We found no studies that directly investigated the possible effects of ART on the retina in PLWH. An earlier review by Abers et al.¹⁷ found that zidovudine, abacavir, efavirenz, didanosine, stavudine, and ritonavir were responsible for mitochondrial dysfunction which manifested as damage to the RPE and with macula telangiectasias and intraretinal crystalline deposits. A case report by Pereira et al.¹⁸ also found atrophy of macula RPE (Bull’s eye maculopathy) in a patient on efavirenz for 10 months. Although they did not report on the mechanism of toxicity, they postulate that an increased plasma concentration of the drug may cause retinal changes. Similar reasoning of accumulation of a xenobiotic substance in optic nerve cells was reported by Riva et al.,¹⁹ who found optic neuropathy in a patient on a combination elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. Other studies report that ritonavir causes bilateral maculopathy with RPE atrophy.^20,21,22 All reports hypothesise that ritonavir may lead to hyperplasia of the RPE and subsequent retinal degeneration. Although further studies are required to characterise ART toxicity, we propose that most of these drugs affect the RPE through different mechanisms of inflammation.

Cellular pro-inflammatory stress is the:

Cellular stress is comprised of various processes that are additive, such as oxidative stress, cell response to DNA damage, mitochondrial stress, formation of an intracellular network of signalling pathways of cellular stress, and formation of pro-inflammatory receptor and secretory cell phenotype.²⁴ Prolonged exposure to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) inhibits DNA polymerase gamma which functions in mitochondrial DNA (mtDNA) replication and maintenance.¹⁷ This results in decreased mtDNA and oxidative stress,²⁵ leading to possible neuronal death.²⁶ Oxidative stress is attributed to RPE damage and outer retinal layer dysfunction.²⁷ Consequently, when these structures are damaged, they may favour the progression of retinal dystrophy typically seen as macula morphological alterations.²⁸ Riva et al.¹⁹ reported a case of combination elvitegravir/cobicistat/tenofovir/emtricitabine with no other comorbidities causing toxic optic neuropathy due to an accumulation of a xenobiotic substance in optic nerve cells affecting the mitochondria of retinal ganglion cells (RGCs) and the papillomacula bundle.

The administration of NRTIs results in inflammatory damage to sensory axons and dorsal root ganglia.²⁹ Small, unmyelinated fibres are vulnerable to these effects of NRTIs. In the eye, this may impact the unmyelinated axons of RGCs that form the RNFL. Didanosine is associated with retinopathy caused by RPE atrophy, resulting in mottling that presents as circumscribed lesions at the periphery of the fundus.³⁰ Abers et al.¹⁷ suggest an eye examination every 6 months to 12 months to monitor for didanosine-induced retinal toxicity. Roe et al.³¹ also reported ritonavir intake for more than 12 months can result in RPE damage but with macular telangiectasias and intraretinal crystalline deposits.³¹

Neuroinflammation describes immune-driven pathology which occurs in the course of disease or infection in the brain tissue.³² This tissue state can be identified by four hallmarks: (1) high levels of pro-inflammatory cytokines; (2) microglia activation; (3) infiltration of peripheral leukocytes (e.g. bone-derived monocytes, T-cells); and (4) blood-brain barrier breakdown and neuron death. During the course of the pathology, the neuro-immune system may experience some homeostatic challenges which lead to para-inflammation.³² Para-inflammation is a tissue adaptive response to harmful stress or malfunction.³³ The physiological role of para-inflammation is to restore tissue functionality and homeostasis in disease events; however, it may become chronic inflammation if tissue stress or malfunction persists for a sustained period over several months and years.³³ Para-inflammation has been identified as a potential role player in both the initiation and progression of the disease.³³ In the retina, para-inflammation plays a protective homeostatic mechanism in the RGC layer and optic nerve head which have both shown to be affected in various HIV studies. Tezel³⁴ suggests that increased stress over prolonged and cumulative periods fails the regulation of retinal immune response, leading to a neuroinflammatory degenerative process in the glial cells of the RGC layer and/or the retinal inner plexiform layer.³⁵

Chronic oxidative stress prompts retinal para-inflammation leading to mitochondrial dysfunction and ultimately to retina dysfunction.³⁶ Over time, oxidative damage causes mtDNA instability which leads to cumulative mitochondrial damage. This pathological process has been described in other ophthalmologic disorders such as diabetic retinopathy, age-related macula degeneration, and glaucoma,³⁷ and therefore may also be related to the changes that are seen in HIV retinas.

Since the optic nerve is saturated with mitochondria, it is susceptible to impairment which can selectively damage RGCs.³⁸ Axons within the optic nerve have a greater mitochondrial load. Underlying any potential loss of vision is the degeneration of the RGCs which form the optic nerve. Parameters to detect and quantify RGC damage are vital in the management of RGC-damaged neuropathies such as glaucoma and have been used in characterising the optic nerve head of HIV individuals on ART.^{5,6,8,9,11,39,40} Optical coherence tomography is the popular method of detecting such changes. However, these remain surrogate measures because they do not quantify the number of remaining or lost RGCs.⁴¹ The most commonly used parameter is the peripapillary retinal nerve fibre layer (ppRNFL) thickness.

Since RNFL is made up mostly of RGC axons, the measured thickness with OCT, it has a strong correlation with optic nerve axon count. The pattern of RGC damage indicates the type of cell that is affected. For instance, axonal damage affecting the magnocellular cells (M-cells), is reflected by RNFL thinning in the superior and inferior quadrants, whereas those that affect the parvocellular cells (P-cells) are reflected by the temporal thinning of the RNFL.⁴² The P-cell pattern is similar to what is described for mitochondrial optic neuropathies and is hallmarked by the temporal pallor of the optic disc.⁴² Various studies have reported that the temporal quadrant ppRNFL in PLWH is thinner than normal.^39,43,44 Therefore, this may be a valid and novel indicator of the role of mitochondrial neuropathy, providing a potential disease mechanism for HIV-associated neuroretinal disorder.

Retinal pigment epithelial cells form a monolayer between the neuroretina and choroid. It has several vital functions, which include acting as an outer blood-retina barrier (oBRB), homeostasis of the neuroretina, and regulating the retinal immune response.⁴⁵ Effects of ART, largely oxidative stress resulting in mitochondrial dysfunction, renders the blood-retina barrier (BRB) vulnerable to dysfunction which manifests as altered functioning and cellular senescence resulting in RPE ageing and age-related diseases similar to that seen in age-related macula degeneration (AMD).³⁷ Since a similar pathogenesis is described in HIV, the functioning of the RPE must be explored.

The retina has an immune system that is coordinated by immune cells such as the microglia, dendritic cells, and macrophages.³³ Retinal microglia, RPE cells, together with choroidal macrophages/dendritic cells play a vital role in retinal homeostasis. In the ageing retina, they are the main contributors in regulating a stressed or malfunctioning retina and bring about retinal homeostasis. If this does not occur, the resultant inflammation causes endothelial dysfunction and microcirculatory abnormalities.³³

Microvascular changes are believed to facilitate disease impairment to the neuroretina and therefore have an important role in exploring the pathogenesis of HIV retinal alterations. HIV infection is associated with increased inflammation-induced endothelial injury, endothelial activation, and endothelial dysfunction.⁴⁶ HIV-related CVD is characterised by vascular endothelial activation and endothelial dysfunction. There is ample evidence about the correlation between retinal vascular changes and CVD.^47,48,49,50

Retinal endothelial cells line the microvasculature that nourishes the neural retina.^48,51 Hence, the inclusion of retinal vascular endothelial function assessment as a surrogate marker of CVD may prove valuable. The ophthalmic parameter that is an appropriate indicator to assess this factor is the ratio between the diameter of retinal arteries and retinal veins (A/V). The A/V ratio has been shown to be a fundamental ocular surrogate marker to reflect hypertension and atherosclerosis.⁵² A decreased A/V ratio is denoted by the narrowing of the arteries and widening of the veins thus indicating the risk of stroke and myocardial infarction ultimately making the retina susceptible to morphological changes in the retinal microvascular bed.

Pathai et al.¹⁰ explored vascular changes in HIV patients, and they discovered that arteriolar diameters narrowed with increasing duration of ART; independent of age; where those who were on 3 years of ART showed diameters of 167.83 mm while those who have taken ART for more than 6 years had diameters of 158.89 mm (P = 0.02). In a follow-up study Pathai et al.,¹⁰ investigating ART influences on retinal morphology, found that longer ART duration was associated with thinning of the inferior (P = 0.03) and nasal (P = 0.04) ppRNFL quadrants, and greater RNFL thickness of the superior quadrant with higher VL (HIV-negative individuals with 132.2 µm, and 133.8 µm in HIV-positive on ART with undetectable VL). Retinal nerve fibre layer thinning and retinal arteriolar narrowing may be associated with early vascular dysfunction in the nerve fibre layer (NFL).¹⁰ This hypothesis is supported by the location of large blood vessels in the retina. Large blood vessels are located in the superior and inferior quadrants and RNFL thinning was observed mainly in these areas in a previous study.¹⁰

Arcinue et al.¹² reported an increased average total retinal thickness (P = 0.001) in the HIV-positive group at the fovea (232.6 µm ± 23.4 µm in HIV-positive patients and 213.1 µm ± 14.5 µm in HIV-negative patients). They reasoned that the retinal changes observed were likely due to retinal toxicity caused by ART used over long periods. Therefore, the association of detectable HIV viraemia and prolonged ART causing RNFL thickness changes is plausible and has been attributed to the process of para-inflammation.³³ HIV viraemia may initiate a para-inflammatory process in the retina, which may manifest as increased thickness of the RNFL. Kalyani et al.³⁹ propose that mitochondrial toxicity (caused by HIV or ART) may cause axonal damage to the RNFL, leading to an initial phase of swelling before atrophy, which is observed in some studies.^9,12,14

While a close relationship between RNFL and the RPE is a prerequisite for normal vision,⁵³ little is known about RPE involvement in PLWH retinas. A significant number of studies demonstrated that infectious agents cause damage to the BRB, specifically the oBRB.^48,54,55,56 Tugizov⁵⁷ showed that exposure to HIV increased the permeability of RPE monolayers due to the decreased expression of several vital proteins (ZO-1, occludin, and claudin), rather than altering cellular functions (Figure 2). These proteins are all involved in the maintenance of the BRB integrity and reduce RPE pathophysiology by stabilising the tight junctions. Disruption of these proteins caused BRB breakdown and resulted in infectious agent entry into the retina.⁵⁸ The literature included in this review point to the source of retinal damage or altered function of the outer retina (RPE), which ultimately affects the inner retina (RNFL, outer plexiform layer [OPL], IPL, INL). The pathogenesis of the retina, particularly RPE, damage highlights a potentially important role of monocytes.

CD16+ monocytes (microglia and macrophages) play a role in autoimmune and chronic inflammatory diseases which contributes to neuroinflammation and neuronal damage which results in HIV-associated disorders in PLWH regardless of ART and immunocompetence.⁵⁹ In the retina, microglia cells are located in the plexiform layers and function as immune surveillance of the retina.³⁸ Research with retinal microglia has discovered, among others, CD4+ and CD16+ receptors; thus, suggesting that HIV infection of retinal microglia contributes to neural damage and RPE (considered the BRB) breakdown.⁶⁰ HIV infection of RPE cells upregulates phagocytosis (destruction of foreign substances and removal of dead cells). When phagocytosis is disrupted, it leads to a build-up of ‘material’ in the retina and leads to an increased number of retinal macrophages within the macula which causes macula thickening that has been observed in PLWH who are immunocompetent.⁶⁰ Similar findings were evident in other ocular conditions such as AMDs and diabetes. Clinical signs in diabetes and AMD, such as retinal hard exudation, oedema, and haemorrhages, indicate BRB impairment of varying severities.⁶¹ Research on retinal diseases (posterior uveitis, AMD, and diabetic retinopathy) has demonstrated BRB alterations at early disease stages promoted neuron injury.⁶¹ Therefore, the only mechanism by which circulating immune and inflammatory cells can enter the retina is through BRB impairment.