Introduction

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pandemic has continued now for more than 25 years [1, 2]. This pandemic and the advent of new antiretrovirals are responsible for an increase in the number of patients with this entity and its survival. It was estimated in 2007 that 33.2 million people were infected with HIV worldwide, accounting for 0.8% of the world’s population. This included roughly 7,000 new infections each day, totaling approximately 2.5 million new infections for the entire year—a figure that was slightly higher than the 2.1 million estimated AIDS-related deaths during the same period [3]. HIV is the fourth largest killer in the world after respiratory infections, diarrheal disorders, and tuberculosis, and the leading cause of death in Africa [4]. While cases of HIV/AIDS have been reported from virtually every part of the world, over 90% of people with HIV/AIDS live in developing countries [5].

Due to global efforts, the epidemic appears to be stabilizing [3, 5]. The incidence of new infections is believed to have peaked in the late 1990s and then declined between 2001 and 2007 [3]. While the global prevalence of HIV/AIDS rose from 29.5 million in 2001 to 33 million in 2007, the prevalence rate stayed level at 0.8% [3]. This is attributable to increased preventive education and dramatically increased availability of antiretroviral medications throughout the world, including a 20-fold increase in sub-Saharan Africa since 2003.

Despite these encouraging trends, the pandemic persists in several areas, including the

ongoing epidemics in sub-Saharan Africa, the Caribbean, and Southeast Asia [6]. Sub-Saharan Africa, with 22 million people infected, accounts for roughly two-thirds of all HIV infections and 90% of all infected children. In South Africa, an astonishing one in five people are infected, and AIDS remains the leading cause of death in this region. A global epidemic also continues among high-risk populations, including intravenous (IV) drug abusers, prostitutes, and men who have sex with men [7].

Moreover, the chances of this group of patients to develop one of its (HIV/AIDS) ocular manifestations also increase. Ocular disease occurs in 50–75% of HIV-infected patients [8–14]. In Western countries, the most common manifestation is HIV microvasculopathy, followed by cytomegalovirus (CMV) retinitis, ocular toxoplasmosis, non-CMV herpetic retinitis, neuro-ophthalmic complications, herpes zoster ophthalmicus (HZO), and ocular neoplasia [9, 10, 15]. This spectrum appears to be different in developing countries [16–18] where poorer access to highly active antiretroviral therapy (HAART) and medications for opportunistic infections translates into higher mortality rates and fewer patients surviving with profound immunosuppression. Ocular complications have been reported in 29–60% of patients in the developing world [8, 19, 20]. In sub-Saharan Africa, CMV retinitis is less common than in the United States or Europe, while anterior segment and external manifestations such as HZO and conjunctival squamous cell carcinoma (SCC) appear to be more common [12, 21–24].

Similarly, the chances that some of these patients are presented to the consultation of a

general ophthalmologist or any subspecialist increase considerably every day, and we must therefore be prepared to recognize these ocular manifestations and management. Infection with HIV leads to a derangement of cell-mediated immunity, which in turn predisposes to a series of events that affect the retina and choroid. These manifestations can be divided into two broad categories: those associated with noninfectious etiologies and a much larger group of secondary infections with varied clinical presentations. With the advent of effective treatments for these infections that threaten the vision of these patients, an accurate differentiation of these entities may allow the clinician to initiate appropriate treatment in many cases with improved quality of life and survival. The matter is highly complicated, however, because many HIV-infected people, even if they know of their HIV status, may be incompletely treated. Thus, knowledge of the actual immune status, best but not perfectly represented by the CD4 T-cell count, is very important for the ophthalmologist.

Posterior Segment Manifestations

of HIV/AIDS

The majority of ocular manifestations of HIV infection involve the posterior segment of the eye. Prior to the introduction of HAART, retinal microvasculopathy and CMV retinitis accounted for more than 80% of the ocular complications in HIV-positive patients. CMV retinitis, in particular, is by far the single most significant cause of loss of vision in this population, affecting up to 40% of patients [25–27] prior to the widespread use of HAART. Since that time, the prevalence of CMV retinitis has fallen dramatically [15].

Noninfectious Retinal Manifestations

The clinical spectrum of HIV retinopathy includes infarct of the nerve fiber layer (often called cotton-wool spots), retinal hemorrhages, telangiectasia, lack of capillary perfusion, and vascular occlusion. This microangiopathy is clinically apparent in 70% of patients with AIDS but is

less frequent as the degree of immunosuppression decreases [28].

Hypotheses regarding the pathogenesis of retinal microvasculopathy parallel those suggested for conjunctival vascular changes [29, 30] and include HIV-induced increase in plasma viscosity, HIV-related immune complex deposition [31], direct infection of the conjunctival vascular endothelium by HIV, and increased rigidity of circulating neutrophils [29, 32–35]. HIVassociated retinal microvasculopathy is typically asymptomatic but may play a role in the progressive optic nerve atrophy [36, 37], electroretinographic abnormalities, [38] loss of color vision, contrast sensitivity, and visual field observed in HIV-infected patients [30, 39]. The role of retinal microvasculopathy in the development of CMV retinitis is controversial, with some investigators finding no relationship [40] and others suggesting that retinal vascular damage may provide increased access to circulating CMV-infected lymphocytes.

Cotton-wool spots are the most common finding and earlier of the noninfectious retinopathy HIV and occur in approximately 50–60% of cases in clinical series [32, 40]. The whitish color by ophthalmoscopy represents areas of focal thickening of the nerve fiber layer caused by infarction of the adjacent capillaries. Histologically, these lesions are known as cytoid bodies and are composed by cytoplasmic accumulation of debris due to obstruction of axoplasmic flow in the ganglion cells. Cotton-wool spots typically cluster around the optic disk and are only rarely seen over 30° of the papilla. Its clinical appearance is that of white opacities with margins as a feather, located in the nerve fiber layer of the retina, and its size is usually larger than one-third of disk diameter (Fig. 1.1). They are by nature evanescent, disappearing within a few weeks and being replaced by new ones in different locations of the retina. Cotton-wool spots may be confused with lesions of very early CMV retinitis but are distinguished by their smaller size, superficial location, and lack of progression. Recent studies of these cotton-wool spots using optical coherence tomography (OCT) have shown that after resolution, there is permanent damage to that area of the retina, particularly destruction

of the inner retina. The accumulation of such areas of damage may play a role in the documented visual dysfunction seen in HIV patients, particularly those with a history of immunocompromise [41].

Hemorrhages associated with HIV infection are less common than cotton-wool spots but occur in approximately 20% of patients with AIDS. These hemorrhages may be present in the nerve fiber layer (hemorrhages in flames) and in deeper layers of the retina (spot or pinpoint hemorrhages) (Fig. 1.2). White center hemorrhages (Roth’s spots) have also been described.

In AIDS patients, telangiectatic retinal vessels are observed frequently and commonly are associated with microaneurysms [32, 40]. In association with these vascular anomalies, it is usual to find the demonstration of nonperfusion areas in the fluorescein angiogram. Less common vascular findings in these patients include arterial and venous occlusions (Fig. 1.3), perivasculitis, and retinal neovascularization. Importantly, these findings (microangiopathy related to AIDS) are nonspecific, but their presence in a young patient should immediately arouse suspicion of HIV seropositivity.

The majority of studies in the post-HAART era report a substantial decline in HIV-related retinal microvasculopathy, likely a result of fewer patients with sustained, profound immune suppression.

Fig. 1.2 Pinpoint and flame hemorrhages on the periphery of an AIDS patient

Fig. 1.3 Superotemporal branch retinal artery occlusion simulating a cytomegalovirus retinitis. Note the presence of flame hemorrhages

Infectious Manifestations

of the Posterior Segment

Cytomegalovirus Retinitis

In most developed countries, CMV seroprevalence steadily increases after infancy, and 10–20% of children are infected before puberty. In adults, the prevalence of antibodies ranges from 40% to 100%. Although CMV has a worldwide distribution, infection with CMV is more common in the developing countries and in areas of low socioeconomic conditions, which is predominantly related to the closeness of contacts within these populations.

Despite a marked decline in incidence since the advent of HAART, CMV retinitis continues to be the most common AIDS-related opportunistic infection and remains an important cause of visual morbidity. CMV retinitis frequently occurs in AIDS patients with a CD4+ count <50 cells/uL and is the most common ocular opportunistic infection associated with AIDS. Prior to HAART, CMV retinitis affected 30–40% of HIVinfected patients [10, 25, 27, 31, 42], whereas most studies in the era of HAART have shown a decline in the incidence of CMV retinitis by about 75% [43], as well as a 50% reduced risk of retinitis progression, even in patients with persistent immune suppression [44, 45]. The use of HAART changed the natural history of HIV-associated CMV retinitis in two important ways. First, since fewer patients have CD4+ T-lymphocyte counts below 100 cells/mL, fewer patients are at risk for the development of CMV retinitis [16]. Second, patients receiving such therapy who have early or partial reconstitution of CD4+ cell populations may have otherwise uncommon features of CMV infection, including moderate-to-severe anterior chamber or vitreous inflammation and spontaneous healing in the absence of specific anticytomegalovirus therapy. Unfortunately, approximately 90% of the world’s AIDS population has no access to HAART and therefore continues to present the classic ocular presentation [1].

Affected patients typically report gradual visual field loss or the onset of floaters. The three main clinical forms of CMV retinitis are a

Fig. 1.4 Cytomegalovirus retinitis along the vascular arcades

hemorrhagic retinitis with prominent edema, a granular type with satellite lesions, and a less common perivascular retinitis. The most important clinical features of CMV retinitis include a white granular border, intraretinal hemorrhages, slow progression of lesions, peripheral location (where they take on a more granular aspect) or along the retinal vascular arcades, and the lack of a prominent intraocular inflammatory reaction (Fig. 1.4). This last feature is observed in most cases; therefore, the presence of severe vitreous inflammation should lead us to consider a different diagnosis.

CMV retinitis is asymptomatic in up to 15% of patients, and all HIV/AIDS patients with a CD4+ cell count under 50 cells/m(mu)L should have a dilated ophthalmoscopic examination every 3 months [46]. The location and extent of CMV retinitis should be determined by indirect ophthalmoscopy, revision of stereo color photographs, and retinal drawings. The Study of Ocular Complications of AIDS (SOCA) [47] has adopted the following division of the retina into zones: zone 1 is the area of the retina surrounding the optic disk by 1,500 m and the center of the fovea by 3,000 m; zone 2 extends anteriorly from the edge of the zone 1 to a circle identified by the vortex veins; and zone 3 extends above the edge of zone 2 to the ora serrata. The total area of retinitis is determined by calculating the area (percentage) of the retina affected by CMV (retinitis healed and active), while the area of the retina with active CMV retinitis is denoted as the

length of active edge (white) measured in disk diameters (DD).

Rhegmatogenous retinal detachment (RD) is a frequent complication in patients with CMV retinitis. Prior to HAART, the incidence of RD in patients with CMV retinitis ranged from 18% to 29%. Jabs and colleagues have reported that there is a cumulative risk of RD up to 50% a year of diagnosis of CMV retinitis [48]. The incidence of bilaterality of RD is also high in this group of patients, and reports in the literature vary from 17% to 67% [48–53]. Risk factors for RD to this group of patients include extension of retinitis and activity [52]. In the era of HAART, the incidence of retinal detachment as a complication of CMV retinitis has declined by more than 60% [54].

Retinal detachments associated with CMV retinitis have characteristics of a rhegmatogenous RD (caused by ruptures of the retina) but are atypical in several ways. These RDs are often associated with multiple breaks or holes, most of which are very difficult to visualize in large areas of gliotic retina (often already healed). Breaks are usually located at the junction between the normal and atrophic retina or in areas of atrophic retina. Since most of these patients are young, the vitreous is well formed, and it may not be fully detached at the time of surgery. This finding explains the relatively flat appearance (nonbullous) for most of these RD (Fig. 1.5) in contrast to the bullous appearance of RD in patients with complete posterior vitreous detachment (PVD) or RD in eyes with greater vitreous pathology (Fig. 1.6) [53]. Vitreoretinal proliferation (PVR) is a rare complication associated with CMV retinitis and is at least seen in 20% of cases.

Several reports have shown good results repairing these detachments with primary vitrectomy, endolaser of retinal breaks, and inferior peripheral retina associated with the use of 5,000cs silicone oil (Fig. 1.7) [48–53]. This method has the advantage of providing a faster visual recovery than if we use gas (C3F8 or SF6) and have a permanent tamponade of multiple retinal holes in the atrophic retina. This is of particular benefit to patients in whom retinitis progresses

Fig. 1.5 Retinal detachment is flat in a patient with cytomegalovirus retinitis without a posterior vitreous detachment

Fig. 1.6 Bullous retinal detachment in a patient with cytomegalovirus retinitis with a posterior vitreous detachment

Fig. 1.7 Appearance of the retina after retinal detachment repair with primary vitrectomy, endolaser, and injection of silicone oil of 5,000 centistokes (cs)

Fig. 1.8 Orally administered valganciclovir appears to be as effective as intravenous ganciclovir for induction treatment and is convenient and effective for the long-term management of cytomegalovirus (CMV) retinitis in patients with AIDS. (a and b) CMV retinitis before valganciclovir. (c and d) After 3 weeks on valganciclovir

900 mg twice a day (Reprinted with permission from Arevalo JF, ed. Manifestaciones Oculares del SIDA en el Nuevo Milenio: Texto y Atlas [Ocular manifestations of AIDS in the New Milenium: Text and Atlas]. Panama City, Panama: Highlights of Ophthalmology 2004 [55]

and has a potential risk of forming new holes in other areas of retinal necrosis.

Treatment of CMV retinitis is complicated and needs to be individualized for each patient. Current US Food and Drug Administration (FDA)-approved treatments for active retinitis include intravenous ganciclovir, foscarnet, or cidofovir, and oral valganciclovir. The standard treatment for CMV retinitis is oral valganciclovir induction followed by maintenance. Intravenous ganciclovir is generally reserved for those with malabsorption syndromes. Probably second-line treatment is cidofovir, and last is foscarnet. The implant can be used in cases of resistance; if it is used for primary therapy, oral valganciclovir maintenance is important to prevent systemic disease. Ganciclovir is administered intravenously at doses of 5 mg/kg every 12 h for

2–4 weeks (induction dose) and then 5 mg/kg/ day (maintenance dose). Foscarnet is administered intravenously at a dose of 180 mg/kg/day for 2–4 weeks (induction dose) and then decreases to a dose of 120 mg/kg/day (maintenance dose). Valganciclovir is given at 900 mg PO twice daily for 2–4 weeks (until retinitis is healing), then 900 mg PO daily (Fig. 1.8). Cidofovir is administered intravenously once a week for 2 weeks at a dose of 5 mg/kg (induction dose) and then once every 2 weeks at the same dose (maintenance). Cidofovir compares favorably to ganciclovir and foscarnet as to its effectiveness against CMV (cidofovir is ten times more powerful). Patients with high-level ganciclovir toxicity may be resistant to cidofovir.

The significant problems of intravenous therapy are the development of resistance to ganciclovir

Fig. 1.9 The ganciclovir intraocular implant confers longer retinitis inactivity

and foscarnet, systemic toxicity of the antivirals, the risk of sepsis (by prolonged use of a central catheter), and the great inconvenience of daily intravenous infusions [56–58]. The significant problems of intravenous therapy have led to local and oral therapy. Currently, local therapy has two clear lines: (1) intravitreal (IVT) implant of ganciclovir (Fig. 1.9) [56] (that is inserted through the pars plana after a limited vitrectomy and has a duration of approximately 8 months) and (2) IVT injections of ganciclovir at doses of 400–2,000 mg two times a week for 3 weeks and then once weekly, IVT injections of ganciclovir at a dose of 5,000 mg once weekly, IVT injections of foscarnet at a dose of 2,400 mg two times a week for 3 weeks and then once weekly, and finally IVT injections of cidofovir administered at a dose of 15–20 mg every 6 weeks [57, 59].

Choice of an appropriate antiviral and route of delivery needs to be individualized, based on consideration of the location and extent of ocular and systemic disease, understanding of potential drug-related side effects, and knowledge of viral response to past treatments. Today, the trend and standard treatment is to combine systemic treatment, intravenous (ganciclovir or foscarnet) or oral with valganciclovir (900 mg BID as induction and 900 mg/day as maintenance), with local treatment (intravitreal injections versus implant of ganciclovir [Vitrasert, Bausch & Lomb, Madison, NJ, USA]).

Fig. 1.10 Papillitis and cystoid macular edema associated to immune recovery uveitis (Reprinted with permission from Arevalo JF, Mendoza AJ, Ferretti Y. Immune recovery uveitis in AIDS patients with cytomegalovirus retinitis treated with highly active antiretroviral therapy in Venezuela. Retina 2003;23:495–502)

Maintenance therapy should be continued for as long as active retinitis is present and/or CD4+ cell counts remain below 150 cells/mL. Only after 3–6 months of inactive disease with CD4+ cell counts above 150 cells/mL and reduced HIV in the blood should consideration be given to discontinuing maintenance therapy [60, 61].

The improvement in immune function in AIDS patients receiving HAART may alter the way the eye responds to CMV. Karavellas and colleagues reported five patients treated with protease inhibitors that had elevated levels of CD4 + T cells and inactivated retinitis by CMV [62]. All showed moderate vitritis and papillitis, some with cystoid macular edema (CME). They attributed these complications to the inflammation induced by increased immunocompetence of these patients. They called this new syndrome “immune recovery vitritis.” Several studies have been published since then, and the term immune recovery uveitis (IRU) has been used extensively to describe various inflammatory ocular manifestations in AIDS patients with inactive CMV retinitis. IRU is a chronic intraocular inflammatory disorder that manifests symptomatically with painless decrease of vision and floaters. The clinical spectrum of IRU includes vitritis, papillitis, cystoid macular edema (CME) (Fig. 1.10),