Browse Subject Areas

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

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

  • Cedric Lamirel ,

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliations Département d’Ophtalmologie, Fondation Adolphe de Rothschild, Paris, France, Service d’Ophtalmologie, APHP, Hôpital Bichat–Claude-Bernard, Paris, France

  • Nadia Valin,

    Roles Investigation, Writing – review & editing

    Affiliation Service des Maladies Infectieuses et Tropicales, APHP, Hôpital Saint-Antoine, Paris, France

  • Julien Savatovsky,

    Roles Investigation

    Affiliation Service d’Imagerie Médicale, Fondation Adolphe de Rothschild, Paris, France

  • François-Xavier Lescure,

    Roles Investigation, Writing – review & editing

    Affiliation Service des Maladies Infectieuses et Tropicales, APHP, Hôpital Bichat–Claude-Bernard Paris, Paris, France

  • Anne-Sophie Alonso,

    Roles Investigation

    Affiliation Unité de Recherche Clinique, Fondation Adolphe de Rothschild, Paris, France

  • Philippe Girard,

    Roles Investigation

    Affiliation Service de Pneumologie, Institut Mutualiste Montsouris, Paris, France

  • Jean-Paul Vincensini,

    Roles Investigation

    Affiliation Service des Maladies Infectieuses et Tropicales, APHP, Hôpital Saint-Antoine, Paris, France

  • Pierre-Marie Girard,

    Roles Investigation, Writing – review & editing

    Affiliation Service des Maladies Infectieuses et Tropicales, APHP, Hôpital Saint-Antoine, Paris, France

  • Laurence Salomon,

    Roles Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing – review & editing

    Affiliation Unité de Recherche Clinique, Fondation Adolphe de Rothschild, Paris, France

  • Isabelle Cochereau,

    Roles Investigation, Writing – review & editing

    Affiliations Département d’Ophtalmologie, Fondation Adolphe de Rothschild, Paris, France, Service d’Ophtalmologie, APHP, Hôpital Bichat–Claude-Bernard, Paris, France, Sorbonne Paris Cité, Université Paris Diderot, Paris, France

  • Antoine Moulignier

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation Service de Neurologie, Fondation Adolphe de Rothschild, Paris, France

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

  • Cedric Lamirel, 
  • Nadia Valin, 
  • Julien Savatovsky, 
  • François-Xavier Lescure, 
  • Anne-Sophie Alonso, 
  • Philippe Girard, 
  • Jean-Paul Vincensini, 
  • Pierre-Marie Girard, 
  • Laurence Salomon, 
  • Isabelle Cochereau


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. 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 ( 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.


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.


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 [9] cerebral small-vessel disease (CSVD) prevalence is doubled in cART-treated, immunovirologically well-controlled, middle-aged PLHIVs compared to age-matched HIV-uninfected individuals [10]. The best-known MRI characteristics of CSVD are white-matter hyperintensities (WMHs) of presumed vascular origin, silent brain infarcts and cerebral microbleeds [11]. 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 [9]. The results of several studies [1215] 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 [16].

The concept of the retina being an anatomical and functional central nervous system surrogate is increasingly recognized [17]. Notably, cerebral and retinal arterioles share similar anatomy, physiology and embryology, and evidence supports an association between retinal vessel changes and CSVD [18]. 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) [2123]. In PLHIVs, GCL thinning has been associated with HAND [24]. 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 [25], and CSVD-surrogate WMHs in the general population [26,27] and HIV-infected children [28].

Table 1. Reported peripapillary retinal nerve-fiber–layer (pRNFL) thicknesses in PLHIV or HUC participants.

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.


Ethics approval

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.

Study population

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) [2931]. 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 [9].

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 [34]. 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.

Statistical analyses

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.

Table 2. Epidemiological, clinical, biological and radiological characteristics of PLHIV and HUC participants.

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.

Table 3. Spectral domain-optical coherence tomography or visual function measurements and ocular findings of PLHIV and HUC participants.

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).

Fig 1. Association between overall peripapillary retinal nerve-fiber–layer (pRNFL) thickness (top) or ganglion-cell–layer (GCL) volume (bottom) and age of PLHIVs and HUCs.

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.

Fig 2. No association between PLHIVs’ overall peripapillary retinal nerve-fiber–layer (pRNFL) thickness (top) or ganglion-cell–layer (GCL) volume (bottom) and CD4+ T-cell count nadirs of the persons living with human immunodeficiency virus (PLHIVs).

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.

Table 4. Associations between structural measurements and other variables of PLHIVs and/or HUCs.

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).

Fig 3. Effect of cerebral small-vessel disease (CSVD) on overall peripapillary retinal nerve-fiber–layer (pRNFL) thickness (top) and ganglion-cell–layer (GCL) volume (bottom) in all participants.

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 [5] or [24], 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. [24], 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. [24], 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 [3541].

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 [22,23,4244], (2) cART duration [2224,44,45], (3) current plVL or duration of undetectability [2123,4243,46] 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 [26] and cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [48], 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 [49]. 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 [50]. Our results agree with an emerging change of the NeuroHIV paradigm, highlighting the potential contribution of vascular brain damage in aging PLHIVs [16].

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 [51]. 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 [52]. 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. [5].

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 [53]. 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 ( Moreover, it was recently demonstrated that low plVLs of 51–200 copies/mL were strongly associated with virological failure [54]. 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 ( 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 [56]. Indeed, the CASCADE study showed that PLHIVs are mostly diagnosed and treated with a CD4+ T-cell count nadir >200 cells/μL [57]. Recent findings showed that full viral suppression may preserve long-term PLHIVs’ brain health [58]. 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 [59] 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 [61]. 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 [28], as in the general population, CSVD in our middle-aged PLHIVs was associated with thinner pRNFLs and GCLs.

Supporting information

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.


S1 File. Excel file containing all the relevant data underlying the findings described in the manuscript.



The authors thank Janet Jacobson for editorial assistance and Gilbert Lesage for bibliographic assistance.


  1. 1. Costagliola D. Demographics of HIV and aging: Curr Opin HIV AIDS. 2014;9:294–301. pmid:24824889
  2. 2. Ghosn J, Taiwo B, Seedat S, Autran B, Katlama C. HIV. The Lancet. 2018;392:685–697.
  3. 3. Gray LR, Roche M, Flynn JK, Wesselingh SL, Gorry PR, Churchill MJ. Is the central nervous system a reservoir of HIV-1? Curr Opin HIV AIDS. 2014;9: 552–558. pmid:25203642
  4. 4. Mzingwane ML, Tiemessen CT. Mechanisms of HIV persistence in HIV reservoirs. Rev Med Virol. 2017;27. pmid:28128885
  5. 5. Demirkaya N, Wit FWNM, van Den Berg TJTP, Kooij KW, Prins M, Schlingemann RO, et al. HIV-Associated Neuroretinal Disorder in Patients With Well-Suppressed HIV-Infection: A Comparative Cohort Study. Investig Opthalmology Vis Sci. 2016;57: 1388. pmid:27018841
  6. 6. Smail RC, Brew BJ. HIV-associated neurocognitive disorder. Handbook of Clinical Neurology. Elsevier; 2018. pp. 75–97.
  7. 7. Wang T, Yi R, Green LA, Chelvanambi S, Seimetz M, Clauss M. Increased cardiovascular disease risk in the HIV-positive population on ART: potential role of HIV-Nef and Tat. Cardiovasc Pathol. 2015;24:279–282. pmid:26233281
  8. 8. Cohen RA, Seider TR, Navia B. HIV effects on age-associated neurocognitive dysfunction: premature cognitive aging or neurodegenerative disease? Alzheimers Res Ther. 2015;7. pmid:25848401
  9. 9. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–838. pmid:23867200
  10. 10. Moulignier A, Savatovsky J, Assoumou L, Lescure F-X, Lamirel C, Godin O, et al. Silent cerebral small-vessel disease is twice as prevalent in middle-aged individuals with well-controlled, combination antiretroviral therapy-treated human immunodeficiency virus (HIV) than in HIV-uninfected individuals. Clin Infect Dis. 2018;66:1762–1769. pmid:29244126
  11. 11. Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019;18: 684–696. pmid:31097385
  12. 12. Su T, Wit FWNM, Caan MWA, Schouten J, Prins M, Geurtsen GJ, et al. White matter hyperintensities in relation to cognition in HIV-infected men with sustained suppressed viral load on combination antiretroviral therapy: AIDS. 2016;30:2329–2339. pmid:27149087
  13. 13. van Zoest RA, Underwood J, De Francesco D, Sabin CA, Cole JH, Wit FW, et al. Structural brain abnormalities in successfully treated HIV infection: associations with disease and cerebrospinal fluid biomarkers. J Infect Dis. 2018;217:69–81. pmid:29069436
  14. 14. Schouten J, Su T, Wit FW, Kootstra NA, Caan MWA, Geurtsen GJ, et al. Determinants of reduced cognitive performance in HIV-1-infected middle-aged men on combination antiretroviral therapy. AIDS. 2016;30:1027–1038. pmid:26752277
  15. 15. Watson C, Busovaca E, Foley JM, Allen IE, Schwarz CG, Jahanshad N, et al. White matter hyperintensities correlate to cognition and fiber tract integrity in older adults with HIV. J Neurovirol. 2017;23:422–429. pmid:28101804
  16. 16. Cysique LA, Brew BJ. Vascular cognitive impairment and HIV-associated neurocognitive disorder: a new paradigm. J Neurovirol. 2019;25:710–721. pmid:30635846
  17. 17. Cameron JR, Tatham AJ. A window to beyond the orbit: the value of optical coherence tomography in non-ocular disease. Acta Ophthalmol (Copenh). 2016;533–539. pmid:26803923
  18. 18. Kwa VI, van der Sande JJ, Stam J, Tijmes N, Vrooland JL. Retinal arterial changes correlate with cerebral small-vessel disease. Neurology 2002;59:1536–1540. pmid:12451193
  19. 19. Blumenthal EZ, Parikh RS, Pe’er J, Naik M, Kaliner E, Cohen MJ, et al. Retinal nerve fibre layer imaging compared with histological measurements in a human eye. Eye. 2009;23:171–175. pmid:17721504
  20. 20. Lamirel C, Newman N, Biousse V. The use of optical coherence tomography in neurology. Rev Neurol Dis. 2009;6:E105–120. pmid:20065921
  21. 21. Faria e Arantes TE, Garcia CR, Mello PA de A, Muccioli C. Structural and functional assessment in HIV-infected patients using optical coherence tomography and frequency-doubling technology perimetry. Am J Ophthalmol. 2010;149:571–576.e2. pmid:20149340
  22. 22. Cheng S, Klein H, Bartsch D-U, Kozak I, Marcotte TD, Freeman WR. Relationship between retinal nerve fiber layer thickness and driving ability in patients with human immunodeficiency virus infection. Graefes Arch Clin Exp Ophthalmol. 2011;249:1643–1647. pmid:21732109
  23. 23. Kozak I, Bartsch D-U, Cheng L, Kosobucki BR, Freeman WR. Objective analysis of retinal damage in HIV-positive patients in the HAART era using OCT. Am J Ophthalmol. 2005;139:295–301. pmid:15733991
  24. 24. Invernizzi A, Acquistapace A, Bochicchio S, Resnati C, Rusconi S, Ferrari M, et al. Correlation between inner retinal layer thickness and cognitive function in HIV: new insights from an exploratory study. AIDS. 2018;32:1485–1490. pmid:29734219
  25. 25. Costello F, Burton JM. Retinal imaging with optical coherence tomography: a biomarker in multiple sclerosis? Eye Brain. 2018;10: 7–63. pmid:30104912
  26. 26. Kim M, Park KH, Kwon JW, Jeoung JW, Kim T-W, Kim DM. Retinal Nerve Fiber Layer Defect and Cerebral Small Vessel Disease. Investig Opthalmology Vis Sci. 2011;52: 6882. pmid:21791593
  27. 27. Ulusoy MO, Horasanlı B, Kal A. Retinal vascular density evaluation of migraine patients with and without aura and association with white matter hyperintensities. Acta Neurol Belg. 2019 [cited 22 Mar 2019]. pmid:30762208
  28. 28. Blokhuis C, Demirkaya N, Cohen S, Wit FWNM, Scherpbier HJ, Reiss P, et al. The eye as a window to the brain: neuroretinal thickness is associated with microstructural white matter injury in HIV-infected children. Investig Opthalmology Vis Sci. 2016;57:3864. pmid:27447087
  29. 29. Sonka M, Abràmoff MD. Quantitative analysis of retinal OCT. Med Image Anal. 2016;33:165–169. pmid:27503080
  30. 30. Garvin MK, Abramoff MD, Xiaodong Wu, Russell SR, Burns TL, Sonka M. Automated 3-D Intraretinal layer segmentation of macular spectral-domain optical coherence tomography images. IEEE Trans Med Imaging. 2009;28:1436–1447. pmid:19278927
  31. 31. Abramoff MD, Garvin MK, Sonka M. Retinal imaging and image analysis. IEEE Rev Biomed Eng. 2010;3: 169–208. pmid:22275207
  32. 32. Fazeli PL, Casaletto KB, Paolillo E, Moore RC, Moore DJ, The Hnrp Group null. Screening for neurocognitive impairment in HIV-positive adults aged 50 years and older: Montreal Cognitive Assessment relates to self-reported and clinician-rated everyday functioning. J Clin Exp Neuropsychol. 2017;39: 842–853. pmid:28122474
  33. 33. Chartier M, Crouch P-C, Tullis V, Catella S, Frawley E, Filanosky C, et al. The Montreal Cognitive Assessment: a pilot study of a brief screening tool for mild and moderate cognitive impairment in HIV-positive veterans. J Int Assoc Provid AIDS Care. 2015;14:197–201. pmid:25487428
  34. 34. Alasil T, Wang K, Keane PA, Lee H, Baniasadi N, de Boer JF, et al. Analysis of normal retinal nerve fiber layer thickness by age, sex, and race using spectral domain optical coherence tomography: J Glaucoma. 2013;22:532–541. pmid:22549477
  35. 35. Foley JM, Ettenhofer ML, Kim MS, Behdin N, Castellon SA, Hinkin CH. Cognitive reserve as a protective factor in older HIV-positive patients at risk for cognitive decline. Appl Neuropsychol Adult. 2012;19:16–25. pmid:22385375
  36. 36. Crum-Cianflone NF, Moore DJ, Letendre S, Roediger MP, Eberly L, Weintrob A, et al. Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons. Neurology. 2013;80: 371–379. pmid:23303852
  37. 37. Vassallo M, Durant J, Lebrun-Frenay C, Fabre R, Ticchioni M, Andersen S, et al. Virologically suppressed patients with asymptomatic and symptomatic HIV-associated neurocognitive disorders do not display the same pattern of immune activation: The CD4:CD8 ratio and neurocognitive disorders. HIV Med. 2015;16:431–440. pmid:25981452
  38. 38. Cole MA, Margolick JB, Cox C, Li X, Selnes OA, Martin EM, et al. Longitudinally preserved psychomotor performance in long-term asymptomatic HIV-infected individuals. Neurology. 2007;69: 2213–2220. pmid:17914066
  39. 39. Cole JH, Caan MWA, Underwood J, De Francesco D, van Zoest RA, Wit FWNM, et al. No evidence for accelerated aging-related brain pathology in treated human immunodeficiency virus: longitudinal neuroimaging results from the comorbidity in relation to AIDS (COBRA) project. Clin Infect Dis. 2018;66: 1899–1909. pmid:29309532
  40. 40. Pedersen KK, Pedersen M, Gaardbo JC, Ronit A, Hartling HJ, Bruunsgaard H, et al. Persisting inflammation and chronic immune activation but intact cognitive function in HIV-infected patients after long-term treatment with combination antiretroviral therapy. J Acquir Immune Defic Syndr. 2013;63:272–279. pmid:23392469
  41. 41. Ellis RJ, Badiee J, Vaida F, Letendre S, Heaton RK, Clifford D, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. 2011;25: 1747–1751. pmid:21750419
  42. 42. Demirkaya N, Wit F, Schlingemann R, Verbraak F. Neuroretinal degeneration in HIV patients without opportunistic ocular infections in the cART era. AIDS Patient Care STDs. 2015;29:519–532. pmid:26258992
  43. 43. Pathai S, Lawn SD, Weiss HA, Cook C, Bekker L-G, Gilbert CE. Retinal nerve fibre layer thickness and contrast sensitivity in HIV-infected individuals in South Africa: a case-control study. PLoS ONE. 2013;8: e73694. pmid:24069225
  44. 44. Bartsch D-U, Kozak I, Grant I, Knudsen VL, Weinreb RN, Lee BR, et al. Retinal nerve fiber and optic disc morphology in patients with human immunodeficiency virus using the Heidelberg retina tomography 3. PLOS ONE. 2015;10: e0133144. pmid:26258547
  45. 45. Barteselli G, Chhablani J, Gomez ML, Doede AL, Dustin L, Kozak I, et al. Visual function assessment in simulated real-life situations in HIV-infected subjects. PLoS ONE. 2014;9: e97023. pmid:24809827
  46. 46. Arantes TE, Garcia CR, Tavares IM, Mello PA, Muccioli C. Relationship between retinal nerve fiber layer and visual field function in human immunodeficiency virus–infected patients without retinitis: Retina. 2012;32:152–159. pmid:21716164
  47. 47. Januel E, Godin O, Moulignier A, Lescure F-X, Savatovsky J, Lamirel C, et al. Impact of ART classes on the increasing risk of cerebral small-vessel disease in middle-aged, well-controlled, cART-treated, HIV-infected individuals. J Acquir Immune Defic Syndr. 2019;81:547–551. pmid:31107300
  48. 48. Rufa A, Pretegiani E, Frezzotti P, De Stefano N, Cevenini G, Dotti MT, et al. Retinal nerve fiber layer thinning in CADASIL: an optical coherence tomography and MRI study. Cerebrovasc Dis. 2011;31:77–82. pmid:21051887
  49. 49. Shi Y, Thrippleton MJ, Makin SD, Marshall I, Geerlings MI, de Craen AJ, et al. Cerebral blood flow in small vessel disease: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2016;36:1653–1667. pmid:27496552
  50. 50. Harju M, Tuominen S, Summanen P, Viitanen M, Pöyhönen M, Nikoskelainen E, et al. Scanning laser doppler flowmetry shows reduced retinal capillary blood flow in CADASIL. Stroke. 2004;35: 2449–2452. pmid:15472092
  51. 51. Tan BB, Natividad M, Chua K-C, Yip LW. Comparison of retinal nerve fiber layer measurement between 2 spectral domain OCT instruments: J Glaucoma. 2012;21:266–273. pmid:21637116
  52. 52. Huque MF, Sankoh AJ. A reviewer’s perspective on multiple endpoint issues in clinical trials. J Biopharm Stat. 1997;7:545–564. pmid:9358328
  53. 53. Mary-Krause M, Grabar S, Lievre L, Abgrall S, Billaud E, Boue F, et al. Cohort profile: French hospital database on HIV (FHDH-ANRS CO4). Int J Epidemiol. 2014;43:1425–1436. pmid:24550249
  54. 54. Fleming J, Mathews WC, Rutstein RM, Aberg J, Somboonwit C, Cheever LW, et al. Low-level viremia and virologic failure in persons with HIV infection treated with antiretroviral therapy. AIDS. 2019;33: 2005–2012. pmid:31306175
  55. 55. Sanford R, Ances BM, Meyerhoff DJ, Price RW, Fuchs D, Zetterberg H, et al. Longitudinal trajectories of brain volume and cortical thickness in treated and untreated primary human immunodeficiency virus infection. Clin Infect Dis. 2018;67:1697–1704. pmid:29697762
  56. 56. The INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795–807. pmid:26192873
  57. 57. Wolbers M, Babiker A, Sabin C, Young J, Dorrucci M, Chêne G, et al. Pretreatment CD4 cell slope and progression to AIDS or death in HIV-infected patients initiating antiretroviral therapy—The CASCADE collaboration: a collaboration of 23 cohort studies. PLoS Med. 2010;7: e1000239. pmid:20186270
  58. 58. Sanford R, Fellows LK, Ances BM, Collins DL. Association of brain structure changes and cognitive function with combination antiretroviral therapy in HIV-positive individuals. JAMA Neurol. 2018;75:72–79. pmid:29131878
  59. 59. Arcinue CA, Bartsch D-U, El-Emam SY, Ma F, Doede A, Sharpsten L, et al. Retinal thickening and photoreceptor loss in HIV eyes without retinitis. PLOS ONE. 2015;10: e0132996. pmid:26244973
  60. 60. Cetin EN, Sayin Kutlu S, Parca O, Kutlu M, Pekel G. The thicknesses of choroid, macular segments, peripapillary retinal nerve fiber layer, and retinal vascular caliber in HIV-1-infected patients without infectious retinitis. Retina. 2019;39:1416–1423. pmid:29528981
  61. 61. Young MT, Melvani RT, Khan FA, Braich PS, Bansal S. Association of intraocular pressure with human immunodeficiency virus. Am J Ophthalmol. 2017;176:203–209. pmid:28147228