Ibrahim Taskintuna

Intravitreal cidofovir for the maintenance treatment of cytomegalovirus retinitis

PURPOSE To evaluate the efficacy and safety of multiple intravitreal cidofovir (HPMPC) injections given every 5 to 6 weeks for the maintenance treatment of cytomegalovirus (CMV) retinitis. METHODS A prospective consecutive case series of 53 eyes in 35 patients with acquired immune deficiency syndrome and CMV retinitis was treated with maintenance intravitreal injections of cidofovir (20 micrograms) at one referral center between April 1994 and September 1995. Twenty-four eyes received intravitreal cidofovir as their initial treatment for CMV retinitis (group A), and 29 eyes previously had received systemic therapy (group B). None of the patients in either group received systemic anti-CMV therapy at any time during the study period. Progression of retinitis was the primary end point. RESULTS All eyes with active retinitis healed in response to treatment. None of the 24 eyes in group A demonstrated any progression during the study period. Four (14%) of the 29 eyes in group B had one episode each of retinitis progression (mean follow-up, 15 weeks; range, 0-58 weeks). In 1 (1.9%) of the 53 eyes, a retinal detachment developed. A mild iritis was observed after 14% of injections, which were prophylaxed with oral probenecid. Irreversible visually significant hypotony developed in two eyes (3.8%). CONCLUSION Treatment and subsequent maintenance therapy of CMV retinitis with 20 micrograms intravitreally injected cidofovir, given at 5- to 6-week intervals, is highly effective, with only rare episodes of re-activation and progression.

Analysis of Visual Dysfunctions in HIV-positive Patients Without Retinitis

PURPOSE To investigate visual dysfunctions in ophthalmoscopically normal human immunodeficiency virus (HIV)-positive patients and to correlate the results to the stage of HIV disease and neuropsychological status. METHODS Fifty-one randomly selected eyes (26 right, 25 left) of 51 HIV-positive patients with visual acuity measurements of 20/20 or better and no ophthalmoscopically detectable disorders were prospectively examined using achromatic and short-wavelength automated perimetry, color vision testing, and contrast sensitivity testing. CD4+ T-lymphocyte count, presence of systemic infection, hemoglobin, hematocrit, serum beta 2-microglobulin levels, and results of neuropsychological testing were also analyzed. RESULTS On achromatic automated perimetry, 21.6% (11/51) of patients performed abnormally according to the mean defect and 27.5% (14/51) according to the Glaucoma Hemifield Test; 29.4% (15/51) performed abnormally on short-wave-length automated perimetry according to the mean defect and 23.5% (12/51) according to the Glaucoma Hemifield Test. On contrast sensitivity, 5.9% (3/51) of patients performed abnormally in the 1.5-cycles per degree (cpd) line, 2.0% (2/51) in the 3-cpd line, 23.5% (12/51) in the 6-cpd line, 25.5% (13/51) in the 12-cpd line, and 33.3% (17/51) in the 18-cpd line. On the Farnsworth-Munsell 100-hue test, 29.4% (15/51) of patients performed abnormally. After correction for multiple correlations, two statistically significant correlations were found: sum of log contrast sensitivity with achromatic automated perimetry and sum of log contrast sensitivity with the Farnsworth-Munsell 100-hue test. CONCLUSIONS A significant percentage of HIV-positive patients with visual acuity of 20/20 or better and no ophthalmologic evidence of retinitis performed abnormally on visual psychophysical tests. The severity of visual dysfunction was not correlated with the stage of HIV infection or the degree of neuropsychological dysfunction.

Intraocular Pressure and Aqueous Humor Dynamics in Patients With AIDS Treated With Intravitreal Cidofovir (HPMPC) for Cytomegalovirus Retinitis

PURPOSE To evaluate the decrease in intraocular pressure associated with cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate; HPMPC) intravitreal injections. METHODS We followed up 97 eyes of 63 patients with acquired immunodeficiency syndrome (AIDS) who had cytomegalovirus retinitis and had been treated with up to nine 20-microgram intravitreal cidofovir injections. Measurements were taken at baseline, between 2 and 3 weeks, and at 5 to 6 weeks after injections. Anterior chamber fluorophotometry was studied in seven eyes (four patients) before and after injections. Ciliary body anatomy was evaluated in two patients. RESULTS After the first intravitreal injection, mean intraocular pressure was 2.2 mm Hg lower than that at baseline at 2 to 3 weeks (P < .001) and 1.3 mm Hg lower than at baseline at 5 to 6 weeks (P = .0025). After the second injection, mean pressure was 2.6 mm Hg lower at 2 to 3 weeks (P = .0013) and 1.5 mm Hg lower at 5 to 6 weeks (P = .043). After subsequent injections, however, the decrease was less than 1 mm Hg, suggesting that a plateau had been reached. Pressure in eyes with anterior uveitis after the first injection was lower than that in eyes without anterior uveitis (P < .0001). The mean rate of aqueous flow decreased from 2.8 to 1.9 microliters per minute 2 to 4 weeks after injection (P < .015). Ultrasound biomicroscopy disclosed that severe hypotony after cidofovir injections is associated with ciliary body atrophy. CONCLUSIONS Intraocular pressure decreases after the initial 20-microgram cidofovir intravitreal injection. However, eyes stabilize (pressure plateaus) after three injections. Effects on the ciliary body are the main cause of the decrease after cidofovir injections.

Adverse events and autopsy findings after intravitreous cidofovir (HPMPC) therapy in patients with acquired immune deficiency syndrome (AIDS)

OBJECTIVE The purpose of the study is to evaluate the adverse events and autopsy findings in a series of consecutive 20-microg intravitreous cidofovir injections at a single institution. DESIGN The study design was a nonrandomized, consecutive case series. PARTICIPANTS Seventy-six patients with acquired immune deficiency syndrome with cytomegalovirus retinitis were studied prospectively. Sixty-three patients had 1 months follow-up or longer, and this comprised the study group. In addition, histopathologic findings from 18 eyes of 9 patients were studied at autopsy. INTERVENTION A total of 296 injections of 20 microg cidofovir were given in 115 eyes. Sixty-three patients who had 246 injections in 93 eyes had 1 months follow-up or longer for the evaluation of adverse events. MAIN OUTCOME MEASURES Postinjection chronic hypotony associated with permanent visual loss, transient hypotony, iritis, and its long-term sequela (posterior synechia and cataract, retinal detachment, extraocular cytomegalovirus involvement) were the outcomes of interest in this study. Additionally, light and electron microscopic studies of human eyes were performed. RESULTS The most severe adverse event was postinjection chronic hypotony. This phenomenon was associated with permanent visual loss. This was observed in 1% of the injections and 3% of the eyes of the patients (95% confidence interval, 0%-6%). Transient hypotony associated with mild-to-moderate visual loss developed in 14%, but vision recovered to baseline levels in these eyes subsequently. Analysis showed that transient hypotony in the injected eye could predict postinjection chronic hypotony in the fellow eye (two-tailed Fishers exact test, P = 0.02). The incidence of iritis was 32%; posterior synechia and cataract were the long-term sequela of the iritis and developed in 19% and 11% of the eyes, respectively. The incidence of retinal detachment was lower (6%). Histopathologic evaluation of the eyes showed mild-to-moderate atrophy of the nonpigmented epithelium of the ciliary body and no other evidence of intraocular toxicity. CONCLUSIONS The most serious adverse event was postinjection chronic hypotony, which occurred in 3% of eyes. Episodes of transient hypotony appear to indicate that the fellow eye was predisposed to chronic hypotony. Therefore, it may be prudent to give intravitreous injections at least 2 weeks apart in the fellow eye to evaluate the clinical response of the injected eye.

Evaluation of a novel lipid prodrug for intraocular drug delivery: effect of acyclovir diphosphate dimyristoylglycerol in a rabbit model with herpes simplex virus-1 retinitis.

BACKGROUND Acyclovir diphosphate dimyristoylglycerol is a lipid prodrug of acyclovir that forms liposomes and provides substantial activity against herpes simplex virus, acyclovir-resistant strains of herpes simplex virus, and human cytomegalovirus. We therefore tested this promising new drug in a rabbit model of herpes simplex retinitis. METHODS A total of 22 pigmented rabbits were pretreated with either acyclovir diphosphate dimyristoylglycerol, ganciclovir, acyclovir, or buffer. Retinae then were inoculated with herpes simplex virus-1 or buffer 1 week after the injection of drug. In another experiment we compared the effects of acyclovir diphosphate dimyristoylglycerol and acyclovir diphosphate dioleoylglycerol on the optical clarity of vitreous. RESULTS Animals injected intravitreally with acyclovir diphosphate dimyristoylglycerol showed retinitis that was less severe than that in animals injected with ganciclovir, acyclovir, and buffer; differences in grading scores of the retinitis between animals injected with acyclovir diphosphate dimyristoylglycerol and those injected with buffer were statistically significant (P = 0.0015). Vitreous and optical media became clear 4 days after acyclovir diphosphate dioleoylglycerol injection compared with 10 days after with acyclovir diphosphate dimyristoylglycerol injections. CONCLUSION Acyclovir diphosphate dimyristoylglycerol had prolonged antiviral activity against herpes simplex virus-1 retinitis in a rabbit model. This drug delivery system, modified to improve optical clarity, may allow long-acting intravitreal treatment of cytomegalovirus retinitis and other retinal diseases.

Effects of topical and subconjunctival cidofovir (HPMPC) in an animal model

PURPOSE To characterize the anterior segment effects of cidofovir, using an animal model. METHODS Cidofovir drops, at concentrations of 0.04%, 0.4% and 4%, were instilled in eyes of guinea pigs once daily for 10 days. Fellow eyes (controls) received normal saline. The corneal epithelium was debrided at day one and then at every other day for 10 days. Subconjunctival injections of 20 microl of 4% cidofovir were given in another group of animals. A micromanometer was used to determine the intraocular pressure (IOP). Eyes were studied histopathologically at the conclusion of the study. RESULTS There was no significant drop in IOP after 10 days, using the 0.04% concentration of cidofovir drops. Histology revealed mild corneal edema and inflammatory infiltrate; iris, ciliary body and retina were normal. There was a statistically significant drop in IOP in the eyes treated with 0.4% and 4.0% cidofovir eye drops at 10 days (p = 0.005 and p < 0.0001, respectively) compared to baseline. Morphological changes included moderate to severe corneal edema, vascularization and inflammatory infiltration. The iris and ciliary body revealed mild inflammatory changes only at the 4% cidofovir dose. No changes were seen in the retina with any doses. No change in IOP was observed following subconjunctival injections of 4% cidofovir, and histologically, only localized inflammatory changes in the conjunctiva were observed. CONCLUSIONS The IOP-decreasing effect of cidofovir occurs at doses below those causing intraocular inflammation and is likely due to an effect on the anterior segment. The anterior segment effects of cidofovir in guinea pigs were similar to those in humans. Thus, the guinea pig appears to be a good animal model for studying the effects of cidofovir on the anterior segment structures.