Michelle Tarver-Carr, M.D., Ph.D.,
James P. Dunn, M.D.
OVERVIEW
Acquired immunodeficiency syndrome (AIDS) is a potentially fatal multisystem disorder in which immunity is severely compromised as a result of infection with the human immunodeficiency virus (HIV). AIDS is defined by the Centers for Disease Control as a CD4+ T-lymphocyte count of less than 200 cells/?L or specific opportunistic disease, including cytomegalovirus (CMV) retinitis.[1] According to the World Health Organization, ~ 38 million people worldwide were infected with HIV in a cross-sectional analysis in 2003. In 2004 alone, 4.8 million new infections developed.[2]
This chapter will focus on the retinal manifestations of AIDS, particularly noninfectious microvasculopathy and CMV retinitis. Other less common viral, bacterial, parasitic, and fungal infections affecting the retina will also be discussed. Lastly, diagnostic methods in cases in which the cause of the ocular disease is not clinically evident will be described, along with current treatments for the opportunistic infections and HIV itself.
EPIDEMIOLOGY OF HIV INFECTION AND AIDS
In 2004, there were 38 730 new cases of HIV with 14.1 cases of AIDS per 100 000 in the United States. There are currently ~ 950 000 individuals with AIDS living in the US, translating to a prevalence rate of 136.7/100 000 of HIV and 168.8/100 000 of AIDS or HIV.[1] The number of HIV cases in the United States has increased linearly over time with almost half of the patients being diagnosed with AIDS within 12 months after becoming HIV seropositive.[3] HIV is transmitted by (1) sexual contact, (2) inoculation from infected sources (especially the sharing of contaminated needles by injection drug users), and (3) exposure to infected blood, tissues, and milk in utero, during or after birth. At 2-4 weeks after infection many patients are asymptomatic; however, ~ 50-70% of patients develop an acute retroviral syndrome typified by myalgias, lymphadenopathy, diarrhea, and other viral symptoms.[4]
Viral invasion and replication occur through attachment of HIV to the CD4+ receptors on CD4+ T-lymphocytes, macrophages, and other dendritic cells. The viral envelope fuses with the cellular membrane, leading to insertion and uncoating of the viral nucleocapsid. HIV reverse transcriptase forms a complementary DNA strand from HIV RNA which inserts into the host genome using HIV integrase. Activation of the CD4+ T-lymphocyte causes transcription and translation of viral proteins and viral assembly. The viral particles bud from the cell surface and mature upon cleavage of viral polyproteins by HIV protease. This process promotes apoptosis of CD4+ cells, decreasing the number of T-lymphocytes available to mount a defense against infections. Macrophages, however, are not lysed in the viral cycle but instead escort the virus to vulnerable host tissues such as the central nervous system.[5]
HIV infection is diagnosed by assaying viral p24 antigenemia, viral culture, or amplification of viral nucleic acids by polymerase chain reaction. People with suspected HIV infection are screened with enzyme-linked immunosorbent assay (ELISA), which detects core HIV proteins and surface glycoproteins. While the ELISA is very sensitive, a positive result must be confirmed by Western blot analysis. Moreover, disease progression is monitored by the viral load of HIV since the HIV-1 RNA assay has been shown to predict the clinical progression of HIV-associated disease.[6] Advanced HIV disease is associated with many ocular and systemic manifestations.
NONINFECTIOUS RETINAL VASCULOPATHY
BACKGROUND AIDS RETINOPATHY
Noninfectious HIV microangiopathy, also called 'background HIV retinopathy', is the most common ophthalmic manifestation of HIV/AIDS. It is uncommon in those with CD4+ cell counts greater than 200 cells/?L but occurs in a majority of patients with CD4+ counts less than 50 cells/?L, and therefore serves as a marker for advanced immunosuppression.[7]
The retinopathy is characterized by cottonwool spots (Fig. 163.1), which occur in 25-50% of patients with AIDS, intraretinal hemorrhages, white-centered hemorrhages, retinal capillary microaneurysms, telangiectasias, and capillary nonperfusion.[8] Affected patients are usually asymptomatic. Cotton-wool spots are a result of microinfarctions and edema in the retinal nerve fiber layer; the histopathologic findings (cytoid bodies) correspond to the reversible feathery whitening seen clinically. They are not pathognomonic, since they also occur in other conditions such as hypertension, diabetes, severe anemia, lupus, and leukemia.[9] As in diabetes, the earliest histopathologic finding in noninfectious HIV-related microvasculopathy is loss of capillary pericytes. Vascular sludging from hypergammaglobulinemia, immune complex deposition on the vascular walls, and local release of cytotoxic substances have all been postulated as causative factors for the hemorrhages.[10] The cotton-wool spots occur in the posterior pole, often near the optic disc. There is no associated vitritis or increased vascular permeability. The time to regression is 6-12 weeks.[11] Cumulative loss of retinal ganglion cells manifests itself as an asymptomatic decrease in visual acuity, color vision, and contrast sensitivity.[12,13] With highly active antiretroviral therapy (HAART), the lesions can disappear, leaving a normal-appearing fundus, although studies of patients with AIDS show a global decrease in the number of optic nerve fibers resulting from axonal degeneration in the absence of infection.
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FIGURE 163.1 HIV microvasculopathy. Note the cottonwool spots and intraretinal hemorrhage in the right eye of this 36-year-old woman with AIDS and a CD4+ count persistently below 10 cells/?L. She had CMV retinitis in the fellow eye. |
The retinal hemorrhages in background retinopathy may appear as including flame-shaped, dot-blot or punctuate peripheral intraretinal hemorrhages; occasionally Roth spots (hemorrhages with a white central region) are seen. The hemorrhages are not associated with a coagulopathy or a bleeding diathesis. Fluorescein angiography may reveal areas of microaneurysms, telangiectasias, and capillary loss.
RETINAL MACROVASCULOPATHY
Branch or central retinal vein occlusions, branch retinal artery occlusion, and ischemic maculopathy have all been described in the literature in persons with HIV/AIDS.[14-17] In one study of nearly 2500 consecutive persons with HIV infection, 1.3% of patients were noted to have retinal vascular occlusion, of whom 48% had central retinal vein occlusion (CRVO), 27.3% branch retinal vein occlusion (BRVO), 12.1% hemitretinal vein occlusion (HRVO), and 3% central retinal artery occlusion. The presence of microvasculopathy was associated with a higher risk of macrovasculopathy.[18] In contrast to noninfectious microvasculopathy, visual loss from these macrovasculopathies can be severe and permanent. The risk of retinal vein occlusion in those with HIV-infection is significantly higher than in their age-matched healthy peers. The cause of the retinal macrovasculopathy is unclear; however, it is presumed that abnormalities of retinal blood are contributing factors.[19,20]
CYTOMEGALOVIRUS RETINITIS
Human cytomegalovirus (CMV) is an enveloped, double-stranded DNA herpes virus. It is most often transmitted by contact with persons shedding the virus in their urine, sputum, breast milk, semen, or cervical secretions. The virus can also be transmitted by solid organ or bone marrow transplantation or through blood transfusions. Between 40 and 100% of healthy adults have antibodies to CMV, confirming prior exposure. Primary CMV infection is usually asymptomatic, although 5% of newly infected individuals may manifest a mononucleosis-like syndrome.[21] The virus is latent in immunocompetent individuals with residence in the bone marrow. In immunocompromised patients, reactivation may lead to clinically significant disease following hematogenous dissemination. The retina is the most commonly affected tissue, occurring in 75-80% of patients with reactivation[22,23]; the gastrointestinal tract, lung, adrenal glands, and nervous system are also common sites of clinical disease. Most patients with AIDS-related CMV retinitis have CD4+ count less than 50 cells/?L.[24]
Histological samples of CMV retinitis demonstrate intracytoplasmic inclusion bodies in vascular endothelial cells.[25] The infection appears to spread by cell-to-cell transmission.
CMV retinitis was one of the first opportunistic infections reported as a complication of AIDS. In the era before HAART, up to 30% of patients with AIDS developed CMV retinitis.[23] In patients taking HAART, the incidence of CMV retinitis has declined dramatically to ~ 20-25% of the pre-HAART era rate (Fig. 163.2).[26]
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FIGURE 163.2 Incidence of CMV retinitis over time standardized by age, race, and CD4+ T-lymphocyte distribution. |
DESCRIPTION
In untreated patients, CMV retinitis spreads relentlessly throughout the retina, causing full-thickness necrosis and blindness. Lesions may be single or multiple and unilateral or bilateral, affecting any part of the retina. Symptoms may include visual field loss, decreased visual acuity, floaters, and photopsias, but it is not uncommon for patients to be completely asymptomatic.[27,28] The presence of subjective scotomata varies with the location of the lesions. In patients with CD4+ counts of less than 50 cells/?L, the prevalence of previously undiagnosed CMV retinitis detected on screening has been reported to be as high at 13-18%.[24] Eye pain and redness are not typical features. CMV retinitis may appear as intraretinal yellow necrotic lesions with retinal hemorrhages (fulminant/edematous retinitis), as less densely necrotic without hemorrhage (indolent/granular retinitis), or some combination of the two. Both types, however, are characterized by a dry-appearing, granular border (Fig. 163.3). There is often a mild vitritis and anterior chamber inflammation.[27] The disease progresses outward in a brushfire pattern, leaving behind an atrophic, avascular, full-thickness retinal necrosis. The disease is described according to the location within the retina: zone 1 is within 3000 ?m of the center of the fovea or 1500 ?m of the optic nerve, zone 2 is located from the periphery of zone 1 to the ampulla of the vortex veins, and zone 3 from the periphery of zone 2 to the ora serrata. Zone 1 lesions are generally considered immediately sight-threatening and usually require more urgent therapy than do more peripheral lesions.
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FIGURE 163.3 CMV retinitis with granular appearance. |
Natural History
If CMV retinitis remains untreated, the lesions spread inexorably to cause total retinal necrosis. The borders of the lesion advance on average one disc diameter every 6 weeks in a centrifugal pattern.[29] The older portion of the advancing lesion becomes gliotic scar tissue. Optic atrophy can also be observed late in the disease from the diffuse retinal damage. Vision loss may occur from retinal necrosis involving the macula, rhegmatogenous retinal detachment, secondary optic nerve involvement, or exudative swelling along an active border adjacent to the fovea.
DIFFERENTIAL DIAGNOSIS
In the early stage of CMV retinitis it may be difficult to distinguish cottonwool spots from foci of viral infection. Cottonwool spots do not cause blurred vision, floaters, or photopsias and are not associated with vitritis or anterior uveitis; they usually have a feathery border rather than the granular border of CMV retinitis. Repeating the ophthalmic exam after 1-2 weeks will aid in making the diagnosis, as cotton-wool spots will not progress in size.
As CMV retinitis progresses, it may resemble other infections of the retina. Toxoplasmic retinochoroiditis can mimic CMV retinitis, but usually presents with a creamy border, prominent vitritis, and the absence of intralesional hemorrhages. Herpetic infections of the retina (e.g., acute retinal necrosis and progressive outer retinal necrosis) are less common than CMV retinitis and have a clinical appearance that is distinctly different. Bacterial and fungal infections, including syphilitic retinitis and aspergillosis or candida retinitis, may also mimic CMV retinitis. Finally, intraocular lymphoma should be considered in the differential diagnosis of CMV retinitis, especially in patients with neurologic abnormalities.
DIAGNOSIS
CMV retinitis is usually diagnosed clinically. The presence of antibodies to CMV indicates prior infection but is neither indicative of concurrent clinical disease nor predictive of future disease. Reactivation of CMV is confirmed by positive cultures for CMV from blood, urine, or throat washings or from polymerase chain reaction (PCR) amplification of CMV DNA.[30] An elevated CMV viral load may be the most predictive risk factor for end-organ disease. In atypical cases, endoretinal biopsy taken at the junction of necrotic and actively infected tissue may be necessary. The pathognomonic finding is the presence of intranuclear and intracytoplasmic inclusion bodies with an 'owl's eye' appearance, or positive CMV staining by immunohistochemistry; electron microscopy demonstrates viral particles.
COMPLICATIONS
Retinal Detachment
Untreated CMV retinitis causing full-thickness retinal necrosis may result in a retinal detachment within 3-6 months of diagnosis.[29] In the pre-HAART era, rhegmatogenous retinal detachment occurred at a rate of 25% per patient-year in patients treated with anti-CMV therapy, and detachments remain a major cause of vision loss in CMV retinitis. Lesions located at the peripheral retina where the vitreous body is adherent to the retina are more likely to be associated with a retinal detachment than those lesions located in the posterior pole. Eyes with larger lesions and a longer duration of active retinitis also have a higher risk of retinal detachment. While the retina can usually be reattached surgically, the ultimate visual acuity is usually worse than the preoperative vision before the detachment. It is presumed that vitreous fluid egresses through the breaks in the necrotic retina, rendering photocoagulation ineffective at promoting adhesion between the retina and the choriocapillaris. Scleral buckling and vitrectomy with gas tamponade are often ineffective in treating CMV-related detachments. Long-term tamponade with oil is often necessary due to the number of holes in atrophic or gliotic retina.[31,32]
Exudative retinal detachments are observed in eyes with involvement of zone 1 and peripapillary lesions.[27] These detachments usually resolve with treatment of the retinitis and vision may improve substantially (Fig. 163.4).[33]
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FIGURE 163.4 CMV retinitis with exudative retinal detachment (a) before and (b) after treatment. |
Immune Recovery Uveitis
Immune recovery uveitis (IRU), also known as immune recovery vitritis, was first described in patients with inactive CMV retinitis who had immune reconstitution following initiation of HAART. The reported incidence ranges widely from 0.109 cases per person-year to 0.83 cases per person-year.[34,35] While differences in the case definition partially explain the difference in incidence, another factor is thought to be changes in the treatment of CMV retinitis; patients initially treated with cidofovir may be at higher risk for IRU. Immune recovery uveitis usually occurs 2-16 weeks after the elevation of the CD4+ lymphocyte counts, which typically is noted 2.5-8 months after starting HAART.[36]
Affected patients develop a painless decrease in visual acuity and floaters without any redness. The vision loss is generally mild, in the range of 20/40 to 20/80. The symptoms often begin within a few weeks or months after the CD4+ counts increase above 100 cells/?L.[37] Examination reveals moderate to severe vitritis, papillitis, cystoid macular edema, and/or epiretinal membranes. Uncommon complications include vitreous hemorrhage, retinal neovascularization, optic disc neovascularization, vitreomacular traction syndrome, proliferative vitreoretinopathy, posterior and anterior subcapsular cataracts, posterior synechiae, and angle closure glaucoma.[38,39] The clinical findings may vary depending on ocular co-morbidities; for instance, eyes that have had a vitrectomy with silicone oil tamponade will not have visible vitritis but instead will have cystoid macular edema or spillover cells in the anterior chamber.[37]
The cause of immune recovery syndrome is not known. Immune reconstitution is thought to occur after depletion of CD4+ lymphocytes is halted, allowing the surviving clones to expand their population.[40] It has been suggested that the recovering immune system reaches a threshold above which the body is able to mount an ocular inflammatory response to CMV antigens in the eye. Some patients, however, may lack the clones capable of responding to cytomegalovirus even though they have elevated CD4+ T-lymphocyte counts. Eyes with inactive retinitis involving over 30% of the retinal area are at a higher risk of developing immune recovery uveitis when compared to eyes with less extensive involvement, presumably because those eyes with a larger area of CMV retinitis may generate a greater antigenic stimulus, prompting a more aggressive inflammatory response.[41] This reaction is analogous to the necrotizing lymphadenitis observed with Mycobacterium avium-complex infections after the initiation of HAART therapy.[42] As immune recovery progresses, the production of CMV antigens stops and the inflammatory reaction subsides.[40] Limited histologic and immunohistochemical studies of epiretinal membranes found in this syndrome have shown a predominately T-lymphocyte population. Surprisingly, higher levels of CD4+ T-lymphocyte levels were not associated with the severity of the inflammation. Some investigators have suggested that variations in the incidence of IRU may also be due to different virus strains which may stimulate different degrees of inflammation or have different replication rates. There may also be differences in the number of clones capable of responding to CMV, even if the CD4+ counts are the same.[43]
Vision loss typically results from the cystoid macular edema or the formation of epiretinal membranes and vitreomacular traction. Less commonly, branch retinal vessel occlusion and retinal neovascularization are the cause. Successful treatment of IRU has not been demonstrated in a randomized clinical trial; however, a few small cohort studies and case reports have shown that treatment with periocular or systemic corticosteroids may result in improved vision.[41,44] On the other hand, Zegans found that the vitreous cells resolved and the vision improved within 6 weeks with or without antiinflammatory therapy.[37] Re-activation of CMV retinitis following corticosteroid therapy appears to be very rare. It is unclear whether resumption of anti-CMV therapy or longer use of anti-CMV therapy prior to discontinuation in patients with immune recovery reduces the risk of IRU.
TREATMENT OPTIONS
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CMV Retinitis Treatment Overview |
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Screeing
Diagnosis
Management
Prevention
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It is essential to realize that CMV retinitis is part of systemic CMV and HIV infection and that treatment must take into account the nonocular effects of disease; the best outcome is obtained in patients treated with both anti-CMV therapy as well as HAART. In the pre-HAART era, patients with AIDS with cytomegaloviremia had a higher risk of end-organ CMV disease and mortality.[45,46] The mechanisms by which CMV increases mortality includes transactivation of HIV, altering the tropism of HIV, production of interleukins, chemokine receptors, and interference with natural killer cells, thereby inhibiting the host's ability to clear viruses.[47] Kempen et al showed ~30% reduction in mortality in patients treated with systemic anti-CMV therapy, after adjusting for HAART.[48] The widespread use of HAART has not only changed the course of AIDS, but has also reduced the rates of vision loss in those with CMV retinitis. Those with HAART-induced immune recovery have half the risk of visual acuity loss.[49] This decrease has been attributed to a reduction in progression (96% reduction), contralateral eye involvement (82%) and associated retinal detachments (88%) in the HAART era.[50-52] Patients with unilateral CMV retinitis are at a significantly higher risk of developing second-eye retinitis of the order of 26.1% per person-year, almost all within the first few months after diagnosis, despite systemic CMV treatment. Those on treatment with anti-CMV therapy and HAART with immune recovery are significantly less likely to develop contralateral eye involvement.[53] However, cytomegalovirus infection worsens the prognosis in patients with AIDS; CMV viral load and active disease are associated with an increased mortality despite the use of HAART.[54]
There are four drugs that have been FDA approved for the treatment of CMV retinitis-ganciclovir, valganciclovir, f oscarnet, and cidofovir. All of these drugs work by inhibiting the activity of CMV DNA polymerase that is essential for replication of the virus (a fifth approved drug, fomvirsen, is an antisense oligonucleotide that works by a different mechanism, but the drug was voluntarily taken off the market in 2003 due to poor sales). All of these drugs are virostatic, not virocidal. The dosing strategy for systemic medications involves an induction period of 2-3 weeks, followed by indefinite, lower- frequency maintenance therapy that must be lifelong in patients with persistent immunosuppression (Table 163.1). In patients with immune recovery (generally defined as a recovery in the CD4+ count by more than 50 cells/?L or to a level greater than 100 cells/?L for at least 3-6 months), discontinuation of maintenance therapy in those with inactive CMV retinitis is usually possible, thereby avoiding the cost and toxicity of treatment.[55,56] Some investigators have suggested that HIV viral load is a better predictor of progression than CD4+ counts.[57] In light of these findings, there is no consensus on when the maintenance therapy can be discontinued.
TABLE 163.1 -- Medication Regimen for the Treatment of CMV Retinitis.
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Drug |
Induction |
Maintenance |
Laboratory Tests |
Toxicity |
Considerations |
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Ganciclovir |
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Anemia, thrombocytopenia, neutropenia |
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Valganciclovir (Valcyte) |
900 mg po bid × 21 days |
900 mg po qday |
Complete blood count weekly |
Bone marrow suppression, nausea, diarrhea |
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Foscarnet Intravenous (Foscavir) Intraocular injections |
90 mg/kg bid × 14 days or 60 mg/kg tid 2400 ?g biweekly |
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Serum creatinine, potassium, magnesium, calcium, phosphorous biweekly during induction, weekly during maintenance; hemoglobin |
Nephrotoxicity, hypokaemia, hypocalcemia, hypomagnesemia, genital ulcers, anemia, headache |
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Cidofovir Intravenous (Visitide) |
5 mg/kg qweek × 14 days |
3-5 mg/kg IV q2weeks |
Serum creatinine, urinary protein, complete blood count before each infusion |
Nephrotoxicity, proteinuria, Fanconi-like syndrome, hypocalcemia, neutropenia, uveitis, hypotony |
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Fomvirsen (Vitravene) |
330 g intraocular qweek |
330 mcg intraocular |
None |
Increased IOP, uveitis |
Withdrawn from the market as of 2003 |
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Ganciclovir is the most commonly used medication for the treatment of CMV retinitis and can be administered intravenously, orally, or intraocularly via an injection or an implant. Activation of ganciclovir requires initial phosphorylation by a CMV-encoded kinase produced by the UL97 gene, followed by additional phosphorylation by host cellular enzymes to the active drug, ganciclovir triphosphate, that inhibits CMV DNA polymerase. In 80-90% of patients, the intravenous administration of ganciclovir at a dosage of 5 mg/kg twice a day during the induction period initially halts retinal cell necrosis and reduces the viral load of CMV. Maintenance therapy at a dosage of 5 mgkg?1day?1 is then continued, but the need for daily intravenous mandates the need for a permanent indwelling catheter and the associated risks of line infection and sepsis. Maintenance therapy with oral ganciclovir was effective in controlling retinitis temporarily and obviated the need for permanent catheterization,[58] but bioavailability is poor (less than 7%) and the risk of progression of retinitis is high. Consequently, vision-threatening lesions (e.g., zone 1 disease) are poor candidates for oral maintenance therapy.
Valganciclovir is an oral prodrug which is hydrolyzed to ganciclovir in the gastrointestinal mucosa and has better bioavailability (61%) than oral ganciclovir. The plasma levels obtained with valganciclovir are comparable to that obtained with intravenous ganciclovir, making it a viable option for both induction and maintenance therapy at dosages of 900 mg twice a day and 900 mg once daily, respectively.[59,60]
The ganciclovir implant is a surgically-implanted, sustained-release, 4.5 mg ganciclovir pellet attached to a nonerodable strut. The pellet is coated with polyvinyl alcohol (which is permeable to ganciclovir) and ethylene vinyl acetate (which is impermeable). The release rate of about 2 ?g/h is determined by the thicknesses of the coatings of the two polymers, providing release of drug for about 7-8 months. The implant is placed in the vitreous cavity through a 5.5 mm pars plana incision made 3.5-4 mm posterior to the limbus; prolapsed vitreous is excised, but an internal vitrectomy is not necessary.[61] The strut attached to the implant is trimmed to a length of about 2 mm and a hole is placed in the end of the strut with a 27- or 30-gauge needle. A double-armed 8-0 nylon or prolene suture is placed through this hole and the device is centered in the wound (Fig. 163.5). A stable intraocular concentration of ganciclovir is obtained within 24-48 h and is roughly fourfold higher than that obtained with intravenous therapy. In a randomized clinical trial of 188 patients with active CMV retinitis and AIDS, the sustained release ganciclovir implant decreased the risk of progression threefold when compared to intravenous ganciclovir. However, the risk of systemic CMV disease as well as involvement of the contralateral eye was significantly higher than that observed in patients receiving intravenous therapy.[62] The implantation procedure typically causes a transient decrease in visual acuity from astigmatism to 20/80 on average which resolves within the first 4 weeks of treatment. The most significant risks are associated with the surgical complications. The presence of silicone oil does not appear to interfere with the functioning of the ganciclovir implant.[63]
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FIGURE 163.5 Placement of ganciclovir implant in the vitreous cavity. |
Following ganciclovir implant placement, the risk of retinal detachment was 11.9%, endophthalmitis was 1.7%, and vitreous hemorrhage was 7.8%.[62,64] Endophthalmitis may occur through introduction of organisms into the eye at the time of surgery or subsequently through incomplete wound closure at the intrascleral location of the suture tab. Because of these potential complications, the implant is avoided if immune reconstitution is expected unless zone 1 is involved.
Foscarnet, a pyrophosphate analog, also inhibits CMV DNA polymerase but does not require phosphorylation. It is comparably effective to ganciclovir in the treatment of CMV retinitis. However, its tedious intravenous administration schedule coupled with its side effect profile, especially nephrotoxicity, has made it a less desirable first-line therapy. Because foscarnet does not require phosphorylation, it may be effective in the treatment of CMV retinitis resistant to ganciclovir as a result of mutations in the UL97 gene.
Intravitreous injections of both ganciclovir and foscarnet have been used off-label to treat CMV retinitis. The usual dosage for ganciclovir is 2 mg in 0.1 ml and for foscarnet 2400 ?g in 0.1 mL. The injections must be given twice weekly as induction therapy and once weekly thereafter, a regimen that is usually not practical for patients in the long term. As with the ganciclovir implant, the use of intravitreal injections does not prevent second-eye or visceral CMV disease. On the other hand, intravitreal injections can be very useful in obtaining rapid control of zone 1 retinitis before more definitive therapy can be instituted, and can serve as a bridge between systemic therapies when toxicity requires temporary cessation. Risks include subconjunctival hemorrhage, pain, acute glaucoma, infection, vitreous hemorrhage, endophthalmitis, and retinal detachment.
Cidofovir is an acyclic nucleotide analog that was found in a series of clinical trials to be effective at preventing the progression of CMV retinitis. Its activity is 10-100 times greater than other available anti-CMV medications. The induction regimen is 5 mg/kg once a week for 2 weeks, followed by 3-5 mg/kg every two weeks. Its prolonged antiviral effect allows for intermittent intravenous administration to control the disease, so that permanent catheterization is not needed. However, the use of cidofovir is limited by potentially irreversible nephrotoxicity through dose-dependent damage to proximal tubular cells of the kidney and by the development of anterior uveitis in 24-59% of patients receiving the drug.[65-67] Another 25% of patients developed hypotony presumed to be secondary to changes in the ciliary epithelium and a reduction of aqueous humor production. Injections of intravitreous cidofovir may result in irreversible hypotony and for this reason should never be used. The anterior uveitis is characterized by pain, ciliary injection, posterior synechiae formation, and decreased visual acuity, and occurs on average after approximately five doses of the medication. The uveitis usually responds to topical steroids and cycloplegia.[65] The risk of anterior uveitis appears to be reduced by the concomitant use of probenecid, which is thought to inhibit secretion of cidofovir by the ciliary body and therefore decreased intraocular drug levels.
Clinical resistance to anti-CMV therapy is estimated to occur in 20-30% of patients after one year of therapy. Mutations at the level of the UL97 gene result in the reduced uptake of phosphorylated ganciclovir into host cells and cause low-level resistance that is often responsive to foscarnet or cidofovir. Mutations at the level of the UL54 gene cause high level resistance that may be resistant to all three medications. Resistance was associated with prior intravenous cidofovir use or prior oral ganciclovir use.[68] Phenotypic resistance is determined by analysis of viral cultures, whereas genotypic resistance is determined by the use of PCR techniques using blood or vitreous specimens; there is a good correlation between resistance determined from blood specimens and those obtained from the vitreous. It is important to distinguish resistant CMV retinitis from progression of disease due to poor compliance or inadequate drug penetration because the former is associated with reduced survival and poorer visual outcomes.[69]
Treatment Effectiveness
Resolution of CMV retinitis is recognized by the loss of satellite lesions, disappearance of vascular sheathing, and the formation of a well-demarcated lesion borders. Systemic therapy may take several weeks or more to control retinitis and therefore may not be adequate in the initial treatment of lesions near the fovea or optic nerve. In these cases, immediate intravitreous injections of ganciclovir or foscarnet, followed by placement of a ganciclovir implant, may be more effective. Secondary prophylaxis with valganciclovir is then indicated to reduce the risk of second-eye and visceral CMV disease. In all patients with CMV retinitis, initiation or maximization of HAART is critical in achieving long-term control of retinitis.
Studies have shown that plasma CMV loads >400 copies/mL and leukocyte CMV loads >400 copies/106 leukocytes are associated with an increased risk of CMV retinitis progression. Unfortunately, the sensitivity and positive predictive value for these markers were low, limiting their global clinical utility.[70] Measurement of the CMV plasma load may aid in rapidly excluding CMV resistance and identifying those patients requiring more detailed and time-consuming resistance testing.
Salvage Therapy
Over time, most patients with CMV retinitis relapse with progression of the disease when treated with systemic therapy alone. Progression is much less common in eyes treated with the ganciclovir implant because of the high-intraocular levels obtained, but will invariably occur when the implant is exhausted of drug after 7-8 months if immune recovery is not established. Therefore, the use of HAART in all patients with CMV retinitis is highly desirable. Reactivation is documented with the reappearance of opacification of the border of the lesion and advancement of the lesion borders or the development of new lesions. Predictors of clinical relapse include HAART failure, weak lymphoproliferative responses to CMV, and a low nadir HIV viral load.[71] Progression of previously inactive lesions ('breakthrough' or 'relapse') in the first year of treatment is most likely due to poor intraocular drug levels as a result of re-establishment of the blood-retinal barrier. Subsequent progression may be due to drug resistance. Various strategies have been used to manage the relapse but there is limited evidence to guide the clinician. Reinduction therapy with a higher dose of drug or by switching from one drug to another, combined therapy with intravenous ganciclovir and foscarnet has been shown to be twice as effective as either drug alone in delaying further progression[72]; however, the added toxicity of the second drug makes combination therapy difficult to administer and reduces quality of life. In cases in which drug resistance is the cause of progression, a change from ganciclovir to foscarnet or cidofovir may be necessary. In patients who are unable to tolerate systemic treatment, intravitreal injections or the ganciclovir implant are options. The ganciclovir implant produces intravitreous drug levels high enough to overcome some cases of low-level ganciclovir resistance (UL97 mutations) but will not control retinitis with UL54 mutations.
INVESTIGATIONAL AGENTS
The dramatic drop in the incidence of CMV retinitis has reduced the interest in developing new anti-CMV agents; nonetheless, several drugs are being examined in early clinical trials. Maribavir is a proposed drug that inhibits the UL97 gene product prohibiting terminal DNA processing and hence arresting nuclear egress of CMV particles. It has shown activity in vitro in suppressing CMV retinitis. The drug does not need intracellular activation and shows promise for retinitis resistant to ganciclovir or foscarnet. Some of the side effects include headache, dysgeusia, diarrhea, and nausea which are dose related. Tomeglovir another orally administered drug still in the early trial phase has also proven to have efficacy against resistant strains of CMV.[73]
PREVENTION
The inhibition of viral replication instigated by HAART coupled with the reconstitution of the immune system of patients with AIDS has led to a dramatic decrease in morbidity and mortality. Periodic CD4+ counts must be monitored in these patients with resumption of secondary prophylaxis in the presence of immunological failure (generally considered a decrease in the CD4+ count to less than 75 cells/?L). Routine use of primary prophylaxis with anti-CMV therapy, including valganciclovir, is not recommended because of the high cost, potential toxicity, and concerns about the development of drug-resistant disease.
OTHER VIRAL INFECTIONS
PROGRESSIVE OUTER RETINAL NECROSIS
Progressive outer retinal necrosis (PORN) was the second most common infectious retinopathy in patients with AIDS before the advent of HAART, occurring in 2% of patients with AIDS with a median CD4+ count of 21 cells/?L.[74] It is generally associated with reactivation of herpes zoster virus, although herpes simplex virus (HSV-1) has also been reported to cause PORN (Fig. 163.6). The retinitis can start in the macula or in the periphery with patchy, multifocal outer retinal lesions coalescing rapidly throughout the retina in the absence of vascular or vitreous inflammation. Severe visual loss from the diffuse retinal necrosis, optic atrophy, and retinal detachment occurs in up to 70% of patients.[75] Progression is extremely rapid, occurring over days or even hours. Some patients have severe vision loss despite minimal or absent retinitis as a result of early optic nerve involvement; in these patients, the onset of pain with vision loss may be a key finding. Treatment with intravenous acyclovir alone results in a final vision of no light perception (NLP) in 67% of affected eyes within 1 month.[74] While there is no standard recommendation for treating PORN, combination therapy appears to result in better visual outcomes. A regimen of intravitreal foscarnet and ganciclovir as well intravenous administration of both drugs was associated with 45% of patients having a vision of 20/80 or better. This same study suggested that laser demarcation may result in better outcomes as well due to a lower risk of retinal detachment.[76] Indefinite maintenance therapy with valacyclovir is necessary in patients with persistent immunosuppression. However, as with CMV retinitis and all viral retinitides, the development of immune recovery by HAART is probably the most important factor in maintaining long-term control of the disease.
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|
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FIGURE 163.6 PORN radiating in posterior pole. |
ACUTE RETINAL NECROSIS
Acute retinal necrosis (ARN) is an aggressive and devastating retinitis characterized by a fulminant panuveitis with well-demarcated confluent areas of full-thickness retinitis, choroiditis, and papillitis. Varicella zoster virus and herpes simplex virus have both been associated with this disease. The retinitis is marked by deep retinal whitening, limited hemorrhage hemorrhage, and a rapid progression over days to weeks. Dense vitritis produces fibrotic bands that exert traction on necrotic retina leading to complex retinal detachments in 75% of patients and blindness in 64% of patients within 2-3 months. Unlike PORN, the CD4+ count is usually greater than 60 cells/?L in these patients. The American Uveitis Society has criteria established for making the diagnosis of ARN (Table 163.2).[77] Late in the course of the disease, retinal breaks and detachments in the area of necrosis are common. Proliferative vitreoretinopathy often accompanies the retinal atrophy in the end-stages of the disease. The treatment for ARN in AIDS patients is similar to that advocated in non-HIV patients. Therapy includes intravenous acyclovir followed by indefinite oral therapy with acyclovir, valacyclovir, or famciclovir. While those immunocompetent patients with ARN are sometimes treated with oral corticosteroids to reduce vitreous inflammation, this approach is controversial in HIV patients because of concerns about additional immunosuppression; short-term prednisone therapy probably does not put the patient at significant risk. Laser demarcation along the posterior border of the retinitis is indicated to reduce the risk of retinal detachment.
TABLE 163.2 -- American Uveitis Society Criteria for Diagnosing ARN
|
Required Clinical Criteria |
|
Rapid progression of disease in absence of therapy |
|
One or more foci of retinal necrosis with discrete borders in peripheral retina |
|
Circumferential spread |
|
Evidence of occlusive vasculopathy and arteriolar involvement |
|
Prominent vitreous inflammation and anterior chamber reaction |
|
Supporting Clinical Criteria |
|
Optic neuropathy/atrophy |
|
Scleritis |
|
pain |
NONVIRAL RETINAL INFECTIONS
PARASITIC INFECTIONS
Pneumocystis carinii Pneumonia
Pneumocystis carinii pneumonia (PCP) was in the pre-HAART era the most common AIDS-defining condition in HIV-infected patients, usually developing in patients with a CD4+ count less than 200 cells/?L. Patients at risk for developing PCP are placed on prophylactic therapy with trimethoprim-sulfmethoxazole (TMP-SMX), or dapsone, or dapsone plus leucovorin and aerosolized pentamidine. Prophylactic treatment with aerosolized pentamidine alone is associated with an increased risk of Pneumocystis carinii choroidopathy, characterized by pale, multifocal, cream- to orange-colored plaques ranging in size from 300-3000 ?m deep in the mid-peripheral and posterior choroid.[78] Except in some cases of subfoveal involvement, vision is typically preserved because neither the retina nor the vitreous are involved.[79]Histopathologically, the choroidopathy is characterized by eosinophilic, acellular, frothy, vacuolated infiltrates within choroidal vessels. The choroiditis takes from 6 weeks to 4 months to resolve after treatment with double strength trimethoprim-sulfmethoxazole. It is usually a marker for disseminated pneumocystosis. In the era of HAART and systemic prophylaxis with systemic therapy such as TMP-SMX, P. carinii choroidopathy has virtually disappeared.
Toxoplasmosis Retinochoroiditis
Toxoplasmosis retinochoroiditis was the third most common infectious retinopathy of AIDS in the pre-HAART era, occurring in 1% of patients.[7] The retinitis is characterized by yellow-white areas of retinal necrosis with smooth, nongranular borders most often involving the posterior pole in the absence of hemorrhages. It is associated with a severe vitritis. In immunocompromised patients, ocular involvement is much less common than central nervous system toxoplasmosis. The ocular involvement is often atypical in patients with AIDS. The various presentations range from acute anterior uveitis to panophthalmitis with a secondary orbititis.[80] Lesions are more frequently multifocal and bilateral than in immunocompetent. Those who are infected have IgG antibodies to T. gondii at the time of diagnosis. Treatment consists of trimethoprim-sulfmethoxazole; maintenance therapy is required because recurrences are frequent in patients without immune recovery but may be discontinued in patients whose CD4+ count is consistently above 200 cells/?L. For patients allergic to sulfa drugs, azithromycin, atovaquone, and clindamycin with pyrimethamine/leucovorin may be effective.[81,82] Primary prophylaxis for toxoplasmosis with TMP-SMX is given to those with CD4+ counts less than 200 cells/?L.
FUNGAL DISEASE
Endogenous endophthalmitis can be caused by a number of fungal infections.
Cryptococcus Neoformans
Cryptococcus neoformans is a common cause of meningitis with central nervous system disease in patients with AIDS. Chorioretinitis and endophthalmitis are both thought to result from direct invasion of the organism usually through neural tissue (e.g., optic nerve). Ocular symptoms often precede the neurological disease.[83] Treatment consists of amphotericin B during the induction phase and oral fluconazole for maintenance therapy. Although many patients with AIDS also use illegal drugs intravenously and Candidal infections are associated with intravenous drug use, Candida endophthalmitis is uncommon in AIDS patients. Endogenous endophthalmitis caused by Aspergillus fumigatus is also very rare in the AIDS population.[84] A systematic review of 77 AIDS patients with coccidiomycosis also found no cases of endogenous endophthalmitis.[85]
In 1987, the Centers for Disease Control (CDC) modified the case definition for AIDS to include extrapulmonary histoplasmosis in a person who is HIV positive. Most cases of histoplasmosis in immunosuppressed individuals are disseminated. The chorioretinitis that results is characterized by perivascular retinal lesions with minimal inflammation. Choroidal infection with H. capsulatum is rare.[86]
Paracoccidioidomycosis
Paracoccidioidomycosis is a granulomatous infection prominent in Latin America. Although, it is the most frequent systemic mycosis in Brazil, it is infrequently seen in patients with AIDS. The disease characteristically begins in the oropharynx and disseminates to lymphoid tissue. In immuno compromised patients, it can result from reactivation of a quiescent lesion since cell-mediated immunity keeps the infection dormant. Choroidal granulomas and endophthalmitis have been described. This fulminant infection can cause a total retinal detachment with marked vitritis and iridocyclitis and in one case resulted in enucleation.[87]
In general, the treatment for fungal endophthalmitis is intravenous amphotericin B since most patients also have systemic fungemia. Because intravenous amphotericin has poor intravitreal penetration, vitrectomy and intravitreal amphotericin B are recommended adjunct therapy for sight-threatening endophthalmitis.
BACTERIAL
Syphilitic (luetic) retinitis is a complication of central nervous system involvement not exclusive to patients with AIDS. However, it may have a very fulminant course in patients with patients with AIDS, resulting in blindness from retinal necrosis, vasculitis, and papillitis. The retinitis can manifest as a localized large, pale yellow, placoid subretinal macular lesion or as a necrotizing retinitis resembling CMV retinitis, ARN and toxoplasmosis retinitis.[88] The diagnosis is based on the clinical appearance and positive serology. Because HIV-positive patients frequently have a false-negative serum rapid plasma reagin (RPR) test, the more specific fluorescent treponemal antibody absorbed (FTA-ABS) test should also be drawn.[88] The treatment consists of 4 weeks of intravenous penicillin, with the same dosage used for treatment of neurosyphilis.
Hematogenous dissemination of Mycobacterium tuberculosis to the choroid results in single or multiple round, yellow-white elevated lesions with indefinite borders ranging from 0.5 to 3.0 mm in diameter in the posterior pole and midperiphery (Fig. 163.7). Only a few cases have been described in the literature.[89] The diagnosis is difficult to establish the diagnosis in the absence of systemic disease, and treatment is often undertaken presumptively, based on the clinical appearance, the patient's history of TB exposure and treatment even in the absence of a positive chest radiograph. Tuberculous choroiditis responds well to systemic therapy with rifampin, ethambutol, isoniazid, and pyrazinamide.
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FIGURE 163.7 Tuberculosis nodule in the choroid. |
TUMORS
HIV-associated primary lymphoma of the choroid is extremely rare. In the reported cases, it appears as a confluent yellowish-white retinochoroidal infiltrate with perivascular sheathing that can mimic CMV retinitis.[90] The diagnosis may be made by endoretinal biopsy but more often treatment is initiated based on a systemic workup, including spinal tap, neuroimaging, and brain biopsy. Survival is poor in affected patients.
DIAGNOSTIC TECHNIQUES FOR DETERMINING CAUSE OF RETINAL LESIONS
In complex cases, where the clinical picture is atypical for any disease, a diagnostic biopsy of the choroid, vitreous, or retina may be necessary. Vitreous sampling is most appropriate if there is a brisk vitritis. At the time of a pars plana vitrectomy, the vitreous washings in the cassettes can be plated for cultures and cytology to further tailor treatment. If there is a choroidal infiltrate, a choroidal biopsy can be performed. In the operating room, a complete peritomy is performed with isolation of the four recti muscles. A half-thickness scleral trapdoor dissection is performed with preplaced sutures, allowing rapid closure of the wound, and is surrounded by cautery. Choroid only is removed and the wound is then closed. Some advocate performing a pars plana vitrectomy prior to choroidal sampling to aid in the maintenance of intraocular pressure. Endoretinal biopsy can be performed at the time of repair of rhegmatogenous retinal detachment in patients with viral retinitis. The sample is taken from the margin of healed and active retinitis. The need for these surgical diagnostic techniques is fortunately uncommon, as most retinal manifestations of AIDS are diagnosed clinically (Fig. 163.8).
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FIGURE 163.8 Toxoplasmosis scar, inactive. |
DRUG TREATMENT
HIV THERAPY
The goals for therapy of HIV include suppression of viral replication, preservation of immune function, with maintenance of quality of life without sacrificing a reduction in HIV-related morbidity and mortality. The Department of Health and Human Services recommends treatment of HIV with a combination of a nonnucleoside reverse transcriptase inhibitor or protease inhibitor with two nucleoside reverse transcriptase inhibitors for the initiation of therapy in treatment-naïve patients. This regimen has been termed highly active antiretroviral therapy (HAART). Treatment for HIV using HAART detailed in Table 163.3 is typically initiated when CD4+ cell counts drop below 200 cells/?L or constitutional symptoms develop. No conclusive benefit has been demonstrated for starting the medication at CD4+ counts above 300 cells/?L. By tracking the CD4+ count as well as the HIV-RNA viral load, response to HAART can be determined. Current treatment recommendations are specified below.[91]
TABLE 163.3 -- Antiretroviral Regimens Recommended for Treatment of HIV Infection in Anti-Retroviral Naïve Patients
|
Recommended Components |
|
|
Non-nucleoside reverse transcriptase inhibitors |
Efavirenz |
|
Nevirapine |
|
|
Protease inhibitors |
Lopinavir + ritonavir |
|
Atazanavir + low-dose ritonavir |
|
|
Saquinavir + low-dose ritonavir |
|
|
Indinavir + low-dose ritonavir |
|
|
Nucleoside reverse transcriptase inhibitors |
Zidovudine or tenofovir) + (lamivudine or emtricitabine) |
|
Didanosien + emtricitabine |
|
|
Alternative Components |
|
|
Protease inhibitors |
Fosamprenavir + low-dose ritonavir |
|
Nucleoside reverse transcriptase inhibitors |
Atazanavir |
|
Nelfinavir |
|
|
Abacavir + lamivudine |
|
|
Didanosine + lamivudine |
|
|
Didanosie + tenofovir |
|
|
Stavudine + lamivudine |
|
|
Zidovudine + abacavir |
(Reference: JAMA (2004) 292: 251-65.)
|
Reference: JAMA (2004) 292: 251-65. |
Nucleoside Reverse Transcriptase Inhibitors
These were the first agents used to treat HIV infection and remain integral to the management. They are competitive inhibitors of reverse transcriptase, active against HIV-1 and HIV-2, prohibiting budding of the virus from the cell. The agents must be phosphorylated by host cell enzymes in the cytoplasm to become active. Once active they are incorporated into the proviral DNA and cause termination of the chain. These compounds have a narrow therapeutic index secondary to their affinity for DNA polymerases. Currently, there are eight available agents. They are associated with myopathy, hepatic steatosis, and polyneuropathy. Macular edema has been described in a patient treated with zidovudine.[92] Didanosine has been linked to optic neuritis and atrophy of the retinal pigment epithelium especially in children. Hence, quarterly indirect ophthalmoscopy should be performed in children on this medication.[93]
Non-nucleoside Reverse Transcriptase Inhibitors
Non-nucleoside reverse transcriptase inhibitors are a structurally diverse group of agents that function as noncompetitive inhibitors of HIV-1 reverse transcriptase and do not exhibit activity against HIV-2 strains. These agents are associated with a hypersensitivity reaction that affects the entire class of agents. These medications also interfere with the cytochrome P450 metabolic pathways.
Protease Inhibitors
In 1995, inhibitors of HIV protease were first introduced and completely altered the natural history of HIV by decreasing morbidity and mortality when combined with other antiretrovirals.[94] Because of their short half-life, co-administration of ritonavir, which inhibits the cytochrome P450-mediated metabolism of these compounds, is advised. Protease inhibitors are often associated with gastrointestinal intolerance and metabolic abnormalities.
Fusion Inhibitors
This is the newest class of antiretroviral agents that works by blocking cellular invasion. It inhibits fusion of the viral envelope glycoprotein (gp41) with the host cell membrane. There is only one fusion inhibitor presently approved for HIV infection treatment and it is administered as repeated subcutaneous injections.
OCULAR COMPLICATIONS OF OTHER MEDICATIONS IN HIV
Treatment of the opportunistic infections associated with AIDS may cause ocular side effects. Rifabutin, cidofovir, and fomivirsen may all induce uveitis.[95] Ethambutol, used to treat tuberculosis and Mycobacterium avium infections, may cause optic neuropathy. Finally, AIDS neuropathy can affect sexual function, necessitating the use of phosphodiesterase inhibitors (e.g., sildenafil) for erectile dysfunction. These drugs cause inhibition of the nitrous oxide pathway and have been linked to anterior ischemic optic neuropathy.[96]
SUMMARY
AIDS is a syndrome that affects all organ systems with frequent retinal findings. In particular, CMV retinitis is an AIDS-defining illness as well as a prognostic indicator for mortality in patients with AIDS. While CMV retinitis is the most common opportunistic infection in patients with AIDS, noninfectious retinal microvasculopathy is the most prevalent finding. Other opportunistic pathogens can destroy retinal and/or choroidal tissue. Aggressive treatment with specific antiviral, antibiotic, antifungal, or antiparasitic drugs and HAART have resulted in reduced ocular morbidity and, in some cases, reduced mortality. Nonetheless, visual loss remains a major cause of impaired quality of life in these patients.
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