Copyright 2002 American Medical Association. All Rights Reserved.
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Cytomegalovirus (CMV) retinitis is the leading cause of visual loss
in patients with acquired immunodeficiency syndrome (AIDS). Treatment modalities
include intravenous ganciclovir sodium, cidofovir, or foscarnet sodium; oral
ganciclovir or valganciclovir hydrochloride; intravitreal (IV) injections
of ganciclovir, cidofovir, or foscarnet; and ganciclovir implants. Foscarnet,
ganciclovir, and cidofovir selectively inhibit viral DNA polymerase. Fomivirsen
sodium (Vitravene, ISIS 2922; ISIS Pharmaceuticals, Carlsbad, Calif) is the
latest addition to the armamentarium of local CMV retinitis treatment options.
A phosphorothioate oligonucleotide administered intravitreally, fomivirsen
inhibits CMV replication through an antisense mechanism, binding to viral
messenger RNA and blocking its transcription.1,2
The Food and Drug Administration approved fomivirsen in August 1998 as highly
active antiretroviral therapy (HAART) began to dramatically decrease the incidence
of CMV retinitis.3
Clinical experience with IV fomivirsen is limited. Reported adverse
effects with the approved dosage include transient and reversible inflammation
in the anterior chamber (19%), increase in intraocular pressure (19%), vitreitis
(11%), and uveitis (5%). Cataract (9%) has also been reported.2
Isolated case reports describe foveal retinal pigment epithelial (RPE) stippling
with reversible bull's-eye maculopathy,4
peripheral RPE stippling5,6
associated with visual field loss,6 and
marked retinal toxic side effects after 495 µg doses.7
Bull's-eye maculopathy was diagnosed after five 330-µg doses in one
case and after 15 injections bilaterally in another. In both cases, fomivirsen
was administered every other week; RPE stippling was diagnosed after weekly
injections of 165 µg for 3 weeks. We report 2 additional cases of peripheral
pigmentary changes accompanied by electroretinogram (ERG) abnormalities following
IV injection of fomivirsen.
A 34- year-old African American man with AIDS had failed HAART. His
CD4 cell count was 20 cells/µL. The patient had human immunodeficiency
virus (HIV) retinopathy in the right eye and CMV retinitis in zones 1 and
2 of the left eye in May 2000 (Figure 1A).
The fovea was involved and vision had decreased to 20/400 OS. Cytomegalovirus
retinitis was initially treated with intravenous ganciclovir followed by IV
fomivirsen. Fomivirsen was used owing to a shortage of ganciclovir. The patient
received a 2-dose induction regimen consisting of 330 µg of IV fomivirsen
sodium injections every other week. His retinitis progressed when he failed
to return for follow-up during the next 7 weeks. The induction regimen was
repeated when the patient returned. He then received a maintenance dose of
330 µg 1 month after the second induction, totaling 5 injections of
fomivirsen. There was no elevated intraocular pressure. Mild anterior chamber
inflammation and mild vitreitis improved while he was receiving topical steroids.
The patient was subsequently readministered intravenous ganciclovir for CMV
colitis. No additional intraocular injections were given. Six months following
the initial IV injection, findings from examination of the left eye revealed
new pigmentary changes in the 360° midperipheral retina previously unaffected
by CMV retinitis (Figure 1B). The
ERG revealed an absent rod response, 40% reduction in cone amplitude, and
normal implicit times (Figure 2).
Visual field testing was not performed because the patient was too debilitated.
No cataract was found at a follow-up examination 3 months after the last injection.
Case 1. A, Left fundus composite
photograph of active cytomegalovirus (CMV) in the macula prior to fomivirsen
sodium injection. No peripheral photographs were taken. B, New pigmentary
changes in the 360° midperipheral retina. The CMV retinitis in the macula
Case 1. Findings from electroretinogram
(ERG) performed following intravitreal injection of fomivirsen sodium in the
left eye. A, Scotopic flash ERG. B, Photopic flash ERG. The right eye results
show normal scotopic and photopic responses. The left eye results show absent
scotopic responses; absent flash photopic response; and decreased cone response
to a 30-Hz stimulus with normal implicit time. a Indicates a wave and b, b
wave. (Electroretinogram test manufacturer information: Nicolet Biomedical,
A 41-year-old white man had AIDS and a CD4 cell count below 50 cells/µL.
He was also failing HAART, and his left eye CMV retinitis was controlled with
a ganciclovir implant. The right eye had HIV retinopathy and lattice degeneration
in the superior and inferior periphery at initial examination (Figure 3A). Cytomegalovirus retinitis involving zone 3 of the superotemporal
quadrant developed in the right eye at 4 months' follow-up in January 2001.
The right eye received one 330-µg IV fomivirsen sodium injection while
he awaited surgery for an IV ganciclovir implant. There was no ocular hypertension
or inflammation in the eye following the injection. Retinitis became inactive,
and he underwent surgery to receive the implant 3 weeks later. During a follow-up
examination 1 month after the injection, new RPE pigmentary changes were found
in the inferior quadrants previously unaffected by retinitis (Figure 3B). The ERG revealed an absent rod response, 50% decrease
in cone response, and a normal implicit time. Goldmann visual field testing
of the right eye showed an absolute scotoma in the area corresponding to the
previous CMV-affected superotemporal retina. Visual field testing results
were normal in the area corresponding to the inferior retina. His vision remained
20/20 OD with no cataract formation at the last follow-up examination 3 months
after fomivirsen injection.
Case 2. A, Right fundus composite
photograph prior to cytomegalovirus retinitis and prior to fomivirsen sodium
injection. B, New pigmentary changes in inferior quadrants 1 month after 1
intravitreal fomivirsen injection.
Treatment of CMV retinitis with IV ganciclovir or foscarnet requires
weekly injections. Intravitreal cidofovir is associated with prolonged ocular
hypotony. Fomivirsen requires less frequent injections. The recommended induction
dose of IV fomivirsen sodium is one 330-µg injection every other week
for 2 doses. subsequent maintenance doses are administered every 4 weeks after
induction. In vitro studies have shown that fomivirsen is active against clinical
isolates of human CMV and drug-resistant mutants of the virus.8
In clinical trials, fomivirsen significantly delayed the progression of CMV
retinitis in previously untreated patients and decreased CMV activity in patients
with refractory CMV retinitis.1 In the United
States, fomivirsen is reserved as a second-line treatment for CMV retinitis
in patients who are intolerant or unresponsive to other forms of treatment.
The only published toxicity profile study, to our knowledge, found that
high concentrations of fomivirsen in the vitreous caused total retinal destruction
in rabbit eyes.9 However, even at lower
concentrations equivalent to human eye injection doses, destruction of the
photoreceptor outer segments and RPE cell changes were noted.9,10
Retinal pigment changes are among the ocular adverse reactions listed
on the fomivirsen package label.11 Frequency
of retinal pigment changes is unknown. We used IV fomivirsen in 10 eyes of
9 patients from 1999 to 2001 as follows: 0
Most of these patients are now deceased. Over 2 years, we noted pigmentary
changes in only the 2 patients reported herein. Neither patient reported nyctalopia.
Both patients died within a few months after diagnosis of retinal toxicity.
Their pigmentary changes persisted until last follow-up. Electrophysiologic
testing could not be repeated to evaluate for reversibility as our patients'
systemic status progressively worsened. Abnormal ERG findings have been noted
in patients with HIV, AIDS, and CMV retinitis.12
In our patients, the reduction in ERG amplitudes of the treated eye is consistent
with photoreceptor dysfunction affecting mainly the rod system. This reduction
may have been induced by fomivirsen given that ERG responses in fellow eyes
were normal. Case 2 developed pigmentary changes and photoreceptor dysfunction
after only 1 injection. Neither patient had ever been treated with didanosine.
Unlike the study by Amin et al,6 visual
field in our patient (case 2) was not constricted. His unaffected visual field
and normal ERG testing implicit time may be consistent with relative sparing
of the peripheral cones. The patient receiving 23 injections (Table) had no
pigmentary changes. This eye underwent 2 ganciclovir implant procedures prior
to our fomivirsen injections. Liquefied vitreous in this eye may have had
more even diffusion of fomivirsen compared with other eyes with formed vitreous.
Our case reports support the view that IV fomivirsen has a narrow therapeutic
index10 for retinal toxicity and should
be used judiciously.
This article was supported by an unrestricted grant from Research to
Prevent Blindness Inc, New York, NY.
Corresponding author: Helen K. Li, MD, University of Texas Medical
Branch, Department of Ophthalmology and Visual Sciences, 301 University Blvd,
Galveston, TX 77555-1106 (e-mail: email@example.com).
Uwaydat SH, Li HK. Pigmentary Retinopathy Associated With Intravitreal Fomivirsen. Arch Ophthalmol. 2002;120(6):854-857. doi: