2-ethylpyridine, a cigarette smoke component, causes mitochondrial damage in human retinal pigment epithelial cells in vitro.

PURPOSE: Our goal was to identify the cellular and molecular effects of 2-ethylpyridine (2-EP, a component of cigarette smoke) on human retinal pigment epithelial cells (ARPE-19) in vitro. MATERIALS AND METHODS: ARPE-19 cells were exposed to varying concentrations of 2-EP. Cell viability (CV) was measured by a trypan blue dye exclusion assay. Caspase-3/7 and caspase-9 activities were measured by fluorochrome assays. The production of reactive oxygen/nitrogen species (ROS/RNS) was detected with a 2',7'-dichlorodihydrofluorescein diacetate dye assay. The JC-1 assay was used to measure mitochondrial membrane potential (ΔΨm). Mitochondrial redox potential was measured using a RedoxSensor Red kit and mitochondria were evaluated with Mitotracker dye. RESULTS: After 2-EP exposure, ARPE-19 cells showed significantly decreased CV, increased caspase-3/7 and caspase-9 activities, elevated ROS/RNS levels, decreased ΔΨm value and decreased redox fluorescence when compared with control samples. CONCLUSIONS: These results show that 2-EP treatment induced cell death by caspase-dependent apoptosis associated with an oxidative stress and mitochondrial dysfunction. These data represent a possible mechanism by which smoking contributes to age-related macular degeneration and other retinal diseases and identify mitochondria as a target for future therapeutic interventions.

Experimental selective choriocapillaris photothrombosis using a modified indocyanine green formulation.

BACKGROUND: This in vivo study assessed and compared the effectiveness of an aqueous indocyanine green (ICG) formulation (R-ICG) and a lipid ICG formulation (L-ICG) in occluding the rabbit choriocapillaris, and determined the singlet oxygen quantum yields and aggregation properties of both formulations in vitro. METHODS: Singlet oxygen production and aggregation were compared. The eye fundus of 30 albino rabbits was irradiated 0-15 min after dye injection using an 810 nm diode laser. Fluorescein angiography and light microscopy were used to evaluate the safety and efficacy of R-ICG and L-ICG. RESULTS: L-ICG decreased the dimerisation constant and the tendency of ICG to form aggregates, and increased the efficiency of ICG in generating singlet oxygen (R-ICG, PhiDelta = 0.120 and L-ICG, PhiDelta = 0.210). Using a 10 mg/kg dose, choriocapillaris occlusion was achieved at a light dose of 35.8 J/cm(2) with L-ICG and 71.6 J/cm(2) with R-ICG with minimal damage to the neurosensory retina. CONCLUSION: Restrictions to the use of ICG in aqueous solution, low singlet oxygen quantum yields and high aggregation tendency, were overcome with L-ICG. The lower laser irradiance required to obtain choriocapillaris occlusion may suggest that L-ICG is a more potent and selective photosensitiser than R-ICG.

A prospective multicenter clinical trial to evaluate the safety and effectiveness of the implantable miniature telescope.

PURPOSE: To evaluate the safety and preliminary efficacy of a novel visual prosthetic device, the Implantable Miniature Telescope, IMT (by Dr Isaac Lipshitz) (IMT), in a phase I trial in patients with significant bilateral central vision impairment from late-stage age-related macular degeneration (AMD). The IMT is designed to reduce the relative size of the scotoma by rendering enlarged (threefold) central visual field images over the central and peripheral retina. DESIGN: Prospective, multicenter, open-label clinical trial. METHODS: In this prospective, multicenter phase I trial, 14 patients aged 60 or older with bilateral geographic atrophy or disciform scar AMD, cataract, and best-corrected visual acuity (BCVA) between 20/80 and 20/400 had an IMT implanted in one eye. Distance and near BCVA, endothelial cell density, and quality of life, measured as activities of daily life (ADL), were evaluated preoperatively and postoperatively. RESULTS: At 12 months, 10 (77%) of 13 patients gained 2 more lines of either distance or near BCVA, and eight (62%) of 13 patients gained 3 or more lines in either distance or near BCVA. Mean endothelial cell density decreased by 13%. All adverse events resolved without sequelae. ADL scores improved in the majority of patients. CONCLUSION: The results of this phase I trial support further evaluation of the IMT in a larger study population with late-stage AMD. A phase II/III trial is in progress.

Differential retinal angiogenic response to sustained intravitreal release of VEGF and bFGF in different pigmented rabbit breeds.

PURPOSE: To determine if two different breeds of pigmented rabbits can demonstrate differences in the degree of inducible angiogenesis within the retina. METHODS: Non-biodegradable Hydron pellets approximately 1.5 mm in diameter containing both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were implanted intravitreally over the optic disk of either Dutch belt rabbits or New Zealand White/Black satin cross rabbits. Control animals from both groups were implanted with blank Hydron pellets. Animals were examined periodically over a 30-day period following implantation. Results were documented by fundus photography and flourescein angiography. Stages of neovascularization (NV) were graded between +1 (preproliferative) and +4 (total NV) with +5 for NV complicated by hemorrhage and/or retinal detachment. RESULTS: The angiogenic response in the retinas of pigmented NZW/Black satin cross rabbits (N = 5) following implantation of VEGF/bFGF-containing pellets varied extensively from the Dutch belt animals (N = 7). In the Dutch belt rabbits, grading of the angiogenic response demonstrated either +4 or +5 between day 20 and day 30 after implantation. In contrast, the NZW/Black satin cross animals gave a more muted response with a maximum grade of +2 following exposure to the same amount of VEGF and bFGF. Control eyes that received only blank pellets showed no evidence of retinal NV in either the Dutch belts (N = 5) or the NZW/Black satin cross rabbits (N = 5). Statistical analysis showed a significant interaction effect for breed and pellet type (F = 44.85 with 1 df, p < 0.00005), indicating a difference between the breeds in the angiogenic response to the pellet. Moreover, both the NZW/BSC and Dutch belt rabbits displayed a significant increase in angiogenesis with the VEGF/bFGF pellet in comparison to the blank pellet (p = 0.037 and p < 0.00005, respectively). CONCLUSIONS: These studies indicate that two different breeds of pigmented rabbits exhibit different angiogenic responses to the same amount of both VEGF and bFGF. Florid retinal NV leading to hemorrhage, fibrovascular membrane formation, and traction retinal detachment occurred in the Dutch belt rabbits while tortuosity and dilatation of existing blood vessels with subsequent regression occurred in the NZW/Black satin cross animals. Such differences in the angio-genic response may be due to differences in the genetic background of these animals. If genetic heteriogeneity exists for angiogenic responses, then understanding the genetic role in the regulation of angiogenesis will lead to the design of more effective anti-angiogenic agents and can provide predictive outcomes of individual responses to therapy.

Prevalence of antiviral drug resistance in untreated patients with cytomegalovirus retinitis.

The purpose of this study was to determine the prevalence of UL97 resistance mutations in cytomegalovirus (CMV) DNA amplified from the eyes of patients with AIDS and newly diagnosed CMV retinitis. Relevant segments of the CMV UL97 gene were amplified from vitreous humor, after which restriction digest screening was performed for resistance mutations at codons 460, 520, 591, 592, 594, 595, and 603. Mutations were confirmed by DNA sequencing. Vitreous from 21 eyes with AIDS-related non-CMV viral retinitis served as negative controls. CMV DNA was successfully amplified from 195 of 204 eyes. A resistance mutation was found in only a single eye, a T-->G mutation at base 1774, predicting a cysteine to glycine mutation at codon 592. The prevalence of UL97 resistance mutations in the eyes of patients with newly diagnosed CMV retinitis is very low.

Vitreoretinal surgery through multifocal intraocular lenses compared with monofocal intraocular lenses in fluid-filled and air-filled rabbit eyes.

PURPOSE: To compare vitrectomy procedures and visualization of posterior segment structures through multifocal silicone intraocular lenses (IOLs) with the same procedures through monofocal silicone IOLs in rabbit eyes. DESIGN: Experimental study. PARTICIPANTS: Twelve eyes of six rabbits. METHODS: Each rabbit eye underwent phacoemulsification of the lens and posterior chamber implantation of a silicone multifocal or silicone monofocal IOL. The type of IOL (monofocal vs. multifocal) implanted in the first eye of each rabbit was randomly decided. The fellow eye then received the other IOL type. Vitrectomy procedures were performed through the IOLs by using a flat contact lens (part 1) or wide-angled contact lens (part 2) for visualization through fluid-filled (parts 1 and 2) and air-filled (part 2) eyes. MAIN OUTCOME MEASURES: Image quality, stereopsis, and contrast were subjectively graded on a scale of 0 (none) to 4 (excellent) for each eye by each surgeon. RESULTS: In part 1, image quality averaged 4 for the monofocal IOL and 3.6 for the multifocal IOL. Stereopsis averaged 4 for the monofocal IOL and 4 for the multifocal IOL. Contrast averaged 4 for the monofocal IOL and 3.9 for the multifocal IOL. Vitrectomy with retinal surface maneuvers was successfully performed in both pigmented and nonpigmented rabbit eyes through both IOL types. In part 2, image quality, stereopsis, and contrast were rated as 4 for both multifocal and monofocal silicone IOLs. Air-fluid exchange was performed without difficulty. Image quality, stereopsis, and contrast were rated as 4 for air-filled eyes. CONCLUSIONS: Visualization of posterior segment structures through multifocal silicone IOLs was sufficient for retinal surface maneuvers during vitrectomy procedures in both fluid-filled and air-filled rabbit eyes.

Antibody-dependent cellular cytotoxicity independently predicts survival in severely immunocompromised human immunodeficiency virus-infected patients.

The exact immune defects leading to human immunodeficiency virus (HIV)-associated opportunistic infections, malignancies, and death are unknown. In this study, the relationship between survival and 2 immune functions, cytomegalovirus-specific antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) activity, was determined by using peripheral blood mononuclear cells from 39 severely immunocompromised patients (median CD4 count, 7). Median follow-up was 414 days; 15 subjects died and 24 remained alive. In a Kaplan-Meier analysis, high baseline ADCC (>median) was associated with improved survival (P=.05). A similar trend was observed for NK activity (P=.1). In a multivariate model controlling for baseline CD4 cell count, HIV RNA, and use of protease inhibitors during follow-up, high ADCC, but not high NK activity, remained significantly associated with a lower risk of death (relative risk, 0.18; 95% confidence interval, 0.05-0.75). ADCC may be an important determinant of disease progression independently of anti-retroviral therapy, CD4 cell count, and HIV RNA.

Acquired immunodeficiency syndrome-related intraocular B-cell lymphoma.

OBJECTIVES: To present the full clinical spectrum of the acquired immunodeficiency syndrome-related intraocular lymphoma as manifested in the eye, specifically retinal lymphoma associated with primary central nervous system lymphoma, isolated ocular lymphoma, and choroidal lymphoma associated with systemic lymphoma. METHODS: Three patients with acquired immunodeficiency syndrome were noted to have atypical retinal lesions. Diagnostic retinal biopsy in 2 patients and postmortem examination of the eyes in the third case were performed. RESULTS: Diagnostic retinal biopsy in the first 2 patients revealed retinal B-cell lymphoma. Initial systemic evaluation showed the eyes to be the sole site of disease. Later, in 1 of these patients, the lymphoma spread to the brain. The third patient developed an acute abdomen 4 months after the development of his ocular findings. The histological evaluation of the resected bowel revealed high-grade B-cell lymphoma. The patient died 1 week later and postmortem analysis of the eyes disclosed the presence of lymphoma in the choroid of both eyes. CONCLUSIONS: This is the most complete series of patients with acquired immunodeficiency syndrome-related intraocular B-cell lymphoma and, to our knowledge, provides the first 2 cases diagnosed by retinal biopsy. These 3 cases present the full clinical spectrum of the disease as manifested in the eye.

Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group.

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 Kaposi's 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 Kaposi's sarcoma.

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 patient's 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.

Glycoprotein B subtyping of cytomegalovirus (CMV) in the vitreous of patients with AIDS and CMV retinitis.

A 550-bp region of the cytomegalovirus (CMV) glycoprotein B (gB) gene was amplified by polymerase chain reaction (PCR) from 141 vitreous specimens of 120 patients with AIDS and CMV retinitis from three different metropolitan centers. The distribution of gB subtypes I, II, III, and IV were 19%, 43%, 12%, and 21%, respectively, based on restriction enzyme digestion patterns of PCR-amplified DNA. Two patients had simultaneous infection with two different gB subtypes. The ratio of gB subtypes was similar among the three geographically distinct patient populations. Two of 14 patients with bilateral vitreous specimens had different viral subtypes in each eye. In addition, different gB subtypes were observed in 1 of 6 patients with serial specimens. The ratio of different gB subtypes in the vitreous of patients with CMV retinitis is similar to that previously reported in the peripheral blood of patients with advanced AIDS.

Mutations in the cytomegalovirus UL97 gene associated with ganciclovir-resistant retinitis.

Vitreous from patients with cytomegalovirus (CMV) retinitis was studied in order to identify mutations in the CMV UL97 gene associated with clinical resistance to ganciclovir. Point mutations known to confer resistance (V460, I460, V594, and S595) were found in 6 of 11 study eyes. Rapid genetic screening by restriction enzyme analysis of viral DNA amplified directly from the vitreous was as effective as conventional sequencing in detecting these mutations. Repeat biopsy of 3 eyes revealed no change in the UL97 genotype. The UL97 genotype differed between eyes in 2 of 3 patients with bilateral, clinically resistant CMV retinitis. In summary, resistance mutations of the CMV UL97 gene are found in the vitreous of some, but not all, eyes with CMV retinitis that have not responded to ganciclovir therapy. These mutations can differ between eyes in patients with bilateral disease and can be rapidly detected using restriction digest analysis of polymerase chain reaction-amplified viral DNA.

Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS.

To assess the effect of intravenous cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.

Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Implant Study Group.

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.

Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial.

BACKGROUND: Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with the acquired immunodeficiency syndrome (AIDS). If left untreated, it may lead to progressive destruction of retinal tissue and blindness. Cidofovir is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against herpesviruses, including many CMV isolates that are resistant to ganciclovir and foscarnet. OBJECTIVE: To determine whether intravenous cidofovir delays progression of previously untreated CMV retinitis. DESIGN: Randomized, controlled trial comparing immediate with deferred cidofovir treatment. Patients in the deferred treatment group were eligible to receive cidofovir after progression of CMV retinitis was documented by retinal photography. SETTING: Eight academic medical centers and an independent center that read retinal photographs. PATIENTS: 48 patients with AIDS and previously untreated peripheral CMV retinitis who were randomly assigned to immediate (n = 25) or deferred treatment (n = 23). INTERVENTION: Intravenous cidofovir, 5 mg/kg of body weight, once weekly for 2 weeks and then once every other week. To minimize nephrotoxicity, oral probenecid and intravenous hydration with normal saline were administered with each cidofovir infusion. MEASUREMENTS: Progression of CMV retinitis was assessed by bilateral, full-field retinal photographs that were read by an ophthalmologist who was masked to treatment assignment. Incidence of side effects, changes in visual acuity, effect on CMV shedding in urine and blood, and mortality were also assessed. RESULTS: The median time to progression of CMV retinitis was 22 days (95% CI, 10 to 27 days) in the deferred treatment group and 120 days (CI, 40 to 134 days) in the immediate treatment group (P < 0.001). Neutropenia (15%) and proteinuria (12%), both asymptomatic, were the most common serious adverse events considered to be possibly related to cidofovir. Cidofovir treatment was discontinued in 10 of 41 patients (24%) because of protocol-defined treatment-limiting nephrotoxicity. Transient reactions to probenecid, including mild to moderate constitutional symptoms or nausea, occurred in 23 of 41 patients (56%) and were dose limiting in 3 (7%). CONCLUSIONS: Cidofovir was efficacious in delaying progression of previously untreated CMV retinitis. Treatment was associated with manageable side effects; strict adherence to monitoring of renal function before cidofovir was administered and concomitant administration of probenecid and saline hydration appeared to minimize drug-related nephrotoxicity.

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.

Therapeutic options for resistant cytomegalovirus retinitis.

Untreated cytomegalovirus (CMV) retinitis is progressive and generally leads to blindness within 6 months. Intravenous (i.v.) therapies such as foscarnet and ganciclovir, which were the first agents approved for the treatment of CMV retinitis, are effective in suppressing CMV replication, but they delay rather than prevent reactivation of CMV infection resulting in relapse of the disease. Furthermore, studies have shown that the time between subsequent reactivations becomes shorter, with each relapse producing more serious disease that may be more difficult to manage. This clinical failure may be caused in part by drug resistance; approximately 10% of all patients receiving systemic treatment with these agents may harbor drug-resistant viral strains. With three systemic therapies (ganciclovir, foscarnet, and cidofovir) now available for the treatment of CMV retinitis, several options exist for patients who have failed therapy with one of these drugs: reinduction with the same i.v. agent, switching therapies, or combining therapies. Resistant or relapsing CMV retinitis may also be treated by local therapies such as intraocular injections of ganciclovir and foscarnet or with a sustained-release ganciclovir implant. However, local therapy is ineffective in controlling extraocular or fellow eye CMV disease. It is likely that the integration of both local and systemic therapies will be required to halt the relentless progression of this debilitating disease, particularly when clinical resistance is encountered.

Clinical experience with cidofovir in the treatment of cytomegalovirus retinitis.

Cidofovir (Vistide, HPMPC) is a nucleotide analogue with potent in vitro activity against cytomegalovirus (CMV) that was recently licensed for treatment of patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis. Cidofovir's prolonged intracellular half-life permits dosing once every 2 weeks for maintenance treatment. The treatment-limiting toxicity of cidofovir is dose- and schedule-dependent nephrotoxicity affecting renal proximal convoluted tubule cells. A treatment regimen that includes concomitant administration of oral probenecid, intravenous hydration, and careful preinfusion evaluation of renal function with conservative dose modification has reduced cidofovir-associated nephrotoxicity. Preliminary results of clinical studies of cidofovir in AIDS patients with newly diagnosed and relapsing CMV retinitis are described.