HIV-Associated Infections: Inflammatory Disease/Uveitis

SECTION
4 Inflammatory Disease/Uveitis
82 HIV-Associated Infections
Igor Kozak, J. Allen McCutchan, Doran Spencer, William R. Freeman
OUTLINE Ocular involvement occurs in up to 73% of AIDS pa-

tients,7,8 with the most common lesions being a retinal vascu-
lopathy consisting of cotton-wool spots, retinal hemorrhages,
INTRODUCTION and infectious retinopathy, such as cytomegalovirus (CMV) or
EPIDEMIOLOGY OF HIV INFECTION AND AIDS herpetic, toxoplasmic, or syphilitic retinitis.
OCCUPATIONAL EXPOSURE TO HIV
HIV VIROLOGY AND PATHOGENESIS
EPIDEMIOLOGY OF HIV INFECTION AND AIDS
THERAPY OF HIV INFECTIONS By 2017, an estimated 1.1 million people were living with HIV
in the United States (CDC.gov).9a Since 1996, AIDS has been
CLINICAL SPECTRUM OF HIV converted from an inevitably progressive and fatal disease into
INFECTION CONTROL RELATED TO HIV a manageable chronic condition by multidrug regimens re-
ferred to as highly active antiretroviral therapy (HAART). HIV
OCULAR FINDINGS IN AIDS: AN OVERVIEW is spread most commonly by homosexual and heterosexual
NONINFECTIOUS RETINOPATHY intercourse, blood exposures through shared needles among
INFECTIOUS RETINOPATHY IV drug users, or peripartum or by breast-feeding of infants.9b–11
Cytomegalovirus Retinitis
Herpetic Retinitis OCCUPATIONAL EXPOSURE TO HIV
Nonviral Intraocular Infections in AIDS Patients The average risk for HIV transmission in healthcare workers
FUNGAL DISEASES after percutaneous exposure to HIV-infected blood is approxi-
Candida albicans mately 0.3% without treatment.12,13 This risk is further low-
Cryptococcus neoformans ered by double-gloving and is probably much lower in the
Histoplasmosis ophthalmic setting.14 Postexposure prophylaxis (PEP) with
two or three antiretroviral drugs appears likely to dramatically
Aspergillosis reduce the transmission of HIV even after high-risk injuries.15
Coccidioidomycosis Because PEP should be started as soon as possible after injury,
Paracoccidioidomycosis healthcare institutions should have well-developed proce-
Advances in Antifungal Therapy dures that provide for expert consultation and ready access to
BACTERIAL RETINITIS a combination of drugs for persons at high risk for injuries,
Syphilis such as surgeons, invasive proceduralists, and phlebotomists.
Currently, for percutaneous injuries, the US Public Health
INVASIVE DIAGNOSTIC TECHNIQUES FOR RETINAL Service recommends 4 weeks of treatment with a three (or
DISEASE more) drug regimen for all occupational exposure to HIV.16
ANTIRETROVIRAL THERAPY
HIV VIROLOGY AND PATHOGENESIS
HIV infection usually gradually depletes CD41 lymphocytes,
resulting in decreased blood levels of this crucial subset of
INTRODUCTION “helper” T cells.17 AIDS patients typically become ill only after
Acquired immunodeficiency syndrome (AIDS) is a potentially CD41 helper T cells reach less than 200/µL, a level that no
fatal multisystem syndrome characterized by profound disrup- longer supports cell-mediated immunity at levels needed to
tion of the immune system and a propensity for various op- contain infections by select opportunistic viral, bacterial, or
portunistic infections and neoplasms. AIDS is caused by either fungal pathogens.
of two human immunodeficiency viruses (HIV-1 [formerly Understanding of HIV infection was revolutionized by the
HTLV-3] or HIV-2).1–3 HIV-1 entered humans from chimpan- development in the mid-1990s of assays that measured the
zees nearly a century ago and, after passing unrecognized levels of HIV in the blood. All stages of HIV infection were seen
among West and Central Africans,4,5 came to the United States to be characterized by a high rate of viral replication in most
via Haiti in the 1970s. AIDS was recognized first in 1981 as patients. Levels of plasma HIV-1 RNA predict the rate of clini-
outbreaks of unusual opportunistic infections (OIs) in homo- cal progression in HIV patients.18–24 Both high replication and
sexual men in three American cities.6 an error-prone reverse transcription process promote frequent
1713
Descargado para Álvaro Loza Sierra (alvaroloza1995@gmail.com) en Marques de Valdecilla Foundation de ClinicalKey.es por Elsevier en noviembre 09,
2022. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.
1714 SECTION 4 Inflammatory Disease/Uveitis
mutations in the HIV genome that result in the emergence of TABLE 82.1 Currently Licensed Antiretroviral Drugs in the United
variants that can better resist either control by the host’s anti- States in 2021 by Class
body and cell-mediated immune responses or by antiretroviral
Brand Name Generic Name(s) Manufacturer Name
drugs, if drugs are present in insufficient numbers or at low
blood levels that fail to fully suppress HIV replication. Under Multiclass Combination Products
selective pressure from antiretroviral agents, mutations that Atripla Efavirenz, emtricitabine, Bristol–Myers
confer a decreased sensitivity to individual drugs are selected and tenofovir disoproxil Squibb and Gilead
and stored in latent cells where they last for decades.25–28 fumarate Sciences
Nucleoside Reverse Transcriptase Inhibitors (NRTIS)
THERAPY OF HIV INFECTIONS Combivir Lamivudine and zidovudine GlaxoSmithKline
Emtriva Emtricitabine, FTC Gilead Sciences
Treatment of HIV has evolved rapidly, with the development of Epivir Lamivudine, 3TC GlaxoSmithKline
more than 30 drugs (as of 2020) that fall into at least six classes Epzicom Abacavir and lamivudine GlaxoSmithKline
based on which of the steps in HIV replication they inhibit Retrovir Zidovudine, azidothymidine, GlaxoSmithKline
(Table 82.1). These steps include (1) binding to receptors and AZT, ZDV
entry into the host cell, (2) reverse transcription of HIV RNA to Trizivir Abacavir, zidovudine, and GlaxoSmithKline
lamivudine
proviral DNA, (3) integration of proviral DNA into the host cell
Truvada Tenofovir disoproxil fuma- Gilead Sciences, Inc.
genome, and (4) maturation of HIV after budding by the action rate and emtricitabine
of HIV protease.29 Coadministration of drugs from several of Videx EC Enteric-coated Bristol–Myers Squibb
the classes delays or prevents the emergence of drug-resistant didanosine, ddI EC
HIV by minimizing viral replication. Nevertheless, HIV may Videx Didanosine, Bristol–Myers Squibb
develop resistance to all available therapy because (1) patients dideoxyinosine, ddI
have difficulty maintaining high levels of adherence over long Viread Tenofovir disoproxil Gilead
periods and (2) cross-resistance is common to drugs within a fumarate, TDF
class.30–33 After failure of a regimen, the next combination of Zerit Stavudine, d4T Bristol–Myers Squibb
Ziagen Abacavir sulfate, ABC GlaxoSmithKline
drugs is less likely to be successful in fully suppressing HIV
replication, which is the necessary condition for prolonged suc- Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIS)
cess. For details of recent expert guidelines on HIV therapy, Edurant Rilpivirine Tibotec Therapeutics
consult “Guidelines for the Use of Antiretroviral Agents in HIV- Intelence Etravirine Tibotec Therapeutics
1-Infected Adults and Adolescents,” which is constantly up- Rescriptor Delavirdine, DLV Pfizer
Sustiva Efavirenz, EFV Bristol–Myers Squibb
dated and available at the NIH website.
Viramune Nevirapine, NVP Boehringer Ingelheim
(immediate
CLINICAL SPECTRUM OF HIV release)
Viramune XR Nevirapine, NVP Boehringer Ingelheim
HIV infection and disease are highly variable in presentation (extended
and include asymptomatic cases, various chronic or recurring release)
constitutional signs and symptoms, and a plethora of opportu- Protease Inhibitors (PIS)
nistic conditions. The “acute retroviral syndrome,” that is, early Agenerase Amprenavir, APV GlaxoSmithKline
or primary infection with HIV, is characterized by fever, phar- Aptivus Tipranavir, TPV Boehringer Ingelheim
yngitis, skin rash, arthralgias, malaise, mucosal ulcerations, Crixivan Indinavir, IDV, Merck
and neurologic manifestations, such as aseptic meningitis.34 Fortovase Saquinavir (no longer Hoffmann–La Roche
Patients chronically infected with HIV may present with a marketed)
prodrome of generalized, nontender lymph node enlargement, Invirase Saquinavir mesylate, SQV Hoffmann–La Roche
fevers and night sweats, weight loss, and diarrhea for weeks or Kaletra Lopinavir and ritonavir, Abbott Laboratories
LPV/RTV
months, formerly termed AIDS-related complex (ARC). Nearly
Lexiva Fosamprenavir calcium, GlaxoSmithKline
all HIV-seropositive patients will progress to AIDS, but a small FOS-APV
minority, called “long-term nonprogressors” or “elite control- Norvir Ritonavir, RTV Abbott Laboratories
lers,” suppress their infections naturally (without treatment) to Prezista Darunavir Tibotec, Inc.
the point of very low or undetectable levels of plasma HIV. Reyataz Atazanavir sulfate, ATV Bristol–Myers Squibb
Although HAART often reduces plasma viremia of HIV-1 to Viracept Nelfinavir mesylate, NFV Agouron Pharmaceu-
undetectable levels, latent viral reservoirs of resting CD4 ticals
lymphocytes persist for years and reappear in the blood if Fusion Inhibitors
therapy is stopped.35 Fuzeon Enfuvirtide, T-20 Hoffmann–La Roche
Opportunistic infections are responsible for the deaths of most & Trimeris
AIDS patients, but consequences of coinfections with hepatitis C Entry Inhibitors – CCR5 Co-Receptor Antagonist
and B, such as hepatic insufficiency or hepatocellular carcinoma, Selzentry Maraviroc Pfizer
have become increasingly important, in part because HIV
Hiv Integrase Strand Transfer Inhibitors
promotes the progression of these infections.36 The most com-
mon pathogens encountered in AIDS patients are CMV, Candida Isentress Raltegravir Merck & Co., Inc.
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).3,37 CMV retinitis can be
INFECTION CONTROL RELATED TO HIV
the initial sign of tissue-invasive systemic CMV infection in The US Centers for Disease Control and Prevention (CDC)
these patients, although it is typically restricted to patients with recommendations for universal precautions to prevent the
advanced immunosuppression (CD41 count less than 50/µL). occupational transmission of HIV and other blood-borne
CMV may present also in the gastrointestinal (GI) tract, brain and viruses in the healthcare setting were provided in 1988 and
spinal cord, or other organs.38 have not been amended.39
HIV-Associated Infections 1715
The CDC provided specific guidelines for ophthalmologic Choroidal infection with Coccidioides, Cryptococcus, Pneumo-
examinations in addition to the general recommendations. cystis, M. tuberculosis, Aspergillus, Toxoplasma, Histoplasma, and M. 82
The use of gloves (especially if the skin of the examiner is avium-intracellulare usually is associated with systemic infection,
compromised in any way) and good handwashing technique although cryptococcal choroiditis has also been described in
after procedures or examinations involving the eye are recom- the absence of systemic infection (e.g., meningitis).63–65 Histo-
mended because HIV may be present in tears. plasma capsulatum chorioretinitis and endophthalmitis,66 Para-
Sterilization of all instruments and equipment that come coccidioidomycosis brasiliensis chorioretinitis,67 keratitis sicca, cra-
into contact with the eye in all patients is necessary using gas or nial nerve paralysis, Roth’s spots, papilledema, perivasculitis,
steam autoclaving or a 5- to 10-minute soak in one of the fol- and fungal corneal ulcers are rare but have been reported.68
lowing solutions: 3% hydrogen peroxide solution, 10% solution
of sodium hypochlorite (common household bleach), or 70%
ethanol or isopropanol. Instruments disinfected in this manner
NONINFECTIOUS RETINOPATHY
should be rinsed in water and dried before reuse.40,41 Damage to Noninfectious retinopathy refers to cotton-wool spots, retinal
tonometer tips has been reported with the use of 70% isopropa- hemorrhages, and microvascular abnormalities that do not
nol; thus a 5- to 10-minute soak in 3% H2O2 or 1:10 dilution of progress, enlarge, or cause visual symptoms. This stands in con-
household bleach may be preferable.42 It should be noted that trast to HIV neuroretinopathy, which may cause color vision
there is no evidence of HIV transmission through contact with deficits because of optic nerve involvement.69 No infectious
tears or instruments used to examine these patients.40 cause of these lesions has been demonstrated, and they appear
Contact lenses used in trial fittings on all patients should to represent nonspecific retinal microvascular disease. A correla-
be disinfected by using any commercially available cleaning tion between the number of cotton-wool spots and decreased
method or solution.43 Inactivation of HIV by various disinfec- cerebral blood flow (as shown by technetium 99m hexamethyl-
tants on surfaces has been reviewed.44 Guidelines for prevent- propyleneamine oxime single photon emission computed to-
ing transmission of HIV through transplantation of human mography [CT]) was shown in 25 patients with AIDS or symp-
tissue and organs (including corneal transplants) have been tomatic HIV infection.70
set forth.45 Specific recommendations for postexposure man- Cotton-wool spots are the most common ocular lesion seen
agement of needlestick injuries or mucosal membrane expo- in AIDS, occurring in 25% to 50% of patients7,71 and in up to
sures to secretions from patients with HIV infection have been 75% of cases by autopsy examination.58 In one study, up to
published.46 92% of AIDS patients were found to have evidence of retinovas-
cular disease when examined using fluorescein angiography.71
Cotton-wool spots seen by ophthalmoscopy are a result of mi-
OCULAR FINDINGS IN AIDS: AN OVERVIEW croinfarction of the nerve fiber layer of the retina. In AIDS these
HIV has been detected in the cornea,47 conjunctival epithe- lesions usually are confined to the posterior pole near the optic
lium,48 and in tears47 but at very low titers. Ocular manifesta- disc71 (Fig. 82.1). Histopathologic study of retinal cotton-wool
tions of AIDS may be seen in up to 100% of patients. They are spots in AIDS patients has demonstrated that these lesions have
less common but may be seen in patients with earlier, symp- pathologic features identical to those seen in cotton-wool spots
tomatic HIV infection.49 Most common are cotton-wool spots of other causes. Similar to the cotton-wool spots seen in other
and other noninfectious retinopathies,50 CMV retinitis, and systemic diseases, this lesion in AIDS demonstrates no associ-
conjunctival Kaposi sarcoma, followed less frequently by her- ated inflammation, no cells in the vitreous, and no vascular
pes zoster ophthalmicus,51,52 retinal toxoplasmosis, choroidal leakage on fluorescein angiography (Fig. 82.2). Attempts to
P. carinii infection, herpes simplex and herpes zoster retinitis isolate organisms from cotton-wool spots in the hope of ex-
(acute retinal necrosis [ARN] and progressive outer retinal plaining their cause in AIDS as infectious have been unsuccess-
necrosis), and cryptococcal choroiditis.6,53–60 ful, and the cause of this lesion in AIDS remains elusive.7,58,72,73
Iritis may occur in association with viral retinitis but espe- Cotton-wool spots have been speculated to be harbingers
cially with CMV; it is typically mild. Acute iritis may be associ- of CMV retinitis or perhaps sites of susceptibility to CMV in-
ated with the use of oral rifabutin (used for the treatment and fection, but substantiation of these ideas is lacking. Histo-
prophylaxis of mycobacterial infections) or IV cidofovir used pathologic studies of eyes at autopsy have failed to show clear
for CMV retinitis, although rifabutin has also been associated evidence of a viral cause of cotton-wool spots.74–76
with severe uveitis when used concomitantly with antiretrovi- We have reported that noninfectious retinopathy is not
ral therapy.61,62 seen in HIV-seronegative men and is rare in ARC, but it is very
A B C
Fig. 82.1 (A) Retinal cotton-wool spot seen inferotemporal to the disc. (B) Early fluorescein angiogram shows blockage and possible nonperfu-
sion. (C) Late angiogram shows staining, presumably from damaged retinal microvasculature.
Fig. 82.2 Photomicrograph of retinal cotton-wool spot shows cytoid

bodies and swelling of the nerve fiber layer of the retina. Retinal cellu-
lar elements are seen at the top of the photograph.
Fig. 82.3 White, centered retinal hemorrhage (Roth spot) seen in an

HIV-infected patient. These lesions do not progress.
common in patients with AIDS, even in the absence of active
opportunistic ophthalmic infection.49 It is striking that this
lesion may be seen in 50% to 75% of AIDS patients, and stud-
ies using multiple examinations indicate that the more fre-
quently these patients are examined, the higher the incidence has been reported to be as high as 40%. Retinal hemorrhages
may be.7,50 Cotton-wool spots probably are ophthalmoscopi- usually take the form of flame-shaped lesions in the posterior
cally visible for 6 to 12 weeks, and because of the transient pole, dot-blot hemorrhages, or as punctate intraretinal hemor-
nature of the lesion and its apparent noninfectious cause, rhages peripherally (Fig. 82.3). Occasionally the hemorrhage
treatment is not indicated at this time.77 On in vivo imaging, is manifested as Roth’s spots (hemorrhage with a white central
they cause the “hyper-reflective sign”78 followed by inner ret- area).53,71 The pattern of retinal hemorrhages changes over
ina thinning years after their disappearance.79 time. The hemorrhages do not appear to be related to a bleed-
In a cross-sectional study, the median CD4 count (per mi- ing diathesis or coagulopathy but rather seem to be a manifes-
croliter [µL]) in patients with cotton-wool spots was 14 cells tation of AIDS itself.7 Vision loss from retinal hemorrhage has
(range 0–160) and was eight cells (range 0–42) in patients not been described, and treatment is conservative if the le-
with CMV retinitis.80 In the absence of other systemic vascular sions are not associated with CMV retinitis or septicemia.
disease, such as hypertension or diabetes mellitus, AIDS must Microvascular pathologic findings are common and varied
be considered in the differential diagnosis of cotton-wool in AIDS, as demonstrated by fluorescein angiography and opti-
spots because of their very high prevalence in these patients. cal coherence tomography (OCT)95 and OCTa,96 and include
Whether these lesions are an early manifestation of AIDS re- microaneurysms, telangiectasias, focal areas of nonperfusion,
mains to be elucidated, but they may be apparent in HIV-in- and capillary loss.71 These changes are similar to the changes
fected persons before the onset of opportunistic infections.49 seen in diabetes mellitus. The histologic findings of periodic
Morphologic studies have shown that the number of retro- acid–Schiff (PAS)-positive thickening of blood vessels and pre-
bulbar optic nerve fibers in patients with AIDS is decreased capillary arteriolar closure also correlate with the findings in
compared with the number of optic nerve fibers in normal diabetes mellitus.
control eyes as a result of axonal degeneration and an associ- Branch or central retinal vein occlusion, branch retinal ar-
ated decrease in the number of optic nerve axons.81–84 Infarc- tery occlusion, and ischemic maculopathy have been reported
tions of the nerve fiber layer develop in most patients with in HIV patients without infectious retinitis. The incidence is
AIDS, and the number of such infarctions increases over unknown. It is possible that the cause may be related to lupus
time.7,50 Visual dysfunction associated with multiple nerve fi- anticoagulant and other clotting abnormalities seen in HIV-
ber layer infarctions may be manifested by defects in color vi- infected patients.97,98 Abnormalities of retinal blood flow have
sion and contrast sensitivity testing in patients with AIDS.85–87 also been reported in HIV patients and may contribute to the
Interestingly, in vivo studies of the retinal nerve fiber layer pathogenesis of microvascular abnormalities.99–102
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 retini- INFECTIOUS RETINOPATHY
tis.78,88 Electroretinographic studies of HIV patients without reti-
nitis also have shown retinal dysfunction.89,90 The complex of Cytomegalovirus Retinitis
the aforementioned vision abnormalities has been termed HIV
neuroretinal disorder, with an incidence in HIV patients between
Pathogenesis, Diagnosis, and Clinical Manifestations
16% to 50% after 20 years of AIDS diagnosis.91,92 The molecular CMV infection is a major cause of morbidity and mortality in
biology of HIV retinopathy and possible pathophysiology of AIDS. CMV retinitis has been reported to occur in 15% to 40%
HIV neuroretinal disorder has been published previously.93 of AIDS patients with the rate declining since the arrival of
Retinal hemorrhages are seen in AIDS in association with HAART.38,53,103,104 In contrast to the noninfectious lesions of
CMV retinitis and cotton-wool spots and as an isolated find- AIDS, CMV retinitis demands aggressive treatment to prevent
ing. These lesions have been reported in up to 30%53,71,94 of severe visual loss.7,105,106 Patients with active CMV disease may
AIDS patients, and autopsy evidence of retinal hemorrhages 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 82
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 im-
munosuppressed patients and infants with cytomegalic inclu-
sion disease.107,108 Correlation of the clinical and typical patho-
logic findings at autopsy has been demonstrated.109 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 le-
sions. Choroidal involvement is rare, and whether vascular
endothelium is involved is unclear. These lesions also may ap-
pear as noncontiguous patches rather than the more com-
monly seen contiguous spreading lesion. Antigens to CMV A
have been found by immunofluorescence (IF), immunoper-
oxidase staining, and DNA hybridization techniques.110,111 The
most distinctive anterior segment finding is the presence of
fine stellate keratic precipitates on the corneal endothelium.112
Retinal vascular nonperfusion and retinal neovascularization
resulting from CMV retinitis and choroiditis also have been
reported.113
CMV is a slowly progressive necrotizing retinitis that may af-
fect the posterior pole, the periphery, or both, and may be uni-
lateral or bilateral. Involved retinal areas appear as white intra-
retinal 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. 82.4). Peripherally, CMV retinitis oc-
curs commonly; it tends to have a less intense white appearance,
with areas of granular, white retinitis that may or may not dem-
onstrate associated retinal hemorrhage (Fig. 82.5).114 As the reti-
nitis progresses, an area of atrophic, avascular retina may remain B
with underlying retinal pigment epithelial atrophy or hyperpla-
sia.7,38,115 Peripheral CMV retinitis is common in AIDS patients Fig. 82.5 (A) Peripheral cytomegalovirus (CMV) retinitis without
who initially may report only floaters with or without a visual retinal hemorrhage is characterized by white areas of retinal necrosis.
field deficit. Wide-angle fundus photography and fluorescein (B) After healing, CMV retinitis leaves behind a glial scar without
angiography may be of benefit if the diagnosis is uncertain. opacification (not same eye as in A). Often only minimal pigmentary
These techniques may be used to document progression of reti- changes are seen.
nitis, and fluorescein leakage in areas of retinitis may be helpful
in confirming the diagnosis (Fig. 82.6).
Fig. 82.4 Cytomegalovirus (CMV) retinitis with hemorrhagic areas are

seen superior to the fovea and a more dense area just below the fo- Fig. 82.6 Fluorescein angiogram of cytomegalovirus (CMV) retinitis
vea. Borders are opaque and associated with variable amounts of lesion shows lack of perfusion and blockage, as well as staining and
hemorrhage. leakage of fluorescein from damaged retinal vessels.
Reactivation of CMV retinitis is characterized by reopacifi- arisen temporally. Despite its foveolar proximity and ultimate
cation of the border of the lesion followed by advancement. significant loss of function, the pattern of progression allows
Smoldering retinitis (Fig. 82.7) and subtle reactivation may be for preservation of useful foveal vision for longer periods than
difficult to recognize without prior fundus photographs. Sev- would have been expected.121
eral studies have shown that wide-angle fundus photographs Other manifestations of CMV retinitis include retinal edema,
are a more sensitive indicator of retinitis progression than attenuated vessels, perivascular sheathing, and exudative retinal
clinical examination by indirect ophthalmoscopy.116,117 detachment122 (Fig. 82.8). In addition, vitritis and anterior uve-
Several investigators have shown that untreated CMV retinitis itis are often seen, and optic atrophy may occur as a late mani-
is inexorably progressive in AIDS patients.7,53,108,110,118 As in our festation resulting from widespread retinal destruction. CMV
experience, untreated CMV becomes bilateral in the vast major- occasionally may be demonstrated in vitreous biopsy speci-
ity of patients. In an observational study of 26 patients treated mens in these patients.109 The yield may be higher in the pres-
for CMV retinitis, vision scores decreased with greater abnor- ence of marked vitritis because CMV is a cell-associated virus.
malities found on ophthalmologic examination. Visual symp- Other causes of retinitis, including herpes simplex retinitis,107,123
toms were most strongly related to findings in the worse eye. toxoplasmosis,64 candidal infection, Behçet disease, syphilis,
Patients reported considerable impairment, including blurred acute retinal necrosis,124,125 and subacute sclerosing panen-
vision (42%), difficulty reading (40%), difficulty driving (44%), cephalitis secondary to measles usually can be distinguished
treatment interference with social activities (40%), and substan- from CMV on clinical grounds, although this may not be the
tial trouble with vision (50%).119 Treatment of AIDS-related case in retinitis caused by other members of the herpesvirus
CMV retinitis minimizes loss of vision and may protect previ- family.124 CMV has a very characteristic clinical appearance, but
ously uninfected eyes, prolonging visual independence.120 the lesions in CMV retinitis vary from patient to patient, and it
Recurrent CMV retinitis exhibiting a foveal-sparing pattern is important to maintain a high index of suspicion for the afore-
within 1500 mm of the foveola has been described and occurs mentioned infections, especially in light of frequent superinfec-
primarily in patients with recurrent CMV retinitis resistant to tion of AIDS patients with multiple organisms.7,94,97
treatment (“clinically resistant”), particularly that which has 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, devel-
opment of focal signs on neurologic examination, or other
symptoms consistent with subacute encephalitis in AIDS pa-
tients, a comprehensive ophthalmologic examination is indi-
cated, and an increased index of suspicion of CMV infection of
the central nervous system (CNS) and possible CMV retinitis is
warranted. There is also evidence that patients with CMV reti-
nitis, especially peripapillary disease, have a much higher inci-
dence of CMV encephalitis. CMV infection of the brain, optic
nerves, and retinas from 47 consecutive autopsies of patients
with AIDS was examined.126 Immunocytochemistry demon-
strated 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. Whereas 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 in-
fected histologically despite extensive peripapillary retinitis.
A
B
Fig. 82.7 Smoldering cytomegalovirus (CMV) retinitis is a low grade
of retinitis border activity that is associated with slow progression of Fig. 82.8 Cytomegalovirus (CMV) affecting the perifoveal area or the
retinitis. It may be difficult to diagnose without fundus photographs. optic nerve can result in an exudative retinal detachment often involv-
(A) Low-grade CMV lesion. (B) Lesion has progressed slowly over ing the macula. If there has not been actual involvement of a vital
2 months. structure, treatment may result in improvement of central vision.
The strength of these associations suggests that CMV retinitis By prospective monitoring for increases in plasma CMV DNA
defines a group of patients with AIDS at risk for development copy number, it may be possible to identify HIV-seropositive 82
of CMV encephalitis (relative risk, 9.5%), especially when the patients who are at imminent risk for developing symptom-
retinitis involves the peripapillary region (relative risk, 13%). atic CMV retinitis.135
Furthermore, in patients with AIDS without CMV retinitis, It is also reasonable and practical to use the CD4 cell count
CNS symptoms are unlikely to be attributable to CMV en- as a threshold below which to screen patients because the risk
cephalitis.126 The pathologic correlation between ocular and for CMV retinitis increases at CD4 cell counts below 50/µL.78
cerebral lesions in patients with AIDS has been reviewed.127 The incidence and prevalence of CMV retinitis in a cohort
CMV retinitis is less frequent in children with AIDS, with study of patients with CD4 cell counts below 0.10 3 109/L
reported rates of approximately 5% to 6%, but rates of extra- (100/µL) revealed a 25% chance for the development of CMV
ocular CMV are higher than in adults. CMV retinitis has been retinitis by 4 years of follow-up. Among those subjects in
reported in young children with high absolute CD4 counts, but whom CMV retinitis developed, about 19% had retinitis be-
these counts are low relative to the child’s age. Older children fore a CD4 cell count of less than 0.05 3 109/L (,50/µL) was
tend to have low absolute CD4 counts, similar to adults. There observed, and 81% had CMV retinitis after the CD4 cell count
is a higher incidence of bilateral and posterior pole disease in reached this threshold.136 In the HAART era, some patients
children, however this is likely due in part to delays in diagnosis may develop CMV retinitis with CD4 counts greater than 100/
in children from lack of subjective vision complaints.127–130 µL, probably because of incomplete restoration of the immune
repertoire against CMV.137
Screening Techniques for Retinal and Systemic A technique for screening for central CMV retinitis, ent-
optic perimetry, which employs patient visualization of
Cytomegalovirus Infection moving particles on a computer monitor, appears to have a
Screening for CMV retinitis is a difficult problem. Many patients very high sensitivity and specificity (over 90%) in detecting
who are CMV-viremic or -viruric may not have end organ dis- CMV retinitis within the central 30-degree radius of fixa-
ease, and studies employing quantitative CMV polymerase tion88 (Fig. 82.9).
chain reaction (PCR) in plasma or CMV antigenemia have not Techniques for detection of CMV DNA based on PCR are
been able to definitively predict the development of CMV reti- increasingly being applied to ocular fluids; however, the clini-
nitis.131 Currently no laboratory marker exists that reliably pre- cal significance of such findings can sometimes be unclear.
dicts the occurrence of clinical CMV retinitis. The application of PCR-based methods to ocular fluids made
Urine is culture-positive for CMV in more than 50% of a useful contribution to the treatment of the patients.138
homosexual men and the majority of AIDS patients; thus This appears to be a sensitive and specific diagnostic assay
urine culture may not be of diagnostic value. Serology in AIDS that could assist in the diagnosis of CMV retinitis.139 PCR de-
patients is nonspecific, and documentation of rising CMV ti- tection of CMV DNA has been reported to be a more sensitive
ters is unusual.7,110 Studies of newly diagnosed CMV retinitis method than analysis of locally produced antibodies by calcu-
patients indicate that many are CMV culture-negative in the lating a Goldman–Witmer coefficient to determine local ocular
blood. Positive blood cultures for CMV, fever, and weight loss antibody production. There is also an immune predisposition
are associated with more extensive CMV retinitis at the time of to the development of CMV retinitis in patients with AIDS.140,141
diagnosis.132 The results of virologic blood assays for CMV
also have been associated with clinical outcome in patients
with CMV retinitis.133 Therefore assays for the detection of
Treatment of CMV Retinitis
CMV antigenemia may be a simple and rapid means of iden- The treatment of CMV retinitis has been reviewed.142,143 Treat-
tifying those patients with unilateral retinitis at highest risk for ment may be systemic, local, or a combination of the two.
developing CMV retinitis of the fellow eye or of visceral CMV There are currently four medications approved by the US Food
disease if intravitreal injections or implants are used as the and Drug Administration (FDA) for the treatment of CMV
sole treatment for CMV retinitis.134 retinitis: ganciclovir, valganciclovir, cidofovir, and foscarnet.
A positive PCR result supports the clinical diagnosis and Fomivirsen, the first antisense drug with a relatively long dura-
may be useful for monitoring response to antiviral treatment. tion of action, is no longer available in the United States.
A B
Fig. 82.9 Entoptic perimetry can allow detection of cytomegalovirus (CMV) retinitis lesions. (A) The patient is asked to view particle motion
programmed on a monitor. (B) An overlay of the CMV lesion (dotted white border) and the patient’s own sketch of the scotoma seen (black line).
Systemic Therapy of Cytomegalovirus Retinitis found that discontinuation or delay of ganciclovir therapy re-
sults in nearly 100% recurrence of retinitis, at which time rein-
CMV retinitis may be treated systemically or intravitreally. stitution of the loading dose regimen often is necessary.149,151,152
Systemic treatment, however, is associated with less spread of Multiple series in patients with AIDS and CMV retinitis have
CMV retinitis from one eye to the other143 In addition, local shown response rates of 80% to 100%, with 60% to 80% of
treatment, including the sustained release ganciclovir implant, patients achieving remission with ganciclovir therapy.38,152–156
has been shown to be associated with a higher risk for devel- The treatment of CMV retinitis usually includes an induc-
oping CMV.144,145 tion phase followed by a maintenance phase to prevent relapse.
Systemic CMV may cause GI disease, with colitis and esopha- Before the advent of HAART, relapse occurred almost univer-
gitis being the most common manifestations. Systemic CMV di- sally, given a sufficiently long period after induction courses of
agnosis may be difficult and usually requires histopathologic ganciclovir. Therapy therefore continued for a lifetime. The me-
evidence of CMV infection. The cumulative incidence of systemic dian time to relapse in patients treated with just an induction
CMV disease that becomes clinically apparent is approximately dose is 3 to 4 weeks.152
25%.146 Therefore, although systemic CMV disease may not be Most clinicians use a 14-day induction course of IV ganci-
clinically apparent at the time of diagnosis of CMV retinitis, some clovir consisting of 5 mg/kg per day every 12 hours and in-
experts believe that initial systemic therapy may be warranted definite maintenance of 5 mg/kg per day. Lower doses and
despite the inconvenience, expense, and potential toxicities. every-other-day dosing schedules have been associated with
high rates for early relapse. Because treatment may be lifelong
Intravenous Ganciclovir. Ganciclovir is a nucleoside analog of if the patient’s CD4 count cannot be elevated with anti-HIV
2-deoxyguanosine, similar to acyclovir.147 Despite its structural therapy, usually a permanent or semipermanent indwelling
similarities with acyclovir, ganciclovir is much more active in venous catheter is placed at the onset of therapy if IV therapy
vitro against CMV than acyclovir.148 Ganciclovir inhibits all is chosen as maintenance therapy. Ganciclovir requires modi-
herpesviruses, including CMV, by preventing DNA elongation. fication of dosing in the presence of renal insufficiency.
CMV lacks the virally encoded thymidine kinase (TK) that con- Side effects of ganciclovir include granulocytopenia, neuro-
verts ganciclovir (or acyclovir) to its monophosphate form.149 logic dysfunction, abnormal liver function tests, and rarely,
TK-altered strains resistant to acyclovir are as sensitive to ganci- thrombocytopenia. The most serious toxicity is granulocyto-
clovir as the unaltered parent strains. Thus ganciclovir is phos- penia, which may occur in up to one-third of patients when
phorylated to its triphosphate form much more efficiently than defined as fewer than 500 neutrophils per microliter.152 Gran-
acyclovir, which accounts for the greater activity of ganciclovir ulocytopenia is generally reversible, and this adverse effect is
against CMV.150 exacerbated when used with AZT.157 The use of colony-stimu-
The majority of AIDS patients treated with ganciclovir re- lating factors rGM-CSF (recombinant granulocyte–macro-
spond within 2 to 4 weeks with decreased retinal opacification phage colony-stimulating factor) and rG-CSF (recombinant
and stabilization of the retinitis103 (Fig. 82.10). Ganciclovir is granulocyte colony-stimulating factor) for reversing or pre-
commercially available as IV and oral formulation (and also is venting neutropenia may be useful.
included in an intraocular device), and indefinite maintenance The prevalence of CMV resistance to ganciclovir is un-
therapy is necessary as long as the patient remains in immune known, but ever-increasing induction regimens may be neces-
failure with a CD4 count of less than 50/µL. An IV loading dose sary to control CMV retinitis. Strains of CMV that develop re-
of 5 mg/kg every 12 hours for 14 to 21 days should be followed sistance to ganciclovir may remain susceptible to foscarnet.
by maintenance doses of 5 mg/kg per day. If the drug is discon- Because of the question of ganciclovir resistance, a trial of
tinued, retinitis often recurs within 10 to 21 days, continuing its combined vs. alternating foscarnet–ganciclovir maintenance
progression at the borders of healed areas.103 Recurrences have therapy has been reported to be effective.158
been common, even during maintenance therapy, being re- Visual acuity depends on the location of the involved ret-
ported 3 weeks to 5 months after institution of therapy and oc- ina, and involvement of the fovea or optic nerve may result in
curring in 30% to 40% of patients.103 Many investigators have decreased visual acuity even if there has been a response to
A B
Fig. 82.10 (A) Active peripheral cytomegalovirus (CMV) retinitis with secondary retinal vasculitis. (B) The area is healed after intravenous
ganciclovir therapy. Note absence of border opacification. Also seen are pigmentary changes characteristic of healed CMV.
therapy. Ganciclovir has been shown to be effective in preserv- the valganciclovir group.164 No clinical trials have been pub-
ing visual acuity. For example, 73% of eyes maintained a vi- lished specifically comparing efficacy of oral versus IV valganci- 82
sual acuity of 20/40 or better when treated with ganciclovir.159 clovir for maintenance therapy of CMV retinitis.
Lalezari et al. (Roche Valganciclovir Study Group) reported
Oral Ganciclovir. Oral ganciclovir (FDA approved, 1994) can a large safety study of valganciclovir. The adverse event profile
be used for maintenance therapy of CMV retinitis after it has was similar to that reported from previous studies of IV
been healed with IV ganciclovir therapy. Studies using this and oral ganciclovir. Adverse events of note were diarrhea
drug regimen have shown efficacy, but it is clear that oral gan- (38%), nausea (23%), fever (18%), neutropenia (absolute
ciclovir is less effective than IV ganciclovir for many patients. neutrophil count , 500 cells/µL; 10%), anemia (hemoglobin
Perhaps the most common use of oral ganciclovir is in pa- , 8.0 g/dL) (12%), and thrombocytopenia (platelet count
tients being treated with intravitreal therapy (injections of cido- , 25,000 cells/µL; 2%).165
fovir or ganciclovir implant) to prevent systemic CMV disease. In summary, oral valganciclovir offers the obvious advan-
Such use of oral ganciclovir also may reduce the IV of CMV in tage of extreme effectiveness against CMV retinitis without the
the fellow eye if it is not involved.160,161 Oral ganciclovir for difficulties and inconveniences of IV administration. Further-
prophylaxis or treatment of CMV retinitis has been replaced by more, because valganciclovir is converted to ganciclovir in the
oral valganciclovir, which provides much higher blood levels. bloodstream, its pharmacologic safety profile, including side
effects, is no different than that of intravenously administered
Valganciclovir. Valganciclovir, the valine ester of ganciclovir, ganciclovir. Thus oral valganciclovir is an effective and safe
is an orally administered formulation of ganciclovir. The va- alternative to IV ganciclovir for the treatment of CMV retinitis.
line ester confers enhanced permeability and absorption of
the molecule through the cell membranes of the gut. Once in Foscarnet. The second drug for the treatment of CMV retini-
the bloodstream, the valine ester is cleaved from the molecule tis in patients with AIDS was licensed by the FDA in 1993.
by esterases, rendering plasma levels of ganciclovir compara- Foscarnet is a pyrophosphate analog with broad antiviral ac-
ble to those achieved with IV ganciclovir administration. A tivity via inhibition of viral polymerases, such inhibition not
single-dose randomized cross-over pharmacokinetic study being dependent on activation or phosphorylation by viral or
reported the absolute ganciclovir bioavailability after oral cellular enzymes. Foscarnet inhibits DNA chain elongation
valganciclovir administration is 60.9% compared with 5.6% by preventing pyrophosphate exchange.166
bioavailability of oral ganciclovir.162 A randomized cross-over Foscarnet inhibits the DNA polymerase of CMV and other
dose-ranging study determined that plasma levels of ganci- herpesviruses (HSV-1, HSV-2, VZV, and Epstein–Barr virus
clovir after an 875 mg dose of valganciclovir are similar to the [EBV]) and the replication of HIV in vitro and in vivo.167 Both
plasma levels achieved with a dose of 5 mg/kg of IV ganciclo- herpesvirus and HIV replication may be inhibited by therapeu-
vir (AUC 24.8 mg/mL per hour vs. 26 mg/mL per hour). The tically achievable concentrations of foscarnet. Because the drug
authors suggested the 900 mg dose of valganciclovir would is not metabolized and is excreted by the kidney, the dosage
approximate the area under the curve (AUC) value of the must be adjusted for renal insufficiency. Foscarnet also has been
5 mg/kg dose of IV ganciclovir.163 used successfully to treat HIV-infected patients with acyclovir-
Valganciclovir has been studied for induction therapy resistant HSV and VZV infections, in addition to CMV retinitis.
for CMV retinitis. Martin et al. (Valganciclovir Study Group) re- Foscarnet acts directly on the viral polymerase of all herpesvi-
ported a multicenter randomized, controlled clinical trial com- ruses and on the reverse transcriptase of HIV-1. Resistance of
paring oral valganciclovir 900 mg twice a day for 3 weeks’ induc- CMV to foscarnet is associated with mutations in the genes of
tion therapy followed by 900 mg daily for 1 week maintenance these polymerases. Cross-resistance to antiviral drugs is likely to
therapy with IV ganciclovir 5 mg/kg twice a day for 3 weeks’ in- be an increasing problem because of patients with AIDS living
duction therapy followed by 5 mg/kg once daily for 1 week of longer as a result of HAART and because of the drugs used in
maintenance therapy. After 4 weeks, both groups received con- the prophylaxis of various opportunistic infections.
tinued maintenance therapy with 900 mg valganciclovir daily. Foscarnet has been shown to be useful against ganciclovir-
Eighty patients with newly diagnosed CMV retinitis were ran- resistant herpesviruses, such as CMV, because a mutation in
domized to each group in a 1:1 ratio. The primary end point was the DNA polymerase gene conferring resistance to ganciclovir
the photographically determined progression of CMV retinitis and acyclovir differs from the region conferring resistance to
within 4 weeks after the initiation of treatment. In the valganci- foscarnet.168 Foscarnet also is an effective inhibitor of the HIV
clovir group, 9.9% of patients had progression of CMV retinitis reverse transcriptase enzyme and acts in a dose-dependent
within the first 4 weeks compared with 10.0% of patients as- manner. AZT and foscarnet have synergistic activity in vitro
signed to IV ganciclovir. This 0.1 percentage point difference was against HIV, and in vivo foscarnet has activity against HIV as
not significant (95% CI 29.7 to 10.0). Secondary end points measured by surrogate markers.169
included the achievement of a prospectively defined successful The use of foscarnet salvage therapy in patients with CMV
response to induction therapy and the time to progression of retinitis who are intolerant of or resistant to ganciclovir was
CMV retinitis. Seventy-seven percent of patients receiving IV studied in AIDS patients with CMV retinitis who had docu-
ganciclovir and 71.9% of patients receiving oral valganciclovir mented hematologic intolerance or resistance to ganciclovir
achieved a satisfactory response to induction therapy. This therapy. This study showed that in patients intolerant of gan-
5.2 percentage point difference was not statistically significant ciclovir, salvage foscarnet therapy resulted in a longer time to
(95% CI 220.4 to 10.1). The median times to progression of retinitis progression than reported previously in historical
retinitis were 125 days in the IV ganciclovir group and 160 days controls who terminated ganciclovir therapy. In patients who
in the oral valganciclovir group. The relative risk for progression exhibited clinical resistance to ganciclovir, foscarnet appeared
of retinitis in the valganciclovir group compared with the ganci- to have efficacy in controlling retinitis. No significant differ-
clovir group was 0.90 (95 CI 0.58–1.38). Diarrhea was the most ences in either efficacy or toxicity were observed in the range
common adverse effect during the study and occurred more of foscarnet maintenance doses studied.170
frequently in the valganciclovir group compared with the ganci- A large, randomized, multicenter, blinded clinical trial (the
clovir group (19% vs. 10%; p 5.11). Neutropenia occurred with Foscarnet–Ganciclovir Cytomegalovirus Retinitis Trial) com-
similar frequency in each group. Catheter-related side effects pared ganciclovir with foscarnet in the treatment of CMV retini-
were seen more frequently in the IV ganciclovir group than in tis in patients with AIDS. No difference was reported between
the treatment groups in the rate of progression of retinitis; how- administration of probenecid; administration of 1 liter of nor-
ever, the median survival was 8.5 months in the ganciclovir mal saline 1 hour before infusion; and extension of the dosing
group and 12.6 months in the foscarnet group. Excess mortality interval.178
was reported in a subset of patients in the foscarnet group The treatment of CMV retinitis with IV cidofovir was dem-
whose renal function was compromised at entry. Differences in onstrated to be effective in slowing the progression of periph-
mortality could not be explained entirely on the basis of less eral CMV retinitis in patients with previously untreated CMV
antiretroviral therapy in the ganciclovir group, which suggests retinitis and AIDS. IV cidofovir also has been used for long-term
beneficial interactions between foscarnet and antiretroviral nu- suppression of CMV retinitis. Biweekly therapy (after induction
cleosides. These results indicate that, for patients with AIDS and therapy) was reported to have a time to progression of CMV
CMV retinitis, treatment with foscarnet initially offers a survival retinitis of 120 days in one randomized controlled trial179 and
advantage over treatment with ganciclovir, although foscarnet 2.5 months in another randomized controlled trial.180,181 Treat-
was not as well tolerated as ganciclovir.171 ment and subsequent maintenance of CMV retinitis with 20 µg
A marginally prolonged survival seen in patients treated of intravitreously injected cidofovir, given at 5- to 6-week inter-
with foscarnet compared with those treated with ganciclovir vals, also is safe and highly effective.182
may have been because of a direct effect on HIV replication. Treatment with parenteral cidofovir is complicated by
Both drugs had a suppressive effect on circulating p24 antigen, nephrotoxicity, which can be reduced with saline hydration
which was predictive of improved survival. The inhibitory ef- and concomitant administration of probenecid. Despite these
fect on CMV replication also may have a beneficial effect on additional treatments, the long-term reports from the HPMPC
limiting HIV replication.172 Peripheral Cytomegalovirus Retinitis Trial showed a rate of
A randomized, controlled, comparative trial of foscarnet proteinuria of 1.22 per patient-year and a rate of elevated se-
and ganciclovir demonstrated that they equally controlled rum creatinine of 0.41 per patient-year. Thus many patients
CMV retinitis but that foscarnet was associated with a longer may have difficulty tolerating cidofovir for a prolonged time.
survival. Nevertheless, foscarnet was less well tolerated than Neutropenia has also been reported with cidofovir.
ganciclovir, primarily because of the nature of its side effects. Unfortunately, parenteral cidofovir has also been found to
Because foscarnet and ganciclovir have different side effects, have ocular toxicity, including a high incidence of iritis (up to
initial treatment of CMV retinitis should be individualized.173 50%), including recurrent iritis, and a risk for profound ocular
The most frequently reported major adverse effect associated hypotony with vision loss, similar to the iritis and hypotony
with foscarnet administration is nephrotoxicity, with dose-lim- seen with intravitreal injections of cidofovir.183–185 It has been
iting toxicity occurring frequently and cases of acute renal fail- estimated in one study that cidofovir-related iritis developed
ure having been observed. Symptomatic hypocalcemia has in half of patients within approximately 4 months. The long-
been reported and may be responsible for arrhythmias and term reports from the HPMPC Peripheral Cytomegalovirus
seizures, and the risk is increased by concurrent administration Retinitis Trial showed a rate of cidofovir-associated uveitis of
of IV pentamidine. Bone-marrow suppression with neutrope- 0.20 per person-year and a rate of significant ocular hypotony
nia, anemia, and thrombocytopenia can be seen with foscarnet of 0.16 per patient-year.181 Thus, in the setting of iritis in HIV-
administration. Neutropenia was reported to be less common infected patients, use of systemic cidofovir or rifabutin should
with foscarnet than with ganciclovir (14% vs. 34%).171 be considered to be potential causes of iritis, and these drugs
Practical guidelines for the use of foscarnet include admin- may need to be discontinued.
istration through an infusion pump to avoid the potential Nephrotoxicity may be cumulative in some patients and ap-
consequences of overdose or too rapid infusion, adequate pears to be related to toxicity in the proximal tubule. This “se-
hydration of patients with saline loading174 to reduce the risk cretory toxicity” also may be responsible for the hypotony and
for nephrotoxicity, avoidance of administration of other po- iritis that the drug causes when given intravenously or intravit-
tentially nephrotoxic agents, and monitoring of renal function really. The ciliary body and the proximal tubule of the kidney
two or three times per week during induction therapy and have many similarities in terms of the mechanism involved in
once per week during maintenance therapy, with the dosage the secretion of fluids across epithelia. Oral administration of
being recalculated on the basis of patient weight and serum probenecid before and after the IV infusion appears to help
creatinine. Studies of foscarnet doses have suggested that pa- ameliorate the nephrotoxicity of the drug, but the ocular side
tients receiving high maintenance doses (120 mg/kg per day) effects of iritis and hypotony occur despite concomitant pro-
have slower rates of retinitis progression.175,176 benecid administration.
Foscarnet is active against HIV, and studies have shown
that it raises the CD4 count transiently and decreases viral Cytomegalovirus Resistance. Many patients taking chronic
antigenemia (p24 antigen). Because of its efficacy against maintenance therapy for CMV retinitis develop resistant virus.
CMV and HIV, it would appear to be a potentially effective Development of in vitro resistance of CMV to ganciclovir and
agent for treating HIV-infected patients; however, it is cur- foscarnet and disease progression has been shown in several
rently only available for IV administration, and its use is as- small studies,186,187 and mechanisms of resistance to ganciclo-
sociated with substantial toxicity (see previous section).169,177 vir have been described.187 In one prospective randomized
study of 207 patients with newly diagnosed CMV retinitis,
Cidofovir. Cidofovir, or (S)-1-[3-hydroxy-2-(phosphonyl drug-resistant CMV occurred in four of nine ganciclovir-treated
methoxy)propyl]cytosine (formerly known as HPMPC), was patients and in none of five foscarnet-treated patients.133 In
the first antiviral nucleotide analog available for the treatment patients with CMV retinitis and AIDS treated with either oral
of CMV retinitis. Cidofovir is active in uninfected cells, may act or IV ganciclovir, isolates of CMV after a median exposure of
preemptively, and may retain activity against ganciclovir-resis- 75 and 165 days, respectively, showed increasing resistance in
tant strains. Preclinical studies showed the major toxicity of vitro.188 Jabs et al. reported that the cumulative incidence of
cidofovir to be dose-, schedule-, and species-dependent neph- ganciclovir resistance at 9 months was 27.5%.187 Similar inci-
rotoxicity. The concomitant administration of probenecid pro- dence rates of resistance occur for foscarnet and cidofovir.189 In
tects animal models against cidofovir-induced nephrotoxicity. addition, the incidence of resistance to valganciclovir appears
Four treatment modifications are indicated clinically to reduce to be similar to that for ganciclovir.190
the incidence of cidofovir-related nephrotoxicity: dose reduc- Resistance to an anti-CMV drug can be described as pheno-
tion or interruption for changes in renal function; concomitant typic, expressed as an inhibitory concentration 50% greater
than a certain threshold (IC50). This is typically determined ganciclovir sodium at 5 mg/kg intravenously every 12 hours for
via plaque reduction assays, DNA hybridization assays, or an- 2 weeks followed by maintenance at 10 mg/kg per day (ganci- 82
tigen-reduction assays that require large amounts of viable vi- clovir group); or continuation of previous maintenance ther-
rus, often requiring culturing.187,191–193 Genotypic resistance is apy plus induction with the other drug (either ganciclovir or
defined by the presence of a mutation in the CMV genome foscarnet) for 2 weeks followed by maintenance therapy with
conferring resistance to a particular drug. PCR amplification both drugs, ganciclovir sodium at 5 mg/kg per day and foscar-
techniques allow fast detection of resistance-conferring muta- net sodium at 90 mg/kg per day (combination therapy group).
tions in the viral genome, requiring only small amounts of vi- The mortality rate was similar among the three groups. Median
ral nucleic acids and can use nonviable virus.194–196 Low-level survival times were as follows: foscarnet group, 8.4 months;
ganciclovir resistance is typically associated with mutations in ganciclovir group, 9.0 months; and combination therapy
the CMV UL97 gene. UL97 codes for a phosphotransferase that group, 8.6 months (p 5.89). Comparison of retinitis progres-
catalyzes the first step of ganciclovir activation to the triphos- sion revealed that combination therapy was the most effective
phate form. High-level ganciclovir resistance is typically caused regimen for controlling the retinitis. The median times to reti-
by mutations in both the CMV UL97 and UL54 genes. UL54 nitis progression were as follows: foscarnet group, 1.3 months;
codes for the cytomegalovirus DNA polymerase.197 Mutations ganciclovir group, 2.0 months; and combination therapy
in the UL54 gene are also responsible for foscarnet and cidofo- group, 4.3 months (p 5.001). Although no difference could be
vir resistance.197–201 UL54 mutations responsible for foscarnet detected in visual acuity outcomes, visual field loss and retinal
resistance are usually distinct from those causing ganciclovir– area involvement on fundus photographs both paralleled the
cidofovir resistance. Nevertheless, low-grade ganciclovir–fos- progression results, with the most favorable results in the com-
carnet cross-resistance has been reported; Chou et al. reported bination therapy group. The rates of visual field loss were as
a DNA polymerase mutation causing resistance to ganciclovir, follows: foscarnet group, 28 degrees per month; ganciclovir
cidofovir, and foscarnet.187,195–199 group, 18 degrees per month; combination therapy group,
16 degrees per month (p 5.009). The rates of increase of
Treatment Strategies in Resistant Cytomegalovirus. When retinal area involved by CMV were as follows: foscarnet group,
clinically resistant retinitis appears, many clinicians employ 2.47% per month; ganciclovir group, 1.40% per month; and
an alternative antiviral agent systemically; IV cidofovir or fos- combination therapy group, 1.19% per month (p 5.04).
carnet are alternatives. Unfortunately, as previously men- Although side effects were similar among the three treatment
tioned, there can be cross-resistance between CMV isolates groups, combination therapy was associated with the greatest
resistant to ganciclovir and resistant to cidofovir and/or fos- negative impact of treatment on quality-of-life measures. This
carnet; this must be borne in mind in such patients. The prob- study suggests that for patients with AIDS and CMV retinitis
ability of developing foscarnet or cidofovir resistance when whose retinitis has relapsed and who can tolerate both drugs,
taking these drugs appears similar to the rates of development combination therapy appears to be the most effective therapy
of resistance to ganciclovir.189 For this reason, clinicians often for controlling CMV retinitis.158 Small series suggest that com-
employ intravitreal therapies, including the ganciclovir intra- bined intravitreal injections of ganciclovir and foscarnet may
ocular device (GIOD), when systemic therapy begins to fail. be effective in treating CMV retinitis when the infection is
Intravitreal therapies appear to be more effective in such cir- clinically resistant to either intravitreal drug alone.206
cumstances, largely because they deliver higher doses of anti-
CMV medication to the retina.202 In such circumstances, it is Summary of Initial Systemic Cytomegalovirus
recommended to continue to treat the patient with some form
of systemic therapy, often oral valganciclovir, to help prevent Retinitis Treatment
systemic CMV infection or infection of the fellow eye. Studies The initial treatment of CMV retinitis is usually oral valganci-
have shown that treatment with the ganciclovir implant alone clovir 900 mg twice a day for induction therapy of approxi-
is associated with a higher risk for contralateral CMV retinitis mately 3 weeks followed by 900 mg daily for maintenance
and extraocular CMV.203,204 therapy. IV ganciclovir can be used if a patient has a contrain-
dication to oral treatment such as malabsorption. The dose for
Combination Therapies: Ganciclovir–Foscarnet. Several IV ganciclovir is 5 mg/kg twice a day for induction therapy for
studies have shown that combinations of foscarnet and ganci- 2 to 3 weeks followed by maintenance therapy at 5 mg/kg
clovir are more effective in the treatment of recurrent or resis- daily or 6 mg/kg 5 days a week. Induction therapy with IV
tant retinitis than continued monotherapy.105,204 Such combi- foscarnet is dosed at 90 mg/kg twice a day for approximately
nation intravenous therapy also has been shown to be safe 2 weeks followed by maintenance therapy at 120 mg/kg daily.
and effective in children with CMV retinitis.205 Unfortunately, IV cidofovir for induction therapy is dosed at 5 mg/kg weekly
combination IV therapy with these two drugs necessitates for approximately 3 weeks followed by maintenance therapy
multiple IV infusions daily and has a marked negative effect dosed at 3 to 5 mg/kg every 2 weeks.
on patients’ lifestyles. A combination of IV foscarnet and oral
valganciclovir has supplanted this combination IV therapy.
The combination of foscarnet and ganciclovir in patients
Intraocular Therapy of Viral Retinitis
with AIDS and CMV retinitis who have relapsed has been Ganciclovir. Because of the difficulties associated with sys-
shown to be more effective than either agent given alone158; temic ganciclovir, foscarnet, and cidofovir, there is significant
however, combination therapy was associated with the great- interest in local administration. Obviously, intraocular (or
est negative impact of treatment on quality-of-life measures. periocular) treatment will not affect the systemic CMV infec-
To determine the best therapeutic systemic regimen for tion, but in some patients, especially those with systemic tox-
treatment of relapsed CMV retinitis, a multicenter randomized icity resulting from the drug, local administration may have
controlled clinical trial of 279 patients with AIDS and either certain advantages.
persistently active or relapsed CMV retinitis was reported. Pa- In 40 patients with primary CMV retinitis involving 57 eyes,
tients were randomized to one of three therapeutic regimens: all had received one 14-day course of IV ganciclovir, and all
induction with foscarnet sodium at 90 mg/kg intravenously were free of other end-organ CMV disease. All affected eyes re-
every 12 hours for 2 weeks, followed by maintenance at a dos- ceived weekly intravitreal injections of 400 micrograms of gan-
age of 120 mg/kg per day (foscarnet group); induction with ciclovir for maintenance therapy. Median survival of patients
was at least 13 months. Fifteen patients had 19 new opportu- through the preplaced hole (the surgeon must make the hole)
nistic infections during the observation period, but none devel- in the strut of the device; 8–0 Prolene can be used. The device
oped new nonocular CMV disease. Active retinitis recurred in is anchored in the middle of the wound and running or inter-
68.4% of the eyes receiving maintenance therapy, with a me- rupted sutures can be used to close the wound. Astigmatism
dian time to progression of 14.7 weeks. CMV retinitis occurred can result from overzealous wound closure; this is usually tran-
in 30.4% of the previously uninvolved eyes (follow-up 3.1 sient. This procedure can be performed in an outpatient setting
years). Bacterial endophthalmitis complicated treatment in one under local anesthesia.
eye, and retinal detachment developed in five eyes. Thus the Despite the relative ease of insertion, it has become clear
long-term treatment of CMV retinitis with weekly intraocular that the risk for retinal detachment in the first 2 months after
injections of ganciclovir was associated with survival and ocular insertion is substantially higher than if other methods are
outcomes similar to those reported with systemic ganciclovir.207 used to control retinitis; in the long term; however, there is
Intravitreal ganciclovir also was shown to be an effective no statistical difference in retinal detachment rate.213,216–218 In
alternative to systemic ganciclovir in patients with severe neu- addition, the risk for postoperative endophthalmitis appears
tropenia and in patients who chose to continue receiving sys- to be a real one, with incidences on the order of 1% or some-
temic zidovudine or didanosine.208 Injections of high-dose times higher.219 The intravitreal levels attained by this drug are
intravitreal ganciclovir using a 2 mg dose revealed that weekly over twice those after IV administration, and this appears to
2 mg injections appear to offer superior control of retinitis for be associated with a lower incidence of resistance and progres-
periods of months or longer.209 Highly concentrated ganciclo- sion of retinitis. This is particularly true in newly diagnosed
vir solution for intravitreal injection also reduced repeated cases, but failure can occur in up to 25% of such cases within
amaurosis and ocular pain and was reported by patients to the first 2 months. In a study of 91 implants in 70 eyes, GIOD
have improved their comfort and quality of life, thus increas- was effective as an adjunct to continued systemic therapy in
ing their compliance to treatment and reducing side effects, those patients with recurrent CMV retinitis.215 Intraocular
compared with usual protocols.210 sustained-release implants have been used to treat acute CMV
disease and to prevent recurrence. Pathology studies of eyes
Foscarnet. Intravitreal foscarnet at a dose of 2.4 mg per injec- having undergone implantation with the GIOD have shown
tion given one or two times weekly also appears to be a safe no evidence of intraocular toxicity.211 It is not certain whether
and effective treatment method for CMV retinitis. Resistance implants should be exchanged at the 7-month time period or
to this treatment regimen may develop, however.211 High- whether retinitis should be allowed to reactivate before replac-
dose intravitreal foscarnet for CMV retinitis was shown to be ing the implant.
a safe, effective, and useful alternative in patients with intoler-
ance to IV therapy.212 Intravitreal Cidofovir. Another form of intraocular therapy
is intravitreal cidofovir (HPMPC), which is injected every 6
Ganciclovir Intraocular Device. An intraocular sustained- weeks. This work was initiated after the discovery of long-act-
release ganciclovir delivery implant that releases drug into the ing properties of the drug in the eye. The safety and efficacy of
vitreous was previously commercially available.213 These sur- intravitreal cidofovir for CMV retinitis in humans were re-
gically implanted, time-release implants have been shown to ported in a phase I/II unmasked, consecutive case series in a
be more effective than IV ganciclovir alone in delaying the single-center institutional referral practice. Eligible patients
progression of CMV retinitis.144,214,215 with AIDS had active CMV retinitis in at least one eye, despite
Insertion of the device requires a pars plana incision and a adequate IV therapy with ganciclovir or foscarnet, were intol-
partial vitrectomy. The implant is sewn into the pars plana erant to IV therapy, were noncompliant with IV therapy, or
behind the lens.213 Insertion of the GIOD requires trimming refused IV therapy. In a preliminary safety study (group 1),
the strut of the device so that it is nearly flush with the drug 10 eyes of nine patients received 14 injections of cidofovir
pellet. A 5.5-mm incision can be made 4 mm posterior to the while being treated concurrently with IV ganciclovir. In a
limbus with a microvitreoretinal blade or similar instrument dose-escalating efficacy study (group 2), eight eyes of seven
(Fig. 82.11). A unimanual bipolar intraocular cautery can be patients received 11 injections of cidofovir as the sole treat-
used to coagulate bleeding choroid. It is important to ensure ment for CMV retinitis. The primary outcome was time to
that the incision is full-thickness because the device can be retinitis progression. In the group 1 eyes that received 20 µg
inserted inadvertently under the pars plana. A suture is placed of cidofovir, the median time to retinitis progression was
A B
Fig. 82.11 (A) Insertion of ganciclovir intraocular device. (B) The device can be seen inferotemporally through a dilated pupil.
between 49 and 92 days (mean, 78 days). In the group 2 eyes acuity of at least two Snellen lines. Acute intraocular inflamma-
that were treated with 20 µg of cidofovir with probenecid, tion may occur with or without hypotony after IV cidofovir 82
the median time to retinitis progression was 64 days (mean therapy, similar to the reactions seen after intravitreal adminis-
63 days). Hypotony occurred in the two eyes treated with a tration. Cidofovir therapy can be continued in some patients if
100 µg dose of cidofovir and in one of three eyes that received medical necessity warrants, but inflammation may recur or
a 40 µg dose. No adverse effects resulted from the remaining permanent hypotony develop.
20 µg cidofovir injections. Cidofovir was found to be safe and A lower cidofovir dose (10 µg) has been used to investigate
effective for the local treatment of CMV retinitis, providing a methods of reducing the toxicity of intravitreal cidofovir. This
long duration of antiviral effect (Fig. 82.12).220 dose is effective in healing retinitis in 75% of patients, but the
It was then shown that injections of 20 µg of intravitreal response in 25% is inadequate. The 10 µg dose, however, is
HPMPC resulted in complete suppression of CMV replication not associated with a significant incidence of iritis or IOP
with no advancement of retinitis borders when given every lowering. Cidofovir should be diluted in a sterile manner by a
6 weeks.185,220–224 This medication must be given with oral pharmacist. It can be diluted in normal saline and frozen for
probenecid. Probenecid 2 g is given orally 2 hours before, and extended periods in single-dose vials.
1 g 2 hours and 8 hours after injection. The efficacy and safety of cidofovir injections given every
Two types of adverse events may occur after intravitreal 5 to 6 weeks for the maintenance treatment of CMV retinitis
cidofovir injection: iritis and hypotony. The incidence of these with 20 µg intravitreally injected was shown to be highly effec-
is not dissimilar to what is seen after IV administration. The tive, with only rare episodes of reactivation and progression.185
incidence of iritis can be reduced from 70% to 18% if oral A correlation between IOP and CD4 T lymphocyte counts in
probenecid is used, and it is now recommended universally. patients with HIV with and without CMV retinitis has been
Iritis can be managed with topical steroids and cycloplegia; described.225 IOP was measured with calibrated Goldmann ap-
however, it may lead to cataract and synechiae in the long planation tonometers in two groups of patients. Group A in-
term. A mild, asymptomatic 20% reduction in intraocular cluded 84 HIV patients (120 eyes) with CMV retinitis, and
pressure (IOP) is seen almost universally after cidofovir injec- group B included 110 HIV patients (183 eyes) without CMV
tion, and this appears to be of no concern. The mechanism of retinitis; 33 patients without HIV (66 eyes) were included as a
this has been defined by ultrasound biomicroscopy, which has control group. Step-wise regression analysis of IOP included
disclosed that severe hypotony after cidofovir injections is as- correlation with CMV retinitis (presence, extent, and activity),
sociated with ciliary body atrophy.221 Reduction in aqueous CD4 T lymphocyte count, age, and gender. The mean IOP was
flow has been demonstrated by aqueous fluorophotometry. 9.8 mm Hg in group A, 12.6 mm Hg in group B, and 16.1 mm
This effect on secretory epithelia also is probably responsible Hg in the control group. All three groups were statistically dif-
for the nephrotoxicity of the drug when given intravenously. ferent from each other when IOP was compared (p , .0001).
Indeed, probenecid also is given before and after each IV infu- Step-wise regression showed that low CD4 T lymphocyte count
sion to prevent uptake by the proximal tubule of the kidney and extent of CMV retinitis both correlated to low IOP. These
and associated nephrotoxicity. Profound hypotony with results demonstrate that IOP is lower than normal in patients
vision loss occurs in approximately 1% of injections. with HIV and that decreased CD4 T lymphocyte count is the
A retrospective cohort study described iritis and hypotony major factor associated with low IOP, accounting for 20% of the
after treatment with IV cidofovir for CMV retinitis in association effect. The extent of CMV retinitis accounts for 8% of the effect.
with intraocular inflammation.183 Eleven cases of iritis (26%)
occurred among 43 patients. In six cases the iritis was bilateral. Fomivirsen. Fomivirsen, formerly called ISIS 2922, was approved
Patients who experienced iritis were more likely to have been by the FDA in August 1998 for the treatment of CMV retinitis in
previously treated for CMV retinitis (p 5.03), to be diabetic AIDS patients intolerant of or who have a contraindication to
(p 5.05), or to be receiving protease inhibitors (p 5.001). The other CMV regimens or who were insufficiently responsive to
onset of iritis occurred at a mean (6SD) of 4.9 days (6 1.8 days) previous treatments for CMV retinitis. Fomivirsen is the first of a
after a cidofovir dose and after a mean (6SD) of 4.2 doses class of antisense oligonucleotides. This compound possesses
(6 1.6 doses) of cidofovir. Six eyes of four patients had hypot- potent anti-CMV activity but does not target the CMV viral DNA
ony. Five eyes of five patients had a persistent decrease in visual polymerase. Fomivirsen is a 21-base synthetic phosphorothioate
A B
Fig. 82.12 (A) Active cytomegalovirus (CMV) retinitis with no systemic treatment. The eye was injected with a single injection of cidofovir 20 µg
via the pars plana. (B) The retinitis remains healed 53 days later, with no other therapy.
oligonucleotide designed to be complementary to CMV mRNA

that encodes for the major immediate early region (IE2) proteins
of CMV. Binding to this location results in specific inhibition of
gene expression that is critical to the production of essential viral
proteins.226–228
After intravitreal administration, the rate of vitreous clear-
ance of fomivirsen is first-order with a half-life of approxi-
mately 55 hours in humans. Measurable concentrations of
drug are not detected in the systemic circulation after intravit-
real injection, making the interaction of fomivirsen with sys-
temic drugs unlikely. Preclinical studies of fomivirsen by Free-
man et al. suggested that this type of antiviral antisense
compound does inhibit viral replication; however, it did cause
changes in the retinal pigment epithelium (RPE) and intra-
ocular inflammation at doses only moderately higher than the
dose needed to treat retinitis by the intravitreal route.229
The Vitravene Study Group published the data from the
clinical trials involving fomivirsen. Two prospective random-
ized open-label controlled clinical trials (US/Brazilian and Fig. 82.13 Retinal breaks (arrow) are seen just peripheral to the area
EuroCanadian Studies) compared two fomivirsen regimens of border opacification; the retina is detached.
for the treatment of reactivated CMV retinitis or CMV retinitis
that was persistently active despite other anti-CMV treatments.
The more intense schedule (regimen A) included 61 patients retinal detachment in immunosuppressed patients with CMV
(67 eyes) and consisted of three weekly 330 µg (0.05 mL) in- retinitis was believed to be higher in patients treated with anti-
travitreal injections for induction, then 330 µg every 2 weeks CMV therapies, specifically ganciclovir.238,239 These retinal de-
for maintenance therapy. The less intense schedule (regimen tachments were characterized by multiple peripheral breaks in
B) included 32 patients (39 eyes) and used a 330 µg injection areas of healed atrophic retinitis, and in some patients severe
for induction on day 1 and day 15, then 330 µg injections proliferative vitreoretinopathy (PVR) resulted (Fig. 82.13).240
every 4 weeks for maintenance therapy. The study end point Detachment occurred from weeks to months after the institu-
was time to progression based on the masked evaluation of tion of IV ganciclovir therapy and was frequently bilateral. Reti-
serial fundus photos. Eligibility criteria included AIDS pa- nal detachment may also complicate the course of CMV retinitis.
tients with active CMV retinitis who had failed prior treatment It now appears, however, that rhegmatogenous retinal de-
with ganciclovir, foscarnet, or cidofovir.230 tachment is associated with healed or active CMV retinitis be-
In the US/Brazilian study, median time to progression was cause of breaks in the necrotic retina.240 Results of a multicenter
106 days (interpolated median 88.6 days) for regimen A and prospective randomized controlled clinical trial analyzing the
267 days (interpolated median 111.3 days) for regimen B (p 5 incidence and risk factors for rhegmatogenous retinal detach-
.2179 Wilcoxon rank sum test; 0.2950 log rank). In the Euro- ment in a population of patients with newly diagnosed CMV
Canadian study the median time to progression was not deter- retinitis treated with foscarnet versus ganciclovir revealed that
minable for regimen A; only four patients progressed (25th retinal detachment in patients with CMV retinitis is unrelated
percentile 91 days). The median time to progression for regi- to the type of IV therapy used or to refractive error. The median
men B was 403 days (interpolated median 182 days).231 time to retinal detachment in an involved eye with CMV retini-
The safety and toxicity of fomivirsen was also reported by tis and free of retinal detachment at baseline was 18.2 months.234
the Vitravene study group. The most often reported adverse Studies have confirmed that the risk factors for retinal de-
events were anterior chamber inflammation and increased tachment in eyes with CMV retinitis include the extent of pe-
IOP. Retinal pigment epitheliopathy occurred in 5 of 100 pa- ripheral CMV disease, as well as retinitis activity and involve-
tients in the trial for newly diagnosed CMV retinitis with the ment of the anterior retina near the vitreous base.218,238–240 This
330 µg dose; this prompted a change to the reported 165 µg is logical, considering that in most cases the causative retinal
dose used for the remainder of the study. No episodes of reti- breaks are within or at the border of healed CMV retinitis le-
nal pigment epitheliopathy were reported with the 165 µg sions. A report from Studies of Ocular Complications of AIDS
dose. No patients developed retinal pigment epitheliopathy in (SOCA) investigators has confirmed the increased prevalence
the 330 µg less intense regimen. and incidence of epiretinal membranes in eyes with inactive
Independent of the randomized clinical trials, there have extramacular CMV retinitis.241 In addition, any intervention
been reports of Vitravene-induced peripheral retinal toxicity that violates the vitreous (e.g., vitreous biopsy or insertion of
and serious inflammation with vision loss. In clinical practice, the ganciclovir implant) would be expected to accelerate the
fomivirsen has been used as a fourth-line drug for CMV reti- development of vitreous detachment or liquefaction, which
nitis resistant to other therapy. The approved dose of fomi- would increase the risk for retinal detachment.214,216,218
virsen is 330 µg intravitreally every 2 weeks for induction With the advent of HAART the incidence of CMV retinitis-
therapy for two doses followed by 330 µg intravitreally every related retinal detachment has decreased by 60%. The success
month for maintenance therapy. Fomivirsen is no longer of HAART in the reduction of retinal detachment risk may be
available in the United States.232 related to the improved immune control over CMV replication,
thus protecting against progression of disease to larger lesion
Rhegmatogenous Retinal Detachment sizes. The altered pattern of inflammation with HAART-medi-
ated immune improvement may also change the course of vitre-
in Cytomegalovirus Retinitis ous detachment, a key step in the development of CMV-related
Retinal detachment is a common cause of vision loss in patients detachments, thus altering the retinal detachment risk.214,218,242
with CMV retinitis. In the pre-HAART era, the incidence rate of Patients with AIDS and CMV retinitis are surviving longer as
retinal detachment in patients with CMV retinitis was approxi- a result of HAART and improved treatment of opportunistic
mately 33% per eye per year.152,159,218,233–237 The incidence of infections. As a result, although the incidence rate of retinal
detachment is lower, the overall prevalence of retinal detach- syndrome and previously treated CMV retinitis. In these eyes,
ment may become an increasingly common cause of visual PVR occasionally is established at the time of detachment or 82
morbidity in these patients. In the pre-HAART era, the inci- has the potential to occur as a result of multiple retinal breaks
dence and outcomes of retinal detachment complicating and necrosis combined with intraocular inflammation. Scleral
CMV retinitis were studied at two London AIDS centers. buckling alone often is unsuccessful in these cases because of
Patients with CMV retinitis were identified prospectively and the numerous areas of retinal necrosis and break formation.
underwent standard treatment. Retinal detachments were diag- Retinal breaks are often not apparent until the time of vitrec-
nosed during regular follow-up. If retinal reattachment surgery tomy, and the configurations of the retinal detachments are
was performed, a standard procedure of vitrectomy and internal atypical because of peripheral retinal scarring and adhesion to
tamponade with silicone oil was employed. Of 147 patients the pigment epithelium and choroid. Thus in these eyes rheg-
with CMV retinitis, 41 (28%) developed retinal detachments matogenous retinal detachments may not extend to the ora
(47 eyes); 43 detachments were rhegmatogenous and four were serrata. In eyes with CMV retinitis, we have favored an approach
exudative. At the last clinic visit, eight eyes (53%) maintained using complete delamination of the posterior hyaloid com-
a visual acuity of 6/60 or better. The visual results of surgery bined with endodrainage and permanent tamponade with sili-
are good in selected patients, bearing in mind the progressive cone oil, although we have had good success with intraocular
nature of the underlying disease and poor life expectancy.243 long-acting gases in cases of more limited retinitis and retinal
Vitrectomy with silicone oil tamponade also was studied in detachment. Patients with AIDS and CMV retinitis are surviving
eyes with retinal detachments related to CMV retinitis or acute longer, and survival after retinal reattachment surgery has been
retinal necrosis.244 Anatomic reattachment was achieved in all increased to between 6 months to 2 years.240
eyes, and preservation of ambulatory vision was achieved in To determine whether scleral buckling is of any benefit in
most eyes. Visual acuity was limited by concomitant optic nerve surgical repair of CMV-associated retinal detachment if com-
disease in some eyes. The authors noted that surgical repair bined with vitrectomy, silicone oil, and inferior midperipheral
employing silicone oil produces excellent results and that prog- endolaser, 22 consecutive eyes with CMV-associated retinal
nosis for vision is strongly related to preoperative visual acuity. detachments were repaired with vitrectomy and endolaser to
Treatment of retinal detachment consists of vitrectomy, all breaks and to the inferior midperipheral retina using sili-
posterior hyaloid removal, and intraocular tamponade with cone oil without scleral buckling. Results were compared with
silicone oil or long-acting gas.244 Retinal reattachment surgery another series of 56 consecutive eyes undergoing vitrectomy,
in 29 eyes of 24 patients with AIDS and retinal detachment silicone oil injection, endolaser to all breaks, and 360 degrees
associated with CMV retinitis was described by Freeman encircling scleral buckling. Total retinal reattachment rates
et al.245 In this study the total retinal reattachment rate was were 84% for group 1 and 86% for group 2. Rates of macular
76%, and the macular attachment rate was 90% after one reattachment were 91% for group 1 and 91% for group 2.
operation. The mean postoperative visual acuity (best cor- Mean best postoperative refracted visual acuity was 20/66 for
rected) was 20/60, but in some patients visual acuity decreased group 1 and 20/67 for group 2. Median best postoperative
because of progressive CMV retinitis. Prophylactic laser photo- refracted visual acuity was 20/74 for group 1 and 20/80 for
coagulation of fellow eyes did not appear to prevent retinal group 2. These differences between the two groups were not
detachment (Fig. 82.14). statistically significant. Patients who underwent surgery with
The repair of retinal detachment in eyes with viral retinitis is the macula attached had a better postoperative visual out-
complex and is performed using a combination of pars plana come. Thus scleral buckling may not be necessary in CMV-re-
vitrectomy and internal tamponade (usually with silicone oil or lated retinal detachment if repaired with vitrectomy, silicone
a long-acting gas such as perfluorooctane and endolaser, often oil, and inferior midperipheral endolaser.247 Elimination of
combined with scleral buckling).246 Pneumatic retinopexy can scleral buckling may reduce intraoperative time, patient mor-
cause retinal traction and seldom is useful in these eyes. The bidity, and the risk for an accidental needle-stick. Patients
most common causes of rhegmatogenous retinal detachment with macula-on retinal detachments also should be consid-
in AIDS patients with viral retinitis are acute retinal necrosis ered for surgery before macular detachment occurs.248
A B
Fig. 82.14 (A) Preoperatively the macula has been shallowly detached, associated with a rhegmatogenous cytomegalovirus (CMV)-related reti-
nal detachment. (B) Postoperatively the retina is reattached; silicone oil is in place, and the visual acuity is 20/40. Good visual recovery may be
possible even with macula-off detachments because the detachment may be shallow as the vitreous is well formed; the retina may not be com-
pletely detached from the macula, and the macular detachments may be shallow.
constant-pressure, sterile, air-delivery pump. Retinopexy is

placed around all breaks in eyes to be treated with a long-act-
ing gas. The peripheral retina may be encircled with either a
small buckle or a band to relieve vitreous base traction, which
may become a problem later in these inflamed eyes. In eyes
with widespread retinal necrosis, most surgeons use silicone
oil because it permanently tamponades all retinal breaks, in-
cluding future sites of retinal necrosis and break formation.
In the HAART era, PVR may be seen in CMV detachment.
This may be because of immune recovery uveitis causing a
propensity to intraocular inflammation.252–254 The manage-
ment of CMV-related rhegmatogenous retinal detachments has
been reviewed.255 Certainly, it may be useful in acute retinal
necrosis (ARN) because rhegmatogenous retinal detachment
develops in a large number of patients with ARN. Similar con-
siderations apply in bilateral healed CMV retinitis. The diffi-
culty in both diseases is that all areas of retinal involvement
must be surrounded with three rows of argon laser treatment.
Fig. 82.15 Postoperatively, inferior retinal redetachment posterior to It is often impossible to carry out treatment to the ora serrata,
scleral buckle with use of silicone oil. The detachment has been however, and fluid may leak anteriorly and cause retinal de-
walled off by a laser that was applied intraoperatively. Inferior laser tachment despite treatment. In addition, subretinal fluid may
photocoagulation may obviate the need for encircling scleral buckling break through a wall of laser treatment if the mass of detached
in cytomegalovirus (CMV)-related retinal detachments. retina and subretinal fluid is relatively large. For this reason,
most surgeons advocate placement of a pan-retinal type of
pattern within the area of healing retinitis as well.256–258
The long-term visual results of CMV retinal detachment
surgery are still in question, however, and visual acuity may be HIV Disease/Cytomegalovirus Retinitis in the
limited by factors such as refractive problems resulting from
silicone oil and cataract239,249,250 (Fig. 82.15). In addition, pos- Antiretroviral Therapy Era
terior capsule fibrosis is very common if subsequent cataract Since the advent of antiretroviral therapy (ART; previously
surgery is performed in the presence of silicone oil. Methods to known as HAART), many patients have had dramatic restoration
reduce visual acuity loss from cataract include judicious use of of immune system function. This also may be associated with a
gas tamponade with scleral buckling instead of silicone oil and sustained drop in the plasma HIV viral load to low or undetect-
removal of silicone oil before or at the time of cataract surgery. able levels. This suppression of plasma viremia may be pro-
Posterior capsule fibrosis can be treated with Nd:YAG capsu- longed; however, the HIV genome may still be found.38,259 As
lotomy, although success is higher if the silicone oil has been mentioned earlier, with the prevalent use of ART, the incidence
previously removed.251 of CMV retinitis has decreased by approximately 75%.260–263 For
The general operative approach to these eyes is by pars patients with CMV retinitis on ART, the risk for vision loss is
plana vitrectomy, and the surgeon should leave the lens intact lower,260 the risk for retinal detachment is approximately 60%
whenever possible. After the vitreous gel is removed, all epiret- less, and long-term survival is much higher.218,260
inal membranes are segmented and traction is removed, allow- In fact, for patients who have healed CMV retinitis and re-
ing the retina to become mobile. In some cases the peripheral spond to ART, discontinuation of maintenance therapy for CMV
vitreous gel is adherent to the necrotic peripheral retina and disease has been shown to be safe in a subset of patients.260,264–269
cannot be removed without causing further retinal damage. We have found that some of these patients may discontinue
The use of a soft-tipped extrusion needle may allow the sur- anti-CMV therapy without reactivation of retinitis (Fig. 82.16).
geon to remove the posterior hyaloid over broad areas of the These data suggest that ART also is permitting at least partial im-
retina. A posterior retinotomy is made, and if an endoretinal mune reconstitution in some patients. Thus a trial of withdrawal
biopsy is to be performed, it is done at the location of the pos- of CMV therapy may be indicated in some patients with good
terior retinotomy that will be used for internal drainage.240,246 response to ART and well-healed CMV retinitis. Patients should
A pneumohydraulic exchange is made through the retinotomy have a sustained CD4 count elevation of over 100 cells/µL for at
site, attaching the retina and filling the eye with air using a least 3 to 6 months before discontinuing anti-CMV treatment
A B C
Fig. 82.16 (A) Active cytomegalovirus (CMV) retinitis required treatment with systemic ganciclovir. (B) The patient was subsequently treated with
highly active antiretroviral therapy, with increase in CD41 cell count to over 100 cells/µL. The retinitis had remained healed. (C) The patient’s sys-
temic anti-CMV therapy was withdrawn, and the retinitis has remained healed for over 6 months. The CD41 cell count remains over 100.
and should be carefully monitored for reactivation. Reactivation stimulates the immune system. It has been reported that CMV
of CMV retinitis may occur after successful ART if the CD4 count antigens persist in cells of all retinal layers at the borders of 82
diminishes.270 In addition, some patients may develop CMV clinically healed CMV lesions and in CMV-infected retinal glial
retinitis on ART with CD4 counts greater than 100/µL, probably cells after treatment with ganciclovir.295–297
because of incomplete restoration of the immune repertoire Periocular steroids may be used successfully to treat this
against CMV.137 disorder, but ophthalmologists should be aware of CD4 cell
The effects of ART on the natural history of other AIDS-re- counts. It appears that if the CD4 cell count is elevated at greater
lated opportunistic disorders have been summarized271,272 and than 60/µL, treatment of immune recovery vitritis can be car-
reflect the improvement or resolution of changes in the natu- ried out without reactivation of retinitis (see Fig. 82.13).275,290
ral history of these disorders with inflammatory syndromes. One case of reactivated CMV retinitis has been reported after
The development of CMV retinitis relatively soon after initia- treatment of IRU with periocular steroids.298 Intravitreal triam-
tion of ART has been described.272 cinolone is also effective in reducing macular edema; however,
caution is needed not to reactivate retinitis.299
Immune Recovery Uveitis. In conjunction with the dra-
matic improvements in the immune system reported in some
patients on HAART therapy, inflammation at sites of oppor-
Other Complications of Cytomegalovirus Retinitis
tunistic infections is common and related to recovery of im- Central visual loss in AIDS patients with CMV retinitis occurs in
munity with effective antiretroviral therapy.273 The syndrome two forms: direct macular tissue destruction and secondary in-
has been described in the eye as “immune recovery vitritis” or volvement as part of rhegmatogenous retinal detachment. We
“immune recovery uveitis” (IRU).274–281 treated 32 patients (35 eyes) with macular exudation that caused
Immune recovery uveitis appears to occur in eyes with reversible visual loss and initially manifested as neurosensory
healed CMV lesions in patients with immune reconstitution retinal detachment and lipid exudates. Of 35 eyes, 25 showed
on ART. The incidence rate of this phenomenon has varied, papillary or peripapillary active retinitis and 10 showed retinitis
with reports from 0.11 to 0.83 per person-year in ART respond- 1500 to 3000 µm from the fovea. Of 23 eyes with reduced vision
ers with CMV retinitis.278,280 Jabs et al. reported the frequency that were followed up until healing of the retinitis and resolu-
of IRU at 15.5% of 200 prevalent cases of CMV retinitis.281 tion of subretinal fluid and lipid exudates, 22 (96%) showed
Arevalo et al. reported IRU in 37.5% of 32 patients.282 Eyes in visual improvement with anti-CMV treatment. Our findings sug-
which CMV retinitis lesions involve large surface areas of retina gest that macular exudation is a reversible cause of visual loss in
seem to be at higher risk for the development of IRU.283 Previ- patients with CMV retinitis.122
ous treatment with cidofovir may also be a risk factor.284 Pa- Cystoid macular edema can occur in the setting of resolv-
tients with IRU exhibit signs of inflammation such as iritis, ing CMV retinitis in patients with immunodeficiency other
vitritis, macular edema, and epiretinal membrane formation than AIDS. This entity is distinct from serous macular exuda-
(Fig. 82.17).285–289 Cataract, vitreomacular traction, PVR, optic tion, which can occur in patients with AIDS with active CMV
disc and retinal neovascularization, panuveitis with hypopyon, retinitis involving the posterior pole.300
and uveitic angle closure glaucoma with posterior synechia
have also been reported in IRU.290–296 Vision loss from these
inflammatory sequelae may range from mild to moderate and Herpetic Retinitis
is usually associated with macular edema and associated macu-
lar surface changes or cataract in most cases.
Acute Retinal Necrosis in HIV Patients
The pathophysiology of IRU is not well understood. One ARN has been reported in AIDS patients.301,302 It is a devastat-
hypothesis is that once the CMV retinitis is healed and the im- ing disease characterized by the acute onset of a fulminant
mune system is reconstituted, the patient can mount an inflam- panuveitis with confluent, well-demarcated areas of retinitis,
matory response to residual CMV antigens in retinal glial cells in plus prominent anterior uveitis, occlusive retinal and choroi-
or adjacent to the necrotic CMV lesion. Another hypothesis is dal vasculitis, vitritis, and papillitis.55,124,303,304 In most cases
that control of CMV retinitis is incomplete in certain individuals the cause of the clinical syndrome of ARN is VZV, but HSV can
with continued subclinical virus or viral protein production that also cause ARN. The retinitis is characterized by deep retinal
whitening, minimal hemorrhage, and a rapid progression. In
some cases, ARN in AIDS patients may be preceded by VZV
optic neuropathy.305 A history of preceding cutaneous zoster
infection may be helpful in making the diagnosis in such
cases.306,307 In addition, the CD4 count is usually greater than
60/µL.305 Diagnostic criteria for ARN that do not include the
immune status of the patient have been published.308
No evidence of retinal vascular abnormalities may be pres-
ent either clinically or angiographically early in the course of
ARN. Retinal detachment is a common sequela, with multiple
retinal breaks evident within areas of retinal necrosis. Retinal
atrophy, often accompanied by PVR, is a common end-stage
finding, and there may be associated anterior uveitis, scleritis,
and ocular hypotension.124
Large numbers of herpesvirus particles in retinal tissue
affected with ARN have been demonstrated by electron micros-
copy using endoretinal biopsy techniques. Virus may be detect-
able only during the acute phase of the disease.124,309 Necrotic
retinal tissue or retina reduced to thin glial remnants may not
demonstrate virus. The difficulty in growing virus from these
specimens is consistent with the hypothesis of VZV as the caus-
Fig. 82.17 Macular edema in a patient with immune recovery uveitis. ative agent because VZV is difficult to isolate and grow in vitro.
CMV initially was believed to be the presumed infectious agent

of ARN, but subsequent studies have not confirmed this.310
Studies employing endoretinal biopsy and PCR techniques
have enabled definitive identification and culture of the caus-
ative virus, which has important diagnostic and therapeutic
implications. Recent studies have suggested that combination
antiviral therapy given intravenously (usually acyclovir or gan-
ciclovir in combination with foscarnet), if given promptly, can
arrest the disease and salvage vision.204 Retinal detachment in
VZV retinitis is common (up to two-thirds of patients) and may
be associated with PVR or retinal shortening. Repair with vitrec-
tomy and silicone oil after relief of traction with membrane
segmentation and sometimes retinotomy may result in useful
vision.204,311 Prophylactic barrier laser around lesions should be
considered to lower the risk for retinal detachment in ARN.
Ganciclovir has good efficacy against all herpesviruses but
has a lower therapeutic index and must be given indefinitely
because it acts as a virostatic agent. Determination of a specific
viral cause early in the course of the disease when large num-
bers of viral particles are present is therefore imperative. Both
HSV and VZV may be sensitive to acyclovir, but VZV requires Fig. 82.18 Deep, round retinal lesions seen superior to the optic disc
higher serum concentrations than HSV. Treatment for ARN in are characteristic of varicella-zoster retinitis in AIDS patients, also
AIDS patients is usually based on established treatment for termed progressive outer retinal necrosis (PORN) syndrome.
non-HIV-infected patients. Acyclovir intravenously 500 mg/m2
or 10 mg/kg every 8 hours is effective, followed by oral famci-
clovir 500 mg three times a day, acyclovir 800 mg five times a
day, or valacyclovir 1000 mg three times a day for maintenance
therapy.99 Duration of maintenance therapy is controversial,
with reports of contralateral ARN infection decades later. This
may support lifetime maintenance therapy, especially in im-
munosuppressed AIDS patients. Valacyclovir 1000 mg three
times a day has been reported effective for initial treatment of
ARN in a small series of immunocompetent individuals.312 IV
foscarnet may be used in acyclovir resistant cases.313 Corticoste-
roids have been used to decrease vitritis in immunocompetent
patients with ARN, but steroids are usually contraindicated in
HIV patients with advanced immunosuppression.99
Progressive Outer Retinal Necrosis

Progressive outer retinal necrosis (PORN) is another variant of
herpetic retinitis in AIDS patients and is nearly always caused
by VZV. The incidence of PORN has decreased during the ART
era.314 It has been described in association with VZV as the on-
set of retinitis either succeeded by or coincident with an erup- Fig. 82.19 Varicella-zoster retinitis in an HIV patient shows retinal
tion of dermatomal zoster.315 Most patients with this syndrome opacification and perivascular “clearing.” The perivascular edema and
have had low CD4 cell counts (i.e., less than 50/µL). PORN necrosis is cleared first; the tissue is not spared.
syndrome is an extremely rapid progressive necrotizing retinitis
characterized by early patchy multifocal deep outer retinal le-
sions (Fig. 82.18) with late diffuse thickening of the retina, ab- to NLP vision using a regimen of intravitreal ganciclovir and
sence of vascular inflammation, and minimal to no vitreous foscarnet plus IV foscarnet and IV ganciclovir or oral valganci-
inflammation.316 Severe vision loss develops as a result of a clovir. In addition, the authors’ data suggested that laser de-
widespread retinal necrosis and from retinal detachment, the marcation may be beneficial to decrease the rate of retinal de-
latter reported in up to 70% of patients in early studies.316–321 tachment. Combination of antiviral drugs and ART preserved
Perivascular clearing of the retinal opacification is characteristic vision in a report by Kim et al.322
of PORN syndrome (Fig. 82.19).
Therapy of PORN often requires immediate high-dose anti-
zoster or anti-HSV therapy. The earliest reports of treatment of
Nonviral Intraocular Infections in AIDS Patients
PORN with single IV antivirals, primarily acyclovir, showed Nonviral intraocular infections have been reported in AIDS pa-
poor visual results. Engstrom et al. reported final vision of no tients. Autopsy studies have documented numerous infections.
light perception (NLP) in 67% of 63 eyes within 4 weeks.315 Many of the opportunistic infections seen in patients with AIDS
Poor outcomes with IV acyclovir were possibly because of de- can be prevented with appropriate prophylactic agents.323
velopment of HSV or VZV resistance to acyclovir in patients
who developed PORN while on prophylactic anti-HSV therapy
with acyclovir. Recent studies have shown improved visual
Pneumocystis carinii Choroidopathy
outcomes employing combination IV and intravitreal antiviral In 1987 Macher et al.324 described a patient with AIDS with dis-
treatment. Scott et al.316 reported final vision of 20/80 or better seminated pneumocystosis, and choroidal P. carinii (now
in 5 of 11 eyes (45%) with only 2 of 11 eyes (18%) progressing P. jiroveci) was found at autopsy; no clinical correlation was
82
A B
Fig. 82.20 (A) Pneumocystis choroiditis. The round lesions are associated with minimal inflammation. Overlying the lesions in the superior
portion of the macula is a typical cytomegalovirus (CMV) retinitis lesion. (B) Electron micrograph of Pneumocystis carinii organisms seen after
choroidal biopsy.
reported. In 1989 Rao and colleagues59 reported the histopath- may be unilateral or bilateral.59,325–330 P. carinii choroidopathy
ologic findings in an autopsy series of three patients with AIDS appears to be a marker for disseminated pneumocystosis and
who clinically demonstrated yellow choroidal infiltrates while should be treated systemically. The need for maintenance sys-
receiving aerosolized pentamidine for P. carinii pneumonia temic therapy for choroidopathy has not been established.
(PCP) prophylaxis. In two cases a presumptive diagnosis of dis- Although the diagnosis of disseminated pneumocystosis
seminated pneumocystosis was made by ophthalmologic ex- may be suggested by the characteristic appearance of P. carinii
amination. Histopathologically, the choroidal infiltrates were choroidopathy, isolated retinal disease may rarely be the earli-
eosinophilic, acellular, vacuolated, and frothy, with the infil- est clinical manifestation of disseminated pneumocystosis.
trates within the choroidal vessels and choriocapillaris. Both The incidence of P. carinii choroiditis has decreased, probably
Gomori’s methenamine-silver stain and electron microscopy because of more widespread use of systemic PCP prophylaxis
demonstrated organisms. such as trimethoprim–sulfamethoxazole, immune restoration
In 1989 Freeman et al. described a woman with AIDS with from ART, and decreased use of aerosolized pentamidine for
multifocal, slowly enlarging, round-to-oval lesions in the cho- prophylaxis and therapy.327
roid.325 Fluorescein angiography revealed early hypofluores-
cence with late staining of the lesions, which appeared deep to
the retinal circulation, without evidence of retinal involve-
Ocular Toxoplasmosis
ment or inflammation (Fig. 82.20). A transscleral choroidal Toxoplasmosis is a common CNS opportunistic infection
biopsy revealed, by electron microscopy, cystic structures char- in patients with AIDS. Ocular toxoplasmosis is much less
acteristic of P. carinii within necrotic choroid. common,64,331–333 with a reported incidence of 3% in HIV-
A multicenter study of pneumocystis choroidopathy in infected patients in France.334 US incidence is decreased in the
1991 reported 21 patients with AIDS and presumed P. carinii ART era by immune restoration and primary toxoplasmosis
choroidopathy.326 The lesions were characteristically yellow to prophylaxis with TMP–SMX for those with CD4 counts less
pale yellow, appeared in the choroid, and were found in the than 200/mL.99 Eight patients with presumed ocular toxoplas-
posterior pole. They enlarged slowly before systemic antipneu- mic retinochoroiditis were described in 1988 by Holland
mocystis therapy and eventually resolved. Of 21 patients, 18 et al.64 In two cases the diagnosis was confirmed histologically.
were receiving therapy with aerosolized pentamidine. There Lesions were usually bilateral (five of eight) and multifocal,
was little evidence of retinal destruction by visual acuity and with vitreous inflammation noted clinically. Therapy resulted
visual field testing. The choroidal infiltrates were not associ- in remission, but reactivation and disease progression fol-
ated with vitreous inflammation unless another infectious reti- lowed in two of three patients when therapy was stopped.
nitis was present. Resolution of choroiditis took from 6 weeks Three patients had retinal tears or detachment as a result
to 4 months after systemic therapy. Survival after the diagnosis of severe retinal necrosis. The ocular lesions were the first
ranged from 2 to 36 weeks. manifestation of toxoplasmosis in four of five patients with
The CDC recommends double-strength trimethoprim– disseminated disease, although all patients had preexisting
sulfamethoxazole (TMP–SMX) daily or three times weekly for HIV infection, and in four the diagnosis of AIDS had not been
primary prophylaxis of PCP when CD4 counts are below 200/ made. In four of five patients with no evidence of nonocular
mL, with alternatives including dapsone, dapsone plus pyri- infection, evidence of Toxoplasma was demonstrated in the
methamine and leucovorin, aerosolized pentamidine admin- CNS (encephalitis or brain abscess). No patient had evidence
istered by the Respirgard II nebulizer, and atovaquone.327 PCP of preexisting chorioretinal scars, and all had immunoglobu-
is the most common AIDS-defining opportunistic infection. lin G (IgG) antibodies to T. gondii at the time of diagnosis.
Choroidal P. carinii infection appears to have been more com- Ocular disease was believed to be secondary to reactivation of
mon when the prophylactic use of nonsystemically absorbed Toxoplasma or to newly acquired or newly disseminated dis-
aerosolized pentamidine for PCP was widespread. The choroi- ease to the eye from nonocular sites of disease (Fig. 82.21).
dal lesions of P. carinii appear as pale, cream- or orange- Retinal toxoplasmosis in HIV infection may present as a focal
colored, space-occupying lesions from several hundred to necrotizing nonhemorrhagic retinitis that does not heal sponta-
several thousand micrometers in size and they rarely are neously and may simulate ARN, CMV, or syphilitic retinitis.99,335
symptomatic or lead to a decrease in visual acuity. The lesions Prominent vitreous and anterior chamber reaction, relative
A B
Fig. 82.21 (A) Toxoplasmosis retinitis in an HIV patient who was healed after antitoxoplasmosis therapy with clindamycin. (B) Systemic
treatment for toxoplasmosis was withdrawn 6 months later, and the retinitis reactivated.
absence of retinal hemorrhage, and thick, densely opaque Toxoplasma retinitis is decreasing because of more wide-
yellow-white lesions with smooth nongranular borders suggest spread use of HAART and of prophylaxis, such as TMP–SMX.
toxoplasmosis. Endoretinal biopsy or PCR techniques may be Currently the CDC recommends considering discontinuing
useful if diagnosis is difficult.99,336,337 maintenance therapy (sulfadiazine plus pyrimethamine/leu-
Ocular toxoplasmosis often presents differently in AIDS covorin with clindamycin used in sulfa-allergic patients) for
compared with immunocompetent individuals, spreading as a toxoplasma encephalitis if a patient maintains a CD4 count
contiguous or multifocal retinitis. AIDS patients more often greater than 200/µL for greater than 6 months.
have extensive areas of retinal necrosis plus multiple areas of
active infection.338,339 Histopathologic studies show absent to
scant inflammatory cells in the infected retina of immunocom- FUNGAL DISEASES
promised patients. AIDS patients can develop ocular toxoplas-
mosis in the absence of preexisting chorioretinal scars. This
Candida albicans
pattern, combined with frequent systemic toxoplasmosis at di- Because HIV can be a consequence of IV drug use, which is
agnosis, suggests that acquired disease is more common than also associated with candidemia, it is surprising that candida
reactivation of congenital disease.99,340 For immunocompetent endophthalmitis is not seen more frequently in HIV patients.
individuals, current evidence also suggests that most patients Focal retinal and chorioretinal lesions and endophthalmitis
with ocular toxoplasmosis were infected postnatally, even from Candida spp. have been described in patients with
though the risk for ocular toxoplasmosis is higher from con- AIDS.56,348 Traditional therapy for candida endophthalmitis
genital infection341 (see Fig. 82.21). Ocular toxoplasmosis in has been systemic amphotericin B. Nevertheless, limited vitre-
AIDS patients has also been reported to cause miliary disease, ous penetration has resulted in treatment failures, plus ad-
optic neuritis, panophthalmitis, and acute unilateral iridocycli- verse effects including nephrotoxicity discourage its use.349
tis without retinal lesions.342,343 Ocular toxoplasmosis is diag- Trials comparing oral fluconazole to IV amphotericin B for
nosed clinically and using PCR from a vitreous fluid sample. systemic candidemia in immunocompetent patients suggested
Ocular, as well as disseminated, toxoplasmosis in patients equivalent efficacy with fluconazole being the less toxic.350
with AIDS is treated with standard antitoxoplasma regimens Vitrectomy and intravitreal amphotericin B or voriconazole
used in immunocompetent patients such as sulfadiazine can be helpful in cases failing systemic therapy.
(4–6 g/day) or clindamycin in sulfa-allergic patients plus pyri-
methamine/leucovorin, with apparent response rates of 80%.
TMP–SMX was reported in a small (77 patients) randomized
Cryptococcus neoformans
trial to be effective and better tolerated than pyrimethamine– Cryptococcal infections may occur in 5% to 10% of patients with
sulfadiazine.344–346 Other treatments for patients unable to AIDS351 and are associated with both direct and indirect ocular
tolerate sulfa drugs such as azithromycin or atovaquone have complications. Cryptococcal infection is a common occurrence
been primarily studied for CNS toxoplasmosis in AIDS patients in AIDS, resulting in meningitis and secondary ocular involve-
and ocular toxoplasmosis in immunocompetent patients.347 ment. Chorioretinitis, endophthalmitis, or both, caused by direct
Atovaquone was originally synthesized as an antimalarial and intraocular invasion of the organism, have been described in im-
has been shown to have activity against both P. carinii and munosuppressed patients.352,353 Visual loss caused by cryptococ-
T. gondii. Ocular toxoplasmosis in patients with AIDS fre- cal infection has been demonstrated to result from invasion of
quently recurs when medical therapy is terminated, so mainte- the visual pathways, including the optic nerve, tract, and chiasm.
nance therapy generally is given. Corticosteroids may be given as The treatment of cryptococcal disease in patients with AIDS usu-
adjunctive therapy for intracranial toxoplasmosis to reduce cere- ally consists of an “induction” phase of about 2 weeks followed
bral edema, although this is unproved; systemic corticosteroids by a “consolidation” phase of about 8 weeks. Amphotericin B
are sometimes given to reduce inflammation in ocular disease, (.7 mg/kg per day) is most commonly used for induction, if
although these should be administered cautiously in HIV- possible combined with 5-flucytosine 100 mg/kg daily in four
infected patients. In addition, resolution of ocular toxoplasmosis divided doses. If necessary because of toxicity, amphotericin can
in AIDS patients has been seen without corticosteroid therapy.64 be replaced by fluconazole (800–1200 mg/day); a third phase of
prolonged maintenance therapy with oral fluconazole (200 mg/ in fungal endophthalmitis. As a result, vitrectomy and intravit-
day) is continued unless CD4 counts are greater than 200/µL. real amphotericin B is usually recommended in serious fungal 82
Ophthalmologic complications of cryptococcal meningitis were endophthalmitis or cases unresponsive to systemic therapy.364
seen infrequently before the description of AIDS. The triazole antifungal medications fluconazole, itracon-
azole, voriconazole, posaconazole, and ravuconazole are
orally available and are less toxic drugs that can treat a variety
Histoplasmosis of fungal organisms.365–369
Histoplasmosis was initially reported in patients with AIDS in Older drugs, such as fluconazole, which treats candidal and
1982, and in the next 8 years more than 100 systemic cases cryptococcal infection, and itraconazole, which treats histo-
were reported,354 mostly disseminated disease that presents as plasmosis and aspergillosis, remain valuable. Voriconazole
fevers without localized symptoms. The treatment of histo- has been shown to have mean aqueous and vitreous mini-
plasmosis in patients with AIDS usually consists of an induc- mum inhibitory concentrations for 90% of isolates (MIC90)
tion phase with amphotericin B followed by a lifelong main- for a wide spectrum of yeast and molds, including Candida
tenance phase with either amphotericin B or itraconazole.355 and Aspergillus spp. after oral administration. Voriconazole
Gonzales et al. reported bilateral endogenous endophthal- and posaconazole have also been reported to successfully treat
mitis in an HIV-positive patient presenting with severe subreti- fungal endophthalmitis that was unresponsive to traditional
nal exudation, choroidal granulomas, and intraretinal hemor- antifungal agents.370 Voriconazole and posaconazole have
rhage leading to bilateral exudative retinal detachments. been shown to have efficacy against Candida albicans isolates
Vitreous cultures grew Histoplasma capsulatum var. capsulatum. from HIV patients.369
Treatment involved systemic and bilateral intravitreal ampho-
tericin B plus vitrectomy/scleral buckle in one eye.356 Ala-
Kauhaluoma et al. reported a case of panuveitis in dissemi- BACTERIAL RETINITIS
nated histoplasmosis in an HIV patient treated with liposomal
amphotericin B, HAART, and topical steroids that ended up
Syphilis
with anterior segment scarring.357 Concurrent ocular syphilis appears to be more common in
HIV-infected than in uninfected persons. Ophthalmic manifes-
tations of syphilis usually occur during or shortly after the sec-
Aspergillosis ondary stage. Syphilitic (luetic) uveitis and chorioretinitis in
Endogenous endophthalmitis caused by Aspergillus fumigatus HIV-infected patients have been described. Nine patients with
rarely has been described in AIDS and can arrive in the eye ocular syphilis and concurrent HIV infection were described by
hematogenously or through extension to the orbit from adja- McLeish et al. in 1990.371 They found iridocyclitis in 3 of 15
cent sinuses. One case of disseminated, invasive aspergillosis eyes, vitritis in one eye, retinitis or neuroretinitis in five eyes,
with ocular involvement noted at autopsy was described in 13 papillitis in two eyes, optic perineuritis in two eyes, and retro-
patients with pulmonary aspergillosis; no clinical correlation bulbar neuritis in two eyes. The three of nine patients with AIDS
of ocular findings was reported.358 Whereas four cases of or- had the worst initial visual acuities. Six of nine had concomi-
bital aspergillosis in HIV were reported, ocular aspergillosis is tant neurosyphilis. Benzathine benzylpenicillin, the only treat-
very rare in the HIV population.359,360 ment in three of the patients, led to relapses in all three. Seven
of nine patients treated with high-dose IV penicillin responded
dramatically to therapy with no evidence of relapse.
Coccidioidomycosis Concurrent ocular syphilis and neurosyphilis reported in
To our knowledge, only one case of ocular coccidioidomycosis two patients with HIV infection, in addition to a review of 13
has been described in a patient with AIDS.65 In a retrospective other HIV-infected patients with ocular syphilis, revealed that
review of 77 patients with HIV infection and coccidioidomyco- 11 of the 13 HIV-infected patients with ocular syphilis had
sis, no case of endogenous endophthalmitis secondary to coc- neurosyphilis.372 The authors stress that neuro-ophthalmic
cidioidomycosis was described, although disseminated disease syphilis may be the presenting feature of HIV infection and
(including meningitis) was described in a majority of pa- that ocular syphilis is strongly associated with concurrent neu-
tients.361 Other unusual mycotic infections causing endo- rosyphilis in patients that are HIV-seropositive (Fig. 82.22).
phthalmitis, some in association with chorioretinitis, but not Necrotizing retinitis occurs frequently in patients with HIV
necessarily HIV-seropositive patients, are reviewed by McDon- and syphilis. In some cases, the appearance of luetic retinitis as
nell and Green.362 a focal expanding white lesion may simulate CMV retinitis,
ARN, or toxoplasmic retinitis. Marked inflammation of the vit-
reous and anterior chamber usually accompanies syphilitic reti-
Paracoccidioidomycosis nal disease with posterior synechiae and keratic precipitates.373
Severe CNS plus ocular infection with Paracoccidioides brasil- Standard treatment of primary and secondary syphilis with
iensis that simulated CNS and ocular toxoplasmosis was re- 2.4 million units of intramuscular benzathine penicillin in pa-
ported in a pregnant HIV-positive patient. The infection tients with and without HIV infection produce similar excellent
caused severe iridocyclitis, vitritis, plus a granulomatous cho- clinical responses. Serologic responses to therapy (reducing
rioretinal lesion also involving the optic nerve that ultimately nontreponemal antibody to unreactive levels), the primary
progressed to retinal detachment, NLP vision, and enucle- method for ascertaining adequate treatment, are less certain in
ation despite treatment.363 HIV patients.374
For retinitis, treatment for neurosyphilis with IV penicillin
should be used, and ceftriaxone may be used when penicillin
Advances in Antifungal Therapy is contraindicated. With regard to diagnosis, false-negative
Fungal endophthalmitis traditionally has been treated with IV serum rapid plasma reagin (RPR) and Venereal Disease Re-
amphotericin B. Limitation of vitreous penetration and sys- search Laboratories (VDRL) tests may occur uncommonly
temic toxicity limit its effectiveness. Flucytosine and flucon- with HIV infection. Thus additional, more specific tests are
azole have higher vitreous penetration but are limited by lack recommended in this population (i.e., fluorescent treponemal
of broad coverage against many of the organisms typically seen antibody, absorbed [FTA-ABS]).375
best; they can be frozen for later evaluation or processed fresh.

In cases of active retinitis, the test is very sensitive, although it
may be somewhat nonspecific because it may detect CMV in
the blood in the absence of retinal infection. Choroidal biop-
sies may be indicated when infiltrative processes of the cho-
roid are seen clinically. Fungal, bacterial, protozoal, or para-
sitic disease may cause metastatic focal or diffuse infiltrative
lesions in the choroid. Tuberculous disease and neoplastic
disorders, including lymphoma, also may produce such le-
sions. All such diseases respond temporarily, if at all, to ste-
roid therapy, and in many cases the diagnosis cannot be made
by study of vitreous cells. Before undertaking this diagnostic
procedure, prior arrangements for appropriate histologic ex-
amination of all materials obtained must be made because the
amount of material that can be obtained is usually small. Any
cultures to be taken should be performed by direct plating of
the tissue onto the appropriate media in the operating room,
as previously outlined.
Thorough preoperative examination of the posterior seg-
ment is necessary. The choroidal lesion to be biopsied must be
well localized. Echography can be used to gain further infor-
Fig. 82.22 Papillitis and vitritis from syphilis in an HIV-positive
mation regarding the consistency of the lesion and the pres-
patient. Intravenous penicillin resolved the findings.
ence of subretinal or suprachoroidal fluid. It can also be useful
in determining whether an intraocular lesion has extraocular
extension. It is best to select a site distant from the macular
INVASIVE DIAGNOSTIC TECHNIQUES area; a nasal area of involvement is best.
In the operating room, the conjunctiva is removed from
FOR RETINAL DISEASE the limbus 360 degrees, and all four rectus muscles are iso-
In difficult cases, biopsy of the vitreous, choroid, or retina may lated. Tenon’s capsule is cleaned from the quadrant to be bi-
allow for diagnosis of retinal disease. Vitreous biopsy may opsied, and the margins of the lesion are marked. It is advan-
yield a diagnosis if a moderate to heavy cellular infiltrate is tageous to choose a site where a serous or exudative retinal
present. Most modern vitrectomy machines use sterile, dispos- detachment is present overlying the lesion in question be-
able tubing and cassettes so that vitreous washings obtained cause this provides an added margin of safety. A half-thickness
are sterile. These washings may be filtered or centrifuged for scleral dissection is performed 5 to 10 mm2 and fashioned
appropriate stains, cultures, and cytologic study. into a “trap door.” Preplaced 5–0 polyester sutures can be
An alternative method may be used to obtain undiluted used to allow the trap door to be closed quickly. A smaller area
vitreous at the time of pars plana vitrectomy. After the infu- of underlying sclera is closed by diathermy to prevent bleed-
sion cannula can be visualized within the eye, the cannula is ing, and then an area 3 to 4 mm on each side is resected. Care
connected to a sterile, constant-air infusion pump, and a vit- is taken to remove choroid and not retina. The trap door is
rectomy is carried out under air. In phakic eyes, a minus- then closed with 5-0 polyester sutures, and the area of resec-
power contact lens is used to visualize the retina under air. In tion is examined with the indirect ophthalmoscope. Some
this way the entire volume of the vitreous cavity may be re- sclera should be visible if a full-thickness choroidal biopsy
moved in an undiluted form for study. was performed. Retinal incarceration in the biopsy site is a
Appropriate processing of vitreous obtained as part of a potential source of problems and may have to be addressed
diagnosis is mandatory, and the testing performed should re- using internal pars plana surgical techniques. Vitreous in the
flect the differential diagnosis. Where infection is suspect, plat- biopsy implies retinal incarceration or a retinal break that
ing of undiluted vitreous on appropriate culture media for must be repaired using pars plana vitrectomy techniques. Us-
aerobic bacteria (chocolate and blood agar, brain–heart me- ing this technique, embolic bacterial endophthalmitis, pneu-
dia), anaerobic bacteria (thioglycolate media and cooked meat mocystis choroidopathy, and other pathologic entities may be
broth), media for acid-fast bacilli, and fungal culture media is diagnosed. Because of the potential to damage the retina or
imperative and should be done in the operating room. Smears perforate the eye, in some cases it may be preferable to per-
of the undiluted gel should be stained for these etiologic form a pars plana vitrectomy before choroidal biopsy. This
agents, and cytologic smears also should be obtained. In addi- will allow for maintenance of intraocular pressure, as well as
tion, histopathologic stains are useful for ruling out intraocular rapid internal access to the retina should complications arise.
neoplasms, particularly intraocular lymphoma. Other impor- Endoretinal biopsy has been reported to be of value in the
tant diagnostic aids include the use of cytospin preparations diagnosis of viral retinitis. Freeman et al.124 first reported this
that concentrate the cells in vitreous washings, and the use of technique in 1986. We pursued this technique in patients with
cell blocks, should enough cellular material be present in a CMV retinitis (Fig. 82.23). After healing of retinitis with gan-
vitreous specimen. The choice of fixatives should be consid- ciclovir, rhegmatogenous retinal detachment developed in a
ered carefully. In general, the use of electron microscopic fixa- large number of these patients as a result of numerous breaks
tives such as glutaraldehyde may destroy the antigenicity of in areas of necrotic and healed retina. We showed in several
proteins, rendering immunostaining impossible. Buffered eyes that persistent infection was present, as viral particles
paraformaldehyde will preserve many antigens, although in were seen. At this time we do not recommend endoretinal
some cases, frozen, nonfixed tissue is required. In situ hybrid- biopsy for all cases of viral retinitis. Rather, we treat such cases
ization may work on fixed or fresh tissue and can be valuable with the appropriate antiviral drug and await a response. The
in determining the presence of pathogenic DNA.376 response may not indicate a specific viral cause, however, be-
PCR techniques also may be useful in analyzing aqueous cause some drugs treat multiple viruses. In certain cases it is
or vitreous specimens in difficult cases. Nonfixed fluids are helpful to obtain an etiologic diagnosis. As new antiviral and
is elevated to the high position. In this way the tissue is hydrau-

lically directed into the sclerotomy site and plugs it. The tissue 82
is gently teased out of the sclerotomy with a 0.12 mm forceps
and spread over the cornea, removing all folds.
Any ocular tissue, but particularly small endoretinal biopsy
specimens, must be processed with care. The surgeon must
decide in advance on the location of the area to be biopsied
and the fixatives and numbers of specimens to be processed.
We have developed a mount that allows for more facile
mounting of retinal biopsy specimens.376 The agar–albumin
sandwich technique allows the small piece of retinal tissue to
be floated onto a slab of clear agar and then “glued” to it with
liquid agar that has been warmed in a microwave oven. When
the tissue is draped on the agar, it can be readily identified and
not lost during processing. Multiple sections of the tissue can
then be cut for processing and immunostaining. The tech-
nique also works well for electron microscopy and other mor-
phologic studies.
Fig. 82.23 Retinal lymphoma in an HIV-positive patient can present ANTIRETROVIRAL THERAPY
as an atypical retinitis. Diagnosis was made by endoretinal biopsy. Expert guidelines for use of these drugs are continuously up-
dated.377,378 Many other antiretroviral agents are undergoing
preclinical and clinical studies. Currently available drugs do
not eradicate latent HIV infection, which returns when drugs
immunostimulating drugs become available, viral retinitis are stopped (see Table 82.1). When used in combination, they
may not take on the so-called “classic clinical appearance,” usually decrease viral replication, improve immunologic sta-
and aggressive diagnostic techniques may become more im- tus, reduce the risk for infectious complications, and prolong
portant. Currently we obtain endoretinal biopsies at the time life. Retinopathy has been associated with HAART.379 Drugs
of pars plana vitrectomy to repair rhegmatogenous retinal active against the patient’s HIV strain should always be used in
detachments in these patients. During these procedures, undi- combination for full potency and prevention of resistance.
luted vitreous specimens are taken for viral cultures, and in
some cases in situ nucleic acid hybridization studies are done.
The retinal biopsy (described later) is divided into three small
REFERENCES
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Mortal Wkly Rep 1991;40:787.
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HIV-Associated Infections: Inflammatory Disease/Uveitis

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HIV-Associated Infections: Inflammatory Disease/Uveitis

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OUTLINE Ocular involvement occurs in up to 73% of AIDS pa-

Fig. 82.2 Photomicrograph of retinal cotton-wool spot shows cytoid

Fig. 82.3 White, centered retinal hemorrhage (Roth spot) seen in an

or leukopenia, retinitis, or hepatitis; blood cultures and urine

Fig. 82.4 Cytomegalovirus (CMV) retinitis with hemorrhagic areas are

oligonucleotide designed to be complementary to CMV mRNA

constant-pressure, sterile, air-delivery pump. Retinopexy is

CMV initially was believed to be the presumed infectious agent

Progressive Outer Retinal Necrosis

best; they can be frozen for later evaluation or processed fresh.

is elevated to the high position. In this way the tissue is hydrau-

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