PubMed · 8891103
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J A Aberg, W G Powderly. 1997. Cryptococcosis.. https://doi.org/10.1016/s1054-3589(08)60951-5
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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.
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 > 0.02), 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 mumol/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.