Daniel F. Martin

ORAL GANCICLOVIR FOR PATIENTS WITH CYTOMEGALOVIRUS RETINITIS TREATED WITH A GANCICLOVIR IMPLANT

BACKGROUND The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. METHODS Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to one of three treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. RESULTS The incidence of new cytomegalovirus disease at six months was 44.3 percent in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3 percent in the group assigned to the ganciclovir implant plus oral ganciclovir (P=0.002) and 19.6 percent in the group assigned to intravenous ganciclovir alone (P<0.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6 percent over the one-year period of the study (P=0.02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P=0.03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposis sarcoma by 75 percent (P=0.008) and 93 percent (P<0.001), respectively, as compared with placebo. CONCLUSIONS In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposis sarcoma.

Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration

Background Recent studies have suggested that vascular endothelial growth factor (VEGF) is an important stimulus for the growth of new blood vessels in the eye. Anti-VEGF therapy is thus a potential treatment for exudative macular degeneration and diabetic retinopathy. Methods Previously described animal models of vascular leakage and ocular neovascularization, including the Miles assay, the rat corneal angiogenesis model, and the mouse retinopathy of prematurity (ROP) model, were used to study this drug. After these studies, a phase IA single ascending dose study of intravitreal injections of the drug was performed in 15 patients with subfoveal choroidal neovascularization secondary to exudative age-related macular degeneration (AMD). Results The Miles assay model showed almost complete attenuation of VEGF-mediated vascular leakage following addition of EYE001, and the corneal angiogenesis model also showed a significant reduction in neovascularization with EYE001. The ROP model showed inhibition of 80% of the retinal neovascularization compared with controls (P = 0.0001). The phase IA safety study of patients with exudative AMD showed no significant safety issues related to the drug. Ophthalmic evaluation revealed that 80% of patients showed stable or improved vision 3 months after treatment and that 27% of eyes demonstrated a three-line or greater improvement in vision on the Early Treatment for Diabetic Retinopathy Study chart at this time. Conclusion Anti-VEGF therapy is a promising new avenue for the treatment of neovascular diseases of the eye, including exudative macular degeneration and diabetic retinopathy. Preclinical data from studies with EYE001 support clinical evaluation of its efficacy in such diseases. This report is the first to describe administration of anti-VEGF therapy in humans for exudative macular degeneration and shows the safety of such therapy for single injections. Further clinical studies are necessary to determine the safety of multiple intravitreal injections of EYE001 and larger studies are needed to prove the efficacy of this novel, potentially therapeutic agent for neovascular AMD.

Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: Phase II study results

PURPOSE There is evidence to suggest that anti-vascular endothelial growth factor (anti-VEGF) therapy may be useful in treating ocular neovascularization. A phase IA single intravitreal injection study of anti-VEGF therapy for patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) revealed a good safety profile. We performed a phase II multiple injection study of anti-VEGF therapy with and without photodynamic therapy for patients with subfoveal CNV secondary to AMD to determine the safety profile of multiple injection therapy. DESIGN A phase II multiple-dose safety study. PARTICIPANTS/METHODS Twenty-one patients were treated with intravitreal injection with and without photodynamic therapy. MAIN OUTCOME MEASURES Clinical evidence of toxicity and complications. RESULTS No drug-related serious adverse events were revealed. Ophthalmic evaluation revealed that 87.5% of patients who received the anti-VEGF aptamer alone showed stabilized or improved vision 3 months after treatment and that 25% of eyes demonstrated a 3 line or greater improvement in vision on the Early Treatment of Diabetic Retinopathy Study chart during this period. A 60% 3 line gain at 3 months was noted in patients who received both the anti-VEGF aptamer and photodynamic therapy. CONCLUSIONS Anti-VEGF therapy is a promising treatment for various forms of ocular neovascularization, including AMD. Multiple intravitreal injections of the anti-VEGF aptamer were well tolerated in this phase II study. Further clinical trials are necessary to demonstrate the efficacy and long-term safety of anti-VEGF therapy for AMD.

Retinal pigment epithelial changes after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling

PURPOSE To report the results of macular hole surgery using indocyanine green to improve visualization and facilitate peeling of the internal limiting membrane. METHODS A retrospective noncomparative review of a consecutive series of 22 patients (22 eyes) who underwent macular hole repair using indocyanine green to facilitate visualization of the internal limiting membrane was performed. One patient was excluded because of a history of a rhegmatogenous retinal detachment. All patients underwent a three-port pars plana vitrectomy with internal limiting membrane peeling. Indocyanine green (0.1% solution) was used to assist in the visualization of the internal limiting membrane. The main outcome measures were postoperative visual acuity, macular hole status, and postoperative retinal pigment epithelial changes. RESULTS In 21 eyes, the median preoperative best-corrected visual acuity was 20/200 (range, 20/60 to counting fingers at 5 feet). The median postoperative visual acuity was 20/400 (range, 20/60-1/200) with an average follow-up of 13 weeks. The macular hole was closed in 18 eyes (86%) at the most recent follow-up. Ten eyes were found to have atrophic retinal pigment epithelium changes in the area of the previous macular hole. CONCLUSIONS Indocyanine green assists in visualization of the internal limiting membrane in macular hole surgery. In our series, 10 eyes had unusual atrophic changes in the retinal pigment epithelium at the site of the previous macular hole, or in the area where the indocyanine green solution would have had direct access to the bare retinal pigment epithelium cells. Although the use of indocyanine green improves visualization and assists with peeling of the internal limiting membrane, the safety and potential toxicity of indocyanine green to the retinal pigment epithelium require further investigation.

Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant

BACKGROUND Sustained-release, intraocular implants that deliver ganciclovir are an alternative method for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). METHODS We conducted a randomized study of 188 patients with AIDS and newly diagnosed cytomegalovirus retinitis. The patients were randomly assigned to treatment with an implant delivering 1 microg of ganciclovir per hour, an implant delivering 2 microg of ganciclovir per hour, or intravenous ganciclovir. The primary outcome we studied was progression of cytomegalovirus retinitis. RESULTS The median time to progression of retinitis was 221 days with the 1-microg-per-hour implant (75 eyes), 191 days with the 2-microg-per-hour implant (71 eyes), and 71 days with ganciclovir administered intravenously (76 eyes; P<0.001). The risk of progression of retinitis was almost three times as great among patients treated with intravenous ganciclovir as among those treated with a ganciclovir implant (risk ratio, 2.8; P<0.001). However, the risk of disease in the initially uninvolved eye was lower with intravenous ganciclovir than with a ganciclovir implant (risk ratio, 0.5; P=0.19). Patients treated with intravenous ganciclovir were also less likely to have extraocular cytomegalovirus infections (0, vs. 10.3 percent in the two implant groups; P=0.04). CONCLUSIONS For the treatment of cytomegalovirus retinitis, the sustained-release ganciclovir implant is more effective than intravenous ganciclovir, but patients treated with a ganciclovir implant alone remain at greater risk for the development of cytomegalovirus disease outside of the treated eye.

Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results.

OBJECTIVES To evaluate the safety and efficacy of 0.59-mg and 2.1-mg fluocinolone acetonide (FA) intravitreous implants in noninfectious posterior uveitis. DESIGN A 3-year, multicenter, randomized, historically controlled trial of the 0.59-mg FA intravitreous implant in 110 patients and the 2.1-mg FA intravitreous implant in 168 patients. MAIN OUTCOME MEASURES Recurrence rate, vision, and complications. RESULTS Uveitis recurrence was reduced in implanted eyes from 62% (during the 1-year preimplantation period) to 4%, 10%, and 20% during the 1-, 2-, and 3-year postimplantation periods, respectively, for the 0.59-mg dose group (P < .01) and from 58% to 7%, 17%, and 41%, respectively, for the 2.1-mg dose group (P < .01). More implanted eyes than nonimplanted eyes had improved visual acuity (P < .01). Implanted eyes had higher incidences of intraocular pressure elevation (> or = 10 mm Hg) than nonimplanted eyes (P < .01), and glaucoma surgery was required in 40% of implanted eyes vs 2% of nonimplanted eyes (P < .01). Cataracts were extracted in 93% of phakic implanted eyes vs 20% of phakic nonimplanted eyes (P < .01). CONCLUSIONS The FA implant significantly reduced uveitis recurrence and improved or stabilized visual acuity in subjects with noninfectious posterior uveitis. Most subjects required cataract extraction, and a significant proportion required intraocular pressure-lowering surgery. APPLICATION TO CLINICAL PRACTICE The FA implant provides an alternative therapy for prolonged control of inflammation in noninfectious posterior uveitis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00407082.

MACULAR HOLE SURGERY USING THROMBIN-ACTIVATED FIBRINOGEN AND SELECTIVE REMOVAL OF THE INTERNAL LIMITING MEMBRANE

Purpose. To evaluate a tissue sealant (autologous cryoprecipitate activated with bovine thrombin) as an adjuvant in macular hole surgery. Methods. Sixty-nine patients with stage 2, 3, or 4 full-thickness macular hole were enrolled consecutively in a prospective pilot study. Anatomic closure of the macular holes with a single operation was the primary outcome. Fifty-eight patients had pre- and postoperative standardized measurements including best refracted visual acuity, reading speed, and contrast sensitivity. Group A patients (45) had primary macular holes; Group B patients (13) had recurrent macular holes or macular holes with “other” retinal pathology. Surgical technique was standardized and membrane dissections were optional. Results. The anatomic closure rate was 80% with a minimum of 6 months follow-up. Mean improvement in visual acuity for Group A (2.9 ± 0.4 lines) was significantly better than for Group B (0.8 ± 0.5 lines; P = 0.008). Eyes that underwent internal limiting membrane (ILM) dissections had an anatomic closure rate of 96% (23/24), compared with 71% (32/45) in “non-ILM” cases (P = 0.034). Adverse reactions included sterile hypopyon (10%), intraretinal hemorrhage (9%), pigmentary hyperplasia (3%), and retinal detachment (3%). Conclusion. Tissue sealants should be evaluated as an adjuvant in macular hole surgery in a randomized clinical trial. Inflammatory reactions may occur in some patients. Internal limiting membrane dissection may improve anatomic closure rates without adversely affecting the visual acuity.

Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: Recommendations of the international AIDS society-USA panel

PURPOSE To describe the risks, benefits, and recommended use of the ganciclovir implant for the treatment of human immunodeficiency virus-related cytomegalovirus (CMV) retinitis in the era of potent antiretroviral therapy. METHODS A panel of physicians with expertise in the use of the ganciclovir implant and in the management of CMV retinitis was convened by the International AIDS Society-USA. The panel reviewed and discussed available data, and developed recommendations for the use of the ganciclovir implant, the surgical technique, and related management issues. Recommendations were rated according to the strength and quality of the supporting evidence. RESULTS The effect of potent antiretroviral therapy on the immunologic status of patients with human immunodeficiency virus disease has changed the manifestation and course of CMV retinitis in many patients. The clinical management of CMV retinitis and the role of the ganciclovir implant are thus changing. Factors in the decision to choose the ganciclovir implant include the patients potential for immunologic improvement, location and severity of CMV retinitis, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy. CONCLUSIONS The ganciclovir implant is safe and effective for the treatment of CMV retinitis. The indications for its use should be modified to account for increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy. Optimal use of the ganciclovir implant and discontinuation of therapy in selected patients with improvement in immunity may result in better long-term visual outcomes.

A Polymerase Chain Reaction-based Assay for Diagnosing Varicella-zoster Virus Retinitis in Patients With Acquired Immunodeficiency Syndrome

PURPOSE To develop a rapid, sensitive, and specific laboratory assay based on the polymerase chain reaction for the diagnosis of varicella-zoster virus retinitis in patients with acquired immunodeficiency syndrome (AIDS). METHODS We developed and tested a polymerase chain reaction-based assay for the detection of varicella-zoster virus DNA in vitreous samples. We attempted to detect varicella-zoster virus DNA in 14 vitreous samples from patients with AIDS and a clinical diagnosis of progressive outer retinal necrosis syndrome. For controls, we also attempted to detect varicella-zoster virus DNA in vitreous samples from 75 immunocompetent patients with vitreoretinal disease and 88 patients with AIDS and vitreoretinal inflammatory disease not related to progressive outer retinal necrosis syndrome. RESULTS Varicella-zoster virus DNA was detected in 11 of 14 vitreous samples from AIDS patients with progressive outer retinal necrosis syndrome. All three samples that scored negative for varicella-zoster virus DNA came from eyes that had been treated aggressively with antiviral drugs and had clinically inactive disease at the time of vitreous biopsy. Varicella-zoster virus DNA was detected in only two of 75 control vitreous samples from immunocompetent patients with vitreoretinal disease and two of 88 control vitreous samples from patients with AIDS and vitreoretinal inflammatory disease not related to progressive outer retinal necrosis syndrome. CONCLUSION We have developed a rapid, sensitive, and specific polymerase chain reaction-based diagnostic assay for varicella-zoster virus DNA that will assist in the diagnosis of varicella-zoster virus retinitis in patients with AIDS.

Uveal lymphoid infiltration. Report of four cases and clinicopathologic review.

PURPOSE The purpose of the study was to report the clinicopathologic features of four patients with uveal lymphoid infiltration who were diagnosed by a conjunctival biopsy. DESIGN A case series. PARTICIPANTS Four patients at four institutions participated. MEASURES The histopathologic findings of the conjunctival and episcleral biopsy specimens from four patients with the diagnosis of uveal lymphoid infiltration were recorded. The conjunctival specimens were placed in 10% neutral buffered formaldehyde solution or B5 solution and processed routinely for light microscopic examination and immunohistochemical analysis for B cells and T cells and kappa and lambda light chains. The clinical and histopathologic findings were compared with 47 previously reported cases of uveal lymphoid infiltration. RESULTS Two men and two women (average age = 57 years) presented with diffuse punctate to coalescent yellow uveal infiltrates and epibulbar pink fleshy lesions. Ultrasonography of the lesions showed diffuse choroidal thickening and a lack of choroidal or scleral excavation. The conjunctival biopsy specimens showed diffuse infiltration of the substantia propria with B lymphocytes with variable kappa and lambda restriction. Scattered T lymphocytes also were present. Plasmacytoid cells and a prominent Grenz zone were present. CONCLUSIONS Patients with solitary or multiple yellow uveal infiltrates should have careful conjunctival evaluation for the presence of pink conjunctival lesions. Biopsy specimens of the conjunctival lesion may establish the diagnosis of uveal lymphoid infiltration.