HIV and Eye Diseases: Our Experience & Review of Literature.
Director and Chief Vitreoretinal Surgeon,
Banker’s Retina Clinic and Laser Centre,
5, Subhash Society, Navrangpura, Ahmedabad, 380009. India.
Phone : 91-79-26569457/26401323.
E mail: alay.banker@gmail.com
Associate Vitreoretinal Surgeon,
Banker’s Retina Clinic and Laser Centre,
5, Subhash Society, Navrangpura, Ahmedabad, 380009. India.
Phone : 91-79-26569457/26401323.
Associate Prof Pediatrics
N.H.L.Municipal Medical College, V.S. Hospital
Ellisbridge, Ahmedabad 380006. India
Phone : 91-79-26569457/26401323.
Introduction:
By 2007, more than one million people were living with HIV infection in the United States, and an estimated 33.2 million people were infected with HIV worldwide.[101] Women all around the world now account for one quarter of HIV infections, and HIV disease disproportionately affects racial and ethnic minorities. Most HIV-infected individuals are in sub-Saharan Africa, but the number of new cases is increasing rapidly in other areas of the world, including India[1] and Southeast Asia. In the vast majority of cases worldwide, HIV transmission occurs through heterosexual contact. Infections attributed to perinatal transmission from mother to child and from transfusion of blood and blood products have dropped markedly.[101] There has also been a steady decline in new HIV/AIDS diagnoses among injection-drug users.[101]
In spite of the widespread use of highly active antiretroviral therapy (HAART) today, ocular manifestations of AIDS at some point affect 50 to 75% of infected persons.[2] Opportunistic infections develop when there is a deterioration of the immune status of the individual which can be measured with the help of CD4 cell counts. Posterior segment lesions, especially cytomegalovirus (CMV) retinitis, can be associated with severe visual morbidity. Corneal and anterior segment lesions affect more than 50% of all HIV patients.[3] Ocular adnexal complications, seen in about 25% of patients,[3] can be a sign of severe systemic immunosuppression. Also, the spectrum of ocular manifestations of AIDS in the developing world differs from that of developed nations.[4]
Treatment of HIV infection with HAART ( highly active anti-retroviral therapy) seeks to inhibit progression to AIDS (defined by a CD4 cell count of < 200 cells/mm3) or death. This is achieved by reducing plasma HIV RNA to permanently low levels, reduction in the viral load and a rise in CD4 cell counts which helps in improvement in the immune status of the individual. [2] With the advent of HAART, HIV and AIDS-related morbidity and mortality have drastically decreased in the developed world, but since more patients live longer and there are more HIV-positive patients, the overall population based prevalence would be expected to creep up. However, the situation in the developing countries is still grim even with advent of HAART. While the clinical immune recovery is, in general, of great benefit to the patient, about 10–25% of people initiated on HAART, experience ''immune recovery'' or immune reconstitution inflammatory problems, including those occurring in the eye leading to severe visual loss.
In a study by Goldberg et al, they showed that in the pre-HAART era, CMV retinitis was the most common HIV-associated retinopathy, occurring in 20%-40% of patients. Retinal detachment occurred in 24%-50% of patients annually. Herpetic retinopathy and toxoplasmosis retinochoroiditis occurred in 1%-3% of patients and Pneumocystis carinii choroiditis, syphilitic retinitis, tuberculous choroiditis, cryptococcal choroiditis, and intraocular lymphoma occurred infrequently. As compared to that, in the HAART era there was a 80% decline in the incidence of CMV retinitis. The incidence, visual morbidity, and mortality of CMV retinitis and other HIV-associated retinopathies decreased in the era of HAART.[5] Similarly, another study from Croatia found that the mortality had decreased to 59.3%, vascular changes had reduced to 54.3% and incidence of CMV retinitis reduced from 57.2% to 7.6% from pre HAART to post HAART era.[6]
The purpose of this article is to provide a comprehensive update of the important anterior, posterior segment and adnexal manifestations in HIV-positive patients.
Ophthalmic Manifestations of AIDS:
Looking back over the past 26 years, from the first case detection in 1982, the study of HIV-related eye disease can be divided into several eras separated by distinct periods of transition.[101] The first era was a short period of rapid discovery, in which the spectrum of ophthalmic disorders associated with AIDS was identified. Ophthalmic manifestations of AIDS can be catagorized as follows:
I. Opportunistic infections
A. Retina
1. CMV retinitis
a. Complications
(1) Immune recovery uveitis
2. Other retinal infections (caused by various agents, VZV, and Toxoplasma gondii being most common; most occur in less than 1% of patients with AIDS).
B. Choroid (uncommon; caused by various agents, fungi and mycobacteria being most common)
C. Ocular surface and adnexa (important agents include VZV, microsporidia, molluscum contagiosum virus).
II. Vascular abnormalities
A. Microvasculopathy
1. HIV retinopathy (cotton-wool spots, retinal haemorrhages)
B. Retinal arteriolar and venular occlusions (uncommon)
III. Neoplasia
A. Kaposi sarcoma (conjunctiva, eyelids)
B. Lymphoma (intraocular)
C. Squamous cell carcinoma (conjunctiva)
IV. Other disorders of uncertain pathogenesis
A. Intraocular inflammation
1. Chronic anterior uveitis (uncommon)
2. Chronic multifocal retinal infiltrates (uncommon)
3. Iatrogenic uveitis (drug related: cidofovir; rifabutin)
B. Blepharitis
C. Dry eye
V. Neuroophthalmic disorders associated with orbital or intracranial disease
The spectrum of AIDS-related eye diseases differs in various parts of the world. Squamous cell carcinoma of the conjunctiva and ocular tuberculosis have been greater problems in Africa than CMV retinitis, attributed to the fact that patients die of other complications before reaching levels of immunodeficiency associated with CMV disease. During the early years of the epidemic in the United States, the prevalence of CMV retinitis increased as treatment of other life-threatening opportunistic infections improved, and patients survived longer. As was feared, the same phenomenon is now being seen in the developing world. As treatments for HIV-associated opportunistic infections and neoplasms improve worldwide, CMV retinitis may emerge as a global problem.
Cytomegalovirus retinitis:
Cytomegalovirus retinitis is the most common AIDS-related ocular opportunistic infection and can develop in up to 40 to 50% of AIDS patients prior to HAART.[7,8] Although its incidence has declined markedly since the advent of HAART in the western world, it still remains the leading cause of ocular morbidity in the developing countries.[9] In India, CMV retinitis still remains the commonest ocular manifestation in AIDS cases.[10,11] In our series of 1286 cases, the incidence of CMV retinitis remains high even in the era of HAART. It may be unilateral to start with, but up to 52% will eventually develop bilateral disease. [12]
Clinical findings: There are three clinical forms of CMV retinitis. The classical form (pizza pie retinopathy or cottage cheese with ketchup) is characterized by confluent retinal necrosis with haemorrhage that develops mostly in the posterior retina. The advancing edge of these lesions is usually very sharp and spreads contiguously. In contrast, the indolent form is recognized as a granular lesion in the peripheral retina, often with little or no haemorrhage. A third uncommon presentation is frosted branch angiitis. Because approximately 15% of patients with active CMV retinitis are asymptomatic, routine screening with dilated indirect ophthalmoscopy has been recommended at three-month intervals in patients with CD4+ counts less than 50 cells/µl.[13] Cytomegalovirus retinitis may result in either serous or rhegmatogenous retinal detachment, although the latter is much more common. Rhegmatogenous retinal detachment has been reported in 13 to 29% of patients with CMV retinitis and may occur during the active or healed phase of the disease. However, since the advent of HAART, incidence of retinal detachment has decreased by approximately 60 to 77% in the western world.[14] In contrast, in our series, the incidence of CMV-related retinal detachment was found to have increased. This may be due to higher number of patients taking inappropriate HAART, or people taking HAART have larger areas of healed CMV retinitis which eventually develop necrotic holes leading to detachment.[15,16]
Treatment:
Treatment of CMV retinitis is individualized and depends upon the location of the active retinitis and the immune status of the patient. Currently available anti-CMV agents include ganciclovir and its prodrug valganciclovir, foscarnet, cidofovir, fomivirsen, ganciclovir implant and oral valganciclovir. A brief summary of these drugs is provided in table 1.(Click here to download the table in pdf format)
Initial Drug Treatment:
The most important therapeutic manoeuvre for the initial treatment of newly diagnosed CMV retinitis is to start HAART (for patients not taking antiretroviral drugs) or to reestablish immune recovery (for HAART-failure patients, by changing antiretroviral medications, if possible); however, it is a common practice among HIV specialists to delay the start of HAART for patients with systemic infectious diseases, such as tuberculosis, until treatments for the infections are started, to reduce the risk of systemic inflammatory reactions against the pathogens. The same may be true for reducing the risk of IRU. After the start of HAART, immune recovery is not achieved immediately; therefore, anti-CMV drugs should be given until certain immunologic (and possibly virologic) parameters are achieved. The induction treatment should be continued until CMV retinitis is inactive, to limit the size of lesions. Doing so presumably reduces the risk of retinal detachment and vision loss in individuals who have the prospect of prolonged survival.
Discontinuation of Anti-Cytomegalovirus Treatment:
Immune recovery allows eventual discontinuation of specific anti-CMV therapy without reactivation of infection. A decision to discontinue anti-CMV drugs usually is based on several factors: a sustained rise in CD4+ T-lymphocyte count; a drop in HIV blood level; duration of HAART that is sufficient to affect immune recovery; and inactivity of CMV retinitis lesions. Patients receiving HAART should have CD4+ T-lymphocyte counts of more than 100 to 150 cells/μl for at least three to six months.[17] Moreover HIV blood levels should have dropped by 2log10 units, to fewer than 200 copies/ml. HIV blood levels can be a useful marker for eventual reactivation.
Monitoring Patients:
CMV retinitis eventually can reactivate after anti-CMV drugs are stopped; studies have estimated that the risk of recurrence is approximately 0.02 events/PY. Thus, continued monitoring of patients is critical. CD4+ T-lymphocyte count is the laboratory measure followed most commonly, but a rising or very high HIV blood level may be an additional important indicator of risk for new CMV retinitis lesions or reactivation of after discontinuation of anti-CMV drugs.
Screening Strategies:
Serial ophthalmic examinations and patient education about symptoms of CMV retinitis are additional components of effective monitoring programs. Periodic screening examinations of patients with CMV retinitis for reactivation (and of people at risk for new disease) is a well-accepted practice, although there is little evidence to support the common recommendation that examinations be performed at three-month intervals. The percentage of asymptomatic patients seems to be higher among those who are experienced with HAART, possibly because of reduced disease activity; this observation highlights the need for screening programs. Because the incidence of CMV retinitis is decreased, screening will need to be targeted to those at greatest risk, and because the infection can occur in patients with good parameters on current laboratory tests, better markers of impaired CMV immunity are needed.
