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.

Vision-threatening complications of surgery for full-thickness macular holes. Vitrectomy for Macular Hole Study Group.

OBJECTIVE: To study complications of vitrectomy surgery for full-thickness macular holes. DESIGN: A multicentered, randomized, controlled clinical trial. PARTICIPANTS: Community and university-based ophthalmology clinics. INTERVENTION: Standardized macular hole surgery versus observation. MAIN OUTCOME MEASURES: Assessment of anatomic and visual outcomes and determination of postoperative complications at 12 months after randomization. RESULTS: Posterior segment complications were noted in 39 eyes (41%). The incidence of retinal pigment epithelium (RPE) alteration and retinal detachment (RD) were 33% and 11%, respectively. One RD due to a giant retinal tear resulted in a visual acuity of light perception. Other complications included a reopening of the macular hole in 2 eyes (2%), cystoid macular edema in 1 eye (1%), a choroidal neovascular membrane in 1 eye (1%) and endophthalmitis in 1 eye (1%). Eyes with complications had significantly worse visual acuity outcomes as determined by the Early Treatment Diabetic Retinopathy Study, Word Reading, and Potential Acuity Meter charts (P < 0.01 for all comparisons). Eyes with macular holes greater than 475 microns were more than twice as likely to have complications than eyes with holes less than 475 microns (odds ratio [OR] = 2.2, P = 0.07). Before surgery, the stage of the hole was related to postoperative RPE changes (P < 0.0001) and the occurrence of postoperative RD (P = 0.0002). Intraoperative trauma was related to the occurrence of these complications (P < 0.0001 for RPE changes, P = 0.02 for RDs). Epiretinal membrane removal was related to RPE changes (P = 0.02) but not RDs. CONCLUSIONS: The RPE alterations and RDs are common after macular hole surgery and result in significantly reduced postoperative visual acuity. The RPE changes may be related to surgical trauma or light toxicity. Further efforts to reduce complications associated with macular hole surgery are indicated.

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.

Low-dose intravitreal cidofovir (HPMPC) therapy of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome.

PURPOSE: The authors have shown that long-term treatment of cytomegalovirus (CMV) retinitis with 20-microgram intravitreal injections of cidofovir (HPMPC) is highly effective but may be associated with iritis and profound hypotony. They evaluated the efficacy and safety of 10-microgram intravitreal injections of cidofovir and made comparisons with their findings of 20-microgram injections. METHODS: The current study was conducted as a nonrandomized consecutive case series at the AIDS Ocular Research Unit of the University of California at San Diego. Twenty-seven eyes of 18 patients were injected with 10 micrograms intravitreal cidofovir and had complete follow-up. These were compared with another consecutive series of 24 eyes of 17 patients injected with 20 micrograms of cidofovir. MAIN OUTCOME MEASURES: The main outcome in this study was the incidence of failure to respond to treatment with 10-microgram injections. The authors also compared the time to progression of CMV retinitis after the initial intravitreal injections of 10 micrograms and 20 micrograms of cidofovir. Secondary outcomes included incidence of iritis and changes in intraocular pressure (IOP) after cidofovir injections. RESULTS: The median time to retinitis progression was 45 days after a single intravitreal injection of 10 micrograms cidofovir compared with 55 days with the authors' series of 20-microgram injections. This difference was statistically significant (P = 0.033, log-rank test) and appeared to be due principally to a 26% incidence of primary failure in the 10-microgram group (progression > or = 750 microns within 28 days, P = 0.0017 Wilcoxon test). Progression after a second injection of 10 micrograms cidofovir was more rapid (32 days, P = 0.037). The incidence of iritis after 10-microgram injections was 2.2% compared with 23% with 20-microgram injections (P = 0.003, Fisher's exact test, two-tailed). There was less decrease in IOP between the baseline injection and subsequent visits in the 10-microgram group. CONCLUSIONS: Treatment of CMV retinitis with 10-microgram intravitreal cidofovir injection was not as effective as with 20 micrograms and may allow development of drug resistance, but there were fewer side effects with the 10-microgram dose. The drug appears to have a narrow therapeutic index, and other attempts at reducing the side effects while preserving the long-acting effect, such as liposome delivery, may be warranted.

Evaluation of retinal toxicity and efficacy of anti-cytomegalovirus and anti-herpes simplex virus antiviral phosphorothioate oligonucleotides ISIS 2922 and ISIS 4015.

Retinal toxicity of ISIS 2922 and ISIS 4015, phosphorothioate oligonucleotides complementary to human cytomegalovirus (CMV) and herpes simplex virus (HSV) RNA, were evaluated. The intravitreal concentration of ISIS 2922 found not to cause permanent toxic changes in the rabbit retina was 10 microM and in the pig retina, 5 microM. The 3 microM concentration was associated with a transient inflammatory response, and 1 microM caused no retinal toxicity or inflammation. ISIS 4015 showed very mild toxicity with no permanent retinal changes and very mild inflammation at doses of 10 microM; this dose was effective in ameliorating or preventing HSV-1 retinitis when injected 1 day and 1 week prior to virus inoculation. These oligonucleotides have a low intraocular therapeutic index. Attempts to improve the therapeutic index of these compounds are indicated. Only a clinical trial can determine the toxicity profile of ISIS 2922 for the treatment of CMV retinitis.

An animal model for cidofovir (HPMPC) toxicity: intraocular pressure and histopathologic effects.

Intravitreal cidofovir has been shown to be a long acting and highly efficacious treatment for CMV retinitis; however decrease in IOP is an adverse effect. We wanted to determine the effect of cidofovir on intraocular pressure (IOP) in the guinea pig, and rabbit eye to develop an animal model of cidofovir induced ocular hypotony and to study the histopathology of this toxicity. Twenty-eight guinea pig eyes were injected with cidofovir yielding final intravitreal concentrations of 25, 200, 625 and 2000 micrograms ml-1. Eighteen eyes of pigmented rabbits were injected with cidofovir yielding final intravitreal concentrations of 625 and 2000 micrograms ml-1. A carefully calibrated low volume displacement manometer system using a micro-transducer was used to determine the IOP measurements in the guinea pig and rabbit eyes. Histology was evaluated using light and electron microscopy. Injection of 6.25 micrograms of cidofovir intravitreally (vitreous concentration of 25 micrograms ml-1) is the highest non-toxic dose in the guinea pig; the IOP was unchanged at two and four weeks after injection with this dose; histologically the eyes were normal. A single injection of 50 micrograms of cidofovir intravitreally (vitreous concentration of 200 micrograms ml-1) caused a long lasting (9.3 mmHg) decrease in IOP (approximately 50% of baseline). At this dose there were only mild and variable histologic changes in the ciliary body and the retina. Higher doses of 156.25 micrograms and 500 micrograms of cidofovir (vitreous concentrations of 625, and 2000 micrograms ml-1, respectively) caused moderate to severe ciliary body and retinal changes. In rabbit eyes there was a mild but statistically insignificant pressure drop with doses of 875 micrograms cidofovir intravitreally (vitreous concentration of 625 micrograms ml-1); retina was within normal limits after injection with this dose, there were mild changes in the ciliary body. There was a total destruction of ciliary body and loss of nonpigmented epithelial cells with injections of 2800 micrograms of cidofovir intravitreally (vitreous concentration of 2000 micrograms ml-1): retina was relatively well preserved. The guinea pig eye shows similar reduction in IOP and ciliary body changes as are seen in the human eye after intravitreal cidofovir and also appears to have a similar dose-response curve. However, the reduction of IOP caused by cidofovir occurs in the guinea pig eye at a concentration 40 times higher than was observed in the human eye.

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; Fisher's 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.

Retinal findings and characteristics in AIDS patients with systemic Mycobacterium avium-intracellulare complex and toxoplasmic encephalitis.

BACKGROUND AND OBJECTIVE: The purpose of this study was to evaluate the incidence and characteristics of retinal and choroidal manifestations of toxoplasmosis and/or Mycobacterium avium-intracellulare complex (MAC) in patients with acquired immunodeficiency syndrome (AIDS). PATIENTS AND METHODS: The authors analyzed their prospectively collected data and found 120 patients with new retinal lesions (group A) that were diagnosed 3 months or longer following the diagnosis of MAC and/or toxoplasmic encephalitis. The authors also performed a point prevalence study of retinal/choroidal findings in 25 consecutive AIDS patients (group B) without known eye disease who had been recently treated for toxoplasmic encephalitis and/or disseminated MAC infections. In addition, the characteristics of retinochoroidal toxoplasmosis scars in 5 AIDS patients were studied and compared with the characteristics of scars in 18 immunocompetent patients. RESULTS: In this study the incidence of ocular manifestations of MAC was zero (95% confidence interval [CI] 0.0% to 3.8%). Two of 25 patients (8%) (95% CI 1% to 26%) in group A and 2 of 11 patients (18.1%) (95% CI 3.3% to 51.8%) in group B had toxoplasmic retinochoroiditis. CONCLUSION: In AIDS patients, ocular manifestations of toxoplasmosis are more common than ocular MAC. In addition, when compared with immunocompetent patients, AIDS patients tend to have retinochoroidal scars with less retinal pigment epithelium hyperplasia (1.8+ vs 3+) (P = .03).

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.

Treatment of cytomegalovirus retinitis with intravitreous cidofovir in patients with AIDS. A preliminary report.

BACKGROUND: Cytomegalovirus retinitis remains a major cause of illness in patients with the acquired immunodeficiency syndrome (AIDS), and existing therapies for this condition are relatively ineffective and toxic. OBJECTIVE: To evaluate the efficacy of intravitreous cidofovir injections alone for initial and maintenance therapy for cytomegalovirus retinitis. DESIGN: Prospective, nonrandomized, consecutive case series. SETTING: University ophthalmology referral clinic. PATIENTS: 22 patients with AIDS and cytomegalovirus retinitis. In 15 of 32 affected eyes, intravitreous cidofovir was administered as the initial treatment for cytomegalovirus retinitis (group A); 17 eyes had previously been treated with intravenous therapy (group B). INTERVENTION: All eyes were intravitreously injected with 20 micrograms of cidofovir at 5- to 6-week intervals. No patient in either group received systemic anticytomegalovirus therapy at any time during the study period. MEASUREMENTS: Healing of retinitis was defined as resolution of retinal opacification and cessation of border progression. Progression, the primary end point, was defined as 750 microns of border progression or development of a new lesion. RESULTS: The mean duration of follow-up was 15.3 weeks (range, 5 to 44 weeks). Of the eyes with active retinitis, 100% (95% CI, 87% to 100%) healed in response to the initial injection. In two eyes (6%; CI, 0% to 15%), two episodes of retinitis progression occurred (one in each eye). Both of these eyes were in a patient with clinically resistant retinitis. In 3% of eyes (CI, 0% to 9%), the retina became detached. Mild iritis developed after 14% of the injections that had been preceded by prophylaxis with oral probenecid. Irreversible, visually significant hypotonia developed in one eye. CONCLUSION: Treatment and subsequent maintenance of cytomegalovirus retinitis with 20 micrograms of intravitreously injected cidofovir, given at 5- to 6-week intervals, is safe and highly effective.

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.

Liposome-encapsulated (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine for long-acting therapy of viral retinitis.

The effect of liposome-encapsulated (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC; cidofovir) was evaluated as prophylaxis in a rabbit model of experimentally induced retinitis caused by preretinal inoculation of herpes simplex virus type 1 (HSV-1). Cidofovir (100 micrograms) in liposomes (0.1 mL) was injected intravitreally 10-120 days before retinal inoculation with HSV-1. Twenty-two of 26 eyes pretreated with liposome-encapsulated cidofovir 10-60 days before HSV-1 inoculation were protected from experimentally induced retinitis, and 2 of 5 eyes pretreated 120 days before inoculation were protected. Intravitreal levels of cidofovir were low (0.7 microgram/mL) but detectable 120 days after injection. One 100-micrograms intravitreal injection of liposome-encapsulated cidofovir appears to have a remarkably potent and prolonged (up to 4 months) antiviral effect in this experimental model of HSV-1 retinitis. Since HPMPC is even more potent against cytomegalovirus than HSV-1, liposome-encapsulated cidofovir may prove to be effective local therapy for AIDS patients with cytomegalovirus retinitis.

Use of perflubron as a new temporary vitreous substitute and manipulation agent for vitreoretinal surgery. Wills Eye Hospital Perflubron Study Group.

PURPOSE: The authors determine the intraocular tolerance of a new widely used liquid perfluorocarbon, perfluoroctylbromide (perflubron). METHODS: Pars plana vitrectomy was performed on 54 eyes of 54 patients with vitreoretinal disorders at three centers. Diagnoses included giant retinal tears, proliferative vitreoretinopathy, and dislocated intraocular and crystalline lenses. At the conclusion of the vitrectomy, perflubron was removed. RESULTS: Perflubron was efficacious for vitreoretinal manipulation. Of the 45 eyes with retinal detachment, 23 (51.1%) of the retinas were reattached after a single surgery; redetachment occurred in 22 (48.9%) after the initial procedure, and further surgery was necessary to reattach the retina. Final retinal reattachment was achieved in 40 (88.9%) eyes. Mean visual acuity improvement was six lines (P < 0.0019). Visualization of the water/perfluorocarbon interface was good. There was no evidence of adverse effects from perflubron on the retina, lens, or anterior segment. CONCLUSION: Findings indicate that perflubron is safe for temporary intraoperative use intravitreally. The absence of adverse effects is consistent with the properties of perflubron that our group has studied in the eyes of animals and in other uses in human patients.

Clinical versus fundus photographic evaluation of the status of cytomegalovirus retinitis in AIDS patients.

PURPOSE: To evaluate the accuracy of clinical examinations and serial fundus photographic readings in determining the response of cytomegalovirus retinitis to antiviral therapy in patients with acquired immune deficiency syndrome. METHODS: Fifty two consecutive patients with cytomegalovirus retinitis who were prospectively evaluated over a 30-month period for a minimum of 6 months (or until death) were included in this study. There was a total of 708 patients visits. The clinical evaluations included indirect ophthalmoscopy, fundus drawings, 60 degrees fundus photographs, and a comparison of the photographs with those of the previous visit. The fundus photographs were reevaluated in a blinded fashion. Cytomegalovirus retinitis was classified as active (progression of border since last examination) intermediate (border activity without progression), healed (no activity since last visit), or normal (no retinitis). RESULTS: Using the photographic data as the measure of cytomegalovirus retinitis activity, the sensitivity and specificity of clinical assessments were determined. The sensitivity and specificity of clinical versus photographic evaluations varied with retinitis status. In healed retinitis the sensitivity of the clinical examination was 98%, and the specificity was 83%. In cases of border opacification without progression the sensitivity was 80%, and the specificity was 96%. In cases of clinically active retinitis the sensitivity was 63% with a specificity of 100%. Clinical detection of active retinitis and border opacification without progression was reduced when potential problems were present that made visualization of the retinitis border difficult, such as smoldering retinitis, progressive retinal destruction without border opacification, poor media, or fundus pigmentation. CONCLUSIONS: Progressive retinal destruction and visual loss can occur in patients with cytomegalovirus retinitis despite antiviral therapy. Examining the patient through indirect ophthalmoscopy only can result in failure to detect subtle changes.

Evaluation of retinal toxicity and efficacy of the anticytomegalovirus compound 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine.

Compound 2242, also known as 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine, is the first known antivirally active nucleoside analog with the side chain substituted at the N-7 position of the purine ring system. Our purpose was to evaluate its retinal toxicity and assess the efficacy of its highest nontoxic concentration in a rabbit model of herpes simplex retinitis. Concentrations of the drug from 0.5 to 2,000 microM were injected intravitreally in twelve New Zealand White rabbits. Fundoscopic, histologic, and electrophysiologic data revealed no evidence of toxicity even at the highest dose of the compound. Dutch pigmented rabbits (n = 34) had their left eyes injected with herpes simplex virus type 1 3 days after, concurrently, or 3 days before intravitreal injection of either 2,000 microM compound 2242 or 480 microM ganciclovir (final concentration in the eye). Both compound 2242 and ganciclovir were equally effective compared with saline when administered simultaneously with the virus (P < 0.0001). In the 3-day pretreatment paradigm, compound 2242 was superior to ganciclovir (P < 0.04), but there was no clear difference between the two with regard to their effects on an established infection. The pharmacokinetics of compound 2242 in 10 rabbits injected intravitreally with 30 microM showed an intravitreal half-life of 8 h. This compound, which may be orally active in its pro form, has a very high therapeutic index in the eye and is more efficient than ganciclovir in this animal model of herpes retinitis.

Antiviral effect in human cytomegalovirus-infected cells, pharmacokinetics, and intravitreal toxicology in rabbits of acyclovir diphosphate dimyristoylglycerol.

Acyclovir diphosphate dimyristoylglycerol (ACVDP-DG) is a lipid prodrug which is active against ACV-resistant strains of herpes simplex virus because of its intracellular metabolism to ACV monophosphate. In human cytomegalovirus (HCMV)-infected MRC-5 cells, ACVDP-DG was ninefold more active than ACV. When liposomal [8-3H]ACVDP-DG was injected intravitreally at the maximum nontoxic dose of 1 mumol in rabbits, the drug remained above its estimated 90% HCMV-inhibitory concentration for 18 days. Intravitreal ganciclovir persists above its 90% inhibitory concentration for only 1 to 2 days. ACVDP-DG may be useful as a local treatment for HCMV retinitis.

Long-term therapy for herpes retinitis in an animal model with high-concentrated liposome-encapsulated HPMPC.

OBJECTIVE: To evaluate(s)-1-(3-hydroxy-2-phosphonyl methoxypropyl) cytosine (HPMPC), a potent antiherpes and anticytomegalovirus drug, as a long-term treatment of experimental retinitis in rabbits. METHODS: The drug was first encapsulated into a liposome delivery system in three different concentrations and injected intravitreally. Sequentially, the highest concentration that was shown to be nontoxic to the retina was evaluated in a model of retinitis at 60, 90, 120, 170, and 240 days, after which herpes simplex virus type 1 was inoculated onto the retinal surface. RESULTS: A dose of 1000 micrograms of HPMPC encapsulated in liposomes gives a protective effect for up to 8 months. CONCLUSIONS: Reduced toxic effects and longer-term efficacy compared with free drug was observed. Given the 50 times higher activity of HPMPC against human cytomegalovirus than herpes simplex virus type 1, a single injection of 1000 micrograms of liposome-encapsulated HPMPC may have a very prolonged effect in the treatment of cytomegalovirus retinitis.

Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome.

PURPOSE: The authors previously conducted a pilot, dose-escalating study which suggested that a 20-micrograms dose of intravitreal cidofovir (HPMPC) may be safe and effective in treating cytomegalovirus (CMV) retinitis in humans. The purpose of this series is to expand the authors' prior experience with the 20-micrograms dose of cidofovir as the sole treatment for CMV retinitis in patients with acquired immune deficiency syndrome. METHODS: The study design was an unmasked consecutive case series trial in a single-center institutional retina referral practice. Eligible patients with acquired immune deficiency syndrome had active CMV retinitis in at least one eye and no evidence of extraocular CMV disease. Patients received a 20-micrograms cidofovir trans pars plana injection and were treated with concomitant oral probenecid. Retreatments were performed for progression of retinitis as determined by serial fundus photographs judged independently by three observers. The primary outcome was time to retinitis progression determined by Kaplan-Meier analysis. Both globes of one patient who had unilateral retinitis were examined pathologically. RESULTS: There were 37 cidofovir injections in 24 eyes of 17 patients. The median time to retinitis progression after the initial 24 injections was 55 days. The median time to retinitis progression after 8 repeat cidofovir injections was 63 days. There was a significant decrease in intraocular pressure from baseline to both 2 and 4 weeks after injection. A mild to moderate iritis developed in five (20.8%) eyes that responded well to topical medications. Results of histopathologic examination of one treated globe did not show any significant toxic effects. CONCLUSIONS: This study demonstrates that prolonged arrest of the progression of CMV retinitis may be obtained with a single 20-micrograms cidofovir intravitreal injection. In addition, the effect of the drug appears to be maintained after a second injection. The effects of cidofovir in causing uveitis and a slight lowering of the intraocular pressure require further study.

Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome.

PURPOSE: In this study we evaluated the safety and efficacy of the nucleoside phosphonate analogue intravitreal cidofovir to treat cytomegalovirus retinitis in humans. METHODS: We conducted a phase I/II unmasked consecutive case series in a single-center institutional referral practice. Eligible patients with the acquired immunodeficiency syndrome had active cytomegalovirus retinitis in at least one eye, despite adequate intravenous therapy with ganciclovir or foscarnet, were intolerant to intravenous therapy, were noncompliant with intravenous therapy, or refused intravenous therapy. In a preliminary safety study (Group 1), ten eyes of nine patients received 14 injections of cidofovir while being treated concurrently with intravenous ganciclovir. In a dose-escalating efficacy study (Group 2), eight eyes of seven patients received 11 injections of cidofovir as sole treatment for cytomegalovirus retinitis. The primary outcome was time to retinitis progression. RESULTS: In the Group 1 eyes receiving 20 micrograms of cidofovir, the median time to retinitis progression was between 49 and 92 days (mean, 78 days). In Group 2 eyes treated with 20 micrograms cidofovir, the median time to retinitis progression was 64 days (mean, 63 days). Hypotony occurred in the two eyes treated with a 100-micrograms dose of cidofovir and in one of three eyes receiving a 40-micrograms dose. No adverse effects resulted from the remaining 20 cidofovir injections. CONCLUSIONS: Cidofovir (also known as HPMPC) appears to be safe and effective for the local treatment of cytomegalovirus retinitis, providing a long duration of antiviral effect. These preliminary results indicate that additional studies should be performed to investigate more fully this promising medication.

Results of rhegmatogenous retinal detachment repair in cytomegalovirus retinitis with and without scleral buckling.

PURPOSE: To determine if scleral buckling is of any benefit in surgical repair of cytomegalovirus (CMV)-associated retinal detachment if combined with vitrectomy, silicone oil, and inferior midperipheral endolaser. MATERIALS AND METHODS: Twenty-two consecutive eyes with CMV-associated retinal detachments were repaired with vitrectomy and endolaser to all breaks and to the inferior midperipheral retina using silicone oil without scleral buckling (group 1, control group) between July 1987 and May 1992. Results were compared with another series of 56 consecutive eyes undergoing vitrectomy, silicone oil injection, endolaser to all breaks, and 360 degrees encircling scleral buckling (group 2, study group) between June 1992 and July 1993. RESULTS: Total retinal reattachment rates were 84% for group 1 and 86% for group 2. Rates of macular reattachment were 91% for group 1 and 91% for group 2. Mean best postoperative refracted visual acuity was 20/66 for group 1 and 20/67 for group 2. Median best postoperative refracted visual acuity was 20/74 for group 1 and 20/80 for group 2. These differences in results between the two groups were not statistically significant. Mean postoperative refractive error was +3.95 for group 1 and +4.92 for group 2. Patients who underwent surgery with the macula attached had a better postoperative visual outcome. CONCLUSION: Scleral buckling may not be necessary in CMV-related retinal detachment if repaired with vitrectomy, silicone oil, and inferior midperipheral endolaser. Elimination of scleral buckling may reduce intraoperative time, patient morbidity, and the risk of an accidental needle stick. Patients with macula-on retinal detachments also should be considered for surgery before macular detachment.