Objective: To evaluate patients with cytomegalovirus (CMV) retinitis treated with intravenous cidofovir for long-term outcomes.Design: Patients with CMV retinitis enrolled in a randomized, controlled clinical trial of intravenous cidofovir as treatment for retinitis were followed for long-term outcomes, including 21 patients initially enrolled in the deferral group who received cidofovir therapy after progression of retinitis.Setting: Thirteen tertiary care clinics specializing in AIDS care and ophthalmology.Participants: Fifty-eight patients with AIDS and small peripheral CMV retinitis lesions.Interventions: Cidofovir 5 mg/kg once weekly for 2 weeks followed by low-dose maintenance cidofovir therapy (3 mg/kg) in 35 patients or high-dose maintenance (5 mg/kg) in 23 patients.Main outcome measures: Time to progression of retinitis, drug toxicities.Results: Median time to progression of retinitis was 2.5 months. Median time to discontinuation of cidofovir because of intolerance was 6.6 months, and did not differ significantly between the two maintenance doses. Median time to discontinuation of cidofovir for intolerance other than probenecid reaction was 16.3 months for patients treated with low-dose maintenance and 5.0 months for patients treated with high-dose maintenance (P = 0.021). Proteinuria of 2+ or more occurred at a rate of 1.22/person year. In patients with sufficient follow-up to determine resolution of proteinuria, 89.9% of episodes resolved, and the median time to resolution was 20 days. Rates of probenecid intolerance and of cidofovir-associated uveitis were 0.35/person-year, and 0.20/person-year, respectively.

Background: Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). Objective: To evaluate intravenous cidofovir as a treatment for CMV retinitis. Design: Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. Setting: Ophthalmology and AIDS services at tertiary care medical centers. Patients: 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). Intervention: Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. Measurements: Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. Results: Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P > 0.2), and 6.8 per person-year in the high-dose cidofovir group (P = 0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 mu mol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. Conclusions: Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity.

The objectives of the study were to examine the clinical significance of cytomegalovirus (CMV) culture results and drug susceptibilities in CMV isolates from patients with AIDS-related CMV retinitis. Blood and urine for CMV culture were obtained from 207 patients with newly diagnosed CMV retinitis who were enrolled in a randomized trial comparing foscarnet and ganciclovir. Culture-positive rates at baseline were 45% and 71% for blood and urine, respectively. Rates decreased 3- to 10-fold after initiation of either treatment. Mortality was related to both positive baseline blood and urine cultures; adjusted relative risks were 1.97 and 2.03, respectively. Positive blood cultures at baseline were associated with more rapid retinitis progression. Drug-resistant CMV was found, over comparable follow-up periods on assigned treatment, in 4 of 8 ganciclovir-assigned patients with persistent viremia and 0 of 5 foscarnet-assigned patients with persistent viremia. Results of virologic assays of blood appear to be associated with clinical outcome of CMV retinitis.

Objective: To evaluate the the efficacy and safety of an intravenous human monoclonal antibody to cytomegalovirus (CMV), MSL-109, as adjuvant treatment for CMV retinitis.Methods: Two hundred nine patients with acquired immunodeficiency syndrome and active CMV retinitis were enrolled in a multicenter, phase 2/3, randomized, placebo-controlled clinical trial. Patients received adjuvant treatment with MSL-109, 60 mg intravenously every 2 weeks, or placebo. Randomization was stratified on the basis of whether patients had untreated or relapsed retinitis. Primary drug therapy for CMV retinitis was determined by the treating physician.Results: The rates of retinitis progression, as evaluated in a masked fashion, were 3.04/person-year in the MSL-109-treated group and 3.05/person-year in the placebo-treated group (P=.98; Wald test); the median times to progression were 67 days in the MSL-109-treated group and 65 days in the placebo-treated group. No differences between the 2 groups were noted in the rates of increase in retinal area involved by CMV, visual field loss, or visual acuity outcomes. The mortality rate in the MSL-109-treated group was 0.68/person-year, and in the placebo-treated group, 0.31/person-year (P=.01). The mortality difference was not explained by differences in baseline variables or in concurrent antiretroviral therapy. Among patients with newly diagnosed retinitis, mortality rates were similar (MSL-109, 0.41/person-year; placebo, 0.42/person-year; P=.95), whereas among patients with relapsed retinitis the MSL-109-treated group had a greater mortality rate (MSL-109, 0.83/person-year, placebo, 0.24/person-year; P=.003). However, the mortality rate in the placebo-treated patients with relapsed CMV retinitis was lower than that in the placebo-treated patients with newly diagnosed CMV retinitis and lower than that in other trials of patients with relapsed CMV retinitis.Conclusions: Intravenous MSL-109, 60 mg every 2 weeks, appeared to be ineffective adjuvant therapy for CMV retinitis. The mortality rate was higher in the MSL-109-treated group, but the reasons for this difference remain uncertain.

Objective: To determine the best therapeutic regimen, using currently approved drugs, for treatment of relapsed cytomegalovirus (CMV) retinitis.Design: Multicenter, randomized, controlled clinical trial.Setting: Ophthalmology and acquired immunodeficiency syndrome (AIDS) services at tertiary care medical centers.Patients: Two hundred seventy-nine patients with AIDS and either persistently active or relapsed CMV retinitis.Intervention: Patients were randomized to one of three therapeutic regimens: induction with foscarnet sodium at 90 mg/kg intravenously every 12 hours for 2 weeks, followed by maintenance at a dosage of 120 mg/kg per day (foscar net group); induction with ganciclovir sodium at 5 mg/kg intravenously every 12 hours for 2 weeks followed by maintenance at 10 mg/kg per day (ganciclovir group); or continuation of previous maintenance therapy plus induction with the other drug (either ganciclovir or foscarnet) for 2 weeks followed by maintenance therapy with both drugs, ganciclovir sodium at 5 mg/kg per day and foscarnet sodium at 90 mg/kg per day (combination therapy group).Outcomes: Mortality, retinitis progression, visual acuity, visual fields, and morbidity.Results: The mortality rate was similar among the three groups. Median survival times were as follows: foscarnet group, 8.4 months; ganciclovir group, 9.0 months; and combination therapy group, 8.6 months (P=.89). Comparison of retinitis progression, as evaluated in a masked fashion by the centralized Fundus Photograph Reading Center (FPRC), revealed that combination therapy was the most effective regimen for controlling the retinitis. The median times to retinitis progression were as follows: foscarnet group, 1.3 months; ganciclovir group, 2.0 months; and combination therapy group, 4.3 months (P<.001). Although no difference could be detected in visual acuity outcomes, visual field loss and retinal area involvement on fundus photographs both paralleled the progression results, with the most favorable results in the combination therapy group. The rates of visual field loss were as follows: foscarnet group, 28 degrees per month; ganciclovir group, 18 degrees per month; combination therapy group, 16 degrees per month (P=.009), and the rates of increase of retinal area involved by CMV were as follows: foscarnet group, 2.47% per month; ganciclovir group, 1.40% per month; and combination therapy group, 1.19% per month (P=.04). While side effects were similar among the three treatment groups, combination therapy was associated with the greatest negative impact of treatment on quality-of-life measures.Conclusions: For patients with AIDS and CMV retinitis whose retinitis has relapsed and who can tolerate both drugs, combination therapy appears to be the most effective therapy for controlling CMV retinitis.

OBJECTIVE:To develop and test a brief questionnaire designed to assess visual symptoms, visual function in daily activities, and impact of treatment administration in patients with cytomegalovirus retinitis related to acquired immunodeficiency syndrome.DESIGN:Observational cross-sectional study. Patients were recruited in June and July 1992.SETTING:Seven university-based sites participating in the Studies of Ocular Complications of AIDS.PATIENTS:Twenty-six subjects enrolled in a randomized trial that compared foscarnet and ganciclovir for the treatment of cytomegalovirus retinitis. MAIN OUTCOME MEASURES AND ANALYSIS: Distributions of scores, reliability, and validity of newly developed scales to assess visual function, visual symptoms, and global vision. Spearman rank correlations with 95% confidence intervals were used to test hypothesized relationships between scale scores, visual acuity, visual field, and findings from visual examination.RESULTS:The final 18-item self-administered questionnaire required 5 minutes to complete. The new scales had high internal consistency (Cronbach alpha = .81 to .94). As hypothesized, patient-reported vision scores decreased with greater abnormalities found on ophthalmologic examination. Visual symptoms were most strongly related to findings in the worse eye. Visual function and global vision scores were moderately correlated with findings from visual testing and examination, and less strongly related to general health perceptions. Patients reported considerable impairment: 42% reported blurred vision; 40%, difficulty reading; 44%, difficulty driving; and 40%, that treatment interfered with social activities; 50% reported substantial trouble with their vision.CONCLUSIONS:The brief questionnaire developed to assess patient-reported visual function in cytomegalovirus retinitis appears reliable and valid as a measure of performance of vision-related activities, visual symptoms, and the impact of treatment administration. Further research is needed to test its utility as an outcome measure in longitudinal studies of cytomegalovirus retinitis.

Background: In the Foscarnet-Ganciclovir Cytomegalovirus (CMV) Retinitis Trial, time to first progression of newly diagnosed CMV retinitis was similar in the 2 treatment groups but was shorter when assessed by grading of fundus photographs at a central reading center than when assessed at the participating clinical centers. This report describes the extent and causes of this disagreement and considers the implications of the findings for clinical practice and future research.Methods: Clinical findings and photographic gradings were compared for extent and activity of retinitis at baseline and during follow-up. In selected cases of disagreement, the photographs and summaries of gradings and clinical findings were reviewed concurrently to determine the cause of disagreement.Results: Movement of the border of retinitis was observed sooner and activity of the border was considered to have increased more often at the reading center than at the clinical centers. Disagreements on time to first progression were more frequent when degree of border movement was small (odds ratios [ORs] for several comparisons ranged from 1.7 to 5.2), when border activity was judged to have decreased or remained the same since the preceding visit (OR, 2.0-193), and when retinitis at baseline did not involve zone 1 (the area within 1 disc diameter of the disc or within 2 disc diameters of the center of the macula [OR, 1.4-3.6]). There were 2 important causes of disagreement between clinical center and reading center. First, difficulty was encountered clinically in recognizing retinitis border movement in the absence of an obvious increase in border activity. Second, the reading center used a threshold for border movement small enough to be crossed by an initial expansion of retinitis borders occurring within 2 to 5 weeks of enrollment in some patients who were responding favorably to treatment (in that retinitis was becoming inactive and showed no further progression for many weeks).Conclusions: Comparisons of photographs from the current visit with those from several previous visits may increase clinicians' abilities to detect progression promptly. The use of additional outcome measures by reading centers, such as border movement of 1500 pm or more and change in area of retina involved by retinitis, may provide more accurate and useful comparisons of treatments. In making such comparisons, centralized photographic grading has the advantages of greater reproducibility and lesser risk of observer bias.

Objective: To illustrate 2 common problems encountered in evaluating the response of cytomegalovirus retinitis to antiviral treatment and to consider their clinical importance.Methods: Four illustrative cases were selected from 76 cases reviewed during a study that compared clinical evaluation and centralized grading of fundus photographs in the assessment of cytomegalovirus retinitis.Results: These cases illustrate 2 problems noted during the review: (1) that progression of retinitis may be difficult to recognize clinically in the absence of an obvious increase in retinitis border activity and (2) that movement of retinitis borders by 750 mu m or more (the principal criterion used to define retinitis progression) during the initial 4 weeks of treatment does not necessarily represent an unfavorable response to treatment.Conclusions: Ophthalmologists who participate in the management of cytomegalovirus retinitis should be aware of the subtlety of retinitis activity that sometimes accompanies progression in patients undergoing treatment with currently approved agents. Side-by-side comparison of good-quality photographs from the current visit (as soon as they are available) with photographs from previous visits, using adequate illumination and magnification, may be helpful in detecting progression promptly. When applying the results of clinical trials to clinical practice, clinicians should not equate retinitis border movement of 750 mu m or more during the first 4 weeks of treatment with treatment failure.

Background: The Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial compared the use of either ganciclovir or foscarnet for the initial treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. We previously reported that patients treated with foscarnet lived longer but were more likely to have their treatment switched, the latter suggesting foscarnet may not have been as well tolerated as ganciclovir. This study compared the morbidity and toxic reactions reported during the trial.Methods: Two hundred thirty-four patients with the acquired immunodeficiency syndrome and preciously untreated cytomegalovirus retinitis at 11 university centers were randomly assigned to receive intravenously either foscarnet (n = 107) or ganciclovir (n = 127). Medical histories, laboratory tests, and drug treatment histories during the first 6 months of treatment were analyzed.Results: Neutropenia was more common in patients assigned to ganciclovir than to foscarnet (34% vs 14%; P = .001). Patients assigned to foscarnet reported more infusion-related symptoms (58% vs 24%; P < .001) and, in male patients, more genitourinary symptoms (36% vs 16%; P > .001); they also experienced a trend toward more nephrotoxic effects (13% vs 6%; P = .082) and electrolyte abnormalities. The incidence of seizures was similar in both groups (foscarnet, 12%; ganciclovir, 9%; P = .511). Patients assigned to foscarnet were more likely to be switched to the alternative treatment (foscarnet to ganciclovir, 46%; ganciclovir to foscarnet, 11%, P < .001), and most of this excess was attributable to toxic reactions. In 88% of cases in which treatment was snitched as a result of toxic reactions and in which follow-up data were available, the toxic reaction resolved after the switch. No permanent disability or death resulted from toxic reactions.Conclusions: Compared with ganciclovir, the use of foscarnet was more frequently limited by the occurrence of toxic reactions. However, these toxic reactions rarely had long-term sequelae. In light of the previously reported survival benefit seen in patients treated with foscarnet, these data support the use of foscarnet for the initial treatment of cytomegalovirus retinitis.

To examine whether the prolonged survival seen in patients treated with foscarnet compared with those treated with ganciclovir was due to a direct effect on human immunodeficiency virus (HIV) replication, HIV p24 antigen was measured. Of 71 receiving foscarnet, 54% were p24 antigen-positive at enrollment (vs. 44% of 79 receiving ganciclovir). By immune complex-dissociated (ICD) p24 antigen analysis, 87% and 78%, respectively, were positive. After 1 month of treatment, there was a significant decline in standard (mean decline, 10.1 pg/mL) and ICD (mean, 39.6 pg/mL) p24 antigen in both groups (P = .0001). Mortality was greater in those who were ICD p24 antigen-positive than in those -negative at baseline (P = .03) and in subjects with an increase in ICD p24 antigen than in those with a decline (P = .09). Thus, each drug had a suppressive effect on circulating p24 antigen, which was predictive of improved survival. The inhibitory effect on CMV replication may have a beneficial effect on limiting HIV replication.