Part 4 • Infectious Uveitic Conditions

Chapter 11 Acquired Immunodeficiency Syndrome

Figure 11-2.  Multiple nerve fiber layer infarcts (cottonwool spots) in patient with AIDS.

endothelial cells has been reported.8 The retinal microvasculopathy of HIV occurs in 25–92% of patients and includes small dot retinal hemorrhages and nerve fiber layer infarcts called cottonwool spots (Fig. 11-2).11–14 This retinopathy may be caused by interactions between viral antigens and antibodies that circulate in the blood and then deposit in the eye, but this has not been clearly shown. The incidence of this retinal microvasculopathy increases with the degree of immunosuppression. The presence of the p24 antigen, a surface HIV antigen, in the blood also increases with more advanced disease, and it is possible that this antigenemia may be a cause of this retinopathy, with immune complex formation in the retinal vasculature. Superficial and deep retinal hemorrhages, retinal perivasculitis, and vascular occlusions also occur. Small peripheral blot hemorrhages are frequently noted on retinal examination and appear to be more common with decreasing CD4+ counts and anemia. Electron microscopic studies of these lesions reveal swollen endothelial cells and degenerating pericytes.15 Inflammatory cell infiltrates and infectious organisms are not seen in cottonwool spots; however, the microvascular abnormalities are widespread throughout the retina and may provide an entrance for opportunistic viral infections of the retina.

Clinically, cottonwool spots are seen as superficial white fluffy lesions in the retina (Fig. 11-2). There may be small dilations of the microvasculature nearby. Visual symptoms are rarely associated with the presence of a cottonwool spot. A cottonwool spot cannot occur in the foveal avascular zone as there is no nerve fiber layer to become infarcted in this part of the retina. Perifoveal cottonwool spots may cause symptoms. Patients may notice a relative, but not absolute, scotoma. This can be useful in distinguishing a cottonwool spot from an early area of viral retinitis in which the scotoma is absolute. In patients with AIDS these lesions can sometimes be more than 0.5 disc diameter in size. They are distinguished from infectious retinitis by the fact that they do not enlarge over time. Although individual lesions will disappear over a period of several months, new lesions often appear. The retinal hemorrhages associated with HIV infection tend to be small dot hemorrhages and rarely cause visual symptoms. Occlusive vasculopathy, such as central retinal vein occlusions, may affect vision.

Box 11-3  Common opportunistic infections

associated with HIV infection

Cytomegalovirus

Pneumocystis

Mycobacterium tuberculosis

Toxoplasma gondii

Mycobacterium avium complex

Varicella-zoster virus

Cryptococcus neoformans

Coccidioides immitis

Candida

Dry eye is also a common finding in patients with HIV infection and may be due to reduced tear production associated with diminished lactoferrin and lysozyme.16 In most patients the condition is mild to moderately severe and can be treated with artificial tears. More severe cases of dry eye can occur. Dry eye associated with Stevens–Johnson syndrome has also been reported in patients with AIDS.17

Even in the HAART era many patients with HIV infection have visual symptoms in the absence of active opportunistic infection.18 Visual acuity, contrast sensitivity, and visual fields are worse than expected compared to a normal agematched control group. Although the exact pathogenesis of this neuroretinopathy is unknown, causes may include HIV vasculopathy or a direct effect of HIV on the retina and optic nerve, undiagnosed coinfection, or effects from therapy.

Ocular infection

There are a number of other opportunistic infections associated with HIV infection (Box 11-3). CMV retinitis is the most common ocular infection in AIDS and is discussed in the next section. Other intraocular infections that more frequently occur in patients with AIDS include syphilis, toxoplasmosis, tuberculosis, Candida infection, and crypto- coccosis.19–23 These have been discussed in previous chapters and must be differentiated from CMV infection. Herpesvirus infections other than CMV infection can also cause a viral retinitis in patients with HIV infection. Herpes zoster ophthalmicus may be an early sign of HIV infection.24 Herpes zoster retinitis accompanied by acute retinal necrosis (see Chapter 12) and herpes simplex retinitis have occasionally been seen in patients with AIDS.15 These viral retinal infections are often difficult to differentiate clinically from CMV retinitis. Autopsy studies have shown that more than 95% of viral retinitis in patients with AIDS is due to CMV infection.11,15 However, these studies were completed early in the history of the AIDS epidemic and the percentages may have changed.

Cytomegalovirus retinitis

CMV is a herpes class virus and contains double-stranded DNA. Systemic infection is a very common infection in the general population and causes a heterophil, antibodynegative mononucleosis syndrome. Therefore, many adults have CMV antibodies because of previous infection.

Approximately 50% of heterosexual men and 95% of homosexual men have evidence of a previous CMV infection. However, with the exception of a few unusual cases, CMV infection of the retina occurs as an opportunistic infection only in immunosuppressed persons or in infants with congenital CMV infection. The disease was first recognized as a congenital infection in 1947. In the past, immunosuppression associated with organ transplantation and chemotherapy was the most common cause of CMV retinitis.25 It is interesting to note that CMV retinitis is much more frequent after renal transplantation than after bone marrow transplantation. In the current era, however, the increasing number of patients with AIDS has led to a marked increase in the number of occurrences of CMV retinitis. CMV retinitis tends to occur in patients whose immune systems are the most significantly suppressed by

HIV infection,11,26 rarely occurring if the CD4+ count is >100 cells/ L and typically occurring when CD4+ counts are <50 cells/ L. Before the widespread use of HAART,

CMV retinitis was reported in 7–40% of patients with AIDS in several series, and probably occurred clinically in at least 15–20% of these patients at some time during the course

of disease.11,12,15,19

CMV retinitis probably reaches the eye via the bloodstream, although the possibility of reactivation of latent virus has not been ruled out. Evidence of hematogenous spread includes the fact that one eye frequently develops retinitis several months before the other, and that new foci of retinitis can appear in an affected eye. It is unusual to see more than three separate areas of CMV retinitis in an eye, and most eyes contain one initial focus that then spreads across the retina.

CMV retinitis begins as small, white retinal infiltrates which, if seen early, may resemble a large cottonwool spot. Two types of clinical appearance may be seen. The first is a perivascular fluffy white lesion with many scattered hemorrhages (Fig. 11-3). Another manifestation is a more granular-appearing lesion that has few associated hemorrhages and often has a central area of clearing, with atrophic retina and stippled retinal pigment epithelium (Fig. 11-4). In autopsy studies CMV has been identified in both types of lesion in patients with AIDS. However, because we do not understand what factors predispose a person to one type of lesion, we cannot exclude the possibility that some of these lesions may be other viral retinal infections. It is possible that the underlying immune status of the patient influences the clinical appearance of the lesion. However, local factors also must be important, as an occasional patient will have different-appearing lesions. Both types of lesion respond to the therapeutic approach that will be discussed later, which is consistent with herpes class viral infections of the retina.

The diagnosis of CMV retinitis is based on clinical criteria. Although it is possible to confirm the diagnosis with a polymerase chain reaction (PCR) performed on a vitreous specimen or by culture of the virus from the vitreous or retina, this is rarely done in practice. As the number of treatment options grows and becomes more specific, accurate diagnosis will be increasingly important. Active CMV retinitis always has a faint granular border of intraretinal infiltrates that represent the new foci of viral activity in normal retina. In addition, the disease grows at approximately 250

Cytomegalovirus retinitis

Figure 11-3.  Cytomegalovirus retinitis in vascular distribution characterized by fluffy white retinal infiltration and small area of retinal hemorrhage.

Figure 11-4.  Cytomegalovirus retinitis may also have a granular appearance with mottling of retinal pigment epithelium and little associated retinal hemorrhage.

microns per week, and therefore there are usually areas that have begun to atrophy, as denoted by retinal pigment epithelial stippling. This is in contrast to acute retinal necrosis, in which the disease spreads rapidly, and one is less likely to find active retinitis surrounding an atrophic center. There is always a low-grade mild vitreous inflammation (vitritis) with CMV retinitis, frequently less than might be expected for the degree of retinal necrosis. Usually there are only trace vitreous cells with minimal vitreous haze. There may be fine anterior-chamber keratic precipitates (KPs), although most patients have no anterior chamber reaction. Vision is normal unless the optic disc or fovea is involved.

Patients with CMV retinitis may not complain of symptoms because the lesions begin in the periphery, or because the patient often does not notice an increase in floaters or a new scotoma. Therefore, it may make clinical sense to

screen patients who are at risk with CD4+ counts <50– 100 cells/ L. A reasonable screening frequency is every 3

or 4 months for this population, although this may need to be modified as use of oral prophylactic therapies becomes widespread. Because children more rarely complain of visual symptoms, ophthalmologic screening should be per-

formed at least every 3 months when the CD4+ count is <50 cells/ L.

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Part 4 • Infectious Uveitic Conditions

Chapter 11 Acquired Immunodeficiency Syndrome

Progression

CMV retinitis progresses in two ways. First, new lesions that are not physically near an old one may form, probably by hematogenous spread. Second, and most commonly, an old lesion spreads at its borders to involve new, previously uninfected retina. In this latter situation the center of the old lesion eventually ceases to be white because the whiteness is due to scattering of light by edematous and necrotic retina. Once retinal cell death has occurred and only a glial scar remains, the atrophic retina is again transparent with underlying retinal pigment epithelial stippling (Fig. 11-4). Therefore, when one assesses the progression and resolution of CMV retinitis it is most important to pay attention to the edge of the lesions to look for advancement of the border, and to not look at the center of the lesion and interpret a decrease in whiteness as an improvement.

CMV infection causes vision loss in several ways. Most commonly the infected retina is destroyed, and patients develop an absolute scotoma due to retinal necrosis. When the macula is involved, central vision is lost. Macular involvement can be a presenting sign of the disease, or occur late in the course. However, until the macula is involved by active retinitis, the vision can be nearly normal unless there is secondary macular edema from a nearby area of retinitis. Patients can retain normal central vision with only a few degrees of visual field in this disease, and they can be significantly disabled by the peripheral retinal destruction. The optic disc can also become involved, and the vision can be lost even when the amount of retinitis is still minimal. In some patients paramacular CMV infection will produce macular edema, which is a reversible cause of visual loss if it can be treated before the active virus progresses through the fovea. Last, CMV retinitis can cause a rhegmatogenous retinal detachment because there is vitreous traction on the thin, atrophic retina. As you will read in more detail later in this chapter, retinal detachments with CMV retinitis are difficult to treat.

CMV retinitis in the era of highly active antiretroviral therapy

The presentation and course of CMV retinitis in patients with AIDS have dramatically changed with the use of HAART: incidence has decreased, progression is slower, and the clinical manifestations have changed. Before HAART was available, untreated CMV retinitis progressed relentlessly, leading to retinal necrosis and blindness. Even with anti-CMV treatment the median time to progression of CMV retinitis was approximately 2 months in patients treated with intravenous ganciclovir or foscarnet,27,28 2–4 months with intravenous cidofovir,29,30 to 7 months with a sustained-release intravitreal ganciclovir implant.31

HAART has led to reduced HIV replication, elevations in CD4+ cell counts, and reduced mortality.32–34 Studying HIVinfected patients with CMV retinitis has allowed us to answer the important clinical question of whether the rejuvenated immune system that results from HAART can effectively control opportunistic infections. The progression of CMV retinitis can be accurately assessed using the masked grading of standard retinal photographs. We know, for example, that

in untreated, immunocompromised patients CMV retinitis progresses within a median of 2–3 weeks.

A number of studies suggest that HAART-induced immune recovery has had a substantial impact on the course of CMV retinitis. The use of HAART has led to a reduction in the incidence of CMV retinitis, altered its clinical appearance, and dramatically changed the clinical course of the disease. Widespread use of HAART has led to a decrease in the annual number of new cases of CMV retinitis by >75%.34,35 In a study of 1255 patients, each of whom had at least one CD4+ cell count <100 cells/ L, the incidence of any of three major opportunistic infections, including CMV retinitis, declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years in mid-1997.34

Evidence from patients with AIDS and CMV retinitis also suggests that immune recovery with HAART can effectively control the disease in the absence of specific anti-CMV therapy. In 1997, we first reported that CMV retinitis did not progress in four patients receiving HAART, despite the fact that they were not receiving anti-CMV therapy.36 Interestingly, one of these patients never received anti-CMV therapy. Since that time, a number of additional studies suggested that CMV retinitis may not reactivate after maintenance antiCMV therapy is stopped in patients with HAART-induced immune recovery, and that active CMV retinitis may resolve in some patients who never receive specific anti-CMV treat- ment.37–43 Reactivation of CMV retinitis can occur, however, especially if CD4+ counts fall to <50 cells/ L.38 Furthermore, there have been some sporadic reports of CMV retinitis occurring in patients receiving HAART who had stable CD4+ counts >100 cells/ L. An observational study conducted in seven European HIV cohorts followed 358 patients taking potent antiretroviral therapy who interrupted maintenance therapy because of opportunistic pathogens at a CD4+ lymphocyte count >50 cells/ L.44 Of these 358 patients, 162 had CMV end-organ disease. Two relapses of CMV retinitis occurred during the study. The CD4+ counts at the time of relapse were 91 cells/ L in one patient and 247 cells/ L in the other. Nevertheless, the CD4+ count appears to be the best predictor of an effective immune response against CMV, including other laboratory parameters such as HIV load and CMV culture data. Researchers have investigated whether CMV load41 or CMV-specific CD4+ cell responses quantified by flow cytometry45 can quantify and predict an effective clinical immune response against CMV, but the incidence is currently so low that adequately powered clinical studies are difficult to conduct.

Some data suggest that patients may need to receive HAART for several months before the immune response against opportunistic infections is effectively restored.46 Because the proportion of naïve T cells increases after about 3 months of HAART,47 specific anti-CMV therapy should be continued for at least 3 months after CD4+ counts have increased with HAART.

Treatment

A number of medications have now been approved by the US Food and Drug Administration (FDA) for the treatment of CMV retinitis: ganciclovir and derivitives, foscarnet, cidofovir, and fomivirsen. There is also a sustained-release ganciclovir implant approved for the treatment of this disease.

Prior to the advent of HAART patients were usually treated with induction doses of intravenous ganciclovir or foscarnet, followed by lower maintenance doses of the drug for life. Even with this therapy, recurrences were common. Use of the sustained-release ganciclovir implant more effectively treated ocular disease, but did not treat the systemic CMV infection. Now, with the use of HAART and the development of orally bioavailable drugs such as valganciclovir, intravenous ganciclovir and foscarnet are used less frequently.

Ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl) guanine] was the first drug approved by the FDA for the treatment of CMV retinitis. Whereas aciclovir is not sufficiently active against CMV infection, ganciclovir is virostatic both in vitro and in vivo. Ganciclovir is triphosphorylated in the cell and then inhibits viral DNA polymerase. Therapy with 5 mg/kg intravenously twice daily for 14 days will halt the progression of CMV infection and the development of a less active lesion in more than 90% of patients48–50 (Fig. 11-5). However, because the drug is virostatic, recurrences are common unless the underlying immunosuppression can be altered. In patients with AIDS the median time to progression of retinitis without treatment is 21 days. Intravenous administration of ganciclovir, 5 mg/kg/day, 7 days per week, prolongs the median time to relapse to 56 days, and many patients go significantly longer without a relapse.51 After treatment visual loss due to macular edema often improves, but visual loss due to retinal necrosis does not. The usual therapy for CMV retinitis in immunocompromised patients includes induction therapy with intravenous ganciclovir at a dose of 5 mg/kg twice daily for 14–21 days, followed by maintenance therapy at a dose of 5 mg/kg once daily. The

main toxicity of ganciclovir therapy is neutropenia.48–51 Neutrophil counts should be maintained higher than 500/ L.

Foscarnet was the second drug approved by the FDA for the treatment of CMV retinitis. It inhibits DNA polymerase in a manner different from that of ganciclovir. In addition to being inhibitory to CMV and other herpes viruses, it inhibits reverse transcriptase and the replication of HIV. It is also administered intravenously with a 2–3-week induction dosage of either 60 mg/kg three times daily or 90 mg/kg twice daily, followed by maintenance therapy with 90 mg/ kg or 120 mg/kg daily.52 Foscarnet is less toxic to the bone marrow than ganciclovir, but is nephrotoxic and leads to

electrolyte abnormalities in serum calcium, phosphate, and magnesium levels.

Ganciclovir and foscarnet were compared in a multicenter trial conducted by Studies of Ocular Complications of AIDS (SOCA)51 in which 234 patients with newly diagnosed CMV retinitis were randomly assigned to receive ganciclovir or foscarnet. Both drugs were found to be equally effective in preventing progression of CMV retinitis, with a median time to progression of approximately 8 weeks for each drug. Although foscarnet was shown to increase survival to 12 months after diagnosis compared to 8 months for ganciclovir in patients with normal renal function, this difference in survival has not been seen in subsequent studies of the two medications. The study also showed that there was more neutropenia with ganciclovir but more infusion-related symptoms, genitourinary symptoms, nephrotoxic effects, and electrolyte abnormalities with foscarnet.53

Cidofovir is a cytosine-derived nucleotide analogue with a long half-life that is also FDA approved for the treatment of CMV retinitis. Cidofovir at a dose of 5 mg/kg is given intravenously once a week for 2 weeks for induction.29 Maintenance doses of cidofovir are 3–5 mg/kg administered intravenously once every other week. Nephrotoxicity is the major adverse event associated with cidofovir. To reduce renal toxicity, cidofovir should be given with probenecid and adequate intravenous hydration. Because of the renal toxicity, cidofovir should not be used with foscarnet and is less commonly used than other available medications.

Two anti-CMV medications have been approved for intravitreal use: fomiversen and a sustained-release ganciclovir implant. Fomivirsen is an antisense oligonucleotide that is complementary to a sequence in messenger RNA of the major immediate early region 2 of human CMV and inhibits replication of the virus.54 Fomivirsen was FDA approved for the local treatment of CMV retinitis but is no longer available from the manufacturer.

Intravitreal ganciclovir implant

The sustained-release intravitreal ganciclovir implant is a useful addition to the therapeutic armamentarium for treating CMV retinitis. This nonbioerodible implant releases 1 g of drug per hour for 8 months, and is surgically implanted

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