Two systemic agents-ganciclovir and foscarnet-are available for the treatment of CMV retinitis. Both delay progression of CMV retinitis, but the median time to disease progression is approximately 7 weeks with either agent [6, 7]. Intravenous ganciclovir or foscarnet is given twice daily during induction therapy and daily during maintenance therapy. This usually necessitates placement of an indwelling catheter, and the morbidity associated with catheter-related complications is substantial [8]. The dose-limiting toxicity of ganciclovir is myelosuppression, a condition that often requires administration of colony-stimulating factors. Nephrotoxicity, anemia, seizures, and electrolyte disturbances have occurred with foscarnet [9]. A recently approved oral formulation of ganciclovir may reduce the need for catheter placement and is less myelosuppressive than intravenous ganciclovir; however, it is also less effective in delaying the time to progression and therefore may have limited usefulness in sight-threatening disease [10, 11].

Cidofovir (Vistide, Gilead Sciences, Inc., Foster City, California) is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against several herpesviruses, including CMV, herpes simplex virus types 1 and 2, varicella-zoster virus, and Epstein-Barr virus [12-14]. Unlike acyclovir or ganciclovir, which require intracellular activation by viral-encoded enzymes, cidofovir is converted to cidofovir diphosphate (the active intracellular metabolite) by host cellular enzymes; thus, conversion is independent of viral infection. Consequently, cidofovir may remain effective against nucleoside-resistant strains of herpesviruses [15, 16]. The long intracellular half-life of the diphosphate (17 to 65 hours) may explain the prolonged antiviral effects of cidofovir [17, 18].

The major dose-limiting toxicity of cidofovir is dose- and schedule-dependent nephrotoxicity, characterized by degeneration and necrosis of renal proximal convoluted tubule cells. Concomitant administration of probenecid is thought to reduce nephrotoxicity by competing for uptake at the basolateral surface of the proximal tubule, thereby minimizing cidofovir uptake and concentration. Phase I and II studies of intravenous cidofovir in patients with human immunodeficiency virus (HIV) infection and asymptomatic CMV shedding in urine or semen showed a dose-dependent anti-CMV effect and dose-dependent nephrotoxicity [19, 20]. In these early trials, 4 of 12 patients who received cidofovir at anti-CMV doses ( 3 mg/kg of body weight) without receiving concomitant probenecid and hydration developed a serum creatinine level greater than 177 µmol/L (2 mg/dL). None of 32 patients who received a greater cumulative dose of cidofovir along with concomitant probenecid and hydration developed a serum creatinine level greater than 177 µmol/L. In addition, evidence of prolonged anti-CMV effect was seen for as long as several weeks after cidofovir infusion. On the basis of these results, intermittent treatment (once weekly for 2 weeks and once every 2 weeks thereafter) with concomitant oral probenecid and intravenous saline hydration was chosen for further study in patients with CMV retinitis. If efficacious, such a regimen would be more convenient than standard daily systemic therapies for CMV retinitis and would obviate the need for an indwelling catheter.

Our study was a multicenter, randomized, controlled trial comparing immediate with deferred intravenous cidofovir treatment in patients with AIDS and previously untreated peripheral CMV retinitis. Patients randomly assigned to the deferred treatment group did not receive cidofovir until progression of CMV retinitis was documented by retinal photography.

Methods

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Enrollment

Patients who were 13 to 60 years of age and had HIV infection and newly diagnosed, previously untreated peripheral CMV retinitis (not immediately sight-threatening) were eligible. These patients were self-referred or were referred by their primary care physicians or ophthalmologists. The diagnosis of CMV retinitis was made by an experienced ophthalmologist on the basis of the presence of characteristic necrotic white, fluffy, or granular retinal opacities with or without associated hemorrhage. Lesions were defined as peripheral if they were located in retinal zones 2 or 3 (that is, at least 1500 µm from the margin of the optic disc and 3000 µm from the center of the fovea) [21].

Additional inclusion criteria were no previous therapy with ganciclovir, foscarnet, or other agents that have activity against CMV end-organ disease; serum creatinine level of 133 µmol/L or less ( 1.5 mg/dL); proteinuria less than 1+; an absolute neutrophil count of at least 0.750 x 10⁹/L ( 750 cells/mm³); a platelet count of at least 50 x 10⁹/L ( 50 000 cells/mm³); a life expectancy of 3 months or longer; and a Karnofsky performance score of at least 60 [22]. Exclusion criteria were ocular media opacity that precluded adequate visualization of the retina for assessment of lesion changes, unrepaired retinal detachment, ongoing therapy with acyclovir or agents that have nephrotoxic potential, and a history of hypersensitivity to probenecid. We also excluded women who were pregnant or nursing. Concomitant antiretroviral therapy with approved or investigational agents and prophylaxis against opportunistic infections were encouraged. The protocol and informed consent documents were approved by the institutional review boards at each of the eight study centers, and patients provided signed, informed consent before randomization.

Study Design and Treatment

A biased-coin adaptive randomization scheme was used to enhance balance (within sites and across study patients) between the immediate and deferred treatment groups [23]. Patients in the immediate treatment group received cidofovir, 5 mg/kg once weekly for 2 weeks (induction), and then 5 mg/kg once every 2 weeks (maintenance). Cidofovir was administered by intravenous infusion in 100 mL of normal saline during a 1-hour period after intravenous hydration with 1 L of normal saline. All patients received concomitant oral probenecid on the day of cidofovir infusion only, administered as 2 g 3 hours before each cidofovir infusion, 1 g 2 hours after each infusion, and 1 g 8 hours after each infusion. Because the concomitant use of probenecid and zidovudine results in a 50% decrease in zidovudine clearance, patients were advised to decrease the zidovudine dose by 50% or to interrupt zidovudine treatment on the day of each cidofovir infusion [24].

Medical history, physical examination, and laboratory evaluation (including complete blood count, chemistry profile, and urinalysis) were done within 24 hours before each cidofovir infusion. In patients who developed mild to moderate nephrotoxicity (serum creatinine level 146 to 175 µmol/L [1.7 to 1.9 mg/dL] or proteinuria of 1+, or both), the cidofovir dose was reduced to 3 mg/kg; in patients with proteinuria of at least 2+ or a serum creatinine level that had increased to at least 177 µmol/L ( 2.0 mg/dL) or both, treatment was discontinued. Patients with symptoms that were temporally related to probenecid received treatment with antipyretic or antiemetic agents, antihistamines, or active probenecid desensitization, at the discretion of the investigator. Patients in the deferred treatment group were eligible to cross over to receive cidofovir after progression of CMV retinitis was documented.

Urine and blood samples were collected at selected sites at baseline and at weeks 3, 11, and 23 for qualitative CMV culture (standard or shell vial method), as described elsewhere [19]. T-lymphocyte subsets were analyzed in all patients at study entry [25]. All patients were followed for determination of mortality rate even if study treatment had been discontinued.

Ophthalmologic Evaluations

Ophthalmologic evaluations, which included assessment of the best corrected visual acuity, dilated indirect ophthalmoscopy, bilateral full-field fundus photography, and intraocular pressure measurement, were done before randomization; during study weeks 1, 3, 5, 7, 11, 15, 19, and 23; and monthly thereafter until progression of CMV retinitis was documented. Visual acuity was assessed using charts from the Early Treatment for Diabetic Retinopathy Study (modified Bailey-Lovie chart). Bilateral, full-field retinal photography was done using a 50- to 60-degree wide-angle camera. Retinal photographs were read at an independent reading center by an ophthalmologist who was unaware of treatment assignment. The primary study end point-progression of CMV retinitis-was defined as either enlargement of a preexisting CMV lesion (the enlargement is identified by a lesion border that advances into the previously uninvolved retina and reaches or exceeds a threshold linear distance of 750 µm in a direction perpendicular to the border position at baseline; the enlargement also involves a segment of border 750 µm in width) or the occurrence in either eye of a new lesion at least 750 µm in diameter.

Statistical Analysis

Study results were independently collected and analyzed by a contract research organization (Corning Besselaar, Inc., Princeton, New Jersey) according to a predetermined report and analysis plan. The funding source did not have veto power over publication of the results. All analyses were done using the SAS software package for Unix, version 6.09 (SAS Institute, Cary, North Carolina). The primary efficacy end point of this study was time to progression of CMV retinitis (based on examination of retinal photographs). On the basis of the assumption that by 1 month, CMV retinitis would progress in 40% of patients receiving cidofovir and 90% of untreated patients in the deferred treatment group, we decided that 17 patients per group were adequate to show differences between the two groups ( = 0.05 and ß = 0.20). Plots of time to progression of CMV retinitis for all randomly assigned patients were derived using the Kaplan-Meier method [26]. Plots were compared using the log-rank test (two-sided) [26]. The relative risk for progression between the two groups was analyzed using the Cox proportional-hazards model [26]. Data on patients who discontinued cidofovir treatment before retinitis progressed or those whose disease had not progressed before the study ended were censored at the date of their last evaluable retinal photograph. A paired analysis using the Prentice modification of the Wilcoxon signed-rank test was done on the time to the second progression of retinitis in patients in the deferred treatment group who crossed over to cidofovir treatment compared with the time to first progression while these patients received no treatment [27]. Additional outcome measures included incidence of drug-related side effects, changes in visual acuity, effect on CMV shedding in urine and blood, and mortality. The study had insufficient power to detect a survival difference between the two groups. All adverse events and reasons for discontinuation of treatment were analyzed on the basis of the investigators' assessment of the relation to cidofovir or probenecid.

Results

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Patient Characteristics

Between December 1993 and November 1994, 48 patients were enrolled in our study. Baseline characteristics of the two groups are summarized in Table 1. Patients were predominantly male and had a median CD4⁺ T-lymphocyte count less than 0.010 x 10⁹/L (10 cells/mm³); both of these characteristics are typical of patients with advanced AIDS and CMV retinitis. No significant differences between the two groups were noted.

Disease Progression and Visual Function

During the study, retinitis progressed in 10 of 25 patients (40%) in the immediate treatment group and 19 of 23 patients (83%) in the deferred treatment group. Median time to progression 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; log-rank test) (Figure 1). The relative risk for progression in the deferred treatment group compared with the immediate treatment group was 6.13 (CI, 2.6 to 14.6).

View larger version (18K): [in this window] [in a new window]   Figure 1. Kaplan-Meier plot of time to progression of cytomegalovirus retinitis in the immediate and deferred cidofovir treatment groups. The estimated median time to progression of cytomegalovirus 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; log-rank test).

Visual acuity did not significantly differ between the groups. During immediate treatment, a transient decrease of at least three lines on the Early Treatment for Diabetic Retinopathy Study chart was noted during one examination in 1 of 25 patients (4%). No retinal detachment or decreases in intraocular pressure were seen.

After progression of retinitis in the deferred treatment group was documented, 16 of 23 patients crossed over to cidofovir treatment. These patients had a second baseline evaluation, including retinal photography, just before the initiation of cidofovir treatment. The median time to progression of retinitis was 169 days (CI, 169 days to unreached upper limit) in patients who crossed over and 21 days (CI, 13 to 23 days) in the same patients while they were not receiving cidofovir (P = 0.0002; paired Prentice-Wilcoxon Z statistic). Seven patients in the deferred treatment group did not cross over to cidofovir treatment: Four developed sight-threatening retinitis, and 1 developed extraocular CMV disease. These 5 patients were required by protocol to receive standard anti-CMV therapy. The 2 remaining patients withdrew consent while in the deferred treatment group.

Virology

Three centers followed all of their patients by using qualitative blood or urine CMV cultures that were obtained at baseline, week 3, and week 11. Culture specimens were obtained before the cidofovir infusion at weeks 3 and 11 (that is, 2 weeks after the preceding dose). Seventeen patients who received cidofovir (both immediately and after cross-over) and 7 patients in the deferred treatment group were followed by using shell vial or standard blood cultures. Of 17 cidofovir recipients, 41% were culture positive at baseline, 31% were culture positive at week 3, and 33% were culture positive at week 11. In comparison, 43% of the 7 patients in the deferred treatment group had positive cultures at baseline and 71% had positive cultures at week 3. No significant differences in the time to progression of CMV retinitis or mortality were seen between patients who were blood culture positive at any time during the study and those who remained blood culture negative during the study.

Fifteen cidofovir recipients and 5 patients in the deferred treatment group were followed by using shell vial or standard urine cultures. Of the 15 cidofovir recipients, 87% were culture positive at baseline, 36% were culture positive at week 3, and 43% were culture positive at week 11. In comparison, 60% of the 5 patients in the deferred treatment group were culture positive at baseline and 100% were culture positive at week 3.

Adverse Events and Mortality

The adverse events that occurred in at least 10% of cidofovir recipients and were considered to be possibly or probably related to cidofovir are summarized in Table 2. The adverse events considered to be serious and possibly or probably related to cidofovir were proteinuria in 5 of 41 patients (12%); neutropenia in 6 of 41 patients (15%); elevated serum creatinine levels in 2 of 41 patients (5%) that occurred after 7 and 22 infusions of cidofovir, respectively; and individual episodes of anemia and headache. Proteinuria and elevated creatinine levels were at least partially reversible after cidofovir treatment was discontinued or interrupted.

The mean duration of cidofovir treatment was 92 days (range, 22 to 343 days; median, 67 days). In 12 of 41 patients (29%), the maintenance dose was decreased to 3 mg/kg because of the appearance of proteinuria or elevated creatinine levels. Ten of 41 patients (24%) discontinued treatment because of protocol-defined treatment-limiting nephrotoxicity (proteinuria 2+ [7] or serum creatinine levels of 177 to 265 µmol/L [2 to 3 mg/dL] [3]). Each case of proteinuria, elevated creatinine level, and neutropenia was asymptomatic and was not associated with clinical sequelae.

Twenty-three of 41 patients (56%) had evidence of mild to moderate probenecid reactions that most commonly presented as fever and chills, headache, rash, or nausea after the third or fourth cidofovir treatment. All side effects of probenecid were reversible after 12 hours to 3 days; however, 3 of 41 patients (7%) discontinued study treatment because of gastrointestinal intolerance of probenecid. Eating before probenecid was administered alleviated gastrointestinal symptoms. Treatment with antipyretic agents, antiemetic agents, antihistamines, or probenecid desensitization appeared to improve patient tolerance.

After randomization, two cidofovir recipients who had gastrointestinal symptoms before the study began and one patient in the deferred treatment group received a diagnosis of biopsy-proven CMV gastrointestinal disease.

Through 4 October 1995, the median duration of survival was 13.5 months in the immediate treatment group and 10.5 months in the deferred treatment group (P = 0.15; log-rank test); 12 of 25 (48%) patients in the immediate treatment group and 17 of 23 (74%) patients in the deferred treatment group had died (Figure 2). Of the 23 patients in the deferred treatment group, 12 of 16 (75%) who crossed over to cidofovir treatment and 5 of 7 (71%) patients who did not cross over had died. The median duration of survival was 10.6 months in the patients who crossed over and 6.6 months in the patients who did not cross over (P = 0.07; log-rank test). No patients died within 2 weeks of a cidofovir infusion, and no deaths were attributed to cidofovir-related toxicity.

View larger version (16K): [in this window] [in a new window]   Figure 2. Kaplan-Meier plot of survival for the immediate and deferred cidofovir treatment groups. The median duration of survival was 13.5 months in the immediate treatment group and 10.5 months in the deferred treatment group (P = 0.15; log-rank test).

Discussion

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We show that intravenous cidofovir delays the progression of previously untreated CMV retinitis in patients with AIDS. Asymptomatic neutropenia and proteinuria were the most prevalent serious adverse events. The use of concomitant oral probenecid and intravenous saline hydration and strict adherence to urinary protein and serum creatinine criteria to guide dose reduction and termination of treatment appeared to minimize clinically significant nephrotoxicity. Only 3 of 41 (7%) cidofovir recipients had a serum creatinine level of 177 to 265 µmol/L (2 to 3 mg/dL). Mild to moderate probenecid reactions, presenting as fever and chills, headache, rash, or nausea after the third or fourth cidofovir infusion, occurred in about half of the patients. Eating before probenecid administration and treatment with antipyretic agents, antiemetic agents, or antihistamines appeared to improve tolerance of probenecid.

Comparison of our data with those from other studies should be done with caution because of potential differences in patient samples, data analysis techniques, and interobserver variability in the masked assessment of retinal photographs [21]. Nevertheless, the time to progression in patients in the deferred treatment group is consistent with outcomes seen in previous studies of similar design; thus, it is appropriate to speculate about the efficacy of cidofovir relative to that of other agents. The median time to first progression in cidofovir recipients was longer than the time to progression seen with ganciclovir and foscarnet [6, 7]. More patients in our study discontinued cidofovir treatment before progression of CMV retinitis than did patients in the studies of ganciclovir and foscarnet. This may reflect the prolonged anti-CMV activity of cidofovir, the drug's side-effect profile, the strict treatment termination criteria used in our trial, and the availability of other agents with which to treat CMV retinitis. Cidofovir treatment may also be more convenient; the long intracellular half-life of cidofovir allows infrequent administration with continued antiviral effect. In contrast to intravenous ganciclovir or foscarnet, which must be administered daily and usually necessitate placement of an indwelling catheter, cidofovir treatment was administered infrequently. This infrequency thereby obviates the need for and risks associated with long-term catheter use. The ganciclovir implant, which continuously releases ganciclovir into the vitreous for 6 to 8 months, has been associated with a longer time to progression in treated eyes than has systemic treatment. However, surgical implantation is associated with decreased visual acuity and risk for ocular toxicity. In addition, systemic anti-CMV therapy must be concomitantly administered to help prevent the development of contralateral eye disease or systemic CMV disease [28].

Probenecid and intravenous hydration appear to be essential for minimizing cidofovir-induced nephrotoxicity. Cidofovir is thought to be concentrated by way of active transport into the proximal convoluted tubule cell by an anion transporter in the basolateral membrane. Export of cidofovir at the luminal surface is believed to be slower than uptake of cidofovir, resulting in high proximal tubule concentrations. The mechanism of cidofovir-induced injury within the tubule cell is unknown. Probenecid appears to compete for uptake within the proximal tubule cell [29] and has been shown in animal models to reduce cidofovir-related nephrotoxicity. Clinical pharmacokinetics results suggest a key role for probenecid [30]. In patients receiving cidofovir alone, renal clearance exceeded measured creatinine clearance by about 50%, suggesting that tubular secretion has an important role as an elimination pathway. In contrast, renal clearance of cidofovir in patients who received probenecid was reduced to the level of creatinine clearance, a finding consistent with probenecid-mediated blockage of the active tubular excretion of cidofovir.

Information on cidofovir's effect on CMV viremia and viruria is limited. Immediate cidofovir treatment appeared to reduce the incidence of positive CMV blood and urine cultures compared with deferred treatment. Because cultures were qualitative rather than quantitative and were obtained 2 weeks after a cidofovir infusion, it is possible that patients who had positive cultures while receiving treatment had quantitative reductions in their viral burden. The clinical significance of these data is unclear. Further study of the effect of cidofovir treatment on CMV viremia and viruria using quantitative methods of assessment is warranted.

The design of our trial-a comparison of immediate with deferred treatment-is similar to the designs used in pivotal studies of ganciclovir and foscarnet [6, 31]. Because untreated CMV retinitis progresses rapidly, this design permits demonstration of a treatment-related effect on disease progression in a relatively small number of patients. Because only patients with peripheral retinitis (that is, retinitis that is not immediately sight-threatening) have been enrolled in these studies, the potential for extension of disease into sight-threatening zones during the period of deferred treatment is limited. Close follow-up, with therapeutic intervention after documentation of progression, further minimizes retinal involvement.

In summary, we show that cidofovir has a beneficial clinical effect in patients with AIDS and previously untreated CMV retinitis. The cidofovir treatment regimen is more convenient than daily intravenous ganciclovir or foscarnet and obviates the need for long-term use of 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.

Appendix

In addition to the authors, the following institutions and persons participated in this trial, enrolled research participants, or both: Kaiser Permanente, San Francisco, California: R. Wolitz; California Pacific Medical Center, San Francisco, California: E. Ai; Davies Medical Center, San Francisco, California: B. Neger and S. Wilson; University of California, San Francisco, California: M. Wieland; Mt. Zion Medical Center, University of California, San Francisco, San Francisco, California: E. Glutzer and D. Miner; University of California, Irvine, Irvine, California: D. Forthal; Jules Stein Eye Institute Fundus Photography Reading Center, University of California, Los Angeles, Los Angeles, California: K. Wittenberg, R. Engstrom Jr., R. Levinson, C. McCannel, A. Tufail, and J. Weisz; University of Southern California, Los Angeles, California: F. Sattler, J. Leedom, A. Rollan, and N. Rao; Beth Israel Hospital, Boston, Massachusetts: S. Hussey, T. Murtha, G. Sharuk, C. Crumpacker, and P. Piliero; Kobler Centre, London, United Kingdom: C. Higgs, A. Newell, and B. Gazzard; Moorfields Eye Hospital, London, United Kingdom: S. Lightman and C. Pavesio; University of Rochester, Rochester, New York: R. Betts; University of California, San Francisco, San Francisco, California: D. Northfelt; University of North Carolina, Chapel Hill, North Carolina: J. Eron; Corning Besselaar, Inc., Princeton, New Jersey: P. Hamilton, C. Lardinois, M. Rauscher, K. Seifert, J. Alladi, and G. Teng; Gilead Sciences, Inc., Foster City, California: P. Fisher, H. Liu, G. Mason, J. Hannigan, D. Laramee, and M. Mitchell; T. Fleming (Chair), R. Nussenblatt, I. Weller, and R. Whitley (Data and Safety Monitoring Board).

From the University of California, San Francisco, San Francisco, California; Gilead Sciences Inc., Foster City, California; the University of California, Irvine, Irvine, California; the University of California, Los Angeles, and the University of Southern California, Los Angeles, California; Harvard Medical School, Boston, Massachusetts; St. Stephen's Clinic, London, United Kingdom; and the University of Rochester Medical Center, Rochester, New York.

Dr. Stagg: Gilead Sciences, Inc., 353 Lakeside Drive, Foster City, CA 94404.

Dr. Kuppermann: Department of Ophthalmology, University of California, Irvine, 118 Med Surge I, Irvine, CA 92697.

Dr. Holland: Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095-7003.

Dr. Kramer: University of Southern California Medical Center, 1200 North State Street, Room 6442, Los Angeles, CA 90033.

Dr. Ives: Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215.

Dr. Youle: Kobler Centre, 369 Fulham Road, London, United Kingdom.

Dr. Robinson: Rochester Eye Center, 30 North Union Street, Rochester, NY 14607.

Dr. Drew: Mt. Zion Medical Center, 1600 Divisadero Street, Box 1629, San Francisco, CA 94143-1629.

Dr. Jaffe: Gilead Sciences, Inc., 353 Lakeside Drive, Foster City, CA 94404.