Firas M. Rahhal

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.

The effect of deep posterior subtenon injection of corticosteroids on intraocular pressure

PURPOSE To investigate the effect of posterior subtenon injections of corticosteroids on intraocular pressure in a variety of ocular diseases. METHODS We retrospectively analyzed 202 consecutive posterior subtenon corticosteroid injections (148 of methylprednisolone acetate, 80 mg, and 54 of triamcinolone acetonide, 40 mg) in 63 eyes of 55 patients (26 male, 29 female; mean age +/- SD, 60.17 +/- 26.55 years). All patients had received topical or systemic corticosteroids before the injection, and no rise in intraocular pressure had been noted. Preinjection and postinjection intraocular pressure measurements were compared by two-tailed paired t test. Statistical analysis was performed separately by patient (first injection of first injected eye), by eye (first injection of each eye), and by all injections. To detect increase in intraocular pressure during follow-up, statistical analysis was performed separately 14 to 90 days, 91 to 150 days, and 151 to 270 days after injection. RESULTS No statistically significant difference was found between preinjection and postinjection intraocular pressure measurements. A power calculation in the most stringent subanalysis (by patient) proved that there is only a 3.87% chance to statistically miss a clinically significant rise in intraocular pressure from 15 to 21 mm Hg. CONCLUSIONS Posterior subtenon injection of corticosteroids does not cause an increase in intraocular pressure. All patients in our study had been treated previously with topical or systemic corticosteroids and did not react with an excessive increase in intraocular pressure. This safety of repository corticosteroids may therefore not apply to patients whose status in responding to corticosteroids is not known.

Anterior nongranulomatous uveitis after intravitreal HPMPC (cidofovir) for the treatment of cytomegalovirus retinitis. Analysis and prevention

BACKGROUND AND OBJECTIVE The authors characterize and analyze the incidence of a previously reported mild anterior nongranulomatous uveitis associated with intravitreal injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), also termed cidofovir (Vistide, Gilead Sciences, Foster City, CA). This is an acyclic nucleoside phosphonate analogue with a potent anticytomegalovirus effect. The authors also analyzed the effects of probenecid therapy, as well as prophylaxis with probenecid plus topical corticosteroids and cycloplegics on the course and outcome of the uveitis. METHODS Prospective case series from a tertiary referral center, which included 46 consecutive patients with acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis. There was a total of 130 injections in 69 eyes treated with 20 micrograms of intravitreal HPMPC. Forty-one patients (119 injections) received oral probenecid, 5 patients (11 injections) did not, and 21 patients (53 injections) received topical corticosteroids and cycloplegics as an adjuvant to probenecid in the prophylaxis of iritis. RESULTS Mild to moderate nongranulomatous iritis was seen in 26% of patients after their first injection (n = 12). Patients receiving probenecid prophylaxis after first injection had a significantly lower frequency of iritis versus patients who did not receive probenecid at the time of first injection (P = 0.0089). In contrast, treatment with topical corticosteroid and cycloplegics after injection did not statistically significantly affect the frequency of iritis in patients (P = 0.44). The development of iritis after a second injection of HPMPC was more likely if it had occurred after the initial injection (P = 0.015; Fishers exact test). All cases of iritis were treated with topical corticosteroids and cycloplegics, and there was no permanent impairment of vision secondary to iritis after HPMPC injection in any eyes. CONCLUSIONS Anterior uveitis was seen in 26% of patients after first-time HPMPC injection. Concomitant use of probenecid appears to decrease the frequency of the iritis from 71% to 18% in patients with AIDS and CMV retinitis after the first intravitreal injection of HPMPC. Topical corticosteroid administration after injection (before iritis) was ineffective in preventing iritis treatment with topical corticosteroids and cycloplegics resulted in resolution of all iritis cases.

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.

Sustained Visual Acuity Loss in the Comparison of Age-Related Macular Degeneration Treatments Trials

IMPORTANCE Although anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration (AMD) results in improved vision overall, loss of substantial vision can occur. Understanding the processes that lead to loss of vision may lead to preventive strategies. OBJECTIVE To determine the incidence, characteristics, causes, and baseline predictors of sustained visual acuity loss after 2 years of treatment with ranibizumab or bevacizumab for neovascular AMD. DESIGN, SETTING, AND PARTICIPANTS A cohort study within a randomized clinical trial of participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). INTERVENTIONS Participants were randomly assigned to treatment with ranibizumab or bevacizumab and to 2 years of monthly or as needed injections or monthly injections for 1 year and as needed injections the following year. MAIN OUTCOMES AND MEASURES Sustained visual acuity loss, defined as loss of 15 or more letters from baseline at weeks 88 and 104. RESULTS Among 1030 participants, 61 eyes (5.9%) developed sustained visual acuity loss in 2 years. Within this group, visual acuity decreased gradually over time, with a mean decrease of 2, 19, and 33 letters from baseline at 4 weeks, 1 year, and 2 years, respectively. At 2 years, eyes with sustained visual acuity loss had more scarring (60.0% vs 41.4%, P = .007), more geographic atrophy (GA) (31.6% vs 20.7%, P = .004), larger lesions (16 vs 8 mm2, P < .001), and higher proportions of intraretinal fluid (82.5% vs 51.0%, P < .001), subretinal hyperreflective material (84.5% vs 44.2%, P < .001), retinal thinning (43.3% vs 23.0%, P < .001), and thickening (20.0% vs 12.1%, P < .001). Likely causes of sustained visual acuity loss included foveal scarring (44.3%), pigmentary abnormalities (27.9%), and foveal GA (11.5%). Baseline factors independently associated with a higher incidence of sustained visual acuity loss were the presence of nonfoveal GA (odds ratio [OR],  2.86; 95% CI, 1.35-6.08; P = .006), larger area of choroidal neovascularization (OR for a >4-disc area vs ≤1-disc area, 3.91; 95% CI, 1.70-9.03; P = .007), and bevacizumab treatment (OR,  1.83; 95% CI, 1.07-3.14; P = .03). CONCLUSIONS AND RELEVANCE Sustained visual acuity loss was relatively rare in CATT. The development of foveal scar, pigmentary abnormalities, or GA contributed to most of the sustained visual acuity loss. Risk was 3% higher among eyes treated with bevacizumab. Treatment that targeted the prevention of scarring or GA may improve vision outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00593450.

Correlation Between Intraocular Pressure and CD4+ T-Lymphocyte Counts in Patients With Human Immunodeficiency Virus With and Without Cytomegalovirus Retinitis

PURPOSE To determine the intraocular pressure in patients with human immunodeficiency virus (HIV) with and without cytomegalovirus retinitis, and to correlate intraocular pressure with CD4+ T-lymphocyte count and the presence, extent, and activity of cytomegalovirus retinitis. METHODS Intraocular pressure was measured with calibrated Goldmann applanation tonometers in two groups of patients. Group A included 84 patients with HIV (120 eyes) with cytomegalovirus retinitis, and Group B included 110 patients with HIV (183 eyes) without cytomegalovirus retinitis. Thirty-three patients without HIV (66 eyes) were included as a control group. Step-wise regression analysis of intraocular pressure included correlation with cytomegalovirus retinitis (presence, extent, and activity), CD4+ T-lymphocyte count, age, and gender. RESULTS The mean intraocular pressure was 9.8 mm Hg in Group A, 12.6 mm Hg in Group B, and 16.1 mm Hg in the control group. All three groups were statistically different from each other when intraocular pressure was compared (P < .0001). Step-wise regression showed that low CD4+ T-lymphocyte count (r2 = .20; P < .0001) and extent of cytomegalovirus retinitis (r2 = .08; P = .007) both correlated to low intraocular pressure. CONCLUSION Intraocular pressure is lower than normal in patients with HIV. Decreased CD4+ T-lymphocyte count is the major association with low intraocular pressure (20% of the effect); extent of cytomegalovirus retinitis accounts for 8% of the effect. Knowledge of the normal range of intraocular pressure in patients with HIV will be important to the understanding and treatment of glaucoma and other disorders or treatments affecting intraocular pressure.

Fluorophotometry in patients with human immunodeficiency virus with and without cytomegalovirus retinitis

OBJECTIVE To study the aqueous humor dynamics in subjects with human immunodeficiency virus (HIV) with and without cytomegalovirus (CMV) retinitis. DESIGN Prospective cross-sectional study. PARTICIPANTS Fourteen HIV-positive subjects (27 eyes, 19 with CMV retinitis and 8 without CMV retinitis), and a control group of 9 HIV-negative subjects (17 eyes). TESTING Fluorophotometry. MAIN OUTCOME MEASURES Aqueous flow rates as measured by fluorophotometry and intraocular pressure (IOP). RESULTS Analysis of variance of the mean corrected aqueous flow rate revealed that both HIV-positive groups had significantly lower aqueous flow rates than did the control group (P < 0.03). No difference in mean aqueous flow rates was found between the HIV-positive eyes with or without CMV retinitis. Comparison of mean IOP revealed that HIV-positive eyes with CMV retinitis had significantly lower IOP than did the HIV-positive eyes without CMV retinitis (P = 0.03) and HIV-negative subjects (P = 0.002). There was no correlation between aqueous flow rate and IOP in HIV-positive subjects (P > 0.5). CONCLUSION The lack of correlation between the aqueous flow rate and IOP suggests that there may be some disassociation between these parameters in HIV-positive patients. Further studies are needed to better understand the mechanism of aqueous formation and in the management of disorders affecting IOP in this population.