What you can see in your patient's eyes? Review of ocular manifestations of HIV in HAART era

Abstract

The early diagnosis and treatment of ocular disease to prevent morbidity and mortality of patients with human immunodeficiency virus (HIV) is of paramount importance. Since the advent of highly active antiretroviral therapy (HAART), the incidence of ocular complications of HIV has decreased and their manifestations and natural course are also modified. This has been observed in the face of emerging immune recovery, which per se has brought new difficulties in the process of diagnosing and management of the ocular disease. Conditions such as immune recovery uveitis could affect eyes with history of opportunistic disease with a potential to cause vision loss; with this regard, differentiation of the inflammatory process from infective causes is essential. The other sexually contracted diseases are also to be included in this complex picture because of their contribution to the clinical picture and also sharing common routes of transmission with HIV. There is very little doubt that visual deterioration would further deteriorate the already compromised quality of life of this group of patients. In this review, authors wish to provide evidence available in the medical literature around the visual health issues in HIV-infected patients and raise awareness towards the changing pattern of the ocular disease in the HAART era.

Keywords

HIV eye immune reconstitution syndrome cytomegalovirus (CMV)HAART ophthalmopathy HSV uveitis syphilis toxoplasmosis Kaposi's sarcoma HIV OPHTHALMOPATHY

Hiv Ophthalmopathy

Use of highly active antiretroviral therapy (HAART) has tipped the balance between the infectious and non-infectious causes of retino-pathy in favour of the latter, and as a result, more cases of human immunodeficiency virus (HIV)-induced retinopathies are diagnosed in recent years.¹ HIV alone without other opportunistic infections is capable of causing ocular abnormalities² with nearly 75% reduction in the incidence of cytomegalovirus (CMV) retinitis in HAART era. HIV retinopathy now constitutes the most common cause of posterior segment disease in HIV-positive patients.³ It is estimated that 50–70% of HIV-positive patients eventually develop ocular complications of some sort^2,4 with anterior segment complications in half of the cases.^2,4,5 Based on autopsy findings, nearly 90% of patients with AIDS have eye involvements.²

Functional visual deficit, as demonstrated by poor performance of HIV-positive patients in colour vision and contrast sensitivity tests, despite normal fundoscopic picture, has been described by several studies, which represents dysfunction at the level of macula, optic nerve or in the higher processing levels.¹

Keratoconjunctivitis sicca was the cause of dry eye in 20% of HIV-positive patients before the widespread use of HAART; together with Sjogren-like syndrome,⁴ they now occur in only 1.5% of patients.⁵ Treatment is with artificial tears and long-acting lubricating ointments.⁶

Retinal microangiopathy, thought to be a multifactorial disease due to HIV and immune-related vasculopathy related to age or hypertension, is still the most common retinal manifestation, and could be a clinical marker predicting the progression of HIV infection in the HAART era.⁷

Retinal microangiopathy, which can lead to retinal cotton wool spots, is the most commonly seen abnormality and reflect nerve fibre infarction.² With direct ophthalmoscopy, cotton wool spots appear as ‘feathery white'⁸ retinal lesions with indistinct borders and result from stasis of axoplasmic flow in the nerve fibre layer of the retina.⁹ This condition occurs predominantly around the optic disc and macula.¹⁰ Cotton wool spots are also observed in other systemic vascular conditions such as diabetes, hypertension and lupus erythema-tosus, as well as in the elderly and individuals treated with interferon-a.⁷ Retinal microangiopathy is used collectively when cotton wool spots are seen in conjunction with retinal haemorrhage and microaneurysms. Usually asymptomatic and self-limiting, it recurs intermittently, affecting between 44 and 60%⁵ of HIV-positive patients in pre-HAART era¹¹ and could lead to decreased visual function and loss of optic nerve fibres.² The loss of optic nerve fibres and thinning of the retinal nerve fibre layer in HIV-positive patients has been demonstrated in a quantifiable and reproducible method using optical coherence tomography.³ Ischaemic maculopathy may cause severe and lasting visual loss in patients with AIDS, and although altered microcirculation has been postulated as the cause, the possibility of occult herpetic infection should be borne in mind as suggested by some studies.¹² Treatment with HAART has reduced the incidence of this condition. However, increased leukocyte rigidity, believed to be important in pathogenicity of the disease, is still observed despite HAART therapy, and will put these patients at risk of retinal vasculopathy.⁵ Other abnormal findings are decreased visual fields, colour vision, and contrast sensitivity and marked loss of retinal ganglion cell nerve fibres. ^2,6

Retinal microangiopathy should be considered part of generalized HIV-associated vasculopathy, which is a predictor of other complications such as cerebral ischaemia and AIDS dementia complex.⁷

Evidence suggests that the incidence of cotton wool spots increase dramatically with the decline of CD4 counts below 0.20 ×10⁹ /L.¹ However, the presence of HIV-related microangiopathy is thought to be associated with higher viral replication, independent of the extent of immunodeficiency of the patients.⁷ Once CD4 counts are higher than 0.10 ×10⁹ /L, other causes of microangiopathy such as diabetes, anaemia or hypertension should be considered in similar clinical situations in HIV-positive patients.⁴

Reduced amplitude of accommodation outside normal limits is reported in around two-third of patients in some studies, with maximal effect on 25-29 years age group, this along with decline in the incidence of opportunistic infections and improved survival rates is going to be a major clinical problem in future and represent a considerable reversible cause of morbidity in the HIV-positive population in the HAART era.¹³

Reduced intraocular pressure (IOP) in HIV-positive patients, is thought to be reversed following increased aqueous flow as a result of HAART therapy.¹⁴ It is then speculated that a rise in IOP is to be expected with immune recovery and after elevation of CD4 count, and with this regard due attention should be drawn to monitoring IOP in the treatment and follow-up of HIV-positive patients with glaucoma.¹⁴

Any degree of visual impairment has important impact on the quality of life (night vision during driving) of patients with HIV, regardless of satisfactory CD4 levels and requires due attention in a holistic approach in maintaining the function and independence of these patients.¹

Immune Reconstitiution Syndrome and Immune Recovery Uveitis

One of the most common cause of visual loss in HIV-positive patients in the HAART era is immune recovery uveitis (IRU),¹⁴ the ocular counterpart of immune reconstitiution syndrome (IRS). IRU is a condition affecting a substantial proportion of patients with CMV retinitis who develop immune recovery in response to HAART demonstrated by some multicentre studies.¹⁵ IRS is a pathological inflammatory response to either previously treated infections or subclinical infections, which complicates the clinical course of 25-35% of HIV seropositive patients after establishment of immune recovery following HAART therapy.¹⁶ Immune recovery following initiation of HAART has resulted in inflammatory disease associated with other opportunistic infections.¹⁷ Immune recovery is defined as CD4 count of more than 0.1 ×10⁹ /L or a rise of more than 0.05 ×10⁹ /L above baseline. ^15,18 The majority of the cases occur within the first 60 days of initiating HAART in those with satisfactory rise in CD4 counts; however, IRS could have a delayed onset of up to two years.¹⁶ The data

suggest that the rejuvenated immune response can induce clinically significant inflammatory response¹⁷ including re-emergence of clinical manifestations of the disease without clinical evidence of CMV ophthalmopathy, disseminated infection with Mycobacterium avium complex and central nervous system (CNS) infection with Cryptococcus neoformans.^4,5,16,18

Although HAART-induced immune recovery is effective in controlling CMV retinitis,¹⁷ it can have untoward effects by causing intense uveitis and vitritis, collectively named IRU. In the era of HAART, the incidence of CMV retinitis has declined by approximately 75-90%, and the prognosis of CMV retinitis for patients who use HAART has substantially improved, with a lower risk of retinitis progression, retinal detachment (RD), vision loss and mortality. More than 80% of the cases occur three months or more after initiation of HAART.⁵ IRU is characterized by vitritis and complications including cystoid macular oedema (CME) epiretinal membrane formation (ERM), cataract,¹⁵ and disc oedema.¹⁷ Symptoms typically include floaters¹⁵ and moderate vision loss.¹⁸ HAART-induced IRU occurs following treatment with HAART, exclusively in eyes with CMV retinitis and despite treatment with anti-CMV medications, and may diminish vision in some patients. ^5,10,17,18 Cataract, ERM and CME constitute most cases of vision loss in patients with HAART-induced immune recovery.^18,19

As a result, patients with CD4 counts of < 0.07 ×10⁹ /L should be referred to be evaluated for ocular CMV prior to commencement of HAART, as management of the CMV retinitis is essential to reduce the chance of IRS.¹⁰

In addition to immune recovery, involvement of a large proportion of the retina with CMV retinitis and prior use of cidofovir are other reported risk factors of IRU.¹⁵ Treatment with cidofovir and more than 30% involvement of surface area with retinitis has shown to increase the chance of IRU by a factor of three¹⁸ and four,¹⁵ respectively.

The inflammatory reaction in the uveal tract is thought to reflect the recovery of specific anti-CMV immunity, probably influenced and reinforced by genetic susceptibility of some patients, as evidenced by lack of CMV DNA and absence of active retinitis. It is more commonly observed in women patients. It is not clear if subclinical replication of the virus is responsible¹⁵ and despite some reports suggesting a beneficial role for valgancyclovir (900 mg once daily),¹⁸ no consistent beneficial role for anti-CMV therapy has been found in different studies.¹⁵

Treatment with corticosteroids⁴ has been recommended, yet evidence has been inconsistent.⁵

Uveitis Due to Other Causes

Uveitis in AIDS patients could be a reaction to prophylactic rifa-butin for opportunistic infections like M. avium complex,⁵ a reaction observed in up to 15% of HIV-positive patients.⁴ Late manifestation is not unusual and right diagnosis and management with topical steroids is essential to avoid unnecessary surgical interventions.² Cidofovir causes uveitis in 25–30% of patients and may be accompanied by low intraocular pressure (hypotony).⁶ Symptoms include pain, redness, photophobia and blurred vision.⁴

Azoles and macrolides used simultaneously with rifabutin increase its toxicity due to higher levels, secondary to reduced hepatic metabolism of rifabutin.^5,10 Unless rifabutin is discontinued and treatment ensued with topical steroids, profound visual loss could occur.¹⁰

Other drugs used to treat opportunistic infections including cidofovir and fomivirsen are also known to cause anterior uveitis.⁵

Anterior uveitis seems to be a more common presentation of other causes of inflammation of the uveal tract in HIV-positive patients, such as herpes zoster (HZ) ophthalmicus, tuberculosis, CMV infection and toxoplasmosis.²⁰

Depigmentation of the peripheral retina with preservation of the central visual acuity is a known side effect of dideoxyino-sine,² seen most commonly in children.⁴

Iridocyclitis due to Reiter's syndrome, is another form of uveitis reported to occur more commonly in patients with HIV infection than those without it.⁶

Infection with DNA Viruses

Before HAART, CMV retinitis, with an incidence of 30%,^11,19 caused by this double-stranded DNA herpes virus, was the most common ocular infection in patients with AIDS, mostly occurring with CD4 values < 0.05 ×10⁹ /L.⁸ High likelihood of progression to full thickness necrosis without treatment was the rule, ending in RD and vision loss within 3-6 months. ^2,18 Since the advent of HAART therapy, opportunistic infections such as CMV retinitis are much less common except in patients who present late in the course of the disease or fail to respond.¹⁰ CMV-related RD remains the most common cause of visual loss among patients with CMV retinitis despite widespread use of HAART. ^5,19

Symptoms like floaters, photopsia and reduced visual acuity and visual field defect should be sought in high-risk patients with suggestive history of CMV retinitis. ^5,21

Varicella zoster virus (VZV) and herpes simplex virus (HSV) are other keratotrophic members of this family and are the most common causes of interstitial keratitis in HIV-positive patients.^5,6 They can also involve the retina and are believed to be responsible for most of the reported cases of acute retinal necrosis (ARN),²² which may occur at any levels of CD4 counts.²³

Symptoms of anterior segment involvement include irritation, pain, photophobia and decreased vision.⁶ Anterior segment complications are often so obvious that they are detectable with a penlight.⁶

Cytomegalovirus

CMV retinitis and its complications of RD and necrosis contribute to the majority of cases of visual loss in HIV-infected individuals.² CMV retinitis accounts for more than three-quarters of retinal infection in AIDS patients. ²⁴ Clinical findings are variable, varying from normal⁸ to profound blindness and serial fundus photographs are the best method of monitoring disease progression or response to treatment.² CMV retinitis severely impairs the quality of life in AIDS patients, especially in those with CD4 counts < 0.05 ×10⁹ /L, an indicator of fullblown AIDS,⁹ either due to being HAART native or treatment failure.¹⁸ Patients with CMV retinitis require more frequent and regular monitoring with serial examinations.² Most cases of new CMV retinitis in the HAART era occur in patients who have tried HAART and failed, and as a result require long period of anti-CMV therapy.¹⁸ Relapse is a potential threat especially with disease resistance, and visual loss may be irreversible.² Systemic gancyclovir is considered the first line treatment in HAART naïve patients, and intraocular implants are recommended in cases of poor tolerance to systemic treatment, poor compliance with HAART, resistance to treatment or evidence of progression of retinitis.² Oral valgancyclovir is equivalent to intravenous gancyclovir for initial therapy of CMV retinitis both for induction (900 mg twice daily for 2-3 weeks) and maintenance (900 mg once daily).¹⁸ Intravenous gancyclovir and foscarnet in combination is recommended⁵ for the recurrent disease to delay progression of the disease.⁴ Better results are achieved with intraocular treatment either with intravitreal injection of gancyclovir or foscarnet, or a gancyclovir implant.¹⁰ Gradual and slow topical delivery of gancyclovir in the form of intraocular implants delays the progression of the disease, but recurrences still occurred once the implant has depleted, necessitating multiple implants.¹⁸ Recurrences are mostly due to progressive immune dysfunction, inadequate intraocular drug levels and drug resistance. Some side effects of systemic administration of these drugs include severe neutropenia with gancyclovir and renal failure with foscarnet and cidofovir.⁵ Gancyclovir implant neither protects the contralateral eye nor does it prevent systemic CMV infection,⁸ and implants are usually combined with other systemic anti-CMV drugs.⁴ Treatment with intravitreal cidofovir has now been used less commonly due to its side effect of uveitis and hypotony. ^4,10 Progression of the disease without immune reconstitution is the rule, with time.² There is risk of recurrence after the discontinuation of CMV treatment.² Nearly half of the cases of local therapy² and 30-50% of cases of systemic antiviral therapy¹⁸ are complicated with recurrence of the disease locally.

Several studies have shown that immune recovery, secondary to highly active antiretroviral therapy (HAART), has had major impact on CMV retinitis including a decrease in incidence by 50-99%, ^5,6,10,18 a change in the clinical course of the disease and an altered clinical presentation.⁴ Immune recovery in these patients is enough to control CMV retinitis.² Lack of reactivation of CMV retinitis in patients receiving HAART is another interesting observation in other studies.² Research has shown that 3 months treatment with HAART, is the minimum time required, after obtaining a sustained surge in T cells (CD4 count), making further specific anti-CMV therapy unnecessary.¹⁸ Successful discontinuation of anti-CMV therapy without reactivation of retinitis is another promising observation in patients with CD4 counts > 0.10 ×10⁹ /L,⁴ regardless of HIV viral load (VL) or CMV culture results. Suboptimal pathogen-specific immune response, however, can complicate the management of some patients even after HAART and a significant increase in CD4 T-lymphocyte count.²¹

Prior to advent of HAART, patients with CMV retinitis would suffer progression within a median of 3 weeks without specific anti-CMV therapy.² This would be delayed up to 3-4 months in patients receiving systemic anti-CMV therapy. Patients with CMV retinitis experience lower rates of disease progression while on HAART therapy¹⁹ with reported 60% reduction in the incidence of RD. ^5,18 It is currently recommended that treatment with specific anti-CMV therapy in patients with quiescent CMV retinitis could be stopped if CD4 cell counts are stable or increasing and have been consistently above 0.10 ×10⁹/L for at least three months.⁵ It is worth mentioning that even patients with immune recovery are at risk for progression of CMV retinitis¹⁹ and as a result should be examined closely for reactivation of retinitis or development of extra-ocular disease⁴ and specific anti-CMV therapy should be considered, if CD4 counts are < 0.05 ×10⁹ / L, despite HAART. ^4,5,17 The risk of RD is significantly less if intravitreal therapy is chosen.⁵

Despite reduced mortality of more than 96%¹⁸ in recent years, CMV retinitis is still associated with increased mortality even in the HAART era, and remains an important factor in the AIDS epidemic.²⁴ The results of some studies suggest that detection of plasma CMV DNA is associated with a higher risk of mortality than a high HIV VL.²¹

However, the initial increase in CD4 numbers may not be all required to halt the progression or induce the regression of the disease and further restoration of anti-CMV function of these new lymphocytes is believed to be more important.¹⁸

Uveitis associated with CMV retinitis does not usually present with a painful red eye. In symptomatic uveitis, other aetiologies such as syphilis, tuberculosis, lymphoma and HZ should be considered as differential diagnosis.⁵

Drug-induced keratopathy is a reversible condition representing toxicity to gancyclovir and atovaquone and should be considered in corneal disease.²¹

Other HSV

Verruca vulgaris

This is a papillomavirus, a kerato-tropic organism, with the ability to involve the skin of the eyelids and eyelid margins or the conjunctival epithelium.² Oculogenital and autoinocu-lation²⁵ methods of transmission are well described.² Visual deficit secondary to corneal abrasion due to conjunctival lesions have been described.² HPV-11 is the most common detected type in all groups of patients.²⁵ HIV-positive patients are of higher risk for developing carcinoma associated with human papillomavirus infection.²¹

A combination of surgical excision for the eyelid lesions and cryotherapy to remove conjunctival warts is effective.²

Conjunctival intraepithelial neoplasia is correlated with HIV seropositivity in half of the cases.¹¹

Herpes simplex virus

HSV type 2 due to oculogenital transmission is the cause of a more resistant type of keratitis.² History of genital HSV and/ or other sexually transmitted infections should be sought as supportive evidence of oculogenital transmission.²⁶ Keratitis tends to recur, causing corneal scarring and vision loss as a result of irreversible corneal disease.² Clinical signs range from slight visual reduction and gritty sensation to severe pain and marked visual loss should ophthalmology consultation be delayed.²

In AIDS patients it tends to be more severe with more frequent recurrences and more peripherally located corneal dendritic lesions with a higher bilateral incidence. ^11,26

Patients treated with HARRT experience shorter periods of reactivation than untreated patients² and treatment with intravenous acyclovir or foscarnet is recommended.²¹

Herpes zoster virus

HZV was the second most common cause of retinopathy in pre-HAART era with 70% chance of RD and 64% risk of blindness if complicated with ARN.¹⁸ With 17% chance of ARN without HAART therapy,⁵ severe necrotizing retinitis with possible extension to the optic nerve head is the most common manifestation of infection with this virus in HIV-positive patients.²⁷ HZ ophthalmicus can be an early clinical marker of HIV seropositivity in healthy carriers and not necessarily a sign of advanced disease.²³ The incidence of HZO in HAART era remains at around 5–15% of HIV-positive patients²¹ with two-fold rise in the incidence reported with use of protease inhibitors. These episodes nevertheless are milder.⁵ Iritis, keratitis, corneal defects and glaucoma are among other clinical manifestations of the ocular disease.⁸ Bilateral disease with predominant involvement of the macula is associated with severe visual loss and RD within weeks if untreated.² Sudden onset deteriorating vision loss, sluggish pupillary reaction to light, and central scotoma in a patient with HIV should suggest VZV as a possible cause of retrobulbar optic neuritis in the presence of normal ophthalmic examination.²⁷ The ocular involvement often presents alongside the classical dermatologic vesicular eruption in the territory of the ophthalmic division of the trigeminal nerve,⁸ although VZV infection can frequently occur without a typical cutaneous dermatomal eruption.²⁷ VZV infection may on occasion be preceded by aseptic meningitis or optic neuritis.² Aggressive treatment of this blinding disease in the context of HIV infection is recommended and should be tried using combined intravitreal and high dose intravenous antiviral²² such as gancyclovir. This is often combined with foscarnet,² which when compared with intravenous acyclovir provides more effective prevention against RD.^5,10 The efficacy of acyclovir and valcyclovir is similar in preventing ocular complications.²¹

The presence of this infection in a young person should alert the physician to the possibility of HIV infection.^11,14

Other Infections and Tumours: New Trends

Syphilis

Syphilis is caused by spirochete bacterium Treponema pallidum.²⁸ Recent studies have shown an increased incidence of ocular syphilis in HIV-infected patients receiving HAART.²⁹ With the decline of CMV retinitis and other opportunistic infections, syphilitic uveitis may become a more common cause of HIV-associated ocular complication in future, replacing CMV and its complications.²⁹ Ocular manifestations of syphilis in adults are protean.²¹ Ocular involvement of syphilis in HIV-infected patients not receiving antiretroviral therapy is more aggressive;^10,29 frequently bilateral and involves the posterior segment²⁹ including iritis, vitritis,⁸ necro-tizing retinitis, serous RD and commonly papillitis.¹⁸ A diagnosis of ocular syphilis should be considered in any HIV-positive patient who presents with visual symptoms regardless of the patient's CD4 count, HIV VL or use of HAART.²⁹ The most important differential diagnosis in patients with HIV presenting with loss of vision is CMV retinitis.³⁰ Ocular syphilis is thought to cause <1–2% of all uveitis cases and should certainly be included in the work-up of any unexplained ocular inflammation.²⁸ The presenting signs of ocular syphilis include blurred vision, loss of vision, central scotoma, and ocular pain and ipsilateral preauricular adenopathy is an associated finding.² Syphilis is by and large the most common bacterial cause of intraocular infection^6,8,21 and

uveitis (1.1% of the cases)³¹ in HIV-positive patients.² This appears to be the most common ocular manifestation of secondary (10%) and tertiary syphilis (5%).^28,32 Patients with syphilitic uveitis should have HIV testing done due to the fact that more than 85% cases of uveitis are associated with neurosyphilis in HIV-infected patients.^5,18 If HIV test is positive, analysis of the cerebrospinal fluid should be performed.³² Syphilitic uveitis is one of the leading causes of secondary glaucoma in uveitis patients.³² Diagnosis is by serologic tests including non-treponemal-specific tests of venereal disease research laboratory (VDRL) and treponemal-specific tests such as TPPA.³² A negative cerebrospinal VDRL does not exclude the possibility of neurosyphilis due to low sensitivity of the test.^28,32 It is worth mentioning that CSF abnormalities are common in HIV-infected patients even in the absence of syphilis or other infective pathogens^28,32 and routine CSF evaluation is not recommended in HIV-positive patients in early syphilis unless there are clinical clues such as treatment failure, cranial nerve palsies, pupillary dysfunction or ocular involvement like uveitis.³² HIV-positive patients have a higher rate of false-positive and false-negative VDRL results compared with immu-nocompetent individuals.^28,32 HIV can lead to false-negative results in treponemal-specific tests²⁸ and hinders the rate of decline of non-treponemal titres after treatment of syphilis.³²

Syphilitic necrotising retinitis has a slow rate of progression and responds dramatically to intravenous penicillin.²⁸ The treatment regimen includes four weeks of intravenous penicillin in HIV-positive patients.^18,29 Other authors recommended a 10–14 days course of 18–24 MU of intravenous aqueous penicillin G per day, or combination of 2.4 MU of intramuscular procaine penicillin and probenicid 500 mg four times a day for the same duration.²⁸

Penicillin is recommended for the treatment of all stages of syphilis in patients co-infected with HIV. Penicillin-allergic patients in those categories may be desensitised and treated with penicillin.²⁸ Assessment and treatment of serologically proven contacts of these patients are necessary.

Recent studies have suggested an increased incidence of neu-rosyphilis in patients infected with HIV.³⁰ Other causes of infectious uveomeningeal syndrome are tuberculosis, infections with fungi, cytomegalovirus, VZV and HSV in patients with HIV-1 infection and present with involvement of retina, uveal tract and brain and must be included in the differential diagnosis, if clinically suggested.³¹

In view of the re-emergence of syphilis in HIV-positive patients, especially the homosexual population, and its capability to mimic any ocular inflammatory disease, it is prudent to bear the diagnosis of this potentially sight-threatening condition in mind.³³

Chlamydia

Chlamydia trachomatis is the most common sexually transmitted bacterium and causes ocular problems including inclusion conjunctivitis which is mediated through oculogenital contact by B, Ba, D-K serotypes.³⁴ Fifty to 90% of adults with ocular infection also have concurrent genital tract infection. The conjunctivitis usually manifest as red eye with foreign body sensation and later development of mucopurulent discharge. Diagnosis is made with culture and polymerase chain reaction (PCR) examination of the specimens from conjunctiva and urethra.^34,35 Treatment is with a single 1 g dose of azithromycin.

The literature related to the incidence and course of ocular chla-mydial disease in AIDS patients is scant.³⁵

Gonorrhoea

Anogenital Neisseria gonorrhoeae should be considered in the differential diagnosis of ocular infection and conjunctivitis in homosexuals.² Keratitis is encountered in < 5% of HIV-positive patients and even though the non-viral causes of corneal infections are not seen more commonly than the general population, they tend to be more severe. A sexual history should be obtained and attention should be paid to the risk factors of HIV transmission.³⁶ Diagnosis is made by demonstration of intracellular gram-negative diplococci in the specimens obtained from eye, throat, urethral and rectal swabs.²

Corynebacterium diphtheroides should be considered in the differential diagnosis.³⁶ Treatment should always be guided by the sensitivities; however, successful management of the ocular disease should be in keeping with local resistance profile (oral high-dose ciprofloxacin has been reported).³⁷ Severe cases require hospital admission and intravenous ceftriaxone is considered the first choice.³⁷ Management of the other STDs and addressing their risk factors, and contact tracing are necessary.³⁷

Ocular tuberculosis

The incidence of extra-pulmonary tuberculosis and, as a result, the ocular disease, has increased in the era of global HIV epi-demics.⁵ Although frequently asymptomatic, ocular tuberculosis can manifest as choroiditis, and anterior uveitis.⁵ A high level of suspicion in HIV-positive patients with non-specific uveitis resistant to steroids is required to guide investigations and the treatment.⁵

Leishmania

Several cases of granulomatous uveitis have been reported due to different species of Leishmania at times in patients already on HAART; and Leishmania should be considered in the differentiation of uveitis in these patients along with tuberculosis, syphilis and IRS.³⁸ The history of Leishmania and lack of response to steroids in the absence of evidence of other infectious aetiologies is helpful. Negative cultures and PCR tests could be misleading and this condition should be remembered, especially in individuals migrating from endemic areas in Africa.³⁸

Toxoplasma

Toxoplasmosis was the third most common infectious retinopathy of AIDS during the pre-HAART era which appears as white yellow areas of retinal necrosis.¹⁸ Toxoplasma retinitis appears usually when the CD4 count falls below 0.15 ×10⁹ /L.¹⁰ The three patterns of infection are primary, metastatic or reactivation.¹⁰ Sulphonamide prophylaxis against Pneumocystis carinii also provides protection against this condition.¹⁰ Ocular lesions may be the first sign of intracranial or disseminated toxoplasmosis.⁸ Also there is strong association between ocular toxoplasmosis with the cerebral lesions ²¹ in one-third of the cases.^5,6 A computerised tomography¹⁰ or magnetic resonance imaging (MRI) ²¹ brain scan is mandatory and brain biopsy is indicated should no clinical response be observed after two weeks of treatment.¹⁰ Treatment with sulphadiazine and pyrimethamine is the first-line therapy¹⁸ and clindamycine plus pyrimethamine, azithromycine or atovaquone would be reserved for cases where the first-line therapy is not tolerated.¹⁰ Discontinuation of the prophylaxis could be tried following HAART-related immune recovery.¹⁸

Pneumocystis jiroveci (previously P. carinii)

Choroiditis due to P. jiroveci was the marker of the systemic disease in the pre-HAART era in patients with CD4 counts below 0.20 ×10⁹ /L (milliary choroiditis).^10,18 requiring systemic therapy.¹⁰ Although the incidence of ocular P. jiroveci has dropped dramatically since the advent of HAART,¹⁰ and patients may discontinue their prophylaxis if they achieve a CD4 of more than 0.20 ×10⁹ /L for more than three months.¹⁸ Its presence should be questioned in cases of coexistent pulmonary involvement and choroidal disease.¹⁰ Other differential diagnoses are tuberculosis, candidaemia and bacterial sepsis.

Cryptococcus

Papilledema or optic neuropathy is a major ocular manifestation of cryptococcal meningitis,²¹ often as a result of direct invasion of the optic nerve by the fungus.¹⁸ Other findings include optic atrophy and cranial nerve palsy with ensuing double vision.⁸ Intravenous amphotericin B in combination with 5-flucytosine, followed by maintenance of oral fluconazole constituted the treatment during pre-HAART era.¹⁰ It is considered safe to stop the maintenance treatment once CD4 count is above 0.10 ×10⁹ /L following HAART therapy.¹⁰ Evidence is also suggestive of a direct inhibitory role for indinavir against C. neoformans¹⁸

Tumours

Kaposi's sarcoma

This condition affects eyelids or conjunctiva in about 5% of HIV-positive patients in the HAART era,⁵,¹⁰ and has been strongly associated with human herpes virus type 8.²¹ It must be considered in the differential diagnosis of painless nodular lesions of eyelids, conjunctiva⁸ and rarely the lacrimal sac and the orbit.¹⁰ It tends to regress following HAART^4,5,10,21

It occurs in about 30% of AIDS patients without treatment and used to be the second most common presenting sign of AIDS, after P. jiroveci.^6,11

Lymphoma

This rare condition in the post-HAART era usually occurs when CD4 count falls below 0.05 ×10⁹ /L, is mostly of large B-cell type and is associated with Epstein-Barr virus infection.¹⁰ The retinal involvement is more often a reflection of a primary CNS lymphoma while choroidal lymphoma is a secondary uveal infiltration of systemic disease¹⁸ which could present as an orbital mass.¹⁰ Its manifestations include yellow-white retinal infiltrate/necrosis, and perivascular sheathing and cytopathology of vitreous aspirate is diagnostic.¹⁸ It should be suspected in steroid-resistant uveitis where biopsy of the vitreous would be diagnostic.⁵ Treatment of the ocular disease is with whole eye radiation¹⁸ and intravitreal methotroxate may be used when recurrences are encountered.^10,18

Molluscum contagiosum

This condition involves the eyelids in up to 5% of HIV-positive patients in whom it tends to be more severe with larger, more numerous and more rapidly growing lesions.^5,6 Eyelid lesions may be the initial manifestation of HIV infection which may coalesce into larger lesions on the lid margin leading to follicu-lar keratoconjunctivitis.⁴ Spontaneous resolution of the lesions after treatment with HAART has been reported.^{4

6}

Neurophthalmologic Conditions

Other than opportunistic infections co-infecting the two organs, progressive multifocal leukoencephalopathy is a demyelinating disease of the CNS, linked to infection by JC polyomavirus, and with ocular manifestations of nystagmus, diplopia due to cranial nerve palsy and cortical blindness in young patients with HIV,⁵ and may represent the first manifestation of the HIV.^5,39 The decline in the incidence of this condition and other severe neuropathological conditions such as CMV encephalitis and lymphoma, is paralleled with the rise in the incidence of less aggressive conditions such as VZV and HSV encephalitis.⁵ Evaluation of these patients should include MRI followed by a lumbar puncture to obtain samples for cell count cytological studies, culture and antibody testing.⁶

Footnotes

CPD Test Questions

CPD TEST QUESTIONS

Approved by the Royal College of Physicians of London for CPD accreditation
Based on: Nasoodi A, Lim LT, Al-Ani A, Quah S and Dinsmore W.
What you can see in your patient's eyes: review of ocular manifestations of HIV in the HAART era.
Int J STD AIDS 2008; 19: 4–11
Minimum score required: 80%. CPD credits for this article: 1
(For each of the following statements circle whether it is true or false)
(1)Which of the statements about HIV ophthalmopathy in the HAART era are true?
(a) 90% of HIV patients would have developed some ophthalmopathy on death.	TRUE/FALSE
(b) Incidence of CMV retinitis in HIV patients has been reduced by 50% in the HAART era.	TRUE/FALSE
(c) Keratoconjunctivitis sicca is more widespread in HIV patients in HAART era.	TRUE/FALSE
(d) Retinal microangiopathy is a clinical marker of HIV patients.	TRUE/FALSE
(e) Cotton wool spots do not occur in HIV retinitis.	TRUE/FALSE
(2)CMV retinitis in HIV patients:
(a) Became more rampant as a result of HAART.	TRUE/FALSE
(b) Before HAART, the incidence in HIV patients was 30%.	TRUE/FALSE
(c) If left untreated will definitely result in retinal detachment.	TRUE/FALSE
(d) Accounts for three quarters of infectious retinitis.	TRUE/FALSE
(e) Oral ganciclovir is first line treatment.	TRUE/FALSE
(3)The following statements are true:
(a) Ganciclovir can cause severe neutropenia.	TRUE/FALSE
(b) Cidofovir can lead to renal failure.	TRUE/FALSE
(c) Gancicolovir intraocular implant of one eye gives protection to the fellow eye.	TRUE/FALSE
(d) Intravitreal cidofovir can lead to uveitis.	TRUE/FALSE
(e) Ganciclovir implant remains in the patients’ eyes and will not deplete.	TRUE/FALSE
(4)The following statements are true.
(a) HIV patients are at higher risk of developing carcinoma related to HPV.	TRUE/FALSE
(b) Conjunctival intraocular neoplasia is associated with half of HIV patients.	TRUE/FALSE
(c) HSV keratitis is more common in HIV patients than the normal population.	TRUE/FALSE
(d) HSV keratitis in HIV patients tends to be more severe than in normal population.	TRUE/FALSE
(e) The incidence of herpes zoster virus ophthalmopathy is around 10% in HIV patients.	TRUE/FALSE
(5)The following are true:
(a) Syphilis in HIV patients receiving HAART is more prevalent.	TRUE/FALSE
(b) Ocular syphilis causes about 2% of uveitis cases in HIV patients.	TRUE/FALSE
(c) Syphilitic uveitis can lead to secondary glaucoma.	TRUE/FALSE
(d) HIV-positive patients have a higher rate of false-positive and false-negative VDRL resultscompared with immunocompetent individuals.	TRUE/FALSE
(e) Syphilitic retinitis respond well to intravenous penicillin.	TRUE/FALSE
(6)The following are true:
(a) Chlamydial conjunctivitis is more common in HIV patients.	TRUE/FALSE
(b) Gonoccocal keratitis is more severe in HIV patients.	TRUE/FALSE
(c) Toxoplasmosis retinitis is more rampant in HIV patients.	TRUE/FALSE
(d) Kaposi's sarcoma of the eyelids and conjunctiva is related to HHV 11.	TRUE/FALSE
(e) Reiter's associated uveitis is more common in HIV patients.	TRUE/FALSE

Regulations

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