Human immune deficiency virus conundrum: An everlasting challenge!

BACKGROUND: Human immune deficiency virus (HIV) causes a wide spectrum of diseases worldwide and has the capability to affect every organ system in the body. Ocular manifestations have been reported in up to 70% of individuals infected with HIV and the ocular manifestations reflect systemic disease and maybe the first sign of disseminated infection.
PURPOSE: To study the pattern of ocular manifestations related to HIV in seropositive patients with the objective of identifying its spectrum in highly active antiretroviral therapy (HAART) era and to emphasize on the role of ophthalmologists in fighting the battle against HIV.
MATERIALS AND METHODS: A cross sectional study was undertaken on 300 HIV positive patients. Data were collected, tabulated and analyzed using MSTAT software. Chi-square test was applied and P < 0.05 was considered significant.
RESULTS: Ocular lesions were observed in 50.33% of patients. Conjunctival microvasculopathy being the most common finding seen in 27 (9%) patients, followed by retinal microvasculopathy and trichomegaly in 20 (6.66%) patients each. Herpes zoster ophthalmicus and cytomegalovirus retinitis were observed in four (1.33%) and three (1%) patients respectively. In the study 78.33% patients were on ART.
CONCLUSION: HAART has reduced serious ocular opportunistic infections and ocular malignancies, but HAART mediated visually disabling immune recovery uveitis has emerged as a clinical challenge for ophthalmologists. Improved communication between the two broad specialties of HIV medicine and ophthalmology will definitely go a long way in the battle against this dreadful disease. Copyright:

Introduction

Acquired immunodeficiency syndrome (AIDS) is a worldwide pandemic since the first case report in 1981. It is a multisystem disorder with a profound impact on ophthalmology. Since the first case of ocular complication reported in 1982 this entity has posed various challenges to ophthalmologists.[1]

In the pre highly active antiretroviral therapy (HAART) era biggest concern was blinding opportunistic infections. However, immune recovery became a reality with the advent of HAART. Again benefits of immune recovery came at a cost of complications of immune recovery that could be sight-threatening. Hence, focus of ophthalmologists was now to get patients through the period of immune recovery without added ocular complications secondary to immune recovery uveitis (IRU). HAART has also increased the life expectancy of patients hence human immune deficiency virus (HIV) is now a chronic disease and long-term monitoring, toxic effect of ART itself are other aspect to be taken care of so that the quality of life of patients can be maintained. Surveys on the ocular involvement of HIV reveals that the spectrum of HIV and AIDS-related ocular diseases is different in various parts of the world.[2] The spectrum of HIV-associated ophthalmic disease is very broad and ranges from adnexal disorders to posterior segment diseases including the optic nerve and the optic tract.[3] These ocular manifestations have shown changes in prevalence in studies done after the advent of HAART in different countries including India.[45] We studied the pattern of ocular manifestations related to HIV/AIDS in seropositive patients at our Tertiary Care Center with the objective of identifying its spectrum in the HAART era and to emphasize on the role of ophthalmologists in fighting this battle against HIV: An Everlasting Challenge!

Materials and Methods

A cross-sectional study was carried out in the Department of Ophthalmology in collaboration with the ART Center.

A total of 300 patients were enrolled, using simple random sampling technique for a period of 1 year. These patients were evaluated, irrespective of the presence or absence of ocular symptoms and their treatment status. Patients who were not willing to give consent and patients having coexisting morbidities (which can obfuscate the clinical picture in HIV/AIDS patients) were excluded from the study. Data were collected by detailed history from patients and attending relatives. Patient's relevant data about the HIV infection, CD4 counts, staging of disease, duration of disease, associated systemic disease, laboratory investigation, and treatment were collected from the patient's treatment record card. The examination protocol included visual acuity, color vision, ocular motility, eyelid and adnexal examination, complete anterior and posterior segment examination. Photographs with the digital camera and fundus photographs with the fundus camera were taken in selected patients. Visual field analysis and radio imaging were done in selected patients where indicated.

Data were collected, tabulated, and analyzed using MSTAT software (Developed by University of Wisconsin, Madison, USA). Chi-square test (χ2-test) was used for statistical analysis, P < 0.05 was considered significant.

Ethical issues

Permission from the institutional review board and approval from National AIDS Control Organization (NACO) was obtained before the commencement of the study. Informed consent was obtained from patients and patient's parents in case of the minor before enrolling them in the study. Confidentiality and privacy were maintained throughout the study, data was stored safely and made accessible to the researchers only.

Observations

A total of 300 patients were studied, age range of the study population was from 4 years to 73 years (mean ± standard deviation = 36.64 ± 12.25) with 173 males (57.66%) and 126 females (42%) and one intersex (0.33%). Of the above 20 (6.66%) were in pediatric age group [<15 years). The most common route of transmission was heterosexual in 263 patients (87.66%). Next common route being vertical transmission in 22 (7.33%) including all pediatric patients.

In the study 151 patients (50.33%) had ocular findings related to HIV/AIDS. The patients were divided into two groups based on ocular complaints: Symptomatic group and the asymptomatic group. Symptomatic group comprised 59 patients, of which 52 had ocular lesions (88.14%). The most common presenting symptom was the diminution of vision. Remaining 241 patients were asymptomatic and 99 (41.07%) of them had ocular lesions.

The association between low CD4 + cell counts and ocular findings was statistically significant (P = 0.0001) [Table 1].

Table 1

Distribution of patients according to CD4+cell counts [n=300]

CD4+ cell count	≤100, n (%)	100-250, n (%)	250-500, n (%)	>500, n (%)	Total, n (%)
Number of patients	28 (9.33)	75 (25)	126 (42)	71 (23.67)	300
Patients with ocular lesions	23 (82.14)	47 (62.66)	56 (44.44)	25 (35.21)	151 (50.33)
Patients without ocular lesions	5 (17.85)	28 (37.33)	70 (55.55)	46 (64.78)	149 (49.66)

The group of patients who required ART but not on ART had the highest prevalence of ocular involvement 24 (68.7%) followed by patients who were on ART 120 (51.06%), minimum ocular involvement was seen in pre ART patients, i.e. seven (23.23%) (P = 0.0001), indicating that ART has protective effect against the development of ocular complication of HIV.

The ocular lesions were observed and were categorized as adnexal 10.33%, anterior segment 25%, posterior segment 23%, and neurophthalmic lesions 8.33% [Table 2].

Table 2

Distribution of Patients According to Segment of the Eye Involved [n=300]

Segment of the eye	Number of patients with ocular findings*	Percentage out of 300
Adnexal lesion	31	10.33
Anterior segment	75	25
Posterior segment	69	23
Neuro-ophthalmic lesions	25	8.33

*Some patients had findings involving more than one segment of eye

Detailed distribution of patients with ocular findings involving adnexa, anterior segment, posterior segment, and neuro-ophthalmic lesions are depicted in Tables 3-6 respectively.

Table 3

Distribution of Patients with Adnexal Findings [n=300]**

Adnexal lesion	Number of patient	Bilateral	Unilateral	Percentage
Trichomegaly	20	20	-	6.67
Dry eyes	7	7	-	2.33
Chalazion	4	2	2	1.33
Herpes zoster	4	-	4	1.33
Blepharitis	3	3	-	1.00
Hordeolum externum	3	2	1	1.00
Molluscum	2	2	-	0.67
Epidermal cyst	1	-	1	0.33
Preseptal cellulitis	1	-	1	0.33
Symblepharon	1	-	1	0.33

*Some patients had more than one lesion

Table 6

Distribution of Patients with Neuro-ophthalmic Findings [n=300]

Neuro-ophthalmic lesions	Number of patient	Bilateral	Unilateral	Finding percentage out of 300
Optic nerve lesion	23	19	4	7.67
Facial palsy	1	-	1	0.33
Visual disturbance due to cerebral infarct	1	1	-	0.33
Total	25	20	5	8.33

The most common adnexal finding was bilateral trichomegaly. Conjunctival microvasculopathy was the most common anterior segment finding.

The most common posterior segment lesion was HIV retinopathy involving 20 patients (6.66%). The association of posterior segment lesions with low CD4 + cell count was highly significant (P = 0.0001).

Optic nerve-related lesions were the most common among neuro-ophthalmic lesions, observed in 23 (7.67%) patients. Statistically, significant association was there between neuro-ophthalmic lesions and low CD4 + cell counts (P = 0.01).

Discussion

Our study was conducted to find out the pattern of ocular manifestation of HIV/AIDS among Patients on HAART at a tertiary care center and emphasizing on the role of ophthalmologists, alongside referring physicians for early diagnosis and prompt treatment.

Based on our observation, ocular lesions were seen in 151 cases (50.33%). The most common adnexal finding was trichomegaly (96.67%) cause of which is yet unknown, although elevated viral titers, drug toxicity of zidovudine, and poor nutrition have been mentioned as contributing factors[678] [Figure 1].

Figure 1

Trichomegaly

Dry eyes observed in 2.33% of patients can be attributed to the combined effect of HIV-mediated inflammatory destruction of primary and accessory lacrimal glands and direct conjunctiva damage due to HIV itself.

Herpes Zoster Ophthalmicus (HZO) found in four of our patients tends to run a more severe course in terms of corneal involvement and post-zoster pain. One of our patients had blinding HZO with total symblepharon and opaque vascularized cornea [Figure 2]. The occurrence of blepharitis (1%), hordeolum (1%) and molluscum contagiosum (0.66%) were also observed in the study. No case of Kaposi's sarcoma was seen in this study and so was in other Indian studies. The absence of Kaposi's sarcoma in the study may have been attributed to the lower proportion of homosexual behavior and low prevalence of human herpes virus-8 in India.

Figure 2

HZO with total symblepharon and vascularized corneal opacity

Conjunctival microvasculopathy was the most common anterior segment finding (9%), presented as microaneurysms, segmental vascular dilatations and narrowing, appearance of comma-shaped vascular fragments, and a visible granularity to the flowing blood-column, (termed “sludging”). These vascular changes are thought to be due to the deposition of immune complexes in blood vessels or the direct infection of the conjunctival vascular endothelium by the HIV virus.[9] [Figure 3]. Different types of conjunctivitis were seen in 5.33% of patients. One of the Vernal Keratoconjunctivitis (VKC).

Figure 3

Conjunctival microvasculopathy

patients had severe form of the disease and was observed with bilateral Shield's corneal ulcer, this severity can be due to altered immune response and a higher level of IgE in HIV patients.[10] The pathogenesis of allergic conjunctivitis in HIV patients has not been elucidated clearly. However, studies have demonstrated an increase in IgE levels in HIV-infected people. IgE levels further increase with disease progression and decrease in CD4 + cell counts.[1011]

Viral keratitis was observed in three patients with the somewhat atypical course. First, there was a definite predilection for marginal, as opposed to central, epithelial keratitis. Second, the keratitis appeared to be more resistant to treatment, the third frequent recurrence of the viral disease.[12]

The fungal corneal ulcer was observed in two patients. Both had severe perforated corneal ulcer. In HIV patients, there are more chances of corneal infections that tend to be more severe and have a higher tendency toward perforation.[1314] In our series, five (1.66%) patients had corneal opacity, probably due to previous corneal ulceration. Corneal opacity following corneal injuries was not included.

The prevalence of IRU in our study was 0.66% (two patients). Both of our patients had bilateral grayish exudative membrane in the pupillary area and complicated cataracts with no perception of light. These patients had progressive severe diminution of vision after 8 months to 1 year of initiation of ART. Their baseline CD4 + cell counts were 40/mm3 and 58/mm3 that had increased to 387/mm3 and 282/mm3 after initiation of ART. Thus occasionally immune recovery following HAART may cause severe vision loss via the mechanism of IRU. Therefore, HIV-infected patients still require close ocular follow-up even if they are being treated with HAART.

As far as posterior segment involvement is concerned HIV retinopathy was observed in 6.66% of patients [Figure 4]. Multiple cotton wool spots and intraretinal hemorrhage were seen in our patient. The pathogenesis of HIV retinopathy seems to be related to the degree of immune suppression and HIV-related microangiopathic syndrome.[1516]

Figure 4

HIV retinopathy

In our series, 4% of patients were found with nonspecific chorioretinal atrophic changes over the posterior pole or around the disc. The exact etiology of this finding could not be determined, but they could be due to ART-associated retinal toxicity as all of these patients were on ART and there have been some reports on ART induced retinal toxicity, which may lead to nonspecific chorioretinal atrophic changes.[171819]

In the present study colloid bodies, mottled pigmentary retinal changes, and hard exudates were observed in 18 (6%), nine (3%) and three (1%) patients respectively. In literature, there are many studies in which researchers have investigated and concluded that HIV impairs the integrity of the retinal pigment epithelium (RPE) barrier and downregulate the expression of tight junction and protein in the RPE barrier. They have also mentioned that HIV gp120 protein causes disruption of RPE.[202122] These could be the possible reasons behind above-mentioned findings.

Perivascular sheathing observed in 10 (3.33%) patients, could be a sequel of active perivasculitis as described in the literature.[23] We did not observe any patient with active perivasculitis (except in one patient, which had frosted branch angitis with CMV retinitis) [Figure 5].

Figure 5

CMV Retinitis with frost branch angitis

The lower frequency of CMV retinitis observed in the study could be attributed to widespread use of HAART. With the advent of HAART, up to 72% reduction in the incidence of CMV retinitis has been observed.[24]

Progressive outer retinal necrosis with optic atrophy was observed in one patient [Figure 6], who had a history of HZO 6 months earlier. Due to the potentially devastating and rapid course of retinal opportunistic infections, all persons with HIV disease should undergo routine baseline ophthalmologic evaluations. Any HIV-infected person who experiences ocular symptoms also should receive prompt and competent ophthalmologic care as a delay in therapy can lead to irreversible visual loss.

Figure 6

Optic atrophy

Papilloedema seen in three (1%) patients, two were diagnosed with tubercular meningitis and one had multiple cerebral tuberculomata. Hyperemia of the optic disc was seen in 3.66% of patients, without any symptoms or signs suggestive of optic neuritis or papilledema or any intracranial pathology. These patients had no visual impairment though eight of them had color vision abnormality. The exact cause behind this finding is yet to be established. In our series, two patients had bilateral anterior ischemic optic neuropathy.[25] Elevated serum titer of antibodies to HIV causes injury to the posterior ciliary arteries and changes in the blood circulation leading to ischemia of the optic nerve head.[25]

Conclusion

HAART has changed the face of HIV-related eye disease with a reduction in serious ocular opportunistic infections and ocular malignancies but HAART-mediated visually disabling IRU has emerged as a clinical challenge for ophthalmologists. Ocular manifestations may reflect systemic disease and can be the initial manifestations of HIV in many cases. Hence, screening after ocular complaints is not a reliable method for identifying those with ocular morbidities. This highlights the need for routine ophthalmic screening with a complete ocular examination in all HIV patients whether patients have any ocular complain or not. An improved communication between the two broad specialties of HIV medicine and ophthalmology will definitely go a long way in the battle against this dreadful disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 4

Distribution of Patients with Anterior Segment Findings [n=300]

Anterior segment	Number of Patients	Bilateral	Unilateral	Ocular finding percentage out of 300
Conjuctival microvasculopathy	27	22	5	9.00
Allergic/angular conjunctivitis and VKC	16	15	1	5.33
Kerato conjunctivitis	8	4	4	2.66
Corneal opacity	5	1	4	1.66
Axenfeld loop	4	4	-	1.33
Pinguiculitis and inflamed pterygium	4	3	1	1.33
Viral corneal ulcer/keratitis	3	-	3	1
Complicated cataract	3	3	-	1.00
Immune recovery uveitis	2	2	-	0.66
Glaucoma	2	2	-	0.66
Episcleritis	1	-	1	0.33
Subconjuctival hemorrhage	1	-	1	0.33
Fungal corneal ulcer	1	-	1	0.33
Fungal endophthalmitis	1	-	1	0.33

VKC: Vernal keratoconjunctivitis

Table 5

Distribution of Patients with Posterior Segment Involvement [n=300]

Posterior segment	Number of patients	Bilateral	Unilateral	Finding percentage out of 300
HIV retinopathy	20	16	4	6.66
Colloid bodies/exudates	12	9	3	4
Chorioretinal atrophic changes	12	7	5	4
Perivascular sheathing	8	5	3	2.66
Retinitis	7	3	4	2.33
Mottled pigmentary changes	6	4	2	2
Uveitis posterior (chorioretinitis)	4	1	3	1.33
Vitritis	2	2	-	0.66
CSR	1	-	1	0.33
Macular edema	1	-	1	0.33

HIV: Human immune deficiency virus, CSR: Central serous retinopathy