HIV-Associated Infections

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Chapter 81 HIV-Associated Infections

Acquired immunodeficiency syndrome (AIDS) is a potentially fatal multisystem syndrome characterized by profound disruption of the immune system and a propensity for various opportunistic infections and neoplasms. AIDS is caused by either of two human immunodeficiency viruses (HIV-1 [formerly HTLV-3] or HIV-2).13 HIV-1 entered humans from chimpanzees nearly a century ago and, after passing unrecognized among West Africans,4,5 came to the United States via Haiti in the 1970s. AIDS was recognized first in 1981 as outbreaks of usual opportunistic infections (OIs) in homosexual men in three American cities.

Ocular involvement occurs in up to 73% of AIDS patients,6,7 with the most common lesions being a retinal vasculopathy consisting of cotton-wool spots, retinal hemorrhages, and infectious retinopathy such as cytomegalovirus (CMV), herpetic, toxoplasmic, or luetic retinitis.

Occupational exposure to HIV

The average risk of HIV transmission in healthcare workers after percutaneous exposure to HIV-infected blood is approximately 0.3% without treatment.12,13 This risk is further lowered by double-gloving and is probably much lower in the ophthalmic setting.14 Postexposure prophylaxis (PEP) with two or three antiretroviral drugs appears likely to dramatically reduce the transmission of HIV even after high-risk injuries.15 Because PEP should be started as soon as possible after injury, healthcare institutions should have well-developed procedures that provide for expert consultation and ready access to a combination of drugs for persons at high risk of injuries, such as surgeons, invasive proceduralists, and phlebotomists.

Currently, for percutaneous injuries, the US Public Health Service recommends 4 weeks of treatment with a two-drug regimen if the exposure is less severe (solid needle and superficial injury) and the source patient has asymptomatic HIV infection or known low viral load (<1500 RNA copies/ml) [class I patient]. An expanded three-drug regimen is recommended if the exposure is severe (large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient’s artery or vein) or if the source patient has symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load [class II patient]. The recommended two-drug regimens for HIV/PEP are: (a) tenofavir plus emtricitabine or (b) zidovudine plus lamivudine. Tenofovir is generally better tolerated, but should not be used in persons with renal insufficiency. Three-drug regimens involve adding ritonavir-boosted (/r) lopinavir/r or darunavir/r. Alternatives for constructing an expanded regimen in cases of resistance, drug interactions, or intolerance include darunavir/r, atazanavir/r, or raltegravir. For mucous membrane or nonintact skin exposures, the two-drug regimen is recommended for all small volume exposures (a few drops) and large volume (major blood splash) exposure in a class I patient, with three-drug expanded regimens recommended for large volume exposure in a class II patient.13

HIV virology and pathogenesis

HIV infection usually gradually depletes CD4 lymphocytes, resulting in decreased blood levels of this crucial subset of “helper” T cells.16 AIDS patients typically become ill only after CD4+ helper T cells reach less than 200/ml, a level that no longer supports cell-mediated immunity at levels needed to contain infections by select opportunistic viral, bacterial, or fungal pathogens.

Understanding of HIV infection was revolutionized by the development in the mid-1990s of assays that measured the levels of HIV in the blood. All stages of HIV infection were seen to be characterized by a high rate of viral replication in most patients. Levels of plasma HIV-1 RNA predict the rate of clinical progression in HIV patients.1723 Both high replication and an error-prone reverse transcription process promote frequent mutations in the HIV genome that result in the emergence of variants that can better resist either control by the hosts antibody and cell-mediated immune responses or by antiretroviral drugs, if drugs are present in insufficient numbers or at low blood levels that fail to fully suppress HIV replication. Under selective pressure from antiretroviral agents, mutations that confer a decreased sensitivity to individual drugs are selected and stored in latent cells where they last for decades.2427

Therapy of HIV infections

Treatment of HIV has evolved rapidly over the past 25 years (1986–2011) with the development of more than 30 drugs that fall into at least four classes based on which of the steps in HIV replication they inhibit. These steps include: (a) binding to receptors and entry into the host cell; (b) reverse transcription of HIV RNA to proviral DNA; (c) integration of proviral DNA into the host cell genome; and (d) maturation of HIV after budding by the action of HIV protease.28 Coadministration of drugs from several of the classes delays or prevents the emergence of drug-resistant HIV by minimizing viral replication. However, HIV may develop resistance to all available therapy because (a) patients have difficulty maintaining high levels of adherence over long periods and (b) cross-resistance is common to drugs within a class.2932 After failure of a regimen, the next combination of drugs is less likely to be successful in fully suppressing HIV replication which is the necessary condition for prolonged success. For details of recent expert guidelines on HIV therapy consult Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, which is constantly updated and available at this NIH website: www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (cited February 2012).

Clincial spectrum of HIV

HIV infection and disease is highly variable in presentation and includes asymptomatic, various chronic or recurring constitutional signs and symptoms, and a plethora of opportunistic conditions. The “acute retroviral syndrome,” that is, early or primary infection with HIV, is characterized by fever, pharyngitis, skin rash, arthralgias, malaise, mucosal ulcerations, and neurologic manifestations such as aseptic meningitis.33

Patients chronically infected with HIV may present with a prodrome of generalized, nontender lymph node enlargement, fevers and night sweats, weight loss, and diarrhea for weeks or months, formerly termed AIDS-related complex (ARC). Nearly all HIV-seropositive patients will progress to AIDS, but a small minority, called “long-term nonprogressors” or “elite controllers,” suppress their infections naturally (without treatment) to the point of very low or undetectable levels of plasma HIV. Although highly active antiretroviral therapy (HAART) often reduces plasma viremia of HIV-1 to undetectable levels, latent viral reservoirs of resting CD4 lymphocytes persist for years and reappear in the blood if therapy is stopped.34

Opportunistic infections are responsible for the deaths of most AIDS patients, but consequences of coinfections with hepatitis C and B, such as hepatic insufficiency or hepatocellular carcinoma, have become increasingly important, in part because HIV promotes progression of these infections.35 The most common pathogens encountered in AIDS patients are cytomegalovirus (CMV), Candida albicans, Pneumocystis jiroveci (formerly carinii), Mycobacterium tuberculosis and M. avium-intracellulare, Cryptococcus neoformans, herpes simplex virus (HSV), Cryptosporidium spp., Toxoplasma gondii, and varicella zoster virus (VZV).3,36 CMV retinitis can be the initial sign of tissue-invasive systemic CMV infection in these patients, although it is restricted to patients with advanced immunosuppression (CD4+ count less than 50). CMV may present also in the gastrointestinal tract, brain and spinal cord, or other organs.37

Infection control related to HIV

The US Centers for Disease Control and Prevention (CDC) recommendations for universal precautions to prevent the occupational transmission of HIV and other bloodborne viruses in the healthcare setting were provided in 1988 and have not been amended.38

The CDC provided specific guidelines for ophthalmologic examinations in addition to the general recommendations. The use of gloves (especially if the skin of the examiner is compromised in any way) and good handwashing technique after procedures or examinations involving the eye are recommended because HIV may be present in tears.

Sterilization of all instruments and equipment that come into contact with the eye in all patients is necessary using gas or steam autoclaving or a 5- to 10-minute soak in one of the following solutions: 3% hydrogen peroxide solution, 10% solution of sodium hypochlorite (common household bleach), or 70% ethanol or isopropanol. Instruments disinfected in this manner should be rinsed in water and dried before reuse.39,40 Damage to tonometer tips has been reported with the use of 70% isopropanol; thus a 5- to 10-minute soak in 3% H2O2 or 1 : 10 dilution of household bleach may be preferable.41 It should be noted that there is no evidence of HIV transmission through contact with tears or instruments used to examine these patients.39

Contact lenses used in trial fittings on all patients should be disinfected by use of any commercially available cleaning method or solution.42 Inactivation of HIV by various disinfectants on surfaces has been reviewed.43 Guidelines for preventing transmission of HIV through transplantation of human tissue and organs (including corneal transplants) have been set forth.44 Specific recommendations for postexposure management of needle-stick injuries or mucosal membrane exposures to secretions from patients with HIV infection have been published.45

Ocular findings in aids: an overview

HIV has been detected in the cornea,46 conjunctival epithelium,47 and in tears,46 but at very low titers. Ocular manifestations of AIDS may be seen in up to 100% of patients. They are less common, but may be seen in patients with earlier, symptomatic HIV infection.48 Most common are cotton-wool spots and other noninfectious retinopathies,49 CMV retinitis, and conjunctival Kaposi sarcoma, followed less frequently by herpes zoster ophthalmicus,50,51 retinal toxoplasmosis, choroidal P. carinii infection, herpes simplex and herpes zoster retinitis (acute retinal necrosis [ARN]), and cryptococcal choroiditis.6,5259

Iritis may occur in association with viral retinitis but especially with CMV; it is mild. Acute iritis may be associated with the use of oral rifabutin (used for the treatment and prophylaxis of mycobacterial infections) or intravenous cidofovir used for CMV retinitis.60

Choroidal infection with Cryptococcus, Pneumocystis, M. tuberculosis, Aspergillus, Toxoplasma, Histoplasma, and M. avium-intracellulare usually is associated with systemic infection.61,62 Histoplasma capsulatum chorioretinitis and endophthalmitis,63 Paracoccidioidomycosis brasiliensis chorioretinitis,64 keratitis sicca, cranial nerve paralysis, Roth’s spots, papilledema, perivasculitis, and fungal corneal ulcers are rare but have been reported.65

Noninfectious retinopathy

Noninfectious retinopathy refers to cotton-wool spots, retinal hemorrhages, and microvascular abnormalities that do not progress, enlarge, or cause visual symptoms. No infectious cause of these lesions has been demonstrated, and they appear to represent nonspecific retinal microvascular disease. A correlation between the number of cotton-wool spots and decreased cerebral blood flow (as shown by technetium 99m hexamethylpropyleneamine oxime single photon emission computed tomography) was shown in 25 patients with AIDS or symptomatic HIV infection.66

Cotton-wool spots are the most common ocular lesion seen in AIDS, occurring in 25–50% of patients6,67 and in up to 75% of cases by autopsy examination.57 In one study, up to 92% of AIDS patients were found to have evidence of retinovascular disease when examined using fluorescein angiography.67

Cotton-wool spots seen by ophthalmoscopy are a result of microinfarction of the nerve fiber layer of the retina. In AIDS these lesions usually are confined to the posterior pole near the optic disc67 (Fig. 81.1). Histopathologic study of retinal cotton-wool spots in AIDS patients has demonstrated that these lesions have pathologic features identical to those seen in cotton-wool spots of other cause. Similar to the cotton-wool spots seen in other systemic diseases, this lesion in AIDS demonstrates no associated inflammation, no cells in the vitreous, and no vascular leakage on fluorescein angiography (Fig. 81.2). Attempts to isolate organisms from cotton-wool spots in the hope of explaining their cause in AIDS as infectious have been unsuccessful, and the cause of this lesion in AIDS remains elusive.6,57,68,69

Cotton-wool spots have been speculated to be harbingers of CMV retinitis or perhaps sites of susceptibility to CMV infection, but substantiation of these ideas is lacking. Histopathologic studies of eyes at autopsy have failed to show clear evidence of a viral cause of cotton-wool spots.7072

We have reported that noninfectious retinopathy is not seen in HIV-seronegative men and is rare in ARC, but it is very common in patients with AIDS even in the absence of active opportunistic ophthalmic infection.48 It is striking that this lesion may be seen in 50–75% of AIDS patients, and studies using multiple examinations indicate that the more frequently these patients are examined, the higher the incidence may be.6,49 Cotton-wool spots probably are ophthalmoscopically visible for 6–12 weeks, and owing to the transient nature of the lesion and its apparent noninfectious cause, treatment is not indicated at this time.73

In a cross-sectional study, the median CD4 count (per microliter [µl]) in patients with cotton-wool spots was 14 cells (range 0–160) and was 8 cells (range 0–42) in patients with CMV retinitis.74 In the absence of other systemic vascular disease, such as hypertension or diabetes mellitus, AIDS must be considered in the differential diagnosis of cotton-wool spots owing to their very high prevalence in these patients. Whether these lesions are an early manifestation of AIDS remains to be elucidated, but they may be apparent in HIV-infected persons before the onset of opportunistic infections.48

Morphologic studies have shown that the number of retrobulbar optic nerve fibers in patients with AIDS is decreased compared with the number of optic nerve fibers in normal control eyes as a result of axonal degeneration and an associated decrease in the number of optic nerve axons.7577 Infarctions of the nerve fiber layer develop in most patients with AIDS, and the number of such infarctions increases over time.6,49 Visual dysfunction associated with multiple nerve fiber layer infarctions may be manifested by defects in color-vision and contrast-sensitivity testing in patients with AIDS.78 Interestingly, in vivo studies of the retinal nerve fiber layer have shown both broad and slit-like defects, suggesting that retinal nerve fiber loss and optic nerve fiber loss are related to subclinical vision loss in HIV patients without infectious retinitis.79 Electroretinographic studies of HIV patients without retinitis also have shown retinal dysfunction.80,81

Retinal hemorrhages are seen in AIDS in association with CMV retinitis, cotton-wool spots, and as an isolated finding. These lesions have been reported in up to 30%52,67,82 of AIDS patients, and autopsy evidence of retinal hemorrhages has been reported to be as high as 40%. Retinal hemorrhages usually take the form of flame-shaped lesions in the posterior pole, dot-blot hemorrhages, or as punctate intraretinal hemorrhages peripherally (Fig. 81.3). Occasionally the hemorrhage is manifested as Roth’s spots (hemorrhage with a white central area).52,67 The pattern of retinal hemorrhages changes over time. The hemorrhages do not appear to be related to a bleeding diathesis or coagulopathy, but rather seem to be a manifestation of AIDS itself.6 Vision loss from retinal hemorrhage has not been described, and treatment is conservative if the lesions are not associated with CMV retinitis or septicemia.

Microvascular pathologic findings in AIDS, as demonstrated by fluorescein angiography, include microaneurysms, telangiectasias, focal areas of nonperfusion, and capillary loss.67 These changes are similar to the changes seen in diabetes mellitus. The histologic findings of periodic acid–Schiff (PAS)-positive thickening of blood vessels and precapillary arteriolar closure also correlate with the findings in diabetes mellitus.

Branch or central retinal vein occlusion, branch retinal artery occlusion, and ischemic maculopathy have been reported in HIV patients without infectious retinitis. The incidence is unknown. It is possible that the cause may be related to lupus anticoagulant and other clotting abnormalities seen in HIV-infected patients.83,84 Abnormalities of retinal blood flow have also been reported in HIV patients and may contribute to the pathogenesis of microvascular abnormalities.8588

Infectious retinopathy

Cytomegalovirus retinitis

Pathogenesis, diagnosis, and clinical manifestations

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in AIDS. CMV retinitis has been reported to occur in 15–40% of AIDS patients with the rate declining since the arrival of HAART.37,52,89,90 In contrast to the noninfectious lesions of AIDS, CMV retinitis demands aggressive treatment to prevent severe visual loss.6,91,92 Patients with active CMV disease may have systemic symptoms of fever, arthralgia, and pneumonitis, or leukopenia, retinitis, or hepatitis; blood cultures and urine specimens may be positive for CMV. CMV retinitis often is the presenting sign of systemic CMV infection, and all patients should be thoroughly evaluated for systemic disease.

The clinical presentation of CMV retinitis in AIDS is similar in many respects to CMV retinitis found in iatrogenically immunosuppressed patients and infants with cytomegalic inclusion disease.93,94 Correlation of the clinical and typical pathologic findings at autopsy has been demonstrated.95 Specifically, it is known that CMV is a neurotropic virus with a tendency to infect neural tissues and the retina. Necrosis of the retina in AIDS-associated CMV retinitis is typical, with pathognomonic cytomegaly and minimal inflammatory cells present in the lesions. Choroidal involvement is rare, and whether vascular endothelium is involved is unclear. These lesions also may appear as noncontiguous patches rather than the more commonly seen contiguous spreading lesion. Antigens to CMV have been found by immunofluorescence, immunoperoxidase staining, and DNA hybridization techniques.96,97 The most distinctive anterior segment finding is the presence of fine stellate keratic precipitates on the corneal endothelium.98 Retinal vascular nonperfusion and retinal neovascularization resulting from CMV retinitis and choroiditis also have been reported.99

CMV is a slowly progressive necrotizing retinitis that may affect the posterior pole, the periphery, or both, and may be unilateral or bilateral. Involved retinal areas appear as white intraretinal lesions, areas of infiltrate, and often necrosis along the vascular arcades in the posterior pole. In addition, prominent retinal hemorrhages often are present within the necrotic area or along its leading edge (Fig. 81.4). Peripherally, CMV retinitis occurs commonly; it tends to have a less intense white appearance, with areas of granular, white retinitis that may or may not demonstrate associated retinal hemorrhage (Fig. 81.5). As the retinitis progresses, an area of atrophic, avascular retina may remain with underlying retinal pigment epithelial atrophy or hyperplasia.6,37,100 Peripheral CMV retinitis is common in AIDS patients who initially may report only floaters with or without a visual field deficit. Wide-angle fundus photography and fluorescein angiography may be of benefit if the diagnosis is uncertain. These techniques may be used to document progression of retinitis, and fluorescein leakage in areas of retinitis may be helpful in confirming the diagnosis (Fig. 81.6).

Reactivation of CMV retinitis is characterized by reopacification of the border of the lesion followed by advancement. Smoldering retinitis (Fig. 81.7) and subtle reactivation may be difficult to recognize without prior fundus photographs. Several studies have shown that wide-angle fundus photographs are a more sensitive indicator of retinitis progression than is clinical examination by indirect ophthalmoscopy.101,102

Several investigators have shown that untreated CMV retinitis is inexorably progressive in AIDS patients.6,52,94,96,102,103 As in our experience, untreated CMV becomes bilateral in the vast majority of patients. In an observational study of 26 patients treated for CMV retinitis, vision scores decreased with greater abnormalities found on ophthalmologic examination. Visual symptoms were most strongly related to findings in the worse eye. Patients reported considerable impairment, including blurred vision (42%), difficulty reading (40%), difficulty driving (44%), treatment interference with social activities (40%), and substantial trouble with vision (50%).104 Treatment of AIDS-related CMV retinitis minimizes loss of vision and may protect previously uninfected eyes, prolonging visual independence.105

Recurrent CMV retinitis exhibiting a foveal-sparing pattern within 1500 mm of the foveola has been described and occurs primarily in patients with recurrent CMV retinitis resistant to treatment (“clinically resistant”), particularly that which has arisen temporally. Despite its foveolar proximity and ultimate significant loss of function, the pattern of progression allows for preservation of useful foveal vision for longer periods than would have been expected.106

Other manifestations of CMV retinitis include retinal edema, attenuated vessels, perivascular sheathing, and exudative retinal detachment107 (Fig. 81.8). In addition, vitritis and anterior uveitis are often seen, and optic atrophy may occur as a late manifestation resulting from widespread retinal destruction. CMV occasionally may be demonstrated in vitreous biopsy specimens in these patients.95 The yield may be higher in the presence of marked vitritis because CMV is a cell-associated virus. Other causes of retinitis, including herpes simplex retinitis,93,108 toxoplasmosis,62 candidal infection, Behçet disease, syphilis, acute retinal necrosis,109,110 and subacute sclerosing panencephalitis, usually can be distinguished from CMV on clinical grounds, although this may not be the case in retinitis caused by other members of the herpesvirus family.109 CMV has a very characteristic clinical appearance, but the lesions in CMV retinitis vary from patient to patient, and it is important to maintain a high index of suspicion for the above infections, especially in light of frequent superinfection of AIDS patients with multiple organisms.6,82,83

CMV retinitis is a reflection of underlying active systemic CMV infection. In almost all cases it is a blinding disease if not controlled. Thus, in the face of changing mental status, development of focal signs on neurologic examination, or other symptoms consistent with subacute encephalitis in AIDS patients, a comprehensive ophthalmologic examination is indicated, and an increased index of suspicion of CMV infection of the CNS and possible CMV retinitis is warranted. There is also evidence that patients with CMV retinitis, especially peripapillary disease, have a much higher incidence of CMV encephalitis. CMV infection of the brain, optic nerves, and retinas from 47 consecutive autopsies of patients with AIDS was examined.111 Immunocytochemistry demonstrated CMV infection in 11 (23%) brains, 2 (2%) of 94 optic nerves, and 38 (40%) of 94 retinas. Ten (91%) of 11 patients with CMV encephalitis had concurrent retinitis. While 10 (42%) of 24 patients with CMV retinitis had CMV encephalitis, when the retinitis included the peripapillary region, 75% had encephalitis. The optic nerve parenchyma usually was not infected histologically despite extensive peripapillary retinitis. The strength of these associations suggests that CMV retinitis defines a group of patients with AIDS at risk for development of CMV encephalitis (relative risk, 9.5%), especially when the retinitis involves the peripapillary region (relative risk, 13%). Furthermore, in patients with AIDS without CMV retinitis, central nervous system symptoms are unlikely to be attributable to CMV encephalitis.111 The pathologic correlation between ocular and cerebral lesions in patients with AIDS has been reviewed.112

CMV retinitis is less frequent in children with AIDS, with reported rates of approximately 5–6%, though rates of extraocular CMV are higher than in adults. CMV retinitis has been reported in young children with high absolute CD4 counts, though these counts are low relative to the child’s age. Older children tend to have low absolute CD4 counts similar to adults. There is a higher incidence of bilateral and posterior pole disease in children, however this is likely due in part to delays in diagnosis in children from lack of subjective vision complaints.113115

Screening techniques for retinal and systemic CMV infection

Screening for CMV retinitis is a difficult problem. Many patients who are CMV-viremic or -viruric may not have end-organ disease, and studies employing quantitative CMV polymerase chain reaction (PCR) in plasma or CMV antigenemia have not been able to definitively predict the development of CMV retinitis.116 Currently no laboratory marker exists that reliably predicts the occurrence of clinical CMV retinitis.

Urine is culture-positive for CMV in more than 50% of homosexual men and the majority of AIDS patients; thus urine culture may not be of diagnostic value. Serology in AIDS patients is nonspecific, and documentation of rising CMV titers is unusual.6,96 Studies of newly diagnosed CMV retinitis patients indicate that many are CMV culture-negative in the blood. Positive blood cultures for CMV, fever, and weight loss are associated with more extensive CMV retinitis at the time of diagnosis.117 The results of virologic blood assays for CMV also have been associated with clinical outcome in patients with CMV retinitis.118 Thus assays for the detection of CMV antigenemia may be a simple and rapid means of identifying those patients with unilateral retinitis at highest risk of developing CMV retinitis of the fellow eye or of visceral CMV disease if intravitreal injections or implants are used as the sole treatment for CMV retinitis.119

A positive PCR result supports the clinical diagnosis and may be useful for monitoring response to antiviral treatment. By prospective monitoring for increases in plasma CMV DNA copy number, it may be possible to identify HIV-seropositive patients who are at imminent risk for development of symptomatic CMV retinitis.120

It is also reasonable and practical to use the CD4 cell count as a threshold below which to screen patients, since the risk of CMV retinitis increases at CD4 cell counts below 50/mm3.74 The incidence and prevalence of CMV retinitis in a cohort study of patients with CD4 cell counts below 0.10 × 109/L (100/µl) revealed a 25% chance for the development of CMV retinitis by 4 years of follow-up. Among those subjects in whom CMV retinitis developed, about 19% had retinitis before a CD4 cell count of less than 0.05 × 109/L (<50/µl) was observed, and 81% had CMV retinitis after the CD4 cell count reached this threshold.121 In the HAART era, some patients may develop CMV retinitis with CD4 counts above 100/ml, probably because of incomplete restoration of the immune repertoire against CMV.122

A technique for screening for central CMV retinitis, entoptic perimetry, employs patient visualization of moving particles on a computer monitor, appears to have a very high sensitivity and specificity (over 90%) in detecting CMV retinitis within the central 30-degrees radius of fixation79 (Fig. 81.9).

Techniques for detection of CMV DNA based on PCR are increasingly being applied to ocular fluids; however, the clinical significance of such findings can sometimes be unclear. The application of PCR-based methods to ocular fluids made a useful contribution to the treatment of the patients.123

This appears to be a sensitive and specific diagnostic assay that could assist in the diagnosis of CMV retinitis.124 PCR detection of CMV DNA has been reported to be a more sensitive method than analysis of locally produced antibodies by calculating a Goldman–Witmer coefficient to determine local ocular antibody production. There is also an immune predisposition to the development of CMV retinitis in patients with AIDS.125,126

Treatment of CMV retinitis

The treatment of CMV retinitis has been reviewed.127,128 Treatment may be systemic, local, or a combination of the two. There are currently five medications approved by the US Food and Drug Administration (FDA) for the treatment of CMV retinitis: ganciclovir, valganciclovir, cidofovir, foscarnet. Fomivirsen, the first antisense drug with a relatively long duration of action, is no longer available in the United States.

Systemic therapy of CMV retinitis

CMV retinitis may be treated systemically or intravitreally. However, systemic treatment is associated with less spread of CMV retinitis from one eye to the other.128 In addition, local treatment including the sustained release ganciclovir implant has been shown to be associated with higher risk of the development of systemic CMV.129,130

Systemic CMV may cause gastrointestinal disease, with colitis being the most common manifestation as well as esophagitis. Systemic CMV diagnosis may be difficult and usually requires histopathologic evidence of CMV infection. The cumulative incidence of systemic CMV disease that becomes clinically apparent is approximately 25%.131 Therefore, although systemic CMV disease may not be clinically apparent at the time of diagnosis of CMV retinitis, some experts believe that initial systemic therapy may be warranted despite the inconvenience, expense, and potential toxicities.

Intravenous ganciclovir

Ganciclovir is a nucleoside analog of 2-deoxyguanosine, similar to acyclovir.132 Despite its structural similarities with acyclovir, ganciclovir is much more active in vitro against CMV than acyclovir.133 Ganciclovir inhibits all herpesviruses, including CMV, by preventing DNA elongation. CMV lacks the virally specified thymidine kinase (TK) that converts ganciclovir (or acyclovir) to its monophosphate form.134 TK-altered strains resistant to acyclovir are as sensitive to ganciclovir as the unaltered parent strains. Thus ganciclovir is phosphorylated to its triphosphate form much more efficiently than acyclovir, which accounts for the greater activity of ganciclovir against CMV.135

The majority of AIDS patients treated with ganciclovir respond within 2–4 weeks with decreased retinal opacification and stabilization of the retinitis89 (Fig. 81.10). Ganciclovir is commercially available as an intravenous and oral formulation (and also is included in an intraocular device), and indefinite maintenance therapy is necessary as long as the patient remains in immune failure with a CD4 count below 50/µl. An intravenous loading dose of 5 mg/kg every 12 hours for 14–21 days should be followed by maintenance doses of 5 mg/kg/day. If the drug is discontinued, retinitis often recurs within 10–21 days, continuing its progression at the borders of healed areas.89 Recurrences have been common, even during maintenance therapy, being reported 3 weeks to 5 months after institution of therapy and occurring in 30–40% of patients.89 Many investigators have found that discontinuation or delay of ganciclovir therapy results in nearly 100% recurrence of retinitis, at which time reinstitution of the loading dose regimen often is necessary.134,136,137 Multiple series in patients with AIDS and CMV retinitis have shown response rates of 80–100%, with 60–80% of patients achieving a remission with ganciclovir therapy.37,137141

The treatment of CMV retinitis usually includes an induction phase followed by a maintenance phase to prevent relapse. Before the advent of HAART, relapse occurred almost universally, given a sufficiently long period after induction courses of ganciclovir. Therapy therefore continued for a lifetime. The median time to relapse in patients treated with just an induction dose is 3–4 weeks.137

Most clinicians use a 14-day induction course of intravenous ganciclovir consisting of 5 mg/kg/day every 12 hours and indefinite maintenance of 5 mg/kg/day. Lower doses and every-other-day dosing schedules have been associated with high rates of early relapse. Since treatment may be lifelong if the patient’s CD4 count cannot be elevated with anti-HIV therapy, usually a permanent or semipermanent indwelling venous catheter is placed at the onset of therapy if intravenous therapy is chosen as maintenance therapy. Ganciclovir requires modification of dosing in the presence of renal insufficiency.

Side-effects of ganciclovir include granulocytopenia, neurologic dysfunction, abnormal liver function tests, and rarely, thrombocytopenia. The most serious toxicity is granulocytopenia, which may occur in up to one-third of patients when defined as less than 500 neutrophils per microliter.137 Granulocytopenia is generally reversible, and this adverse effect is exacerbated when used with AZT.142 The use of colony-stimulating factors rGM-CSF (recombinant granulocyte–macrophage colony-stimulating factor) and rG-CSF (recombinant granulocyte colony-stimulating factor) for reversing or preventing neutropenia may be useful.

The prevalence of CMV resistance to ganciclovir is unknown, but ever-increasing induction regimens may be necessary to control CMV retinitis. Strains of CMV that develop resistance to ganciclovir may remain susceptible to foscarnet. Because of the question of ganciclovir resistance, a trial of combined vs alternating foscarnet–ganciclovir maintenance therapy has been reported to be effective.143

Visual acuity depends on the location of the involved retina, and involvement of the fovea or optic nerve may result in decreased visual acuity even if there has been a response to therapy. Ganciclovir has been shown to be effective in preserving visual acuity. For example, 73% of eyes maintained a visual acuity of 20/40 or better when treated with ganciclovir.144

Valganciclovir

Valganciclovir, the valine ester of ganciclovir, is an orally administered formulation of ganciclovir. The valine ester confers enhanced permeability and absorption of the molecule through the cell membranes of the gut. Once in the bloodstream, the valine ester is cleaved from the molecule by esterases, rendering plasma levels of ganciclovir comparable to those achieved with intravenous ganciclovir administration. A single-dose randomized crossover pharmacokinetic study reported the absolute ganciclovir bioavailability after oral valganciclovir administration is 60.9% compared to 5.6% bioavailability of oral ganciclovir.147 A randomized crossover dose-ranging study determined that plasma levels of ganciclovir after an 875 mg dose of valganciclovir are similar to the plasma levels achieved with a dose of 5 mg/kg of intravenous ganciclovir (AUC 24.8 mg/ml per h vs 26 mg/ml per h). The authors suggested the 900 mg dose of valganciclovir would approximate the AUC value of the 5 mg/kg dose of IV ganciclovir.148

Valganciclovir has been studied for induction therapy for CMV retinitis. Martin et al. (Valganciclovir Study Group) reported a multicenter randomized, controlled clinical trial comparing oral valganciclovir 900 mg twice a day for 3 weeks’ induction therapy followed by 900 mg daily for 1 week maintenance therapy with intravenous ganciclovir 5 mg/kg twice a day for 3 weeks’ induction therapy followed by 5 mg/kg once daily for one week of maintenance therapy. After 4 weeks both groups received continued maintenance therapy with 900 mg valganciclovir daily. Eighty patients with newly diagnosed CMV retinitis were randomized to each group in a 1 : 1 ratio. Primary endpoint was photographically determined progression of CMV retinitis within 4 weeks after the initiation of treatment. In the valganciclovir group, 9.9% of patients had progression of CMV retinitis within the first 4 weeks compared to 10.0% of patients assigned to IV ganciclovir. This 0.1 percentage point difference was not significant (95% CI −9.7 to 10.0). Secondary endpoints included the achievement of a prospectively defined successful response to induction therapy and the time to progression of CMV retinitis. Seventy-seven percent of patients receiving IV ganciclovir and 71.9% of patients receiving oral valganciclovir achieved a satisfactory response to induction therapy. This 5.2 percentage point difference was not significant (95% CI −20.4 to 10.1). The median times to progression of retinitis were 125 days in the IV ganciclovir group and 160 days in the oral valganciclovir group. The relative risk of progression of retinitis in the valganciclovir group compared to the ganciclovir group was 0.90 (95 CI 0.58–1.38). Diarrhea was the most common adverse effect during the study and occurred more frequently in the valganciclovir group compared to the ganciclovir group (19% vs 10%, P = 0.11). Neutropenia occurred with similar frequency in each group. Catheter-related side-effects were seen more frequently in the IV ganciclovir group than in the valganciclovir group.149 No clinical trials have been published specifically comparing efficacy of valganciclovir for maintenance therapy of CMV retinitis.

Lalezari et al. (Roche Valganciclovir Study Group) reported a large safety study of valganciclovir. The adverse event profile was similar to that reported from previous studies of intravenous and oral ganciclovir. Adverse events of note were diarrhea (38%), nausea (23%), fever (18%), neutropenia (absolute neutrophil count <500 cells/mm3) (10%), and anemia (hemoglobin <8.0 g/dl) (12%), thrombocytopenia (platelet count <25 000 cells/mm3) (2%).150

In summary, oral valganciclovir offers the obvious advantage of extreme effectiveness against CMV retinitis without the difficulties and inconveniences of intravenous administration. Furthermore, because valganciclovir is converted to ganciclovir in the bloodstream, its pharmacologic safety profile, including side-effects, is no different than that of intravenously administered ganciclovir. Thus oral valganciclovir is an effective and safe alternative to intravenous ganciclovir for the treatment of CMV retinitis. Oral ganciclovir has become unavailable but is now supplanted by valganciclovir.

Foscarnet

The second drug for the treatment of CMV retinitis in patients with AIDS was licensed by the FDA in 1993. Foscarnet is a pyrophosphate analog with broad antiviral activity via inhibition of viral polymerases, such inhibition not being dependent on activation or phosphorylation by viral or cellular enzymes. Foscarnet inhibits DNA chain elongation by preventing pyrophosphate exchange.151

Foscarnet inhibits the DNA polymerase of CMV and other herpesviruses (HSV-1, HSV-2, VZV, and Epstein–Barr virus [EBV]) and the replication of HIV in vitro and in vivo.152 Both herpesvirus and HIV replication may be inhibited by therapeutically achievable concentrations of foscarnet. Since the drug is not metabolized and is excreted by the kidney, the dosage must be adjusted for renal insufficiency. Foscarnet also has been used successfully to treat HIV-infected patients with acyclovir-resistant HSV and VZV infections, in addition to CMV retinitis. Foscarnet acts directly on the viral polymerase of all herpesviruses and on the reverse transcriptase of HIV-1. Resistance of CMV to foscarnet is associated with mutations in the genes of these polymerases. Cross-resistance to antiviral drugs is likely to be an increasing problem, since patients with AIDS are living longer as a result of HAART and of the drugs used in the prophylaxis of various opportunistic infections, as well as because of the experience gained in the management of HIV-related problems.

Foscarnet has been shown to be useful against ganciclovir-resistant herpesviruses, such as CMV, because a mutation in a DNA polymerase gene conferring resistance to ganciclovir and acyclovir differs from the region conferring resistance to foscarnet.153 Foscarnet also is an effective inhibitor of the HIV reverse transcriptase enzyme and acts in a dose-dependent manner. AZT and foscarnet have synergistic activity in vitro against HIV, and in vivo, foscarnet has activity against HIV as measured by surrogate markers.154

The use of foscarnet salvage therapy in patients with CMV retinitis who are intolerant of or resistant to ganciclovir was studied in AIDS patients with CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy. This study showed that in patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.155

A large, randomized, multicenter, blinded clinical trial (the Foscarnet–Ganciclovir Cytomegalovirus Retinitis Trial) compared ganciclovir with foscarnet in the treatment of CMV retinitis in patients with AIDS. No difference was reported between the treatment groups in the rate of progression of retinitis; however, the median survival was 8.5 months in the ganciclovir group and 12.6 months in the foscarnet group. Excess mortality was reported in a subset of patients in the foscarnet group whose renal function was compromised at entry. Differences in mortality could not be explained entirely on the basis of less antiretroviral therapy in the ganciclovir group, which suggests beneficial interactions between foscarnet and antiretroviral nucleosides. These results indicate that, for patients with AIDS and CMV retinitis, treatment with foscarnet initially offers a survival advantage over treatment with ganciclovir, although foscarnet was not as well tolerated as ganciclovir.156

A marginally prolonged survival seen in patients treated with foscarnet compared with those treated with ganciclovir may have been due to a direct effect on HIV replication. Both drugs had a suppressive effect on circulating p24 antigen, which was predictive of improved survival. The inhibitory effect on CMV replication also may have a beneficial effect on limiting HIV replication.157

A randomized, controlled, comparative trial of foscarnet and ganciclovir demonstrated that they equally controlled CMV retinitis but that foscarnet was associated with a longer survival. However, foscarnet was less well tolerated than ganciclovir, primarily because of the nature of its side-effects. Since foscarnet and ganciclovir have different side-effects, initial treatment of CMV retinitis should be individualized.158

The most frequently reported major adverse effect associated with foscarnet administration is nephrotoxicity, with dose-limiting toxicity occurring frequently and cases of acute renal failure having been observed. Symptomatic hypocalcemia has been reported and may be responsible for arrhythmias and seizures, and the risk is increased by concurrent administration of intravenous pentamidine. Bone marrow suppression with neutropenia, anemia, and thrombocytopenia can be seen with foscarnet administration. Neutropenia was reported to be less common with foscarnet than with ganciclovir (14% vs 34%).156

Practical guidelines for the use of foscarnet include administration through an infusion pump to avoid the potential consequences of overdose or too rapid infusion, adequate hydration of patients with saline loading159 to reduce the risk of nephrotoxicity, avoidance of administration of other potentially nephrotoxic agents, and monitoring of renal function two or three times per week during induction therapy and once per week during maintenance therapy, with the dosage being recalculated on the basis of patient weight and serum creatinine. Studies of foscarnet doses have suggested that patients receiving high maintenance doses (120 mg/kg/day) have slower rates of retinitis progression.160,161

Foscarnet is active against HIV, and studies have shown that it raises the CD4 count transiently and decreases viral antigenemia (p24 antigen). Because of its efficacy against CMV and HIV, it would appear to be a potentially effective agent for treating HIV-infected patients; however, it is currently only available for intravenous administration, and its use is associated with substantial toxicity (see above).154,162

Cidofovir

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, formerly known as HPMPC, was the first antiviral nucleotide analog available for the treatment of CMV retinitis. Cidofovir is active in uninfected cells, may act preemptively, and may retain activity against ganciclovir-resistant strains. Preclinical studies showed the major toxicity of cidofovir to be dose-, schedule-, and species-dependent nephrotoxicity. The concomitant administration of probenecid protects animal models against cidofovir-induced nephrotoxicity. Four treatment modifications are indicated clinically to reduce the incidence of cidofovir-related nephrotoxicity: dose reduction or interruption for changes in renal function; concomitant administration of probenecid; administration of 1 liter of normal saline 1 hour before infusion; and extension of the dosing interval.163

The treatment of CMV retinitis with intravenous cidofovir was demonstrated to be effective in slowing the progression of peripheral CMV retinitis in patients with previously untreated CMV retinitis and AIDS. Intravenous cidofovir also has been used for long-term suppression of CMV retinitis. Biweekly therapy (after induction therapy) was reported to have a time to progression of CMV retinitis of 120 days in one randomized, controlled trial164 and 2.5 months in another randomized, controlled trial.165,166 Treatment and subsequent maintenance of CMV retinitis with 20 µg of intravitreously injected cidofovir, given at 5- to 6-week intervals, also is safe and highly effective.167

Treatment with parenteral cidofovir is complicated by nephrotoxicity, which can be reduced with saline hydration and concomitant administration of probenecid. Despite these additional treatments, the long-term reports from the HPMPC Peripheral Cytomegalovirus Retinitis Trial showed a rate of proteinuria of 1.22 per patient-year and a rate of elevated serum creatinine of 0.41 per patient-year. Thus many patients may have difficulty tolerating cidofovir for a prolonged time. Neutropenia has also been reported with cidofovir.

Unfortunately parenteral cidofovir has also been found to have ocular toxicity, including a high incidence of iritis (up to 50%), including recurrent iritis, and a risk of profound ocular hypotony with vision loss, similar to the iritis and hypotony seen with intravitreal injections of cidofovir.168170 It has been estimated in one study that cidofovir-related iritis developed in half of patients within approximately 4 months. The long-term reports from the HPMPC Peripheral Cytomegalovirus Retinitis Trial showed a rate of cidofovir-associated uveitis of 0.20 per person-year and a rate of significant ocular hypotony of 0.16 per patient-year.166 Thus in the setting of iritis in HIV-infected patients, use of systemic cidofovir or rifabutin should be considered potential causes of iritis, and these drugs may need to be discontinued.

Nephrotoxicity may be cumulative in some patients and appears to be related to toxicity in the proximal tubule. This “secretory toxicity” also may be responsible for the hypotony and iritis that the drug causes when given intravenously or intravitreously. The ciliary body and the proximal tubule of the kidney have many similarities in terms of the mechanism involved in the secretion of fluids across epithelia. Oral administration of probenecid before and after the intravenous infusion appears to help ameliorate the nephrotoxicity of the drug, but the ocular side-effects of iritis and hypotony occur despite concomitant probenecid administration.

CMV resistance

Many patients taking chronic maintenance therapy for CMV retinitis develop resistant virus. Development of in vitro resistance of CMV to ganciclovir and foscarnet and disease progression has been shown in several small studies,171,172 and mechanisms of resistance to ganciclovir have been described.173 In one prospective, randomized study of 207 patients with newly diagnosed CMV retinitis, drug-resistant CMV occurred in four of nine ganciclovir-treated patients and in none of five foscarnet-treated patients.118 In patients with CMV retinitis and AIDS treated with either oral or intravenous ganciclovir, isolates of CMV after a median exposure of 75 and 165 days, respectively, showed increasing resistance in vitro.174 Jabs et al. reported that the cumulative incidence of ganciclovir resistance at 9 months was 27.5%.172 Similar incidence rates of resistance occur for foscarnet and cidofovir.175 In addition, the incidence of resistance to valganciclovir appears to be similar to that for ganciclovir.176

Resistance to an anti-CMV drug can be described as phenotypic, expressed as an inhibitory concentration 50% greater than a certain threshold (IC50). This is determined typically via plaque reduction assays, DNA hybridization assays, or antigen-reduction assays that require large amounts of viable virus often requiring culturing.174,177179 Genotypic resistance is defined by the presence of a mutation in the CMV genome conferring resistance to a particular drug. PCR amplification techniques allow fast detection of resistance-conferring mutations in the viral genome, requiring only small amounts of viral nucleic acids and can use nonviable virus.180182 Low-level ganciclovir resistance is typically associated with mutations in the CMV UL97 gene. UL97 codes for a phosphotransferase that catalyzes the first step of ganciclovir activation to the triphosphate form. High-level ganciclovir resistance is typically caused by mutations in both the CMV UL97 and UL54 genes. UL54 codes for the cytomegalovirus DNA polymerase.173 Mutations in the UL54 gene are also responsible for foscarnet and cidofovir resistance.173,183186 UL54 mutations responsible for foscarnet resistance are usually distinct from those causing ganciclovir–cidofovir resistance. However, low-grade ganciclovir–foscarnet cross-resistance has been reported, plus Chou et al. reported a DNA polymerase mutation causing resistance to ganciclovir, cidofovir, and foscarnet.172,173,182184

Treatment strategies in resistant CMV

When clinically resistant retinitis appears, many clinicians employ an alternative antiviral agent systemically; intravenous cidofovir or foscarnet are alternatives. Unfortunately, as mentioned above, there can be cross-resistance between CMV isolates resistant to ganciclovir and resistant to cidofovir and/or foscarnet; this must be borne in mind in such patients. The probability of developing foscarnet or cidofovir resistance while taking these drugs appears similar to the rates of development of resistance to ganciclovir.175 For this reason, clinicians often employ intravitreal therapies including the ganciclovir intraocular device when systemic therapy begins to fail. Intravitreal therapies appear to be more effective in such circumstances, largely because they deliver higher doses of anti-CMV medication to the retina.187 In such circumstances, it is recommended to continue to treat the patient with some form of systemic therapy, often oral valganciclovir, to help prevent systemic CMV infection or infection of the fellow eye. Studies have shown that treatment with the ganciclovir implant alone is associated with a higher risk of contralateral CMV retinitis and extraocular CMV.188,189

Combination therapies: ganciclovir–foscarnet

Several studies have shown that combinations of foscarnet and ganciclovir are more effective in the treatment of recurrent or resistant retinitis than is continued monotherapy.91,189 Such combination intravenous therapy also has been shown to be safe and effective in children with CMV retinitis.190 Unfortunately, combination intravenous therapy with these two drugs necessitates multiple intravenous infusions daily and has a marked negative effect on patients’ lifestyle. Combination of IV foscarnet and oral valganciclovir has supplanted this combination intravenous therapy.

The combination of foscarnet and ganciclovir in patients with AIDS and CMV retinitis who have relapsed has been shown to be more effective than either agent given alone;143 however, combination therapy was associated with the greatest negative impact of treatment on quality-of-life measures.

To determine the best therapeutic systemic regimen for treatment of relapsed CMV retinitis, a multicenter randomized controlled clinical trial of 279 patients with AIDS and either persistently active or relapsed CMV retinitis was reported. Patients were randomized to one of three therapeutic regimens: induction with foscarnet sodium at 90 mg/kg intravenously every 12 hours for 2 weeks, followed by maintenance at a dosage of 120 mg/kg per day (foscarnet group); induction with ganciclovir sodium at 5 mg/kg intravenously every 12 hours for 2 weeks followed by maintenance at 10 mg/kg per day (ganciclovir group); or continuation of previous maintenance therapy plus induction with the other drug (either ganciclovir or foscarnet) for 2 weeks followed by maintenance therapy with both drugs, ganciclovir sodium at 5 mg/kg per day and foscarnet sodium at 90 mg/kg per day (combination therapy group). The mortality rate was similar among the three groups. Median survival times were as follows: foscarnet group, 8.4 months; ganciclovir group, 9.0 months; and combination therapy group, 8.6 months (P = 0.89). Comparison of retinitis progression revealed that combination therapy was the most effective regimen for controlling the retinitis. The median times to retinitis progression were as follows: foscarnet group, 1.3 months; ganciclovir group, 2.0 months; and combination therapy group, 4.3 months (P = 0.001). Although no difference could be detected in visual acuity outcomes, visual field loss and retinal area involvement on fundus photographs both paralleled the progression results, with the most favorable results in the combination therapy group. The rates of visual field loss were as follows: foscarnet group, 28 degrees per month; ganciclovir group, 18 degrees per month; combination therapy group, 16 degrees per month (P = 0.009). The rates of increase of retinal area involved by CMV were as follows: foscarnet group, 2.47% per month; ganciclovir group, 1.40% per month; and combination therapy group, 1.19% per month (P = 0.04). Although side-effects were similar among the three treatment groups, combination therapy was associated with the greatest negative impact of treatment on quality-of-life measures. This study suggests that for patients with AIDS and CMV retinitis whose retinitis has relapsed and who can tolerate both drugs, combination therapy appears to be the most effective therapy for controlling CMV retinitis.143 Small series suggest that combined intravitreal injections of ganciclovir and foscarnet may be effective in treating CMV retinitis when the infection is clinically resistant to either intravitreal drug alone.191

Intraocular therapy of viral retinitis

Ganciclovir

Because of the difficulties associated with systemic ganciclovir, foscarnet, and cidofovir, interest in local administration has increased. Obviously, intraocular (or periocular) treatment will not affect the systemic CMV infection, but in some patients, especially those with systemic toxicity resulting from the drug, local administration may have certain advantages.

In 40 patients with primary CMV retinitis involving 57 eyes, all had received one 14-day course of intravenous ganciclovir and all were free of other end-organ CMV disease. All affected eyes received weekly intravitreal injections of 400 mg of ganciclovir for maintenance therapy. Median survival of patients was at least 13 months. Fifteen patients had 19 new opportunistic infections during the observation period, but none developed new nonocular CMV disease. Active retinitis recurred in 68.4% of the eyes while receiving maintenance therapy, with a median time to progression of 14.7 weeks. CMV retinitis occurred in 30.4% of the previously uninvolved eyes (follow-up 3.1 years). Bacterial endophthalmitis complicated treatment in one eye, and retinal detachment developed in five eyes. Thus the long-term treatment of CMV retinitis with weekly intraocular injections of ganciclovir was associated with survival and ocular outcomes similar to those reported with systemic ganciclovir.192

Intravitreal ganciclovir also was shown to be an effective alternative to systemic ganciclovir in patients with severe neutropenia and in patients who chose to continue receiving systemic zidovudine or didanosine.193 Injections of high-dose intravitreal ganciclovir using a 2 mg dose revealed that weekly 2 mg injections appear to offer superior control of retinitis for periods of months or longer.194 Highly concentrated ganciclovir solution for intravitreal injection also reduced repeated amaurosis and ocular pain and was reported by patients to have improved their comfort and quality of life, thus increasing their compliance to treatment and reducing side-effects, as compared with usual protocols.195

Foscarnet

Intravitreal foscarnet at a dose of 2.4 mg per injection given one or two times weekly also appears to be a safe and effective treatment method for CMV retinitis. Resistance to this treatment regimen may develop, however.196 High-dose intravitreal foscarnet for CMV retinitis was shown to be a safe, effective, and useful alternative in patients with intolerance to intravenous therapy.197

Ganciclovir intraocular device

An intraocular sustained-release ganciclovir delivery implant that releases drug into the vitreous is commercially available.198 These surgically implanted, time-release implants have been shown to be more effective than intravenous ganciclovir alone in delaying the progression of CMV retinitis.129,199,200

Insertion of the device requires a pars plana incision and a partial vitrectomy. The implant is sewn into the pars plana behind the lens.198 Insertion of the ganciclovir intraocular device (GIOD) requires trimming the strut of the device so that it is nearly flush with the drug pellet. A 5.5 mm incision can be made 4 mm posterior to the limbus with a microvitreoretinal blade or similar instrument (Fig. 81.11). A unimanual bipolar intraocular cautery can be used to coagulate bleeding choroid. It is important to ensure that the incision is full-thickness, since the device can be inserted inadvertently under the pars plana. A suture is placed through the preplaced hole (the surgeon must make the hole) in the strut of the device; 8–0 Prolene can be used. The device is anchored in the middle of the wound, and running or interrupted sutures can be used to close the wound. Astigmatism can result from overzealous wound closure; this is usually transient. This procedure can be performed in an outpatient setting under local anesthesia.

Despite the relative ease of insertion, it has become clear that the risk of retinal detachment in the first 2 months after insertion is substantially higher than if other methods are used to control retinitis, though in the long term there is no statistical difference in retinal detachment rate.198,201203 In addition, the risk of postoperative endophthalmitis appears to be a real one, with incidences on the order of 1% or sometimes higher.204 The intravitreal levels attained by this drug are over twice those after intravenous administration, and this appears to be associated with a lower incidence of resistance and progression of retinitis. This is particularly true in newly diagnosed cases, but failure can occur in up to 25% of such cases within the first 2 months. In a study of 91 implants in 70 eyes, GIOD was effective as an adjunct to continued systemic therapy in those patients with recurrent CMV retinitis.200 Intraocular sustained-release implants have been used to treat acute CMV disease and to prevent recurrence. Pathology studies of eyes having undergone implantation with the GIOD have shown no evidence of intraocular toxicity.136 It is not certain whether implants should be exchanged at the 7-month time period or whether retinitis should be allowed to reactivate before replacing the implant.

Intravitreal cidofovir

Another form of intraocular therapy is intravitreal cidofovir (HPMPC), which is injected every 6 weeks. This work was initiated after discovery of long-acting properties of the drug in the eye. The safety and efficacy of intravitreal cidofovir for CMV retinitis in humans were reported in a phase I/II unmasked, consecutive case series in a single-center institutional referral practice. Eligible patients with AIDS had active CMV retinitis in at least one eye, despite adequate intravenous therapy with ganciclovir or foscarnet, were intolerant to intravenous therapy, were noncompliant with intravenous therapy, or refused intravenous therapy. In a preliminary safety study (group 1), 10 eyes of nine patients received 14 injections of cidofovir while being treated concurrently with intravenous ganciclovir. In a dose-escalating efficacy study (group 2), eight eyes of seven patients received 11 injections of cidofovir as sole treatment for CMV retinitis. The primary outcome was time to retinitis progression. In group 1 eyes receiving 20 µg of cidofovir, the median time to retinitis progression was between 49 and 92 days (mean, 78 days). In group 2 eyes treated with 20 µg of cidofovir with probenecid, the median time to retinitis progression was 64 days (mean 63 days). Hypotony occurred in the two eyes treated with a 100 µg dose of cidofovir and in one of three eyes receiving a 40 µg dose. No adverse effects resulted from the remaining 20 µg cidofovir injections. Cidofovir was found to be safe and effective for the local treatment of CMV retinitis, providing a long duration of antiviral effect (Fig. 81.12).205

It was then shown that injections of 20 µg of intravitreal HPMPC resulted in complete suppression of CMV replication with no advancement of retinitis borders when given every 6 weeks.170,205209 This medication must be given with oral probenecid. Probenecid 2 g is given orally 2 hours before, and 1 g 2 hours and 8 hours after injection.

Two types of adverse events may occur after intravitreal cidofovir injection: iritis and hypotony. The incidence of these is not dissimilar to what is seen after intravenous administration. The incidence of iritis can be reduced from 70% to 18% if oral probenecid is used, and it is now recommended universally. Iritis can be managed with topical steroids and cycloplegia; however, it may lead to cataract and synechiae in the long term. A mild, asymptomatic 20% reduction in intraocular pressure (IOP) is seen almost universally after cidofovir injection, and this appears to be of no concern. The mechanism of this has been defined by ultrasound biomicroscopy, which has disclosed that severe hypotony after cidofovir injections is associated with ciliary body atrophy.206 Reduction in aqueous flow has been demonstrated by aqueous fluorophotometry. This effect on secretory epithelia also is probably responsible for the nephrotoxicity of the drug when given intravenously. Indeed, probenecid also is given before and after each intravenous infusion to prevent uptake by the proximal tubule of the kidney and associated nephrotoxicity. Profound hypotony with vision loss occurs in approximately 1% of injections.

A retrospective, cohort study described iritis and hypotony after treatment with intravenous cidofovir for CMV retinitis in association with intraocular inflammation.168

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