Electrophysiological techniques such as VEP and electroretinograms convey the integrity of the transmissions of the signals from the eye to the brain at different levels of transmission. Any changes in these electrical transmissions independently and objectively affirm clinical signs of damage in the retina and visual pathway, which may aid in a timeous diagnosis.

The pattern visual evoked potential (PVEP) is designed to establish the functional integrity of the entire visual pathway, while the pattern electroretinogram (PERG) assesses the functional integrity of the inner retina. These are observed at a sensitivity beyond funduscopic examination, which refers to the examination of the physical integrity of the inner eye, namely the retina and optic nerve. Axonal pathology in the optic nerve can be recognised by VEP independent of clinical signs and detectable morphology.¹⁴ The full field monocular PVEP P100 peak shows activation of the primary visual cortex (V1) and illustrates integrity of the pre-chiasmatic pathway.¹⁴

Both VEP and PERG have shown defects in activity of the ganglion cell layer in PLHIV without retinitis.¹⁵ This suggests that beyond psychophysical visual tests, the integrity of the visual function in PLHIV on ART without retinitis is affected.

Iragui et al.¹⁶ found that in PLHIV with a CD4 count of less than 200 cells/mm³ there was reduced P1 transient PERG amplitude, implying ganglion cell dysfunction, as well as latency delay of the transient PVEP (P100), implying that this extends to the visual pathway. Furthermore, PLHIV with a CD4 count of greater than or equal to 200 cells/mm³ showed a reduced amplitude of the transient PERG P1 potential. This establishes the dysfunctional changes at low CD4 counts in the visual pathway in PLHIV on ART without retinitis, as shown in Table 2.

Multifocal ERG is valuable in assessing visual function when the retina appears normal, as in this case of no retinitis in PLHIV. It can further distinguish retinal from optic nerve changes and most specifically focal retinal damage. In mERG studies, the first-order kernel represents outer retinal function whilst the second-order kernel is representative of inner retinal function.

Studies using mERG found reduced amplitudes and delayed latencies functionally; whilst this may not translate to the direct impact on the quality of life, it does show the impaired function of the inner retina and the visual pathway at low CD4 counts in PLHIV.

Falkenstein et al.,¹⁵ using only mERG, suggests that the outer retina, which contains the photoreceptors, is quiescient in PLHIV on ART without retinopathy. Falkenstein et al.¹⁷ went on to show that HIV’s effects are subtle in amplitudes between PLHIV with nadir CD4 counts of less than and greater than 100 cell/mm³ for both kernels; but found widespread delays in implicit times or latent periods in both kernels for nadir CD4 counts of less than or greater than 100 cells/mm³. Goldbaum et al.¹⁸ went further to show that apart from second-order kernels in mERG being a sensitive detector for inner retinal abnormalities, it separated HIV-positive eyes from normal eyes by showing the delayed implicit times in b-latency of the second-order kernels of mERG, thus showing impaired transmission of electrical stimuli. All this highlights that PLHIV on ART without retinopathy had retinal-processing abnormalities in both prolonged immunosuppression and PLHIV who have never been compromised immunologically.

Table 2 summarises, in PLHIV on ART without retinitis, that: the amplitude of transient PERG is less than 0.89 μV; the latency P100 in transient PVEP is greater than 106.98 ms; the P1 latency of the first-order kernel is delayed compared to HIV-negative persons; and that for the second-order kernel the P1 and b-latencies are prolonged. These electrophysiological changes provide evidence that, functionally, the retina is compromised in PLHIV on ART without retinitis, at low CD4 counts. What is yet to be proven is if this dysfunction extends to patients with higher CD4 counts, in light of the fact that PLHIV today live longer and in an immunocompetent state. The threat lies with the identified dysfunction compounding over time, translating into quality of life changes.

Exploratory studies in the last two decades have sought to find the underlying causes of visual changes amongst PLHIV. These studies first reported associations between HIV infection and the erosion of visual functionalities amongst PLHIV.

Psychophysical assessments refer to the analysis of visual function changes such as visual fields (perimetry), the effect on visual acuity (CS vision) and colour vision.

Perimetry (visual field) in people living with HIV: As early as 1997, Mueller et al.¹⁹ found abnormal changes using achromatic automated perimetry in PLHIV. These changes were at a mean CD4 count of 173 cells/mm³ in PLHIV with 20/20 visual acuity and no retinitis. Specifically, it was showed that 21.6% of PLHIV had a mean deviation of less than -2.10 dB and that 27.5% had a GHT ‘outside normal limits’. These findings suggest global and local changes in visual fields, where global or general loss of the visual field is represented by mean deviation scores, and sectoral loss of the visual fields by GHT. In 2008, Freeman et al.¹³ went on to find that 39% of PLHIV had abnormal mean deviations of less than -2.63 dB and 33% had abnormal pattern standard deviation (PSD) of greater than 2.57 dB, in a sample with a median current CD4 count of 180 cells/mm³. Despite the mean versus median CD4 counts in these studies, both are in agreement that in immunocompromised PLHIV (with a CD4 count of less than 200 cells/mm³) there are losses, albeit subtle, demonstrated by perimetry.

In 2015, Jabs et al.²⁰ defined HIV as a neuroretinal disorder (HIVNRD) in PLHIV, if mean deviations on the 24-2 programme (Humphrey’s perimeter) was worse than -3 dB and CS was worse than log 1.5. It was found, using this criterion, in a sample with a median CD4 count of 178 cells/mm³ that 16% were classified with HIVNRD. The median mean deviation for those with HIVNRD was -4.9 dB. These perimetric changes support the argument that HIV is an immune disorder, resulting in the addition of a specific neuroretinal disorder in the absence of retinal or central nervous system (CNS) infections.

The evidence summarised in Table 2 suggests that perimetric changes in PLHIV without retinopathy occurs at a CD4 count of less than 200 cells/mm³. This manifests as reduced mean deviations by at least 2 dB in the central 24 degrees of the visual field, and local field changes manifest by changes occurring in PSD and GHT. This suggests that visual fields are generally depressed as local defects, and in specific areas of vulnerability, as sub-served by the GHT. The magnitude of perimetric changes may appear subtle but over time this may threaten vision loss. Studies of PLHIV with CD4 counts of above 500 are not included in this review.

Contrast sensitivity in people living with HIV: The value of assessing CS over plain visual acuity is that CS measures visual performance at varying contrasts and spatial frequencies while visual acuity is limited to high spatial frequencies (superior vision) at a single contrast level. This therefore makes CS assessment a more sensitive evaluation of vision. Contrast sensitivity in PLHIV has been investigated primarily using two techniques: the Vistech CS Test which was mostly used in the 1990s and, more recently, the Pelli-Robson Chart.

The Mueller et al.¹⁹ study, described earlier, recorded a general loss of CS amongst individuals and showed that amongst PLHIV there was a correlation between CS and perimetry and between CS and colour vision.

The 2000s marked the start of the common use of the Pelli-Robson CS Test. Studies^13,21 on HIV and CS using the Pelli-Robson Chart found a median CS log of 1.65 and concluded that in PLHIV the CS was abnormal for scores of less than log 1.5, benchmarking and providing empirical evidence for CS in PLHIV for subsequent studies. Using this criterion, Shah et al.²¹ found 7% of PLHIV with abnormal CS and, furthermore, reported that abnormal colour vision and CS can occur independently in these patients. Freeman et al.¹³ found 12% of PLHIV with CD4 counts of less than 200 cells/mm³ with abnormal CS in PLHIV. In addition to Shah et al.,²¹ the study findings with regards to CS were that there was a correlation between diminishing CS and decreasing levels of CD4 count levels (180 cells/mm³).

In 2015, Jabs et al.²⁰ reported findings from a longitudinal study of the ocular complications of AIDS (LSOCA) between 1998 and 2013, and reported on CS abnormalities amongst PLHIV. These researchers asserted that the abnormalities should be defined as HIVNRD when visual field assessments showed mean deviations that were worse than -3 dB and CS tests produced scores that were worse than log 1.5. Using these terms of reference, 16% of the study sample could be classified as exhibiting HIVNRD and, notably, the visual field functionality of these individuals was more reduced. Importantly, the study reported that the risk of HIVNRD doubled when PLHIV had CD4 counts of less than 100 cells/mm³.

In 2012, Holland et al.²² concluded that abnormal CS was associated with increased mortality and is an independent risk factor for death amongst PLHIV in view of the association with microvascular pathology, similar to diabetes mellitus. Eight percent of the sample was assessed to have abnormal CS, using a median CS of log 1.65.

Table 2 provides quantitative evidence that CS is affected in PLHIV on ART without retinopathy and with CD4 counts of less than 200 cells/mm³, and that this can be evaluated when the Pelli-Robson score is less than log 1.5. There is a dearth of evidence amongst PLHIV with high immuno-competence in an age where ART is lengthening the lifespan of PLHIV, which questions if these observed changes will increase over time.

Colour vision in people living with HIV: The evidence for the prevalence of colour vision loss amongst PLHIV is limited and broad in terms of its findings. This may be owing to the differences in the types of tool used to test colour vision and the varied ranges of CD4 counts and immunocompetence. The tools used include the anomaloscope, which is a colour-matching test that utilises illumination of three spectral sensitivities, viz. red, green and yellow, based on the long-, medium- and short photoreceptor cones in the eye to detect normal matches. The other test is the Farnsworth-Munsell (FM) Test, which is a pigment colour arrangement test that utilises caps that need to be arranged sequentially according to the visible spectrum of light. The studies using the Farnsworth-Munsell 100 Hue (FM100) version of the test analysed the root mean square of the total error score to gauge severity, whereby an increase in this magnitude is regarded as poor colour vision. Both techniques together can assess various colour defects and colour acuity.

Sommerhalder et al.,²³ using the anomaloscope, found no significant colour vision anomalies in PLHIV with no retinitis at a median CD4 count of 70 cells/mm³. In contrast, Mueller et al.,¹⁹ using the FM100 Test, reported that 29.4% of the individuals had abnormal colour vision, with the root mean square of the total error score being 8.31 (normal = 5.16) with a median CD4 count of 173 cell/mm³. However, Shah et al.,²¹ in the mid-2000s, using the same test and on a similar sample with a median CD4 count of 330 cell/mm³, reported that 9.9% of the sample had abnormal colour vision with the root mean square of the total error score being 10.20. These FM100 Test studies indirectly show that as the CD4 count increases, the prevalence of colour vision loss is reduced but without an axis of defect, therefore suggesting no predilection to a particular cone dysfunction but a general depression in retinal function.²⁴

The changes in colour vision suggest the involvement of the photoreceptor, which therefore extends retinal involvement to the outer retina and beyond the RNFL. Kozak et al.²⁴ refuted the categorical involvement of the inner retina alone, as shown with RNFL, by stating that photoreceptor dysfunction also implied outer retinal involvement in PLHIV. Table 2 quantitatively allows for the conclusion that colour vision is affected in PLHIV without retinitis, and manifested a higher root mean square of the total error scores of above 8 on the FM100.

In summation, it is clear that among PLHIV on ART without retinitis, the psychophysical visual function is affected but is limited to CD4 counts of between 200 cells/mm³ and 500 cell/mm³. However, the identified gap in the literature should examine whether or not these changes extend to a higher level of immunocompetence where there is viral suppression and CD4 counts of greater than 500 cells/mm³. The question still to be answered is whether the maintenance of ART and the elevation of CD4 count actually guard against further deterioration, or if the compounded presence of the virus over time affects the tissues of the eye and threatens vision loss in light of the extended lifespan expectation of PLHIV.

Despite limited studies, the attempt to relate visual field changes with RNFL changes is evident. Studies in glaucoma have shown that there is an association between RNFL, the ganglion cell layer and perimetric changes. Perimetric assessment using either Humphrey’s frequency doubling technique (FDT) or short wavelength automated perimetry (SWAP) is influenced by RNFL and changes in ganglion cell thickness.

Arantes et al.²⁵ managed to find RNFL thinning nasally, with FDT perimetric loss in PLHIV with CD4 < 100 cells/mm³. It showed the low CD4 count group to have a reduction in average ppRNFL thickness with the exception of the temporal zone but also showed thinning in the temporal and inferior outer macula zones. All this occurred with concurrent reduced values in the MD and the PSD. It was further shown that the eyes with affected PSD and GHT outside normal limits had a thinner average ppRNFL in PLHIV on ART without retinitis. Arantes et al.²⁶ went on in 2012 to specifically show independent thinning in the ppRNFL in the nasal, inferior and temporal zones, respectively. Independent defects in the nasal visual field zones also occurred. An association between the PSD and the average ppRNFL was shown and the strongest correlations occurred between the superior ppRNFL and inferior visual field, and the nasal ppRNFL and the temporal visual field in PLHIV on ART without retinitis.

A noteworthy observation is the use of the FDT perimeter in these studies, which has been shown to target ganglion cells of the magnocellular pathway and has the ability to predict field loss before standard automated perimetry. This is significant in light of the fact that PLHIV on ART without retinitis are the focus of this review. Table 3 provides quantitative evidence which concludes that reduced MD, PSD and GHT are all affected concurrently with a thinning of ppRNFL in PLHIV on ART without retinitis at reduced CD4 counts of 100 cell/mm³.

Kalyani et al.¹² noted temporal ppRNFL loss and reduced CS in PLHIV for more than 180 months, which shows a positive correlation. Pathai et al.²⁷ specifically showed an association of lower CS at log 1.70 and a thinner temporal ppRNFL. Most recently, Paul et al.²⁸ also found a positive correlation of reduced CS at log 1.33 with the temporal ppRNFL.

Gender bias may not be an influence, as the sample profile used by Kalyani et al.¹² was predominantly male and that of Pathai et al.²⁷ was predominantly female, and both results showed a favourable agreement. Furthermore, the study by Pathai et al.²⁷ was geographically located in South Africa, while Paul et al.²⁸ studied a sample in India and also found similar results, suggesting that race and geography may not be an influencer. Table 3 provides evidence and allows for the conclusion: that the temporal ppRNFL is associated with reduced CS in PLHIV on ART without retinitis. However, the agreement of the magnitudes of the reduced CS and the temporal ppRNFL still requires more investigation.

The review for the assessment of visual acuity and the RNFL in PLHIV on ART without retinitis is limited to Barteselli et al.²⁹ who showed for patients with CD4 counts of less than 100 cells/mm³ a loss of inferior-temporal ppRNFL, for varying contrasts and illumination. The study suggests that the HIV status independently predicts visual performance under varying contrasts at 100%, 64% and 43%. Accordingly, visual acuity using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts (logMAR acuity) at varying contrasts behaves in a similar way to CS, but both showed temporal RNFL associations in PLHIV on ART without retinitis.

The review for the assessment of colour vision and the ppRNFL in PLHIV on ART without retinitis is limited to Kalyani et al.¹² This study showed an inverse correlation of the temporal ppRNFL with the colour confusion index (CCI) for the Lanthony D15. Higher CCI indices suggest poorer colour acuity, which occurred with the thinning of the temporal RNFL in PLHIV on ART without retinitis. It is important to remember that colour vision involvement extends beyond the RNFL because the photoreceptors lie in the outer retina.

Table 3 provides the evidence for HIV causing ppRNFL loss at low CD4 counts, and that the visual functions at risk are CS, colour vision and visual fields concurrently. Most specifically, similar correlations for CS, visual acuity and colour vision changes with the temporal ppRNFL were established. However, the majority of the studies limit interest to CD4 < 200 cells/mm³ and to an area of visual function that is sub-clinical. More research is required in PLHIV with elevated CD4 counts regarding visual function and the manner in which this has an impact on daily functioning in light of PLHIV living longer. Consequently, this threat of vision loss needs addressing.