life expectancy persistently lags behind that of the general population, predominantly because of their heightened risk for age-related comorbidities, to which they might be more vulnerable [7,8]. Among those age-related comorbidities, magnetic resonance imaging (MRI)-detected  cerebral small-vessel disease (CSVD) prevalence is doubled in cART-treated, immunovirologically well-controlled, middle-aged PLHIVs compared to age-matched HIV-uninfected individuals . The best-known MRI characteristics of CSVD are white-matter hyperintensities (WMHs) of presumed vascular origin, silent brain infarcts and cerebral microbleeds . To better characterize and differentiate CSVD-surrogate WMHs from WMHs of other origins, the STandards for ReportIng Vascular changes on Euroimaging (STRIVE) criteria, developed to standardize reading of CSVD neuroimages, were applied . The results of several studies [12–15] documented the cognitive impact of CSVD-surrogate WMHs on cART-treated PLHIVs with long-term virus suppression, leading to the recent paradigm of vascular-driven, milder HAND forms .
The concept of the retina being an anatomical and functional central nervous system surrogate is increasingly recognized . Notably, cerebral and retinal arterioles share similar anatomy, physiology and embryology, and evidence supports an association between retinal vessel changes and CSVD . Optical coherence tomography (OCT) is an in situ micrometer-scale imaging technique that closely correlates with histological retinal structures [19,20]. Indeed, OCT accurately and reproducibly measures the peripapillary retinal nerve-fiber–layer (pRNFL) thickness that reflects the number of ganglion-cell axons leaving the retina to form the optic nerve. OCT can also evaluate the thickness of the ganglion-cell–layer (GCL) macula that contains mostly ganglion-cell bodies.
Spectral-domain (SD)-OCT detected significant pRNFL thinning in severely immunodeficient PLHIVs (i.e., CD4+ T-cell count <100/μL) [21–23]. In PLHIVs, GCL thinning has been associated with HAND . However, those findings were heterogeneous, and all studies were hampered by the absence of brain and orbit MRI to exclude optic neuropathy or CSVD (Table 1). Indeed, pRNFL thinning has been associated with optic neuropathies , and CSVD-surrogate WMHs in the general population [26,27] and HIV-infected children .
We undertook this concurrent cohort study to investigate pRNFL and GCL thicknesses in PLHIVs with well-sustained, cART-controlled, immunovirological parameters and HIV-uninfected controls (HUCs). Because we wanted to examine the role of chronic HIV infection itself, we selected PLHIVs with cART-sustained, immunovirological control for at least 5 years, without hepatitis C virus (HCV) infection, past or ongoing acquired immune deficiency syndrome (AIDS)-defining neurological events (ADNEs), and/or alcohol or illicit drug abuse.
This study, approved by the CPP Île-de-France VI Ethics Committee, adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.
In this cross-sectional study (NCT02003989), we prospectively included PLHIVs followed in two Infectious Diseases Departments in University Hospitals, caring for about 8,000 PLHIVs in the Paris area (France). Inclusion criteria were: (1) HIV seropositivity known for ≥10 years; sustained CD4+ T-cell count ≥350/μL and plasma HIV load (plVL) <20 copies/mL for ≥5 years on cART. plVL was quantified using the Amplicor monitor assay (Cobas 2.0, Roche Diagnostics, Basel, Switzerland), which has a lower detection limit of 20 HIV-1 RNA copies/mL. Exclusion criteria were: (1) transient low-level viremias ≥20 but ≤200 copies/mL (viral blip) once within the previous 5 years; (2) history/concomitant ocular trauma or diseases; (3) family history of glaucoma; (4) prior/current treatment with drugs associated with toxic optic neuropathy or retinopathy; (5) prior/current neurological/psychiatric disorders, including ADNE; (6) prior/current diabetes mellitus; (7) prior/current alcohol or illicit substance abuse (with the exception of occasional cannabis use); (8) HCV infection. Cognitive decay was not sought prior to inclusion and was not an exclusion criterion.
Age (±5 years)- and sex-matched (1:1) HUCs were selected on a voluntary basis; exclusion criteria were the same as for PLHIVs. The absence of HIV infection was confirmed by ELISA or rapid HIV test.
All participants underwent the same comprehensive neurological and ophthalmological examinations. All SD-OCT were obtained with a Spectralis OCT, which generates four sectoral pRNFL thicknesses and an overall value that is the average of the four quadrants, using the new Nsite Axonal Analytics software (Heidelberg Engineering GmbH, Heidelberg, Germany). Overall and sectoral pRNFL thicknesses were recorded for each eye. The total retinal macular volume was calculated with the Heidelberg software using the Early Treatment for Diabetic Retinopathy Study (ETDRS) grid. We used the Iowa Reference Algorithm to segment the GCL and calculated the GCL thickness for each of the 9 ETDRS-grid subfields and the total GCL macular volume within the ETDRS grid (S1 Fig) [29–31]. Cognition was assessed using the Montreal Cognitive Assessment (MoCA), known to be an adequate clinical and ecological screening tool for PLHIVs [32,33]. 3-Tesla brain MRI and orbit images (Philips Healthcare, Best, The Netherlands) were analyzed by one neuroradiologist (J.S.) blinded to all parameters. CSVD was defined according to the Standards for Reporting Vascular Changes on Neuroimaging (STRIVE) Criteria .
Main outcome measure and estimated number of participants
The main outcome measure was the overall pRNFL thickness. Previous studies found a standard deviation of ~9 μm for it with the OCT machine used herein . With that standard deviation, a unilateral 5% alpha-risk and 95% power, we estimated that 50 participants in each group would be sufficient to detect ≥7-μm pRNFL thinning in PLHIVs compared to HUCs.
Only one eye of each participant was randomly selected for analysis. The non-parametric Mann-Whitney U-test and chi2 or Fisher’s exact test were used as appropriate to compare groups. Analysis of variance (ANOVA) of repeated measures was used to detect differences among the different pRNFL quadrants and among the different GCL ETDRS-grid subfields.
Linear-regression models were used to test associations between OCT measurements (outcome variables: overall and temporal pRNFL thicknesses, total retinal macular volumes, GCL macular volumes) and visual function measurements, axial length and age (predictor variables). HIV status was included in all these linear-regression models to test a possible HIV effect on an association.
For the PLHIV group, associations between overall and temporal pRNFL thicknesses, total retinal macular volumes, GCL macular volumes (outcome variables) and duration of HIV infection (predictor variable) were tested with a multivariate model including age as a covariate. Univariate regression analyses were used to identify associations between PLHIVs’ overall and temporal pRNFL thicknesses, total retinal macular volumes or GCL macular volumes (outcome variables) and CD4+ T-cell nadirs (predictor variable).
Significance was defined as p<0.05. All analyses were computed with Statistica software (Statsoft, Inc, Maison Alfort, France) and no statistical correction was made for multiple comparisons.
Among 71 PLHIVs initially included, 15 were secondarily excluded because of bilateral glaucoma (n = 1), bilateral high ametropia (n = 6), previous bilateral ocular surgery (n = 3), alcoholism (n = 1), diabetes (n = 2), HCV infection (n = 1) or missing MRI (n = 1). Among 65 HUCs initially included, nine were secondarily excluded because of bilateral high ametropia (n = 4), bilateral glaucoma (n = 1), diabetes (n = 1), HCV infection (n = 1), missing MRI (n = 1) or MRI-detected meningioma (n = 1). A total of 56 PLHIV-eyes and 56 HUC-eyes were included in the statistical analyses. Participants’ characteristics are summarized in Table 2.
The median CD4+ T-cell nadir was 249 cells/μL and median CD4/CD8 T-cell ratio was 0.95. All PLHIVs had plVLs <20 copies/mL for 11±4 years and achieved immune recovery on cART, including aviremia and CD4+ T-cell counts >350 cells/μL for 10±3 years.
pRNFL thicknesses, total retinal macular volumes and GCL macular volumes and thicknesses (Table 3) did not differ between PLHIVs and HUCs. These analyses were repeated using the other eye when both eyes were assessable and the results were comparable (S1 Table). Potential confounding factors (axial length, spherical equivalent and Optical Quality Analyzing System (OQAS)-assessed media opacity) were comparable for PLHIVs and HUCs.
Among the functional parameters (Table 3), high contrast VA, low contrast VA and color vision were comparable for PLHIVs and HUCs. However, visual field mean deviations (MDs) and intraocular pressure (IOP) differed significantly, being slightly lower for PLHIVs than HUCs but still within normal limits.
Associations between structural measures and other variables are reported in Table 4. Age was associated with overall pRNFL thickness, GCL macular volume and total retinal macular volume, with HIV status having no significant effect (Fig 1). Among the PLHIVs, no significant association between structural measures and HIV-infection duration or CD4+ T-cell nadir was found (Table 4, Fig 2).
Significant linear correlations were found between the overall pRNFL or macular GCL volume and the ages of the persons living with human immunodeficiency virus (PLHIVs) or the HIV-uninfected controls (HUCs). The HIV status had no significant effect on this association. The linear-regression equation is given.
The vertical line represents the CD4+ T-cell count nadir of 100 cells/μL, because previous studies found that only PLHIVs with nadirs <100 cells/μL were more likely to have thinner pRNFLs. In our study only nine PLHIVs had a nadir <100 cells/μL but their pRNFL thicknesses and macular GCL volumes did not differ from those of the other PLHIVs.
MRIs did not reveal a lesion that could cause optic neuropathy or trans-synaptic retrograde degeneration within the optic nerves. MRI detected CSVD in 21 (38%) PLHIVs and 14 (25%) HUCs (p = 0.15); it mainly reflected WMHs of presumed vascular origin (21 PLHIVs versus 12 HUCs, p = 0.06). Documented CSVD was associated with overall thinner pRNFLs, smaller whole retinal macular volumes and smaller GCL macular volumes for all participants, with HIV status having no significant effect (Fig 3, S1 Table).
The mean overall pRNFL thickness (top) and the mean macular GCL volume (bottom) are reported for all participants, persons living with human immunodeficiency virus (PLHIVs) and for HIV-uninfected controls (HUCs). Error bars represent the standard deviation. Participants with MRI-defined CSVD had significantly thinner pRNFL (p = 0.04; ANOVA) and smaller macular GCL volume (p<0.01; ANOVA) compared to the participants with no CSVD. HIV status had no significant effect on pRNFL and no significant interaction with the effect of CSVD on pRNFL (S2 Table).
Our results showed that overall and 4-quadrant (localized) pRNFLs, total retinal macular volumes, GCL macular volumes and EDTRS-grid–defined GCL regional thicknesses were not smaller in long-term–sustained, immunovirologically controlled PLHIVs compared to age- and sex-matched HUCs.
Our results agree with those of two studies [5,24] that had included long-term, cART-treated, immunovirologically well-controlled HIV+ individuals. However, our results (versus  or , respectively) extend their findings because our population is more homogenous, facilitating exploration of the impact of: (1) longer-known HIV infection (median 20 [range 11–30] versus median 15 [range 1–27] or mean 15 [range 1–30] years), (2) longer cART exposure (median 17 [range 6–22] versus median 12 [range 1–21] years or unavailable), (3) more prolonged plVL undetectability (median 11 [range 5–17] versus median 10 [range 0–15] years or unavailable), (4) less severe immunosuppression (CD4+ T-count nadir median 249 [range 158–350] versus median 180 [range 0–620] and mean 172 [range 1–552] cells/μL) and (5) well-sustained immunovirological variables (duration of plVL undetectability and CD4+ T-cell counts >350 μL (median 11 [range 5–17] years versus unavailable for both studies; CD4/CD8 T-cell ratio (median 0.95 [range 0.67–1.10] versus median 0.75 [range 0.29–4.13] or unavailable).
According to Invernizzi et al. , the GCL was thinner only for the subgroup of cART-treated PLHIVs with a mean MoCA score <26/30 (n = 34) compared to HUCs. For PLHIVs with a MoCA score ≥26/30 (n = 35), GCL thickness was comparable to that of HUCs, as we found. As for Invernizzi et al. , the MoCA score was neither an inclusion nor exclusion criterion for our study. Only one of our PLHIVs had a MoCA score <26/30 (i.e., 25/30), probably because they met the parameters associated with the most preserved cognitive functions, i.e.: high educational level, CD4+ T-cell count nadir >200 cells/μL and current CD4/CD8 T-cell ratio ~1 [35–41].
Significant overall pRNFL thinning was found in other studies, but affected only PLHIVs with CD4+ T-cell count nadirs <100 cells/μL for ≥6 months, compared to PLHIVs with nadirs >100 cells/μL [21,22] or HUCs [21,23]. However, many HIV variables were missing in those reports: (1) HIV-seropositivity duration [22,23,42–44], (2) cART duration [22–24,44,45], (3) current plVL or duration of undetectability [21–23,42–43,46] and (4) current CD4+ T-cell counts [22,23,43,45]. Hence, those studies’ results cannot explain whether the pRNFL thinning could be attributed to severe immunodeficiency alone or its combination with prolonged HIV infection without sustained immunovirological control.
The higher frequency of CVSD-surrogate WMHs in aviremic, cART-treated PLHIVs compared to HUCs, not related to any ART classes, was recently reported [10,47]. We found only a trend toward significance for WMHs of presumed vascular origin between PLHIVs and HUC (p = 0.06). That failure to reach significance is probably due to a lack of statistical power of our study. These vascular abnormalities were associated with thinner overall pRNFLs, smaller total retina macular volumes and smaller CGL macular volumes, independently of HIV status. A pRNFL thinning or defect was reported previously for the arteriosclerotic CSVD form  and cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) , a genetic form of CSVD. To the best of our knowledge, that association has not been reported previously in adult, cART-treated PLHIVs with CSVD. CSVD is characterized by thickening of the walls of the small perforating arteries in the brain, resulting in low cerebral blood flow . A causative role of cerebral hypoperfusion and decreased perfusion of the inner retinal layers has been advanced to explain the association of CSVD with pRNFL and GCL thinning, as shown for CADASIL . Our results agree with an emerging change of the NeuroHIV paradigm, highlighting the potential contribution of vascular brain damage in aging PLHIVs .
Despite being the first combined OCT–MRI study in middle-aged, cART-treated PLHIVs with well-sustained immune restoration, our study might suffer from a lack statistical power. Although our study-sample size might be considered relatively small, it is in accordance with previous similar publications (Table 1) and is sufficient to highlight pRNFL differences in these subjects. Although PLHIV and HUC pRNFL-thickness sameness cannot be established, our study’s statistical power to detect thinning of –5 μm was 90%. Interestingly, the test–retest variability of SD-OCT–measured pRNFL thickness was ~5 μm . Because the primary endpoint and the power calculation were based on the overall pRNFL thickness, interpretation of the lack of a smaller GCL volume and localized pRNFL thinning in our study requires prudence. Localized pRNFL thinning could result from methodological biases secondary to the multiplicity of statistical comparisons without control for inflation of the type-1 error . That bias was also seen in macula studies, in which multiple quadrants and multiple retinal layer thicknesses generated high numbers of p values. Such methodological biases were previously highlighted by Demirkaya et al. .
Although our series is not representative of the entire HIV+ population, it is representative of PLHIVs receiving care in northern Europe, where >90% are successfully treated . However, the 2019 UNAIDS world epidemiological data showed that 79% of PLHIVs are aware of their seropositivity, 78% of PLHIVs knowing their HIV status are cART-treated and 86% of those cART-treated PLHIVs have a plVL below the detection threshold (unaids.org). Moreover, it was recently demonstrated that low plVLs of 51–200 copies/mL were strongly associated with virological failure . Thus, HIV-induced brain damage may be more a legacy effect resulting from prior incomplete virus control [54,55]. Those findings provide support for the European definition of virological failure as persistent plVLs of >50 copies/mL (eacsociety.org). Our findings should not be compared or held as a contradiction to historical studies and may better apply to future PLHIV cohorts, for whom the therapeutic guidelines recommend that cART must be initiated for a CD4+ T-cell count threshold ≥500 cells/μL . Indeed, the CASCADE study showed that PLHIVs are mostly diagnosed and treated with a CD4+ T-cell count nadir >200 cells/μL . Recent findings showed that full viral suppression may preserve long-term PLHIVs’ brain health . Hence, continuing to report results concerning virologically uncontrolled, cART-treated PLHIVs is not really suitable [54,55,58].
In addition to the OCT evaluation of visual pathway structures, most visual evaluation and ocular parameters were similar for PLHIVs and HUCs, with the exception of visual field MDs and IOP. Decreased visual field MD is a classic sign of HIV–NRD but in our study it cannot be explained by pRNFL thinning or decreased GCL macular volume. That decline could however be explained by functional changes without structural damage of the retinal ganglion cells or other cells implicated in vision. Indeed, decreased cone-photoreceptor density in HIV+ participants was found using an adaptive optics camera  and SD-OCT visualized possible changes in retinal layers other than GCL and RNFL [5,60,61]. Lower IOP in HIV+ participants was previously described and its causes are more likely multifactorial . Our results showed that this diminished IOP persists in PLHIVs with long-term, well-sustained immune control.
Our results showed that cART-treated PLHIVs who successfully achieved sustained immunovirological control, even with HIV infection lasting 20 years, do not have pRNFL thinning. That is an optimistic finding in terms of PLHIVs aging. However, in line with recent results from a study on HIV-infected children , as in the general population, CSVD in our middle-aged PLHIVs was associated with thinner pRNFLs and GCLs.
S1 Fig. The 9 Early Treatment Diabetic Retinopathy Study (ETDRS)-grid subfields used to analyze ganglion-cell layer thickness in right and left eyes.
1, fovea; 2, parafovea superior; 3, parafovea temporal; 4, parafovea inferior; 5, parafovea nasal; 6, perifovea superior; 7, perifovea temporal; 8, perifovea inferior; and 9, perifovea nasal.
S1 Table. Associations between radiological and spectral-domain optical coherence tomography findings and HIV status.
S2 Table. Optical coherence tomography measurements in PLHIVs and HUCs using the other eye when both eyes were assessable.
PLHIVs, persons living with HIV: HUCs, healthy uninfected controls.
The authors thank Janet Jacobson for editorial assistance and Gilbert Lesage for bibliographic assistance.
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