JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS

Volume 33, Number 4, 2017

ª Mary Ann Liebert, Inc.
DOI: 10.1089/jop.2016.0140

Cytomegalovirus Retinitis:
A Review

Alexander D. Port, Anton Orlin, Szilard Kiss, Sarju Patel, Donald J. D’Amico, and Mrinali P. Gupta

Abstract

Cytomegalovirus (CMV) is a ubiquitous DNA herpes virus that causes significant morbidity and mortality in
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immunocompromised individuals. CMV retinitis is a potentially blinding manifestation of CMV infection that
was commonly seen in advanced acquired immunodeficiency syndrome (AIDS) in the era before modern
combination antiretroviral therapy era, but is also recognized in patients with immune deficiency from multiple
causes. The advent of and advances in antiretroviral therapies for human immunodeficiency virus have de-
creased the incidence of CMV retinitis by over 90% among AIDS patients, and improved visual outcomes in
those affected. The diagnosis is generally a clinical one, and treatment modalities include systemic and in-
travitreal antiviral medications. Retinal detachment and immune recovery uveitis are sight-threatening com-
plications of CMV retinitis that require specific treatments.

Keywords: cytomegalovirus, retinitis, immune recovery uveitis

Introduction individuals, reactivation can cause frank CMV infection

C ytomegalovirus (CMV) is a ubiquitous, enveloped,
double-stranded DNA virus in the Herpesviridae family.1
Within the United States, seroprevalence is estimated to be
*60% overall, and rises with age, ranging from 36.3% in
children ages 6–11 years to 90.8% in adults 80 years and older.2
Primary CMV infection is typically mild or asymptomatic
in young, healthy individuals. However, CMV infections
can have devastating effects in the setting of congenital
infection and in immunocompromised individuals.
CMV is spread through person-to-person transmission in
bodily fluids, but may also be transmitted in donor organs
from CMV-positive donors. At the outset of CMV infection,
the viral DNA is transfected into the host cell’s nucleus.
Typically, this leads to transcription of viral DNA and
production of viral particles, which in turn activates an
immune response. However, in CD34+ myeloid precursors,
specific DNA-binding proteins within the nucleus bind to
the viral DNA promoter regions and block transcription and
production of viral particles, thus inducing a latent infec-
tion.1 These myeloid precursors produce monocytes and
tissue macrophages that disseminate latent infection
throughout the body. During times of monocyte activation,
transcription is upregulated and CMV viral particles may be
transiently produced. In the immunocompetent host, viral
reactivation is kept in check, but in immunocompromised
with serious morbidity and mortality. CMV infection in the
eye has been associated with anterior uveitis and corneal
endotheliitis, but the most well-known and dreaded com-
plication is the potentially blinding chorioretinitis.1
Epidemiology
CMV retinitis is primarily a disease of immunocompro-
mised hosts, occurring in neonates, bone marrow and solid-
organ transplant recipients, and persons with acquired im-
munodeficiency syndrome (AIDS) from the human immu-
nodeficiency virus (HIV). Rarely, CMV retinitis occurs in
individuals immunocompromised from other causes, in-
cluding malignancy, systemic immunosuppressive therapy,
primary immunodeficiencies, and intravitreal corticosteroid
injections.3–10 In patients with AIDS, CMV retinitis is the
most common opportunistic ocular infection. It is an AIDS-
defining illness, occurring primarily in infected individuals
with CD4 T lymphocyte counts <50 cells per microliter. The
Longitudinal Study of Ocular Complications of AIDS
(LSOCA) found that CD4+ T cell count below 50 cells/mL
was the single most important risk factor for the develop-
ment of CMV retinitis (hazard ratio 136, 95% confidence
interval 30–605, P < 0.0001).11
Advances in the management of HIV with combination
antiretroviral therapy (cART) have significantly reduced the

Department of Ophthalmology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York.

224
 CYTOMEGALOVIRUS RETINITIS: A REVIEW
incidence and morbidity of CMV retinitis in the HIV pop-
ulation. In the pre-cART era, the lifetime risk of CMV
retinitis was estimated to be 30% among persons with
AIDS.12 CMV retinitis was associated with significant oc-
ular morbidity, with a rate of 52–98 events per 100 eye-
years for visual acuity worse than 20/40 and 19–49 events
per 100 eye-years for visual acuity worse than 20/200.13
Following the introduction of cART therapy, the incidence
of CMV retinitis has declined sharply among patients with
HIV/AIDS. Visual morbidity has also declined, with the rate
of bilateral blindness (vision loss to 20/200 or worse) from
CMV retinitis decreasing from 14.8/100 person-years in
the pre-cART era to 0.4/100 person-years in the modern
era.11,12,14. LSOCA studies early in the cART era14 found
that CMV retinitis accounted for 40% of vision loss of
20/200 or worse in AIDS patients. In light of the decreasing
incidence of CMV retinitis among AIDS patients as well
as the decreased rates of blindness in AIDS patients with
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CMV retinitis,11,12,14 the contribution of CMV retinitis to
blindness in the AIDS population likewise may be de-
creasing. Severe vision loss typically occurs as a result of
macular or optic nerve involvement or retinal detachment
(RD). In the modern cART era, patients with immune
recovery have significantly reduced ocular morbidity
compared with those without immune recovery, and also
have a lower mortality than those without immune re-
covery. cART decreases the risk of RD by 60%–75% in
those without immune recovery to 2.7–8.7/100 eye-years
and up to 95% in the eyes of patients with immune re-
covery to 1.0–1.3/100 eye-years.12,14 In a long-term study
of patients with CMV retinitis, patients without immune
recovery had a mortality of 44.4/100 person-years and a
median survival of 13.5 months after diagnosis, compared
with a mortality of 2.7/100 person-years in patients with
immune recovery, who had an estimated mean survival of
27 years after diagnosis.12
Among solid organ transplant recipients, the greatest risk
of developing CMV infections occurs in CMV-negative
individuals who receive organs from CMV-positive donors.
These patients lack T cells primed to respond to CMV in-
fection and often require lifelong immune suppression to
treat or prevent graft rejection. As such, these patients are
unable to mount an immune response to CMV infection and
require CMV prophylaxis following organ transplantation.
In this setting, active CMV disease often occurs when
prophylaxis is stopped, at a median of 9 months after
transplantation, and is often bilateral.1
Conversely, among allogeneic bone marrow transplant
recipients, the greatest risk of CMV retinitis is among CMV-
positive patients with CMV-negative donors.15 In these
cases, the recipients’ bone marrow (and T cell immunity to
CMV) is depleted pretransplantation and replaced by the
donor immune system and T cells, which are CMV naive.
The risk is potentiated by the need for immunosuppression
either for maintenance or consolidative chemotherapy for
the cancer itself and/or to treat or prevent graft versus host
disease. The median onset is 8 months following transplant.1
Recently, the use of intravitreal steroids has been recog-
nized as a risk factor for the development of CMV retinitis
in otherwise immunocompetent patients. Cases of CMV
retinitis have been reported in patients receiving intravitreal
steroid injections or steroid implants for diabetic retinopa-
thy, uveitis, and vein occlusions.3–6,16
225
Clinical Manifestations
CMV infection reaches the eye through hematogenous
spread.17 Histologically, CMV retinitis appears as areas of
full-thickness retinal necrosis and edema or exudative de-
tachment.18,19 Clinically, there are several recognized oph-
thalmoscopic patterns of CMV retinitis: wedge-shaped areas
of whitening with associated hemorrhage (brush-fire)
(Fig. 1), variable small dot-like lesions (granular type), or
rarely, retinal vasculitis with perivascular sheathing (an
atypical manifestation with clinical appearance similar to
frosted branch angiitis).18,20–22 CMV retinitis typically be-
gins in the peripheral retina and progresses centrifugally
toward the posterior pole at an average rate of 24 mm per
day.20,21 Significant visual impairment is caused by retinal
necrosis involving the macula or optic nerve (zone 1 dis-
ease).14,20,21 Vision loss or blindness may also occur as a
result of RD, cataract formation, or epiretinal membrane.14
CMV retinitis is a clinical diagnosis, based on the classic
appearance of lesions in susceptible individuals.23 In cases
where the diagnosis is unclear, CMV polymerase chain re-
action (PCR) may be performed on aqueous samples, and is
highly correlated with active retinitis.24 Fundus photography
may have utility for screening and monitoring CMV retinitis
and may enable the use of telemedicine for screening in
areas with limited access to qualified providers.25–28
Although case series report characteristic fundus auto-
fluorescence and/or fluorescein angiography (FA) findings
in CMV retinitis, the condition remains a clinical diagnosis
at this time, with no clear data that these imaging modalities
have additive value for diagnosis or management of CMV
retinitis. Case series have shown hyperautofluorescence at
the advancing border of retinitis, which may be helpful for
identifying subtle areas of CMV reactivation. Areas of
hemorrhage and active retinitis may exhibit hypoauto-
fluorescence sometimes with stippled hyperauto-
fluorescence, and areas of atrophy from healed retinitis
exhibit hypoautofluorescence (Fig. 1).29 Retinal vasculitis
with perivascular sheathing may demonstrate perivascular
hypoautofluorescence that persists from the early to late
phases.30 Further studies are necessary to compare fundus
autofluorescence imaging to clinical diagnosis and/or pho-
tographs to determine whether it has any additive value. FA,
which is typically not necessary for diagnosis or manage-
ment, reveals leakage and nonperfusion from affected areas,
as well as blocking defects from hemorrhage.23 Retinal
vasculitis with perivascular sheathing (frosted branch an-
giitis) demonstrates FA findings of normal vascular filling
pattern in early stages, followed by leakage of fluorescein
from the affected vessels in later stages.31 Kyrieleis plaques
(segmental retinal periarteritis) may be seen in patients with
CMV retinitis, and can be differentiated from retinal vas-
culitis on FA by the absence of leakage.32 In patients with
resolved retinitis, FA commonly demonstrates retinal non-
perfusion, corresponding to areas of total retinal destruction.
Neovascularization is rare, but choroidal neovascularization
and optic disc neovascularization have been reported.33–35
Treatment of CMV Retinitis
At the beginning of the AIDS epidemic in the early
1980s, there were no effective treatments for CMV retinitis
or for systemic infection. A diagnosis of CMV retinitis
 226 PORT ET AL.
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FIG. 1. (A, B) Patient with active cytomegalovirus retinitis of the right eye involving the macula and threatening fixation
and the optic nerve. Wide-field fundus photograph (A) demonstrates an area of active retinitis with hemorrhage and a white,
irregular border at the leading edge. Fundus autofluorescence (B) demonstrates hypoautofluorescence in areas of active full-
thickness retinitis and hemorrhage, along with a hypofluorescent halo involving and extending beyond the evident leading
edge of retinitis on fundus photographs. Repeat imaging in the same patient 16 months later (C, D) following treatment with
intravitreal foscarnet and ganciclovir, along with systemic valganciclovir, demonstrates interval resolution of the retinitis
with areas of retinal atrophy on fundus photography (C). Fundus autofluorescence (D) exhibits hypoautofluorescence in
areas of the atrophy, as well as areas of stippled hyperautofluorescence.

carried with it high ocular morbidity and high mortality. progression of retinitis.36 In a trial comparing the ganci-
One series of untreated patients noted a survival of no more clovir implant to intravenous ganciclovir, the median time to
than 6 weeks after diagnosis.19 This bleak outlook has progression (defined as extension of a lesion border by
changed dramatically over the ensuing decades with the 750 mm over a 750 mm front, the development a 750 mm area
advent of effective antiviral agents for systemic and intra-
ocular use, and further with the advent of cART for immune
reconstitution. Table 1. Typical Dosing Regimens for Therapies
Beginning in 1984, ganciclovir was made available for for Cytomegalovirus Retinitis
compassionate use, and became the first drug that demon-
Induction Maintenance
strated efficacy against CMV.17,18 Ganciclovir was approved
by the FDA in 1989 and was followed closely by foscarnet Medication
(1991), cidofovir (1996), and fomivirsen (1998), all available Ganciclovir 5 mg/kg twice 5 mg/kg/day
as intravenous therapy. A sustained-release intravitreal gan- (intravenous) daily for
ciclovir implant (Vitrasertª; Bausch and Lomb) was ap- 14–21 days
proved in 1995, but was discontinued by the manufacturer in Valganciclovir 900 mg twice 900 mg daily
2013 on the basis of decreasing demand. Similarly, fomi- (oral) daily
virsen was discontinued in 2004. The most recently approved Foscarnet 90 mg/kg twice 120 mg/kg/day
anti-CMV drug is valganciclovir (2001), an oral prodrug of (intravenous) daily for 14 days
Cidofovir 5 mg/kg weekly 5 mg/kg every
ganciclovir with excellent bioavailability.17 (intravenous) for 3 weeks 2 weeks
Currently available therapies for CMV retinitis include Intravitreal
intravenous and intravitreal ganciclovir and foscarnet, in- Ganciclovir 2 mg 1–4 times 2 mg weekly
travenous cidofovir, and oral valgancyclovir (Table 1). as needed to
halt retinitis
Foscarnet 1.2–2.4 mg 1–2 1.2 mg weekly
Systemic versus ocular treatment times weekly
Cidofovir 20 mg 1–8 times 20 mg every
In the pre-cART era, the ganciclovir intravitreal implant 5–6 weeks
was found to be superior to systemic therapy at delaying the
 CYTOMEGALOVIRUS RETINITIS: A REVIEW
of new retinitis, or RD within an area of retinitis, assessed
by clinical examination and 9-field fundus photographs) was
71 days with intravenous (IV) ganciclovir compared to 221
for the intraocular implant.37 However, later LSOCA data
suggest that intravitreal injections alone were worse than the
ganciclovir implant or systemic therapy, and found rates of
progression (extension of a lesion border by >1/2 disc area
over a >1/2 disc area front, or the development >1/2 disc
area of new retinitis, as assessed by photographic grading)
of 96.1/100 eye-years for injections, compared to 22.3/100
eye-years for the ganciclovir implant and 16.5/100 eye-years
for systemic therapy.36 The same study found a higher rate
of visual acuity loss (to worse than 20/40) among patients
treated with intravitreal injections alone (84.6/100 eye-
years) compared to the ganciclovir implant (32.8/100 eye-
years) or systemic therapy (18.1/100 eye years), although
the authors acknowledge that these results may be affected
by potential unknown bias or confounders, such as the
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greater proportion of vision-threatening zone one disease
among patients treated with intravitreal injections.36
Systemic therapy was also associated with decreased
mortality, decreased visceral disease, and a decreased risk of
second eye disease by 50%, 80%, and 90%, respectively
compared with intraocular therapy alone.37 In a randomized
controlled trial, 377 patients with unilateral CMV retinitis
were randomized to the ganciclovir implant plus oral gan-
ciclovir, ganciclovir implant plus placebo or intravenous
ganciclovir alone.38 This study found that combination of
oral and intraocular therapy decreased the risk of new CMV
disease at 6 months from 44.3% for implant plus placebo to
24.3% for implant plus oral ganciclovir and 19.6% for in-
travenous ganciclovir alone.38 The addition of systemic
therapy also delayed progression of retinitis (movement of
the border of a lesion by at least 750 mm over a 750-mm front
or development of a new retinitis at least 750 mm in diam-
eter, assessed by clinical examination and 9-field fundus
photographs) and reduced the risk of Kaposi sarcoma.38
Systemic ganciclovir
Ganciclovir is an acyclic purine nucleoside with activ-
ity against herpesviruses, including herpes simplex virus,
varicella-zoster virus, Epstein-Barr virus, and CMV.
Ganciclovir’s action is dependent upon 2 viral proteins, a
viral kinase encoded by the viral UL97 gene and viral
DNA polymerase encoded by the UL54 gene. The viral
kinase catalyzes the first step in the phosphorylation of
ganciclovir to the active form ganciclovir triphosphate,
which specifically binds to CMV DNA polymerase to in-
hibit CMV DNA replication.39
In the mid-1980s, during the height of the AIDS epidemic,
ganciclovir was made available for use on a compassionate
basis, and in 1985, Felsenstein et al. demonstrated control of
CMV retinitis in 2 patients with AIDS and CMV retinitis.18,40
Treatment with systemic intravenous ganciclovir may con-
trol, but does not eliminate CMV infection. Early pathologi-
cal studies revealed that CMV remained present in patients
treated with ganciclovir, and clinical studies showed that
retinitis recurred within 3 weeks of stopping ganciclovir.41,42
Shortly thereafter, small randomized trials demonstrated the
benefits of maintenance therapy, extending the median time
to progression (defined as a lesion crossing a major vessel,
entering a new sector, increasing in size >2 disc diameters or a
227
new lesion >1 disc diameter, assessed by clinical examination
and fundus photographs) from 16 to 42 days (P = 0.07) in one
trial,43 and from 13.5 to 49.5 days in another.44 Induction
therapy is given at a dose of 5 mg/kg every 12 h for 14–
21 days followed by a maintenance dose of 5 mg/kg/day.23
The principle side effect of ganciclovir is myelosuppression,
with significant neutropenia occurring in 16% of patients and
thrombocytopenia in 5% of patients. An oral formulation of
ganciclovir is available and is effective for maintenance
therapy,45 but has poor bioavailability and has largely been
replaced by oral valganciclovir, discussed below.
Intravitreal ganciclovir
Intravitreal ganciclovir injection delivers a high concen-
tration of drug to the eye with minimal systemic toxicity.
Initially, intravitreal injection was used in patients who
could not tolerate systemic ganciclovir because of myelo-
suppression.46 In early studies, there were no drug side ef-
fects from intravitreal injections and the majority of eyes
showed suppression of retinitis after injection.46,47 Case
series suggest potential efficacy for intravitreal ganciclovir
in CMV retinitis, although there is a significant mortality
benefit when patients are also given systemic therapy.12,36
Intravitreal ganciclovir is typically given as a high-dose
2 mg injection 1–4 times during the induction phase, fol-
lowed by weekly maintenance injections of 2 mg until the
retinitis shows consolidation.23
Ganciclovir implant
To improve drug delivery in patients who had failed in-
travenous ganciclovir or foscarnet and to reduce the burden of
the frequent longstanding intravitreal injections required to
control CMV retinitis, an intravitreal ganciclovir implant was
developed, and received FDA approval in 1996. The ganci-
clovir 6 mm implant was surgically implanted through the
pars plana and designed to provide sustained release of gan-
ciclovir over 7–8 months. A randomized, controlled trial
comparing the 1 mg/h ganciclovir implant to deferred therapy
found that the ganciclovir implant delayed progression (ad-
vancement of 750 mm over a 750 mm front of any lesion border
or new lesion >750 mm in diameter as determined by 9-field
fundus photographs) from a median of 15 days in the deferred
treatment group to an estimated median of 226 days in the
ganciclovir implant group.48 A separate trial randomized 188
patients to treatment with the 1 mg/h ganciclovir implant,
2 mg/h ganciclovir implant, or intravenous ganciclovir, and
found the greatest median time to progression (extension of a
lesion border by at least 750 mm over a 750-mm front; a new
area of retinitis >750 mm in diameter; occurrence of a RD in an
area of active retinitis; or a decrease in best corrected visual
acuity to less than 20/200 with active retinitis at or near the
optic nerve, based on 9-field photographs) in the 1 mg/h
ganciclovir implant group at 221 days, compared with
191 days for the 2 mg/h implant and 71 days for intravenous
ganciclovir.37 However, the same study also found that pa-
tients treated with ganciclovir implants alone had a greater
risk of second eye disease (relative risk 2.0, P = 0.19) and
higher rates of extraocular CMV disease (10.3% vs. 0%)
compared with patients treated with intravenous ganciclovir.37
Complications of the ganciclovir implant included en-
dophthalmitis, RD, vitreous hemorrhage, cataract, and hy-
potony.37,38,49 Two chart review studies found a relatively
 228
low rate of implant-related complications (0.064–0.377 per
patient-year), and a low rate of severe vision loss (‡6
Snellen lines) after ganciclovir implant (0.005 per eye-
year).50,51 The rate of endophthalmitis was 0.017 per eye-
year for ganciclovir injections and 0.01 per eye-year for the
ganciclovir implant.36 Owing to market considerations, the
ganciclovir implant was discontinued by the manufacturer in
2013 when the patent expired.
Foscarnet
Foscarnet is a pyrophosphate analogue that specifically
binds CMV DNA polymerase (encoded by the viral UL54
gene) to inhibit DNA replication.52 Foscarnet has a lower
plasma solubility and higher ionization that requires higher
doses to be administered than for intravenous ganciclovir.
Efficacy, in terms of median time to progression of retinitis,
is similar for both drugs. In a randomized, controlled trials,
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intravenous foscarnet delayed the median time to progres-
sion (defined as extension by 750 mm or more or develop-
ment of a new lesion >750 mm as assessed by fundus
photographs) from 3.2 weeks in the control group to 13.3
weeks in the treatment group (P < 0.001).53 A randomized,
head-to-head comparison of foscarnet and ganciclovir was
halted early due to excess mortality concerns in the ganci-
clovir group based on intention-to-treat analyses.54 How-
ever, there was no difference between the 2 groups in terms
of the rate of progression of retinitis (extension of a lesion
border by >1/2 disc area over a >1/2 disc area front, or the
development >1/2 disc area of new retinitis, assessed by
clinical examination and fundus photographs).54 The most
worrisome side effect of foscarnet is nephrotoxicity, with
dose-limiting renal toxicity occurring in 10%–23% of
cases.52 Foscarnet also provides a useful alternative therapy
for patients with CMV isolates that have become resistant to
ganciclovir. Similar to ganciclovir, intravenous foscarnet is
given as an initial induction therapy followed by chronic
maintenance therapy. The induction dose of intravenous
foscarnet is 90 mg/kg twice daily for 2 weeks followed by a
maintenance dose of 120 mg/kg daily.23
Intravitreal foscarnet
Foscarnet may also be administered intravitreally at a
dose of 1.2 or 2.4 mg per injection, 1–2 times weekly.23
Although not as well studied as ganciclovir, reported case
series suggest efficacy of intravitreal foscarnet for CMV
retinitis.55,56 In these case series, foscarnet was well toler-
ated in the eye and halted progression of retinitis (advance
of 750 mm from an existing lesion or development of new
foci as assessed by clinical examination) in approximately
two-thirds of patients.55,56 In a retrospective study of 301
eyes with CMV retinitis treated with intravitreal foscarnet,
the median time to progression (extension of lesions by >1/2
disc area or new lesions >1/2 disc area assessed by clinical
exam and fundus photographs) was 15 weeks, and visual
acuity was stable or improved in 66% of patients.57
Cidofovir
Cidofovir is a nucleotide with 1 phosphate group. Cido-
fovir is diphosphorylated to its active form by cellular en-
zymes and then acts as a competitive inhibitor of viral DNA
polymerase (which is encoded by the viral UL54 gene).39
PORT ET AL.
Unlike ganciclovir, cidofovir does not require activation by
viral kinases. Therefore, mutations in UL97 (which encodes
the viral kinase) that cause low-level ganciclovir resistance do
not cause resistance to cidofovir.58 The principle advantage of
cidofovir is its long intracellular half-life, which allows for
dosing every 2 weeks as opposed to daily dosing for intra-
venous ganciclovir or foscarnet. Cidofovir is administered as
an intravenous infusion of 5 mg/kg over 1 h weekly for the
first 3 weeks of induction therapy and then every 2 weeks for
maintenance.39 Initial randomized clinical trials of cidofovir
demonstrated efficacy in slowing the progression of CMV
retinitis (advancement of >750 mm over a lesion >750 mm or
an occurrence of a new lesion >750 mm as assessed by clinical
exam and full-field fundus photographs) from an average of
22 days in the control group to 120 days in the cidofovir
group.58 However, cidofovir treatment has several serious
potential side effects, including drug-related nephrotoxicity,
neutropenia, and anterior uveitis or iritis. Despite attempts to
limit nephrotoxicity with the coadministration of probenecid
(2 g given 3 h before and 1 g at 2 and 8 h after cidofovir) and
intravenous hydration, 24% of patients enrolled in 1 trial had
to stop cidofovir because of nephrotoxicity.58,59 The Cido-
fovir Ganciclovir Cytomegalovirus Retinitis Trial directly
compared intravenous cidofovir with the ganciclovir implant
plus oral ganciclovir and suggested that the 2 agents are
similar for treatment of CMV retinitis, but found higher rates
of uveitis (0.35 vs. 0.09 per person-year) and nephrotoxicity
(0.48 vs. 0.18 per person-year) among the cidofovir group,
although these findings were limited by the small study size
(n = 61).60 Intravitreal cidofovir has also been shown to be
effective, at a dose of 20 mg, but is rarely used given an
association with iritis (in 15%–20%), cystoid macular edema,
and irreversible visually significant hypotony.61–63
Valganciclovir
Valganciclovir (Valcyte) is a prodrug of ganciclovir with
oral bioavailability similar to intravenous ganciclovir. Once-
daily administration of 900 mg of oral valganciclovir pro-
vides an equivalent dose to 5 mg/kg daily of intravenous
ganciclovir.39 Valganciclovir is given as 900 mg twice daily
during induction therapy, followed by 900 mg daily for
maintenance.23 A randomized, controlled comparison trial
of 160 patients demonstrated that oral valganciclovir is as
effective as IV ganciclovir when used as initial treatment for
CMV retinitis.64 Both drugs had a similar number of pa-
tients with progression within 4 weeks, frequency of adverse
events, and median time to progression 125 days for IV
ganciclovir, and 160 days for per os valganciclovir (pro-
gression defined as movement of a lesion border at least
750 mm over a 750 mm front or new lesion >750 mm in di-
ameter as assessed by fundus photographs).64 In contrast to
other available treatment options, once-daily oral dosing of
valganciclovir is simple and convenient, increasing com-
pliance with treatment. Cost comparison also favors val-
ganciclovir, which is less expensive to administer than
similarly efficacious IV regimens.65
Fomivirsen
Fomivirsen is a 21-nucleotide phosphorothioate oligonu-
cleotide that was the first anti-sense DNA drug to be ap-
proved by the FDA.66 Fomivirsen was specifically designed
 CYTOMEGALOVIRUS RETINITIS: A REVIEW
to be complementary to mRNA sequences encoding the
major immediate-early proteins of CMV and was intended
to be used for intravitreal injection.66 Fomivirsen was ap-
proved in August 1998, after cART therapy became widely
available, and clinical trials were limited in size owing to
the decreased incidence of CMV retinitis.67,68 In a ran-
domized, controlled trial of 18 patients with newly diag-
nosed CMV retinitis, fomivirsen was effective in delaying
the mean time to progression of retinitis (advancement of a
lesion by 750 mm along a 750 mm front or appearance of a
new lesion >750 mm, assessed by fundus photographs) from
a median of 13 days in the control group to 71 days in the
treatment group (P = 0.0001).69 The most common adverse
effects of fomivirsen were elevated intraocular pressure and
moderate intraocular inflammation, which were treatable
with topical steroids.70 Due to limited demand and poor
sales, fomivirsen was withdrawn from the market in 2002,
shortly after its introduction.
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Leflunomide
Leflunomide is an immunosuppressive agent that inhibits
virion assembly rather than DNA synthesis. Its use was initially
reported in patients in India who could not afford preferred anti-
CMV therapy,71 and has since been used in patients with drug-
resistant CMV retinitis.72,73 Recent published reports have
described long-term suppression of CMV retinitis with the
addition of oral leflunomide in patients with drug-resistant
CMV retinitis.73,74 Leflunomide use for CMV retinitis is off-
label and some authors recommend using the standard dosing
of 100 mg once daily for 3 days followed by 20 mg once daily,
whereas others recommend a dose of 100–200 mg daily for
5–7 days, followed by 40–60 mg daily.71,75,76
Antiviral resistance
Drug resistance is a significant challenge in the adequate
treatment of CMV retinitis. Drug resistance is associated with
poorer outcomes, including greater area of retinitis, decreased
visual acuity, and greater than 9-fold increase in the rate of
second eye disease in initially unilateral cases.77,78
The reported incidence of drug resistance increases with
duration of therapy, and in the early cART era was reported
to range from 0.9% at diagnosis to *25%–30% at 9
months.77,79,80 Resistance is also known to occur in patients
who are immunosuppressed after solid-organ or hemato-
poetic stem cell transplants. Ganciclovir-resistant UL97
mutants were detected in 2.2% of 1,244 renal transplant
recipients in 1 series, where chronic valganciclovir pro-
phylaxis was used.81
CMV resistance to antiviral therapy occurs as a result of
mutations in either the UL97 or UL54 viral genes. The UL97
gene encodes a viral kinase responsible for 1 step of gan-
ciclovir activation. Therefore, UL97 mutations confer low-
level resistance to ganciclovir and valganciclovir, but not
foscarnet or cidofovir.39 The UL54 viral gene encodes the
viral DNA polymerase. Mutations in the UL54 gene occur
more rarely and are associated with higher-level resistance
and confer resistance to all antiviral agents that work
through inhibition of the viral DNA polymerase, including
ganciclovir, valganciclovir, foscarnet, and cidofovir. Muta-
tions in both UL97 and UL54 confer high-level ganciclovir
or valganciclovir resistance.
229
Potential emerging therapies
T cell-mediated immunity is essential for control and
clearance of CMV infections. Therefore, immune reconsti-
tution, whether through cART therapy or modulation of
immunosuppressive therapy (when possible) is key to the
long-term control of CMV retinitis. However, in some cases,
immune reconstitution is not possible.
Adoptive transfer of immune cells effective against CMV
through CMV-specific donor cytotoxic T lymphocytes have
been administered to patients with systemic CMV infection
after stem cell transplant and appear to be effective at de-
creasing viral titers and controlling systemic CMV infection,
although no large randomized or well-controlled trials have
been conducted.82–84
Unlike for CMV viremia and systemic CMV infections,
the use of CMV-specific T lymphocytes for the treatment of
CMV retinitis specifically remains to be demonstrated in
large or prospective studies. A single case of long-term
successful treatment of CMV retinitis, without concurrent
systemic or intravitreal therapy, has been reported with in-
travenous infusion of donor CMV-specific T lymphocytes.85
Further studies are necessary to parse out the role, if any, of
these CMV-specific T cell infusions in patients with retinitis
and to determine long-term efficacy and safety profile.
General therapeutic approach
The goal of anti-CMV therapy is to preserve vision and
reduce risk of CMV-related visual complications. The center-
stone toward long-term control of CMV retinitis is immune
reconstitution, whether through cART therapy in patients with
AIDS or through modulation of medications in patients on
immunosuppressive therapy. For AIDS-related CMV retinitis,
CDC guidelines recommend that chronic maintenance ther-
apy be continued for life or until immune reconstitution oc-
curs, defined as a sustained (>6 month) increase in the CD4+
lymphocyte count to greater than 100–150 cells/mL.86 The
LSOCA study group compared 31 patients with immune re-
covery who continued anti-CMV therapy and 37 patients that
discontinued therapy and found no significant difference in
outcomes between the 2 groups.87 No specific guidelines are
available for non-AIDS CMV retinitis population. As dis-
cussed in the Epidemiology section above, advances in the
ability to achieve immune reconstitution have carried with
them a remarkable improvement in visual morbidity from
CMV retinitis. Generally, peripheral non-sight-threatening
lesions may be managed with systemic therapy alone.23 Pa-
tients with sight-threatening lesions near the macula or optic
nerve, those that progress despite systemic therapy, and pa-
tients who are unable to tolerate systemic therapy may be
treated with intravitreal injections. When possible, systemic
therapy is continued along with intravitreal injections to
control the systemic CMV viral load, thereby conferring a
significant survival benefit36 and reducing the risk of CMV
retinitis in the fellow uninvolved eye in unilateral cases. In
cases of drug resistant CMV, most practitioners switch
agents.23,36 Viral PCR testing for resistance-conferring mu-
tations may also be obtained to guide therapy. Intravitreal
therapy often can remain useful despite resistance to systemic
therapy because the drug concentrations in vitreous after in-
jection are significantly higher than with systemic therapy.
Once control of active infection is achieved and the lesions
 230
begin consolidating, intravitreal injections can be reduced in
frequency and ultimately stopped in most cases. Likewise,
after completion of the induction phase of systemic antiviral
treatment, systemic therapies can be shifted to maintenance
dosing which is usually continued until the retinitis is con-
solidated and immune reconstitution is achieved.
Secondary Ocular Complications
from CMV Retinitis
Two secondary complications from CMV retinitis, in-
cluding RD and immune recovery uveitis can also cause
significant vision loss.
Retinal detachment
RD is a significant cause of vision loss in CMV retinitis,
approaching an incidence of 33% per eye per year in the
Downloaded by East Carolina University from www.liebertpub.com at 12/31/18. For personal use only.
pre-cART era.23 cART therapy has decreased the risk of RD
substantially to an incidence of 1.0–8.7/100 eye years, but
RD nonetheless remains a significant cause of vision loss in
patients with CMV retinitis.12,87,88 Once RD occurs, out-
comes are similar among patients in both the pre-cART and
modern cART era.89 RDs in CMV retinitis are typically
rhegmatogenous and arise from breaks within the necrotic
retina. These detachments are characterized by multiple
retinal breaks within areas of active or atrophic retinitis.23
Risk factors for RD include larger area of retinitis, bilateral
disease, and active retinitis near the vitreous base.90,91 Re-
tinitis involving 25% of the peripheral retina has a 5-fold
greater risk of RD than an eye with only 10% of peripheral
retina involved.90 RD repair in eyes with CMV retinitis
presents a therapeutic challenge in light of atrophic changes
in the retina and alterations in the vitreous, and is ap-
proached in a stepwise manner.92 RD may be treated with
laser retinopexy to prevent posterior progression, with
scleral buckle, vitrectomy with silicone oil, or a combina-
tion of modalities.92–93
Surgical management of RD in eyes with CMV retinitis is
challenging and typically involves pars plana vitrectomy
followed by tamponade with either silicone oil or gas.23
Anatomical outcomes for patients with rhegmatogenous RD
are favorable for vast majority of patients (78%) with fa-
vorable visual outcomes in a majority (56%).94
Immune recovery uveitis
Immune recovery uveitis (IRU) is a potentially sight-
threatening complication in patients initiating cART therapy or
recovering immune function after hematopoeitic stem cell
transplant. In these patients, a vigorous immune response de-
velops with an increase in the level of CD4+ T cells by greater
than 50 cells/mL or to a level greater than 100 cells/mL, and
may cause anterior uveitis, vitritis, cystoid macular edema,
cataract, and epiretinal membrane (ERM) formation.95–97
These complications often require aggressive and prolonged
steroid therapy. A large study in the early cART era found that
IRU affected *10% of patients with CMV retinitis, and
found significant ocular morbidity among these patients with
vision-limiting CME and ERM affecting nearly half of pa-
tients with IRU.98 In the modern cART era, IRU occurs at a
rate of 2.2/100 person-years and is associated with higher
rates of vision loss (3.8/100 person-years) and blindness
PORT ET AL.
(0.6/100 person-years) compared with those with immune
recovery, but without IRU.12 The greatest risk of IRU is in
patients with CMV retinitis affecting the posterior pole or
large areas of retina.95,96,98 Intravitreal cidofovir use (but not
systemic cidofovir) is also associated with the development of
IRU.97 A large study found that IRU affected *10% of pa-
tients with CMV retinitis, and found significant ocular mor-
bidity among these patients with vision-limiting CME and
ERM affecting nearly half of patients with IRU.98
Corticosteroids may be used for the treatment for IRU.
The dose and mode of delivery vary depending on the
clinical situation, including the location and severity of the
ocular inflammation. Mild uveitis with good visual acuity
may be observed.99 Anterior uveitis is commonly treated
with topical corticosteroids, similar to other forms of uve-
itis.97 Severe vitritis or macular edema are typically treated
with periocular corticosteroid injection (ie, triamcinolone)
or a short course of oral corticosteroids. Sub-tenon’s corti-
costeroid injection has been studied in IRU-related CME,
but was only effective in improving visual acuity for a
minority (40%) of patients.99 The most severe forms of IRU
may require intravitreal corticosteroid injection, and case
reports suggest that intravitreal triamcinolone may be ef-
fective in improving the visual acuity of patients with IRU-
related CME.100 Use of the implantable fluocinolone acetate
implant (Retisert) has been reported in case series.101 The
fluocinolone implant by itself has been associated with de-
velopment of CMV retinitis in immunocompetent hosts, and
patients treated for IRU with a a fluocinolone implant re-
quire concurrent anti-CMV therapy to prevent reactivation
throughout the entire duration of action of the implant.101,102
Finally, surgical management may be necessary for com-
plications of IRU such as epiretinal membrane formation.
El-Bradey et al. found that vitrectomy with removal of
epiretinal membranes improved visual acuity in 3 of 4 eyes,
and may be a useful therapy for visual improvement in af-
fected patients.99
Telemedicine for CMV Retinitis
Given the significant burden of disease of AIDS in the de-
veloping world and a lack of qualified providers, there is sig-
nificant interest in telemedicine applications for the diagnosis
and monitoring of CMV retinitis. CMV retinitis is clinically
apparent on fundus photography, and serial photographs can be
used to monitor progression. Telemedical screening for CMV
retinitis is reliable and has a sensitivity of 88.8%–100% and a
specificity of 84.5%–99.9% with the use of expert graders.27,28
A study of nonexpert graders demonstrated promise for using
trained, nonophthalmologist practitioners to review photo-
graphs.25 However, telemedical applications may be limited by
the quality and portability of photographs, and may lack the
ability to detect subtle findings.26 Finally, fundus photography
may be unable to detect active disease in the far periphery such
as in zone 3 or anterior zone 2.26
Conclusions
CMV retinitis is a potentially blinding disease that occurs
in patients with diminished T cell immunity such as those
with AIDS and those receiving immunosuppressive therapy.
Our understanding of CMV retinitis is intertwined with the
history of the AIDS epidemic, and indeed all of the available
 CYTOMEGALOVIRUS RETINITIS: A REVIEW
mainstream treatments were developed and tested in patients
with advanced AIDS. Beginning with ganciclovir, several
drugs, including foscarnet, cidofovir, valganciclovir, and
fomivirsen have obtained FDA approval for treatment of
CMV retinitis. Following the advent of ART therapy in the
mid 1990s, the demographics of CMV have shifted as fewer
HIV-positive patients develop AIDS, and CMV retinitis has
been increasingly recognized in patients with immune sup-
pression from other causes. The changing epidemiology of
CMV retinitis has led to a shrinking armamentarium of ef-
fective treatment options, with the withdrawal of fomivirsen
and the ganciclovir implant due to decreased demand.
Nevertheless, CMV retinitis treatment remains a clinical
challenge. Patients require anti-CMV maintenance therapy
for many months, and drug resistance frequently develops.
Additional challenges include RDs in patients with CMV
retinitis and immune recovery uveitis in persons with im-
mune reconstitution. Current imaging techniques make it
Downloaded by East Carolina University from www.liebertpub.com at 12/31/18. For personal use only.
easier to monitor for progression of retinitis and may even
enable telemedical monitoring of patients in areas without
qualified eye care providers.
Author Disclosure Statement
S.K.—has intellectual property related to the use of
CMV-specific T lymphocytes for treatment of CMV retini-
tis. The remaining authors (A.D.P., A.O., S.P., D.J.D.,
M.P.G.) have no relevant financial disclosures.
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