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Arch Ophthalmol. 2002;120:854-857.

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 stippling^5-6 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.

Report of a Case
Case 1

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.

View larger version (19K): [in this window] [in a new window] Figure 1. 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 is inactive.

View larger version (32K): [in this window] [in a new window] Figure 2. 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, Madison, Wis.)

Case 2

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.

View larger version (18K): [in this window] [in a new window] Figure 3. 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.

Comment
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:

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.

AUTHOR INFORMATION
This article was supported by an unrestricted grant from Research to Prevent Blindness Inc, New York, NY.

Sami H. Uwaydat, MD; Helen K. Li, MD
Galveston, Tex

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: hli{at}utmb.edu).

REFERENCES
1. Perry CM, Balfour JAB. Fomivirsen. Drugs. 1999;57:375-380. FULL TEXT | WEB OF SCIENCE | PUBMED 2. de Semet MD, Meenken C, van den Horn GJ. Fomivirsen: a phosphorothioate oligonucleotide for the treatment of CMV retinitis. Ocul Immunol Inflamm. 1999;7:189-198. FULL TEXT | WEB OF SCIENCE | PUBMED 3. Jalali S, Reed JB, Mizogushi M, et al. Effect of highly active antiretroviral therapy on the incidence of HIV-related cytomegalovirus retinitis and retinal detachment. AIDS Patient Care STDS. 2000;14:343-346. PUBMED 4. Stone TW, Jaffe GJ. Reversible bull's-eye maculopathy associated with intravitreal fomivirsen therapy for cytomegalovirus retinitis. Am J Ophthalmol. 2000;130:242-243. PUBMED 5. Hudson HL, Boyer DS, Kupperman BD. Future trends and experimental modalities in the therapeutics of cytomegalovirus retinitis. Ophthalmol Clin North Am. 1997;10:61-71. 6. Amin HI, Ai E, McDonald HR, Johnson RN. Retinal toxic effects associated with intravitreal fomivirsen. Arch Ophthalmol. 2000;118:426-427. FREE FULL TEXT 7. Hutcherson SL, Palestine AG, Cantrill HL, et al. Antisense oligonucleotide safety and efficacy for CMV retinitis in AIDS patients. Paper presented at: 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17, 1995; San Francisco, Calif. Abstract 204. 8. Anderson KP, Fox MC, Brown-Driver V, et al. Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediate-early RNA. Antimicrob Agents Chemother. 1996;40:2004-2011. ABSTRACT 9. Flores-Aguilar M, Besen G, Vuong C, et al. Evaluation of retinal toxicity of anti-cytomegalovirus and anti-herpes simplex virus antiviral phosphorothioate oligonucleotides ISIS 2922 and 4015. J Infect Dis. 1997;175:1308-1316. WEB OF SCIENCE | PUBMED 10. Freeman WR. Retinal toxic effects associated with intravitreal fomivirsen [letter]. Arch Ophthalmol. 2001;119:458. FREE FULL TEXT 11. Vitravene. [package insert]. Carlsbad, Calif: ISIS Pharmaceuticals, 1998. 12. Latkany PA, Holopigian K, Lorenzo-Latkany M, et al. Electroretinographic and psychophysical findings during early and late stages of human immunodeficiency virus infection and cytomegalovirus retinitis. Ophthalmology. 1997;104:445-453. WEB OF SCIENCE | PUBMED

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