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  • Ocular Complications of HIV/AIDS

    Uveitis
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    The ocular manifestations of human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) can be categorized in 5 areas: noninfectious retinal microvasculopathy, ocular infections, neuro-ophthalmologic disorders, ocular neoplasms, and ocular side effects of systemic medications (Outline 1). Although widespread use of highly active antiretroviral therapy (HAART) has significantly decreased the frequency and severity of many of these manifestations, they remain common causes of diminished quality of life in patients with HIV/AIDS. Clinicians should be aware of the most important changes in ocular complications of HIV/AIDS in the era of HAART: decreased but still significant risk of cytomegalovirus (CMV) retinitis; immune-recovery uveitis; and possible discontinuation of anti-CMV therapy in patients with immune recovery. In addition, noninfectious causes of decreased vision (such as cataract) appear to be substantially more common in patients with HIV/AIDS than in age-matched controls (Ophthalmology. 2007;114(4):787–793). Simple measures such as a proper refraction or cataract surgery can have a markedly beneficial effect in this group of patients.

    Ocular Manifestations of HIV/AIDS.

    A. Noninfectious retinal vasculopathy
         1. microvasculopathy (background HIV retinopathy, AIDS retinopathy: cotton-wool spots, intraretinal hemorrhages, capillary nonperfusion)
         2. macrovasculopathy (retinal vein occlusion, retinal artery occlusion)
    B. Ocular infections
         1. anterior segment
             a. herpes zoster ophthalmicus
             b. molluscum contagiosum
             c. herpes simplex keratitis
         2. posterior segment
             a. CMV retinitis
             b. necrotizing herpetic retinopathy
                 i. progressive outer retinal necrosis
                 ii. acute retinal necrosis
             c. toxoplasmic retinochoroiditis
             d. syphilitic retinitis
             e. tuberculous choroiditis
             f. metastatic fungal endophthalmitis
    C. Neuro-ophthalmologic disorders
         1. cryptococcal meningitis
         2. CNS toxoplasmosis
         3. intracranial varicella zoster
         4. tuberculous meningitis
         5. syphilitic meningitis
         6. CNS lymphoma
         7. progressive multifocal leukoencephalopathy
    D. Ocular neoplasms
         1. Kaposi sarcoma
         2. conjunctival squamous cell carcinoma
    E. Ocular side effects of systemic medications
         1. ethambutol (optic neuropathy)
         2. cidofovir (uveitis)
         3. rifabutin (uveitis)

    CMV Retinitis

    In the pre-HAART era, CMV retinitis occurred in about 30% of patients with AIDS, but with widespread use of HAART, the incidence has decreased by approximately 80%. Nonetheless, CMV retinitis remains the most common of all ocular opportunistic infections. Women, African Americans, and patients not taking HAART are most likely to develop CMV retinitis; the mean CD4+ count at the time of diagnosis is <20 cells/µL (Am J Ophthalmol. 2002;133(1):48–61). Symptoms of CMV retinitis include floaters, photopsias, and visual field deficits without pain, redness, or photophobia; however, many patients are asymptomatic. Patients with newly diagnosed CMV retinitis usually have eye-examination findings similar to those seen in the pre-HAART era, including a mild anterior and intermediate uveitis with necrotizing retinitis characterized by a dry, granular-appearing border (Figure 1). Retinal hemorrhage is common but may be absent.

    Image courtesy James P. Dunn, MD
    Figure 1. Cytomegalovirus retinitis.

    A number of drugs are available for the treatment of CMV retinitis (Table 1), but oral valganciclovir and the ganciclovir implant are most commonly used. Lesions near the fovea and optic nerve are often treated with “local??? therapy, such as intravitreous ganciclovir or foscarnet injections, followed by placement of a ganciclovir intraocular implant. However, an important recent study found that the presence of CMV retinitis with a detectable CMV viral load was associated with an increased risk for mortality, even after adjusting for demographic, treatment, immunologic, and HIV virologic factors (Ophthalmology. 2005;112(5):771–779); local therapy alone does not address this concern. Valganciclovir is the most commonly used systemic drug (alone or in combination with local therapy), because of its generally low side-effect profile and high oral bioavailability.

    Table 1. Treatment for Cytomegalovirus Retinitis.

    Drug Route of Administration Dosage FDA-Approved? Primary Adverse Effects
    Ganciclovir Intraocular implant 4 mg Yes Vitreous hemorrhage; wound leak; infection
     Intravitreous injection 2 mg/0.1 ml No (used off-label) Same
    Valganciclovir Oral 900 mg twice a day for 3 wks (induction); then 900 mg once daily (maintenance) Yes Bone marrow suppression; diarrhea; nausea
    Foscarnet Intravenous 90 mg/kg twice a day (induction); then 90–120 mg/kg/day (maintenance) Yes Nephrotoxicity; hypertension; electrolyte abnormalities
     Intravitreous injection 2400 µg/0.1 ml No (used off-label) Vitreous hemorrhage; infection
    Cidofovir Intravenous 5 mg/kg/week (induction); then 5 mg/kg every 2 weeks (maintenance) Yes Nephrotoxicity; hypertension

    All these drugs are virostatic only, so that chronic (maintenance) anti-CMV therapy is necessary in patients who remain substantially immunosuppressed. In patients who develop immune recovery from HAART (generally defined as a CD4+ count >100 cells/µL for at least 3 months, typically with a 2-log unit or greater decrease in the HIV viral load), anti-CMV therapy can usually be discontinued safely. Ocular morbidity is greater in patients with CMV retinitis than in those without, including cataracts, retinal detachment, macular edema, and epiretinal membrane.

    Patients with CMV retinitis should be examined regularly (at least monthly while the disease is active and every 3 after months thereafter). Vision loss in patients with active disease is most commonly due to macular or optic nerve involvement or retinal detachment, but this accounts for less than half of visual loss overall; cataracts account for 25% of visual loss, and macular edema and epiretinal membrane formation are also common among patients with long-standing retinitis and immune recovery (Ophthalmology. 2006;113(8):1432–1440).

    Compared with the rate of retinitis progression (approximately 3.0 episodes per person-year) reported in the pre-HAART era, the rate of retinitis progression is much lower among patients in the HAART era, even among those with low CD4+ T-cell counts. The risk of CMV retinitis–related retinal detachment is also decreased in patients taking HAART. However, because progression can occur (albeit rarely) even in patients with CD4+ counts of 200 cells/µL, continued ophthalmologic follow up of patients with immune recovery is recommended to detect early retinitis progression (Ophthalmology. 2004;111(12):2224–2231).

    Other Ocular Complications of HIV/AIDS

    Immune-recovery uveitis (IRU) is a syndrome of uveitis, vitreitis, and macular edema (Figure 2) that occurs in up to 60% of patients with CMV retinitis who have developed a substantial degree of immune recovery from HAART. The condition occurs only in eyes with CMV retinitis. Risk factors include the presence of CMV retinitis involving more than 25% of the total retinal area and the prior use of intravitreous cidofovir (Ophthalmology. 2006;113(4):684–694). While no proven treatment exists, the use of intravitreous triamcinolone acetonide can be an effective short-term treatment for macular edema (Ophthalmology. 2007;114:334–339).

    Image courtesy James P. Dunn, MD.
    Figure 2. Fluorescein angiogram demonstrating cystoid macular edema.

    Enrollment studies may yield under-representation of some ocular infections, such as progressive outer retinal necrosis (PORN), a devastating form of necrotizing herpetic retinopathy. In fact, some investigators have noticed that PORN is now almost as common as CMV retinitis (Janet Davis, MD, personal communication). Because PORN is much more rapidly progressive than CMV retinitis and requires a different and more aggressive regimen of antiviral therapy, it is essential that clinicians be able to distinguish these disorders. Endoretinal biopsy may rarely be necessary, but in most cases, PCR testing from aqueous or vitreous humor can yield the causative agent rapidly.

    Summary

    The widespread use of HAART has significantly altered the treatment CMV retinitis, but it has not eliminated the incidence of this disease, and it has been associated with new ophthalmic syndromes such as immune-recovery uveitis. Clinicians must be aware of changing treatment options and the importance of routine eye examinations in patients with HIV/AIDS.

     

    References

    1. Jabs DA, Van Natta ML, Holbrook JT, et al. Longitudinal Study of the Ocular Complications of AIDS: 2. Ocular examination results at enrollment.Ophthalmology. 2007;114(4):787–793.
    2. Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy.Am J Ophthalmol. 2002;133(1):48–61.
    3. Jabs DA, Holbrook JT, Van Natta ML, et al. Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy.Ophthalmology. 2005;112(5):771–779.
    4. Thorne JE, Jabs DA, Kempen JH, et al. Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy.Ophthalmology. 2006;113(8):1432–1440.
    5. Jabs DA, Van Natta ML, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 1. Retinitis progression.Ophthalmology. 2004;111(12):2224–2231.
    6. Kempen JH, Min YI, Freeman WR, et al. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis.Ophthalmology. 2006;113(4):684–694.
    7. Morrison VL, Kozak I, LaBree LD, et al. Intravitreal triamcinolone acetonide for the treatment of immune recovery uveitis macular edema.Ophthalmology. 2007;114:334–339.

    Author Disclosure

    Dr. Dunn states that he has no financial relationship with the manufacturer of any product discussed in this article or with the manufacturer of any competing product.