Evaluation of macula and optic disc changes in human immunodeficiency virus-infected patients without infectious retinopathy by optical coherence tomography angiography

Abstract

Purpose:

To detect early-stage changes in the macula, choroid, and optic disc with optic coherence tomography angiography (OCTA) in human immunodeficiency virus (HIV)-infected patients without retinitis.

Design:

Cross-sectional study.

Methods:

Twenty Turkish HIV-positive patients without retinitis and a control group of 20 healthy Turkish people were included in the study. CD4 T-cell counts and HIV RNA levels of the HIV-positive patient group were determined. Data were collected by performing OCTA following a complete ophthalmologic examination for all participants. The right eyes of all participants were included in the study.

Results:

The average CD4 T-cell count was 688 ± 198/mm³, the median value of the plasma HIV RNA count was 0 (0–27) copy/ml, and the mean disease duration was 5.65 ± 3.6 years in HIV-positive patients. In measurements made with OCTA, no significant difference was detected in retinal nerve fiber thickness, peripapillary capillary density, foveal density, superficial vascular density, deep vascular density, and foveal avascular zone in HIV-positive patients compared to the control group (P > 0.05). A moderate positive correlation was found between HIV infection duration and foveal density (r = 0.466, P = 0.002). Similarly, a moderate positive correlation was found between the duration of HIV infection and foveal thickness (r = 0.462, P = 0.003).

Conclusions:

Except for the moderate positive correlation between duration of HIV infection and foveal density and foveal thickness, the absence of significant changes in OCTA may be explained by the high CD4 T-cell counts and low HIV RNA levels, indicating well-suppressed disease in our study. For more information on this subject, studies with large series and different HIV RNA and CD4 T-cell counts are needed.

Human immunodeficiency virus (HIV) targets CD4 T cells and causes progressive immunodeficiency due to a decrease in the number of these cells.[1] Ophthalmologic pathologies resulting from opportunistic infections may occur in HIV-infected patients and may cause blindness.[2] Although the highly active antiretroviral therapy (HAART) reduces ophthalmologic morbidity, many patients worldwide continue to experience sight-threatening ocular manifestations of HIV infection.

Retinal microangiopathy is the most common ophthalmic manifestation of HIV. It is associated with low CD4 T cells and is characterized by cotton wool spots, retinal hemorrhages, and microaneurysms.[3] In some studies, including patients without retinitis, the peripapillary retinal nerve fiber layer (RNFL) was demonstrated to be thinner, especially in patients with CD4 counts <100 cells/mm³.[4,5,6] In addition, visual field, contrast sensitivity, and electrophysiological responses were found to be impaired in HIV-positive patients without retinitis.[7,8,9,10,11,12]

Optical coherence tomography angiography (OCTA) is a novel device that provides detailed imaging of the retinal vascular network by obtaining the contrast of the luminal flow.[13] It can detect early-stage abnormalities in the retinal vasculature that are difficult to detect by fluorescein angiography or indocyanine green angiography.[14] Studies using OCTA in HIV-positive patients without retinitis are quite limited in the literature, and changes in various OCTA parameters have been demonstrated.[15,16,17,18,19] In our study, we aimed to detect early changes in the retina and optic disc with OCTA in HIV-positive patients without retinitis.

Methods

Inclusion criteria

Participants without chronic ophthalmologic or systemic diseases and smoking history, participants having normal ophthalmologic examination findings and body mass index (BMI) (18.5–24.9 kg/m²), and participants without hematological disorders and over 18 years of age were included in the study.

Exclusion criteria

Participants who had undergone any posterior segment surgery or anterior segment surgery in the last 6 months, participants with chronic ophthalmologic pathology such as uveitis or diabetic retinopathy, participants with a diagnosis of glaucoma or with a corrected intraocular pressure greater than 21 mmHg on examination, participants with media opacity that may interfere with imaging, participants with systemic diseases like diabetes mellitus and hypertension, and participants with smoking history and BMI outside the normal range were excluded.

Preparation and pre-evaluation

HIV-positive patients referred to the Ophthalmology Clinic from the Infectious Diseases and Clinical Microbiology Clinic of Haseki Training and Research Hospital and a healthy control group of similar age and sex were included in the study. All HIV-positive patients had received the ‘HAART'’ regimen. Twelve patients had received tenofovir alafenamide–emtricitabine–bictegravir, three patients had received tenofovir disoproxil fumarate–emtricitabine–dolutegravir, two patients had received dolutegravir–abacavir–lamivudine, one patient had received tenofovir alafenamide–emtricitabine–cobicistat–elvitegravir, one patient had received tenofovir disoproxil fumarate–emtricitabine–dolutegravir, and one patient had received lamivudine–dolutegravir. The patients had no microvascular complication in any other organ. They had no other ocular or systemic infections. There was no history of inflammatory or chronic ocular disease in both HIV-positive patients and the control group. All participants had no anemia and were hematologically stable.

CD4 T cell and plasma HIV RNA levels of HIV-positive patients were determined. A complete ophthalmologic examination was performed on all patients and the control group, and no retinopathy was observed. OCTA was performed on the right eyes of all HIV-positive patients and the control group using the AngioVue Imaging System version 2017.1 (Optovue. Inc., Fremont, CA, USA) by the same ophthalmologist at the same time of day (between 9 a.m. and 12 p.m.), 30 minutes after administration of topical tropicamide 1% drops. OCTA data of the two groups were compared.

OCTA parameters

For macular evaluation, in an area of 6 × 6 mm² centered on the fovea, foveal avascular zone (FAZ) parameters, including the FAZ area and perimeter circumference of the FAZ (PERIM) area and the vessel density (VD) parameters at the levels of both the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) were calculated by the software. The upper and lower boundaries of SCP were 3 µm below the internal limiting membrane and 15 µm below the inner plexiform layer (IPL), respectively. DCP was defined as the area between 15 and 70 µm below IPL. In SCP and DCP levels, VD parameters of fovea, parafovea, and perifovea were evaluated separately. Central macular thickness (CMT) was measured using the retina map mode.

For the optic disc evaluation, radial peripapillary capillary (RPC) small vessel VD as the whole image VD (an area scan of 4.5 × 4.5 mm²), VD inside the disc, and peripapillary VD (measured in a 750-mm-wide annulus extending outward from the boundary of the optic disc) was calculated automatically by the software. The peripapillary region was divided into four segments: superior, inferior, nasal, and temporal. Average RNFL thickness and RNFL thicknesses in four quadrants (superior, inferior, nasal, and temporal) were also evaluated.

Statistical analysis

Statistical Package for the Social Sciences 15.0 for Windows program was used for statistical analysis. Descriptive statistics as numbers and percentages were used for categorical variables, and mean, standard deviation, median, minimum, and maximum were used for numerical variables. Rates in groups were compared with the Chi-squared test. Comparisons of numerical variables between two independent groups were made with the Student’s t-test when the normal distribution condition was met and with the Mann–Whitney U test when the condition was not met. For correlation analysis, the Pearson test was used when the distribution was normal and the Spearman’s rho test was used when the distribution was not normal. The cut-off value analysis was performed using receiver operating characteristic curve analysis. P < 0.05 was accepted as the statistical significance level.

Results

Twenty Turkish HIV-positive patients and a control group of 20 Turkish people were included in our study. The characteristics of the patient and control groups are shown in Table 1.

Table 1.

Demographic parameters of HIV-positive patients and control group

Parameters		HIV-positive patients (n=20)		Control group (n=20)		P
Age (years) (mean±SD)		40.1±10.9		39.8±10.2		0.917a
Sex (n, %)
Female		4 (20%)		6 (30%)		0.465b
Male		16 (80%)		14 (70%)
HIV RNA (copy/ml) (IQR)		0 (0–27)		---
CD4 T cells (mm3) (mean±SD)		688±198		---
Duration (years) (mean±SD)		5.65±3.6		---

HIV=human immunodeficiency virus, IQR=interquartile range, SD=Standard deviation. ^aStudent’s t-test. ^bChi-squared test

There was no statistically significant difference between the groups in the RPC-VD whole image, VD inside the disc, peripapillary VD, and mean and four-quadrant RNFL thickness (P > 0.05). Optic disc values are shown in Table 2.

Table 2.

Optic disc and peripapillary parameters of HIV-positive patients and control group

Parameters		HIV-positive patients (n=20)		Control group (n=20)		P a
RNFL thickness (μm) (mean±SD)		110.1±15.4		113.9±10.6		0.220
Superior		129.6±19.2		132.7±13.8		0.421
Inferior		140.5±22.2		145.0±15.4		0.305
Nasal		101.2±19.6		103.3±15.3		0.603
Temporal		72.2±11.1		75.8±9.5		0.134
RPC VD whole density (%) (mean±SD)		50.0±2.6		49.9±1.9		0.763
RPC VD inside the disc (%) (mean±SD)		52.1±4.3		51.8±3.2		0.760
RPC peripapillary VD (%) (mean±SD)		51.8±3.0		51.9±2.4		0.799
Superior		52.1±4.1		51.8±3.0		0.793
Inferior		53.0±3.8		53.4±3.3		0.548
Nasal		49.1±3.7		49.1±3.0		0.954
Temporal		53.5±3.7		54.2±3.4		0.569b

HIV=human immunodeficiency virus, RNFL=retinal nerve fiber layer, RPC=radial peripapillary capillary, SD=standard deviation, VD=vascular density. ^aStudent’s t-test. ^bMann–Whitney U test

No statistically significant difference was found in CMT, FAZ, PERIM, SCP, and DCP vascular densities in fovea, parafovea, and perifovea (P > 0.05). Macular parameters are shown in Table 3.

Table 3.

Macula parameters of HIV-positive patients and control group

Parameters		HIV-positive patients (n=20)		Control group (n=20)		P a
CMT (μm) (mean±SD)		255.5±14.9		253.4±23.7		0.644
FAZ area (mm2) (mean±SD)		0.241±0.076		0.238±0.104		0.874
PERIM (mm) (mean±SD)		1.879±0.297		1.857±0.466		0.767b
SCP-VD in fovea (%) (mean±SD)		23.7±5.5		24.4±6.9		0.616
SCP-VD in parafovea (%) (mean±SD)		53.9±3.6		54.2±2.1		0.658b
SCP-VD in perifovea (%) (mean±SD)		51.9±3.4		52.6±2.0		0.839b
DCP-VD in fovea (%) (mean±SD)		41.0±5.1		41.0±6.7		0.975
DCP-VD in parafovea (%) (mean±SD)		58.4±3.8		57.3±3.3		0.194
DCP-VD in perifovea (%) (mean±SD)		57.8±5.7		56.7±4.4		0.352

CMT=central macular thickness, DCP=deep capillary plexus, FAZ=foveal avascular zone, HIV=human immunodeficiency virus, PERIM=perimeter circumference of the foveal avascular zone, SCP=superficial capillary plexus, SD=standard deviation, VD=vascular density. ^aStudent’s t-test. ^bMann–Whitney U test

A moderate positive correlation was found between the duration of HIV infection and foveal density (r = 0.466, P = 0.002). Similarly, a moderate positive correlation was found between the duration of HIV infection and foveal thickness (r = 0.462, P = 0.003). There was no correlation between the duration of HIV infection and RPC-VD whole image, VD inside the disc, peripapillary VD, and mean and four-quadrant RNFL thickness, FAZ, PERIM, SCP, and DCP-VD in fovea, parafovea, and perifovea (r < 0.20, P > 0.05).

Discussion

It is emphasized that HIV infection causes inflammation and endothelial dysfunction, leading to angiopathy.[20] It has been reported that HIV RNA levels are detected in ocular tissues, even though no viral load is detected in blood.[21] It has been mentioned that HIV penetrating the blood–retinal barrier is related to causing RPE inflammation.[22] In HIV-positive patients, viral particles cause retinal thinning by chronic hypoxia and cell death.[6] In addition, increased retinal thickness occurs due to chronic low-grade inflammation and swelling of the retinal cells.[23]

OCTA is a novel device that provides detailed imaging of the retinal vascular network. The increased detection of abnormal microvasculature on OCTA may be attributed to the better visualization of retinal microanatomy on OCTA compared to conventional fluorescein angiography.[16]

In our study, no significant change was found in the OCTA parameters in the HIV-positive patient group compared to the control group. In the literature, studies examining HIV-positive patients with OCTA are quite limited and different results have been reported.

Brandão et al.[19] compared a group of 25 HIV-positive patients to a group of 25 controls in terms of OCTA parameters. While lower flow density was observed in SCP in the HIV-positive patient group compared to the control group (P < 0.05), no significant difference was found in DCP (P > 0.05). No significant difference was found in terms of flow density in the optic disc and peripapillary region (P > 0.05).

In the study by Du et al.,[17] HIV-positive patient group without retinopathy, HIV-positive patient group with microvasculopathy, and a control group were compared in terms of OCTA parameters. The CD4 T-cell count of HIV-positive patients with and without retinal microvasculopathy was calculated as 16/mm³ and 102/mm³, respectively. When compared to the control group, the superficial retinal VD and choroidal vascularity index in all parafoveal quadrants were found to be significantly reduced in the HIV-positive groups with and without microvasculopathy (P < 0.05). No differences were found in the OCTA parameters between the HIV-positive and HIV-positive with microvasculopathy groups. However, the HIV-positive with microvasculopathy group showed a significantly higher inner nuclear layer (INL) thickness and lower photoreceptor-retinal pigment epithelium thickness than the control group (P = 0.021 and 0.023, respectively).

Akmaz et al.[15] compared a group of 45 HIV-positive patients to a group of 45 controls in terms of OCTA parameters. The mean diagnosis time of the patients in the study was 7.13 years, the mean CD4 T-cell count was 147.09/mm≥, and the mean HIV RNA was 174.6 copies/ml. Peripapillary perfusion density and ganglion cell layer (GCL)–IPL thicknesses were found to be lower in the HIV-positive group (P < 0.05). No significant correlation was found between the duration of HIV infection and these values using Pearson’s correlation analysis.

Esen et al.[18] compared a group of 42 HIV-positive patients to a group of 42 controls in terms of OCTA parameters. In the HIV-positive group, parafoveal SCP-VD, DCP-VD, and foveal VD mean were found to be lower than in the control group (P < 0.001, P = 0.01, and P = 0.02, respectively). Low SCP-VD was found to be associated with high HIV RNA level and low CD4 T-cell count (r = −0.40, P = 0.02 and r = 0.31, P = 0.04, respectively). Furrer et al.[24] evaluated HIV-positive patients from a viral and immunological perspective. Retinal microangiopathy was found to be associated with low CD4 T-cell and high HIV-1 plasma viral load. In another study by Agarwal et al.,[16] VD in SCP was higher in patients with higher CD4 T-cell counts and FAZ was enlarged in patients with lower CD4 T-cell counts.

Our study results do not match the literature because there was no difference in the OCTA parameters of the HIV-positive group and the control group in our study. We suppose this situation may be explained by the high CD4 T-cell counts and low HIV RNA levels, indicating well-suppressed disease in our study. In contrast to our study, in the studies Esen et al.,[18] Furrer et al.,[24] and Agarwal et al.[16] mentioned above, significant differences were found in OCTA parameters in patients with high HIV RNA levels and low CD4 T-cell counts, indicating high viral load. This situation may support our idea.

Another result we found in our study was that foveal thickness and foveal vascular density showed a moderate positive correlation with the duration of HIV infection. There is no generally accepted relationship between the duration of HIV infection and retinal structures in the literature. Du et al.[17] reported that retinal thickness, RNFL–GCL–IPL, RNFL, GCL–IPL, and INL in patients with HIV infection had a strong negative correlation with the duration of HIV infection, while Akmaz et al.[15] did not find a significant correlation with the duration of HIV infection and GCL, macular thickness, VD, and perfusion density. There is no generally accepted conclusion on this subject. Further studies are needed to determine the correlation between the duration of HIV infection and OCTA parameters.

There are some limitations to this study. The first of these is the small sample size and its cross-sectional design. A longitudinal study with a large sample size would more effectively evaluate the modifications in the retinal capillary network in patients with HIV infection. Secondly, although macular parameters regarding structure and microvasculature were investigated in this study, it lacked the data on visual function such as contrast sensitivity, color vision, visual fields, and multifocal electroretinography.

Conclusion

Our study is one of the limited number of studies in the literature and has shown that OCTA findings may be prevented in well-suppressed HIV-positive patients. Some OCTA parameters may change depending on the duration of HIV infection. Regarding these ideas, our study may provide a different perspective to the literature and guide future studies. Studies with larger case series and patients with different viral and immunological values are needed on this subject.

Ethical approval

The study was conducted following the Declaration of Helsinki principles and was approved by the Institutional Ethics Committee of Haseki Training and Research Hospital (No: 178-2023).

Author contributions

All authors contributed to the study’s design and conception. Material preparation, data collection, and analysis were performed by Çağlar Bildirici, Mine Ozturk, and Gülsah Tunçer. The first draft of the manuscript was written by Çağlar Bildirici, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.