Ocular manifestations of HIV and AIDS patients on antiretroviral therapy in a tertiary hospital in South Africa

cell counts, which could be regarded as predictors for the occurrence of ocular morbidity in HIV and AIDS patients.


Introduction
The human immunodeficiency virus (HIV) is a retrovirus which replicates in cluster of differentiation 4 (CD4+) lymphocytes. 1,2 It causes impairment to the human immune system, which leads to immunocompromised conditions and allows for opportunistic infections to invade many organs. The multisystem disorders caused by HIV are grouped under the name acquired immunodeficiency syndrome (AIDS). Human immunodeficiency virus and acquired immunodeficiency syndrome are still a major public health problem in South Africa, even though there are many campaigns to publicise the importance of HIV treatment. The 2018 report on HIV/AIDS shows that the number of newly diagnosed HIV patients is still increasing. Since the first case of HIV in 1981, it has become a worldwide pandemic; ocular involvement has been a common finding and loss of vision is a serious problem in people living with HIV/ AIDS. 3,4,5,6,7,8,9,10,11,12,13,14 It is estimated that approximately 50% to 80% of HIV-infected patients are expected to be treated for HIV-related eye disorders in the course of their illness. 3,4,5,6,7,8,9,10,11,12,13,14 The ocular manifestations of HIV and AIDS can affect almost all the structures of the eye, from the adnexa and anterior segment to posterior segment of the eye and the optic nerve.
With the advent of highly active antiretroviral therapy (HAART), there is a reduction in the number of opportunistic infections and a general improvement in the length and quality of life, but the longer survival rate may lead to an increased prevalence of blindness because of immune recovery uveitis (IRU) and unknown disorders caused by antiretroviral drugs.
Knowledge of the effect of HIV and AIDS on the eye is important, as ocular manifestations may be the cause of visual impairment or blindness, which may compromise the quality of life for patients living with HIV and AIDS. Ophthalmic clinicians are faced with the challenge of recognising, identifying and treating unusual presentations of HIV and AIDS. If these ocular manifestations are detected at an early stage and treated promptly, it is possible to prevent or minimise the consequences of visual damage. This study was undertaken to identify and document ocular manifestation of HIV/AIDS in a tertiary referral hospital. Ocular manifestation may be the primary presentation of the diseases, so ophthalmologists and optometrists may make the initial diagnosis of HIV/AIDS.

Methods
This was a prospective cross-sectional descriptive study, conducted from April 2016 to December 2018 at the Department of Ophthalmology, Steve Biko Academic Hospital in Pretoria, South Africa, which is a tertiary healthcare centre and teaching hospital. The participants, who were all above the age of 18, signed informed consent document before participating in the study. They were informed about the purpose and details of the study and it was stressed that their participation was entirely voluntary. The study followed all the tenets of the Helsinki Declaration on human participants (subjects). The study was carried out on every consecutive HIV-positive patient receiving antiretroviral treatment (ART) at the hospital's ART clinic.
For each participant, a detailed ocular history including demographic information was recorded, such as age, gender, duration of HIV infection, recent CD4+ cell count and associated systemic symptoms. A detailed ocular examination was carried out which included slit lamp biomicroscopy, visual acuity, ocular motility, colour vision, pupillary reflexes and dry eye. The dry eye diagnosis criteria included both of subjective discomfort symptoms (if one or more symptoms were noted as severe from the questionnaire) and clinical sign of ocular surface disorder using the Schirmer 1 test. The posterior segment was evaluated using the fundus imaging technology. Those participants who needed relevant treatment or surgical interventions for systemic conditions were treated in consultation with the physician. Those who needed further refraction were assisted by optometrists.
Participants were HIV-positive patients of both genders, registered at the ART clinic and referred to the Department of Ophthalmology for treatment of ocular complaints. Patients were excluded as participants if referred directly from other clinics and hospitals and were not originally known to be HIV-positive. They were referred to the ART clinic and subsequently tested for HIV because of suspicious ocular disorders. Patients with additional medical conditions such as diabetes mellitus, hypertension and ocular trauma (which can have manifestations overlapping with the HIV and AIDS), and those who were not willing to give informed consent or who were younger than 18, were excluded. Participants' anonymity was guaranteed and their medical records and personal information were kept confidential.

Statistical analysis
Statistical Package for Social Sciences (SPSS) version 26 (IBM Corp., Armonk, NY, United States [US]) was used to perform statistical analyses. Descriptive statistics was utilised to determine the percentages of the ocular manifestation of HIV and AIDS of the total participants examined. Relevant variables were age, gender, visual acuity and ocular findings. The association between ocular manifestations of HIV/AIDS and CD4+ cell counts was analysed using the chi-square test.

Ethical considerations
Ethical approval was obtained from the Ethics Committee of the University of Pretoria, Faculty of Health Sciences (ethical clearance number 253-2016). Permission to conduct the study was granted by the hospital administration. Informed and written consents were obtained from every participant in the study. Privacy and confidentiality were maintained throughout the study period.

Results
A total of 177 HIV and AIDS participants were assessed during the study period: 118 (67.2%) females and 57 (32.8%) males. The female-to-male ratio was 1:0.5. Their ages ranged from 18 to 73 years, with a mean age of 42.78 ± 12.4 years (see Table 1). The most common age group was 31-40 years in 28.8% of the participants. The youngest participant was 18 years old and the oldest was 73 years of age. The total number of affected participants was 128 (72.3%).
The participants were divided into groups according to their visual acuities, which ranged from 6/3 to 6/18, and 6/48 to 6/90, counting fingers, hand movement, light perception and no light perception ( Table 2). About 69.3% of the participants were found to have normal visual acuity. About 25.0% of the participants had a history of eye problems. Pain, blurring of vision and photophobia were the most reported symptoms. Other variables investigated are presented in Table 4. Colour vision defects were observed in 53 (29.9%) whilst pupillary abnormalities were seen in 42 (63.3%). Twenty-two (23.7%) participants had unresponsive pupils whilst abnormal ocular motility was seen in 48 (27.1%).
The prevalence of ocular manifestations of HIV and AIDS was 72.3% with 95% CI: 65.4% -81.2%. Table 5 shows the anterior segment manifestation of the HIV and AIDS. A total of 42 (23.7%) had anterior segment lesions. The most common were uveitis, dry eye, conjunctival growth and molluscum contagiosum. There was a wide range of severity of dry eye with deposit on the ocular surface.
The frequency of participants with posterior segment disorders is shown in Table 6. The posterior ocular manifestations were seen in 56 (31.6%) participants. Human immunodeficiency virus-related retinopathy was seen in 25 (44.6%) participants, followed by papilledema and cytomegalovirus (CMV) retinitis at 19.6%. The incidence of posterior segment ocular manifestations was higher than the anterior segment manifestations. Table 7 lists 30 neuro-ophthalmologic lesions found in the study participants. Papilloedema was the most common finding followed by optic atrophy. Third cranial nerve palsies were seen in three participants. However, no significant association was found between cranial nerve palsies and CD4+ cell count of participants, p > 0.05.

Discussion
Human immunodeficiency virus and acquired immunodeficiency syndrome causes a wide spectrum of diseases, and ocular manifestations are amongst the most common clinical features manifesting in HIV and AIDS individuals. These manifestations are varied, can affect almost all the structures of the eye, and can occur throughout the illness, with an increasing HIV virulence and a progressive loss of CD4+ cell numbers. Various studies have shown that the prevalence of the ocular manifestations in HIV/AIDS individuals can range from 50% to 80%. 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 These ocular manifestations can be the presenting sign of a systemic infection of an otherwise asymptomatic individual. The lifetime risk of having at least one abnormal ocular lesion amongst HIV and AIDS individuals ranges from 52% to 100%. 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30 The results of this study showed that 72.3% of HIV and AIDS participants seen at Steve Biko Academic Hospital had ocular lesions or disorders. In this study, 89 (50.3%) belonged to the economically productive age group of 31-50 years. This needs to be emphasised as the morbidity of these individuals has a considerable impact on the economy of their families. The prevalence found in this study is higher than the studies done elsewhere in Africa. Assefa et al. 12 found a prevalence of 60% in a study done in Ethiopia. Martin-Odoom et al. 14 found a prevalence of 48% of ocular complications in HIV patients on antiretroviral therapy in Ghana.
The study showed that 42 (23.7%) had anterior segment manifestations of HIV/AIDS. The most frequent disorders were anterior uveitis, dry eye, conjunctival growth, herpes zoster ophthalmicus and molluscum contagiosum. The anterior uveitis (21.4%) was the most common anterior segment finding. Gogri et al. 19 and Sahoo et al. 8 found anterior uveitis in 21.5% and 16.1% of participants in their recent works of ocular lesions in HIV and AIDS patients. The anterior uveitis could have been caused by the low immune status of participants, which resulted in opportunistic infections invading the body and causing inflammatory reactions. 17,18,21 The more viral antigen in the eye could lead to IRU. Immune recovery uveitis is believed to be a result of a partially restored immune system after the initiation of HAART, which mounted an exuberant inflammatory response called immune reconstitution syndrome (IRS). 2,21 Dry eyes were found in eight (19.1%) of the study participants. Dry eye or keratoconjunctivitis sicca in HIV and AIDS participants may result from an autoimmune pathogenesis of disorders of tear production, which may infiltrate and damage the lacrimal gland acini and ducts. 16 The dry eye diseases   were commonly seen with blepharitis. Dry eye in HIV and AIDS patients may be related to the possibility of an auto-immune-like pathogenesis of abnormal tear production, which is associated with lymphocytic infiltration, and eventual destruction of the lacrimal gland acini and ducts. Extensive molluscum contagiosum lesions were also found (14.3%). The possible cause of these lesions is unknown but could result from disorders or dysfunction of the T-lymphocytemediated immune response. 10,11,12,13,14 Sharma et al. 18 in their study found that the anterior segment manifestations of HIV and AIDS were present in 13.3% of their study participants. Before the introduction of HAART, CMV retinitis affected 30% -40% of HIV-infected individuals, with visual loss because of involvement of the posterior retina and retinal detachments. 10,21 In the era of HAART, there has been an estimated 80% decrease in the incidence of CMV retinitis. In this study, the prevalence of CMV retinitis was lower. All the participants in the study were on HAART treatment, which had reduced the risk of opportunistic infection.
This study also found that participants with CD4+ cell count below 200 cells/μL were more likely to have ocular manifestation than those whose CD4+ count was greater than 200 cells/μL. This finding is consistent with the general facts of immunosuppression where a CD4+ count less than 200 is a predictor of ocular disorders in HIV and AIDS patients. 19,20,21,22,23,24,25,26,27,28,29,30 Participants who had a low duration on HAART showed higher occurrence of ocular disorders compared to those with more than five years. This could be as a result of the longer use of ART drugs increasing the CD4+ cell counts, boosting the immune system and reducing the occurrence of opportunistic infections. 21,23 Neuro-ophthalmic manifestations such as papilloedema, optic neuritis and optic atrophy are some known disorders to occur in HIV and AIDS patients. 19,20,21,22,23,24,25,26,27,28,29,30 In this study, 30 (16.9%) of the participant had neuro-ophthalmic lesions. The findings of this study were higher than those reported by Sudharshan et al. (8.9%), Biswas et al. 22 (9.3%), Assefa et al. 12 (9.6%) and Gogri et al. 19 (10%).

Conclusion
In this study, the prevalence of ocular complications in HIV and AIDS participants on antiretroviral drugs was high. Most ocular complications were seen in participants with less than 200 cells/μL, low visual acuities and less than 5 years of ART. Clinicians should be aware of the possible clinical presentation of ocular signs of HIV and AIDS. It is recommended that all HIV and AIDS patients with CD4+ cell counts below 200 cells/ μL and low duration on ART be subjected to screening for visual loss and routine ocular examination. Furthermore, the findings of this study recommend that the eye examination be integrated in ART clinics to ensure early identification and treatment of ocular complications.