Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in patients with AIDS or other immunocompromised states. Approximately 20% to 40% of AIDS patients develop CMV retinitis, gastrointestinal disease, or other systemic end-organ disease (1,2). CMV retinitis is the most common intraocular infection in patients with AIDS and, if left untreated, may lead to progressive destruction of retinal tissue and result in blindness (3-5).
Cidofovir is a nucleotide analogue of cytosine with potent in vitro and in vivo activity of prolonged duration against a broad spectrum of herpesviruses including CMV, herpes simplex virus types 1 and 2, varicellazoster virus, and Epstein-Barr virus, and human herpesviruses 6 and 8 (6-9). Unlike acyclovir or ganciclovir, which require intracellular activation by viral-encoded enzymes, conversion of cidofovir to cidofovir diphosphate (the active intracellular metabolite) is performed by host cellular enzymes and is therefore independent of viral infection. Consequently, cidofovir may remain effective against nucleoside-resistant strains of herpesviruses (10,11). The diphosphate form has a long intracellular half-life (17-65 hours), which may explain the prolonged antiviral effects of cidofovir (12,13).
The major dose-limiting toxicity of cidofovir is dose- and schedule-dependent nephrotoxicity, characterized by degeneration and necrosis of renal proximal convoluted tubular cells (14,15). Concomitant administration of probenecid is believed to reduce nephrotoxicity by competing for uptake at the basolateral surface of the proximal tubule, thereby minimizing cidofovir intratubular concentration. Additionally, evidence of prolonged anti-CMV effect up to several weeks postdosing has been observed (14,15). Based on this, intermittent cidofovir therapy, obviating the need for an indwelling catheter, was chosen for further study in patients with CMV retinitis. Recently, cidofovir has been shown to be effective for delaying progression of retinitis in patients with previously untreated disease (16,17).
PATIENTS AND METHODS
This study was a prospective, multicenter, randomized, controlled trial of two maintenance dose levels of intravenous cidofovir in patients with AIDS and previously treated, relapsing CMV retinitis.
Patients between 13 and 60 years of age with HIV infection and previously treated CMV retinitis that was persistently active or had reactivated and progressed following treatment with ganciclovir, foscarnet, or both at doses that could be tolerated were eligible. CMV retinitis was diagnosed clinically by an experienced ophthalmologist based on the presence of characteristic necrotic white, fluffy, or granular retinal opacities with or without associated hemorrhage and vasculitis.
Additional entry criteria included serum creatinine ≤133 μmol/L (≤1.5 mg/dl), proteinuria <2+, absolute neutrophil count ≥0.750 × 109 cells/L (≥750 cells/mm3), platelet count ≥50 × 109 cells/L (≥50,000 cells/mm3), and a Karnofsky performance score of ≥60 (18). Exclusion criteria included unrepaired retinal detachment, ongoing therapy with anti-CMV therapies or agents having nephrotoxic potential, or history of probenecid hypersensitivity. Also excluded were female patients who were pregnant or nursing. Concomitant antiretroviral and prophylactic treatment for opportunistic infections were encouraged. The protocol and informed consent documents were approved by institutional review boards at each study center; patients provided signed, informed consent before randomization. The initial protocol had a target enrollment of 100 patients; however, following analysis of a contemporaneous study of cidofovir for the treatment of newly diagnosed CMV retinitis (16), enrollment was extended to 150 patients.
Patients were randomized to receive cidofovir 5 mg/kg once weekly for 2 weeks (induction), followed by either 5 or 3 mg/kg once every 2 weeks thereafter (maintenance). Cidofovir (Vistide; Gilead Sciences, Inc., Foster City, CA, U.S.A.) was administered in a closely monitored medical setting by intravenous infusion in 100 ml normal saline for 1 hour following intravenous prehydration with 1 L normal saline. An additional 1 L of normal saline was administered during or after the cidofovir infusion. All patients received concomitant oral probenecid on the day of cidofovir infusion only, administered as 2 g at 3 hours before and 1 g at 2 and again at 8 hours after each cidofovir infusion. Because concomitant use of probenecid and zidovudine results in a 50% decrease in zidovudine clearance, patients were advised either to decrease by 50% or to interrupt zidovudine dosing on the day of each cidofovir infusion (19).
Medical history, physical examination, and laboratory evaluations including complete blood count, chemistry profile, and urinalysis, were performed within 24 hours prior to each cidofovir infusion. Patients developing serum creatinine increases of 26 to 40 μmol/L (0.3 to 0.4 mg/dl) above baseline had dose reduction of cidofovir from 5 to 3 mg/kg (or from 3 to 1.5 mg/kg); patients with ≥3+ proteinuria, an increase in serum creatinine of ≥45 μmol/L (≥0.5 mg/dl) above baseline, or both were discontinued. Patients experiencing symptoms temporally related to probenecid received treatment with antipyretics, antiemetics, or antihistamines according to investigator discretion. Patients were instructed to eat immediately before probenecid dosing to reduce the potential for gastrointestinal side effects.
Ophthalmologic evaluations including assessment of best corrected visual acuity, dilated indirect ophthalmoscopy, bilateral full-field fundus photography (first 100 patients), and intraocular pressure measurement were performed prior to study treatment, during study weeks 1, 3, 5, 7, and then monthly thereafter, until documentation of CMV retinitis progression. Visual acuity was assessed with Ferris Early Treatment for Diabetic Retinopathy Study (ETDRS) charts. Photography was performed with a 50- to 60-degree wide-angle fundus camera. Retinal photographs were read at an independent reading center by an experienced ophthalmologist masked to randomization assignment. The primary study endpoint of CMV retinitis progression, based on retinal photographs, was defined as either enlargement of a preexisting CMV retinal lesion, identified by lesion border advancement into previously uninvolved retina that reached or exceeded a threshold linear distance of 750 μ in a direction perpendicular to the border position at baseline, and involving a segment of border ≥750 μ in width, or the occurrence of a new lesion ≥750 μ in diameter in either eye. Patients 101 through 150 were evaluated for retinitis progression by clinical ophthalmoscopic examination only. Data on patients who discontinued cidofovir treatment before progression or those whose disease had not progressed before the study ended were censored at the date of their last evaluable retinal photographs or clinical examination.
Time-to-progression plots were derived by the method of Kaplan and Meier for all randomized patients (29). Comparisons of plots were conducted by two-sided log-rank test. Relative risk of progression between the two groups was analyzed with the Cox proportional hazard model. Additional outcome measures included incidence of drug-related side effects, changes in visual acuity, clinical assessment of progression, and mortality.
One hundred and fifty patients were enrolled; baseline characteristics of the two groups are summarized in Table 1. Two randomized patients did not receive the study drug. Patients had previously received a median of 4 previous induction courses of ganciclovir or foscarnet based on clinical evidence of retinitis progression; intraocular therapies had been used in 20%. No significant differences between randomization groups were noted.
Thirteen of 49 patients (27%) in the 5-mg/kg group and 25 of 51 (49%) patients in the 3-mg/kg group developed retinitis progression as evaluated through retinal photographs. Median time to progression for the first 100 patients evaluated by photographs was not reached in the 5-mg/kg group (95% confidence interval [CI], 115 days-upper limit not reached) compared with a median time of 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006, log-rank test) (Fig. 1). Relative risk of progression in the 3-mg/kg group compared with the 5-mg/kg group was 3.05 (95% CI, 1.6-6.0). Median time to CMV retinitis progression for the last 50 patients evaluated by clinical examination only was not reached (95% CI, 215 days-upper limit not reached) in the 5-mg/kg group and was 105 days (95% CI, 43-170 days) in the 3-mg/kg group (p = .21). Relative risk of progression in the 3-mg/kg group compared with the 5-mg/kg group for these 50 patients was 1.91 (95% CI, 0.7-5.3). One patient in each group was diagnosed with new onset biopsy-proven CMV gastrointestinal disease.
No significant differences between the treatment groups were noted in visual acuity while on study. Sixteen of 74 (22%) 5-mg/kg patients and 18 of 74 (24%) 3-mg/kg patients had evidence of decline of ≥3 lines on an ETDRS chart. Nine (12%) and 1 (1%) of patients developed iritis, uveitis, or both in the 5- and 3-mg/kg groups, respectively.
Adverse events occurring in at least 10% of patients and considered to be possibly or probably related to cidofovir are summarized in Table 2. Mean duration of cidofovir treatment was 104 days for the 5-mg/kg group (range, 7-372 days) and 66 days for the 3 mg/kg group (range, 7-363 days). Twenty-seven of 148 (18%) patients discontinued therapy because of protocol-defined treatment-limiting nephrotoxicity: 19 (26%) patients receiving 5 mg/kg and 8 (11%) patients receiving 3 mg/kg. Three of 74 (4%) 5-mg/kg patients discontinued therapy because of protocol-defined treatment-limiting decreases in intraocular pressure. Hospitalization for assessment and treatment of cidofovir-related nephrotoxicity occurred in 4 patients in the 5-mg/kg group and 1 patient in the 3-mg/kg group. Nineteen of 74 (26%) 5-mg/kg patients underwent dose reduction to 3-mg/kg following creatinine elevation or development of proteinuria; 3 of 74 (4%) 3-mg/kg patients had dose reduction to 1.5 mg/kg. Development of nephrotoxicity appeared to be dose dependent; incidence of proteinuria ≥3+ (24% versus 14%) and creatinine elevation to ≥176 μmol/L (≥2 mg/dl; 12% versus 7%) was greater at 5 mg/kg than at 3 mg/kg (p = .14 and 0.40, Fisher's exact test, respectively). Incidence of investigator-determined creatinine level elevation of any degree following initiation of study treatment was 35% in the 5-mg/kg group compared with 12% in the 3-mg/kg group (p = .001). Proteinuria and creatinine elevation were at least partially reversible after discontinuation or interruption of cidofovir therapy. In all cases with follow-up assessment off cidofovir, repeat serum creatinine was below peak elevation. However, persistent renal insufficiency was evident in some patients; 10 of 14 patients developing creatinine ≥2 mg/dl did not have a return to <2 mg/dl. No patients required dialysis as a direct consequence of cidofovir-related nephrotoxicity. However, one black male patient who was receiving angiotensin-converting enzyme inhibitor and calcium channel blocker therapy for a history of hypertension and who had an intolerance to ganciclovir and foscarnet was diagnosed with HIV nephropathy and, while hospitalized for Pneumocystis carinii infection and CMV pneumonia, received hemodialysis for 1 day. Cidofovir had been discontinued 2 months earlier because of decreased intraocular pressure. The patient's course was complicated by intercurrent administration of an experimental monoclonal antibody fragment.
Prior foscarnet exposure appeared to be a risk factor for nephrotoxicity in the 5-mg/kg group; patients with evidence of cidofovir-related proteinuria or creatinine elevation had received a median of 95 days of foscarnet compared with 23 days of foscarnet in patients without renal toxicity (p = .015, Wilcoxon test).
Sixty-five (44%) patients had probenecid-associated side effects including nausea, emesis, or both (28%); fever (15%); and rash (15%). These typically ensued after the third or fourth cidofovir treatment. Probenecid side effects were reversible after 12 hours to 3 days; however, 6 (4%) patients discontinued study treatment because of presumed probenecid intolerance, including 2 patients requiring inpatient treatment for anaphylactoid reactions (constitutional symptoms including fever and chills as well as rash, airway reactivity, or hypotension) following attempts at probenecid desensitization (probenecid, 500 mg for 3-5 days, followed by 1 g for up to 10 days). Eating before probenecid dosing ameliorated gastrointestinal symptoms. Prophylactic treatment with antipyretics, antiemetics, antihistamines, or a combination of these appeared to improve tolerance to probenecid.
Through July 31, 1996, Kaplan-Meier estimated median survival was 5.9 months in the 5-mg/kg group and 4.9 months in the 3-mg/kg group (p = .17, log-rank test); 49 of 75 (65%) patients in the 5-mg/kg group and 55 of 75 (73%) patients in the 3-mg/kg group had died (Fig. 2). No deaths occurred within 2 weeks of cidofovir dosing and none were attributed to cidofovir-related toxicity.
This study demonstrates that intravenous cidofovir delays further progression of heavily pretreated CMV retinitis in patients with AIDS. Concomitant oral probenecid, intravenous saline hydration, and careful attention to levels of protein in urine and serum creatinine criteria to guide dosage reduction or termination of therapy were employed to manage potential toxicity. Mortality was consistent with historical controls (21,22).
Comparison of data from this study with other studies of anti-CMV therapies should be performed with caution as a result of potential differences in patient populations, data analysis techniques, and interobserver variability in the masked assessment of retinal photographs. Additionally, discontinuation of study treatment occurred more frequently on this trial. Nonetheless, the median time to progression after initiation of cidofovir treatment was longer than the times to progression demonstrated with single-agent ganciclovir or foscarnet for newly diagnosed patients (47 and 53 days, respectively) or patients with secondary relapse (42 and 35 days, respectively) (23). These results suggest greater potency of intravenous cidofovir relative to other systemic therapies and extend findings of efficacy in patients with newly diagnosed disease to previously treated retinitis. In both this study and in a prior study of cidofovir in patients with previously untreated retinitis conducted by the Studies of the Ocular Complications of AIDS (SOCA) Group, which used a different reading center and techniques, patients did not reach a median time to progression when receiving 5-mg/kg maintenance treatment. These results suggest the potential for alternative schedules to improve tolerance while maintaining efficacy. Specifically, consideration and evaluation of increasing the maintenance treatment interval from 2 to 3 weeks should be performed.
This study also supports the efficacy of maintenance treatment with 3-mg/kg dosage based on times to progression for patients receiving 3 mg/kg or no treatment reported in the SOCA trial (17). Development of nephrotoxicity appeared to be dose related; both retinal photography and clinical examination provide support for the beneficial effects of 3-mg/kg maintenance dosage. Choice of maintenance dose should be individualized based on prior medical history (e.g., previous foscarnet use), renal function, and hydration and performance status.
In summary, this study demonstrates that 5 mg/kg of cidofovir as a maintenance dose is more effective than 3 mg/kg for the treatment of previously treated CMV retinitis that has relapsed in patients with AIDS. The cidofovir treatment regimen can be more convenient than daily intravenous ganciclovir or foscarnet and obviates the need for chronic indwelling catheters. Careful predose monitoring of patients for proximal tubular cell dysfunction and concomitant administration of oral probenecid and intravenous saline hydration appear to be necessary to minimize drug-related toxicity.
In addition to the authors, the following persons and institutions participated in this trial, enrolled research subjects, or both: E. Ai (California Pacific Medical Center, San Francisco); S. Wilson (Davies Medical Center, San Francisco); W.L. Drew, M. Wieland, R. Neger, E. Glutzer, D. Miner (Mt. Zion, University of California, San Francisco); K. Wittenberg, R. Engstrom Jr, R. Levinson, C. McCannel, A. Tufail, J. Weisz (Jules Stein Eye Institute Fundus Photography Reading Center, University of California, Los Angeles); F. Sattler, J. Leedom, A. Rollan. N. Rao (University of Southern California, Los Angeles); T.E. Flynn, M.H. Grieco, J.L. Rivera, J.I. O'Connor (St. Luke's-Roosevelt Hospital Center, Columbia University, New York); S. Mansour, C. Kane (Santa Clara Valley Medical Center, Santa Clara); S. Hussey, T. Murtha, G. Sharuk, C. Crumpacker, P. Piliero (Beth Israel Deaconess Medical Center, Boston); D. Norris, R.F. Lockey, C. Reichert, P.R. Pavan (University of South Florida, Tampa); A. Moe, M. Martin, S. Chafey, M. Carlson, A. Johiro (Center for Clinical AIDS Research and Education, University of California, Los Angeles); D. Forthal (University of California, Irvine); C. Higgs, A. Newell, C. Pavesio, B. Gazzard (Kobler Centre, London); S. Lightman (Moorfields Eye Hospital, London); A. Lyon, R. Murphy, A. Muñana (Northwestern University, Chicago); M. Wulfsohn, P. Fisher, H. Liu, G. Mason, D. Laramee, M. Mitchell (Gilead Sciences, Inc., Foster City). Chair: T. Fleming. Data and Safety Monitoring Board: R. Nussenblatt, I. Weller, R. Whitley.
Acknowledgments: Supported by Gilead Sciences, Inc. R.A. Lewis is a Senior Scientific Investigator of Research to Prevent Blindness, New York, NY, U.S.A. G.N. Holland is recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award.
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