J. Fernando Arevalo

Phase I/II Study of Intravitreal Cidofovir for the Treatment of Cytomegalovirus Retinitis in Patients With the Acquired Immunodeficiency Syndrome

PURPOSE In this study we evaluated the safety and efficacy of the nucleoside phosphonate analogue intravitreal cidofovir to treat cytomegalovirus retinitis in humans. METHODS We conducted a phase I/II unmasked consecutive case series in a single-center institutional referral practice. Eligible patients with the acquired immunodeficiency syndrome had active cytomegalovirus retinitis in at least one eye, despite adequate intravenous therapy with ganciclovir or foscarnet, were intolerant to intravenous therapy, were noncompliant with intravenous therapy, or refused intravenous therapy. In a preliminary safety study (Group 1), ten eyes of nine patients received 14 injections of cidofovir while being treated concurrently with intravenous ganciclovir. In a dose-escalating efficacy study (Group 2), eight eyes of seven patients received 11 injections of cidofovir as sole treatment for cytomegalovirus retinitis. The primary outcome was time to retinitis progression. RESULTS In the Group 1 eyes receiving 20 micrograms of cidofovir, the median time to retinitis progression was between 49 and 92 days (mean, 78 days). In Group 2 eyes treated with 20 micrograms cidofovir, the median time to retinitis progression was 64 days (mean, 63 days). Hypotony occurred in the two eyes treated with a 100-micrograms dose of cidofovir and in one of three eyes receiving a 40-micrograms dose. No adverse effects resulted from the remaining 20 cidofovir injections. CONCLUSIONS Cidofovir (also known as HPMPC) appears to be safe and effective for the local treatment of cytomegalovirus retinitis, providing a long duration of antiviral effect. These preliminary results indicate that additional studies should be performed to investigate more fully this promising medication.

Intravitreal cidofovir for the maintenance treatment of cytomegalovirus retinitis

PURPOSE To evaluate the efficacy and safety of multiple intravitreal cidofovir (HPMPC) injections given every 5 to 6 weeks for the maintenance treatment of cytomegalovirus (CMV) retinitis. METHODS A prospective consecutive case series of 53 eyes in 35 patients with acquired immune deficiency syndrome and CMV retinitis was treated with maintenance intravitreal injections of cidofovir (20 micrograms) at one referral center between April 1994 and September 1995. Twenty-four eyes received intravitreal cidofovir as their initial treatment for CMV retinitis (group A), and 29 eyes previously had received systemic therapy (group B). None of the patients in either group received systemic anti-CMV therapy at any time during the study period. Progression of retinitis was the primary end point. RESULTS All eyes with active retinitis healed in response to treatment. None of the 24 eyes in group A demonstrated any progression during the study period. Four (14%) of the 29 eyes in group B had one episode each of retinitis progression (mean follow-up, 15 weeks; range, 0-58 weeks). In 1 (1.9%) of the 53 eyes, a retinal detachment developed. A mild iritis was observed after 14% of injections, which were prophylaxed with oral probenecid. Irreversible visually significant hypotony developed in two eyes (3.8%). CONCLUSION Treatment and subsequent maintenance therapy of CMV retinitis with 20 micrograms intravitreally injected cidofovir, given at 5- to 6-week intervals, is highly effective, with only rare episodes of re-activation and progression.

Anterior nongranulomatous uveitis after intravitreal HPMPC (cidofovir) for the treatment of cytomegalovirus retinitis. Analysis and prevention

BACKGROUND AND OBJECTIVE The authors characterize and analyze the incidence of a previously reported mild anterior nongranulomatous uveitis associated with intravitreal injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), also termed cidofovir (Vistide, Gilead Sciences, Foster City, CA). This is an acyclic nucleoside phosphonate analogue with a potent anticytomegalovirus effect. The authors also analyzed the effects of probenecid therapy, as well as prophylaxis with probenecid plus topical corticosteroids and cycloplegics on the course and outcome of the uveitis. METHODS Prospective case series from a tertiary referral center, which included 46 consecutive patients with acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis. There was a total of 130 injections in 69 eyes treated with 20 micrograms of intravitreal HPMPC. Forty-one patients (119 injections) received oral probenecid, 5 patients (11 injections) did not, and 21 patients (53 injections) received topical corticosteroids and cycloplegics as an adjuvant to probenecid in the prophylaxis of iritis. RESULTS Mild to moderate nongranulomatous iritis was seen in 26% of patients after their first injection (n = 12). Patients receiving probenecid prophylaxis after first injection had a significantly lower frequency of iritis versus patients who did not receive probenecid at the time of first injection (P = 0.0089). In contrast, treatment with topical corticosteroid and cycloplegics after injection did not statistically significantly affect the frequency of iritis in patients (P = 0.44). The development of iritis after a second injection of HPMPC was more likely if it had occurred after the initial injection (P = 0.015; Fishers exact test). All cases of iritis were treated with topical corticosteroids and cycloplegics, and there was no permanent impairment of vision secondary to iritis after HPMPC injection in any eyes. CONCLUSIONS Anterior uveitis was seen in 26% of patients after first-time HPMPC injection. Concomitant use of probenecid appears to decrease the frequency of the iritis from 71% to 18% in patients with AIDS and CMV retinitis after the first intravitreal injection of HPMPC. Topical corticosteroid administration after injection (before iritis) was ineffective in preventing iritis treatment with topical corticosteroids and cycloplegics resulted in resolution of all iritis cases.

Visual Field Loss in HIV-positive Patients Without Infectious Retinopathy

PURPOSE To determine the extent of vision loss in a cross-sectional study of HIV-positive individuals who had no infectious retinopathy. METHODS Visual field loss was determined by computerized achromatic automated perimetry and short-wavelength automated perimetry in both eyes in 65 HIV-positive individuals without infectious retinopathy and in one randomly selected eye each in 57 age-matched normal controls. Results were analyzed using the global index of mean defect and the Glaucoma Hemifield Test, and significance was determined through analysis of variance, chi-square, and Tukey-Kramer tests. RESULTS We found that HIV-positive patients, compared with age-matched HIV-negative controls, demonstrated significant (at least P < .01) localized defects as well as an increased mean defect. The HIV-positive patients also had a significantly greater number of defective points, especially on short-wavelength automated perimetry, even while ophthalmoscopic examination and fundus photographs suggested that the retinas were normal. CONCLUSIONS There is a significant loss of visual function in HIV-positive individuals that is not the result of infectious retinopathies. The finding by short-wavelength perimetry of more severe defects suggests that the vision defects are not caused by attentional or other suprachiasmatic problems because the neurologic difficulty of both achromatic and short-wavelength perimetry is similar. The effects of this vision loss on the daily living and occupational tasks of this population require further study.

Intraocular Pressure and Aqueous Humor Dynamics in Patients With AIDS Treated With Intravitreal Cidofovir (HPMPC) for Cytomegalovirus Retinitis

PURPOSE To evaluate the decrease in intraocular pressure associated with cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate; HPMPC) intravitreal injections. METHODS We followed up 97 eyes of 63 patients with acquired immunodeficiency syndrome (AIDS) who had cytomegalovirus retinitis and had been treated with up to nine 20-microgram intravitreal cidofovir injections. Measurements were taken at baseline, between 2 and 3 weeks, and at 5 to 6 weeks after injections. Anterior chamber fluorophotometry was studied in seven eyes (four patients) before and after injections. Ciliary body anatomy was evaluated in two patients. RESULTS After the first intravitreal injection, mean intraocular pressure was 2.2 mm Hg lower than that at baseline at 2 to 3 weeks (P < .001) and 1.3 mm Hg lower than at baseline at 5 to 6 weeks (P = .0025). After the second injection, mean pressure was 2.6 mm Hg lower at 2 to 3 weeks (P = .0013) and 1.5 mm Hg lower at 5 to 6 weeks (P = .043). After subsequent injections, however, the decrease was less than 1 mm Hg, suggesting that a plateau had been reached. Pressure in eyes with anterior uveitis after the first injection was lower than that in eyes without anterior uveitis (P < .0001). The mean rate of aqueous flow decreased from 2.8 to 1.9 microliters per minute 2 to 4 weeks after injection (P < .015). Ultrasound biomicroscopy disclosed that severe hypotony after cidofovir injections is associated with ciliary body atrophy. CONCLUSIONS Intraocular pressure decreases after the initial 20-microgram cidofovir intravitreal injection. However, eyes stabilize (pressure plateaus) after three injections. Effects on the ciliary body are the main cause of the decrease after cidofovir injections.

Adverse events and autopsy findings after intravitreous cidofovir (HPMPC) therapy in patients with acquired immune deficiency syndrome (AIDS)

OBJECTIVE The purpose of the study is to evaluate the adverse events and autopsy findings in a series of consecutive 20-microg intravitreous cidofovir injections at a single institution. DESIGN The study design was a nonrandomized, consecutive case series. PARTICIPANTS Seventy-six patients with acquired immune deficiency syndrome with cytomegalovirus retinitis were studied prospectively. Sixty-three patients had 1 months follow-up or longer, and this comprised the study group. In addition, histopathologic findings from 18 eyes of 9 patients were studied at autopsy. INTERVENTION A total of 296 injections of 20 microg cidofovir were given in 115 eyes. Sixty-three patients who had 246 injections in 93 eyes had 1 months follow-up or longer for the evaluation of adverse events. MAIN OUTCOME MEASURES Postinjection chronic hypotony associated with permanent visual loss, transient hypotony, iritis, and its long-term sequela (posterior synechia and cataract, retinal detachment, extraocular cytomegalovirus involvement) were the outcomes of interest in this study. Additionally, light and electron microscopic studies of human eyes were performed. RESULTS The most severe adverse event was postinjection chronic hypotony. This phenomenon was associated with permanent visual loss. This was observed in 1% of the injections and 3% of the eyes of the patients (95% confidence interval, 0%-6%). Transient hypotony associated with mild-to-moderate visual loss developed in 14%, but vision recovered to baseline levels in these eyes subsequently. Analysis showed that transient hypotony in the injected eye could predict postinjection chronic hypotony in the fellow eye (two-tailed Fishers exact test, P = 0.02). The incidence of iritis was 32%; posterior synechia and cataract were the long-term sequela of the iritis and developed in 19% and 11% of the eyes, respectively. The incidence of retinal detachment was lower (6%). Histopathologic evaluation of the eyes showed mild-to-moderate atrophy of the nonpigmented epithelium of the ciliary body and no other evidence of intraocular toxicity. CONCLUSIONS The most serious adverse event was postinjection chronic hypotony, which occurred in 3% of eyes. Episodes of transient hypotony appear to indicate that the fellow eye was predisposed to chronic hypotony. Therefore, it may be prudent to give intravitreous injections at least 2 weeks apart in the fellow eye to evaluate the clinical response of the injected eye.

Correlation Between Intraocular Pressure and CD4+ T-Lymphocyte Counts in Patients With Human Immunodeficiency Virus With and Without Cytomegalovirus Retinitis

PURPOSE To determine the intraocular pressure in patients with human immunodeficiency virus (HIV) with and without cytomegalovirus retinitis, and to correlate intraocular pressure with CD4+ T-lymphocyte count and the presence, extent, and activity of cytomegalovirus retinitis. METHODS Intraocular pressure was measured with calibrated Goldmann applanation tonometers in two groups of patients. Group A included 84 patients with HIV (120 eyes) with cytomegalovirus retinitis, and Group B included 110 patients with HIV (183 eyes) without cytomegalovirus retinitis. Thirty-three patients without HIV (66 eyes) were included as a control group. Step-wise regression analysis of intraocular pressure included correlation with cytomegalovirus retinitis (presence, extent, and activity), CD4+ T-lymphocyte count, age, and gender. RESULTS The mean intraocular pressure was 9.8 mm Hg in Group A, 12.6 mm Hg in Group B, and 16.1 mm Hg in the control group. All three groups were statistically different from each other when intraocular pressure was compared (P < .0001). Step-wise regression showed that low CD4+ T-lymphocyte count (r2 = .20; P < .0001) and extent of cytomegalovirus retinitis (r2 = .08; P = .007) both correlated to low intraocular pressure. CONCLUSION Intraocular pressure is lower than normal in patients with HIV. Decreased CD4+ T-lymphocyte count is the major association with low intraocular pressure (20% of the effect); extent of cytomegalovirus retinitis accounts for 8% of the effect. Knowledge of the normal range of intraocular pressure in patients with HIV will be important to the understanding and treatment of glaucoma and other disorders or treatments affecting intraocular pressure.

Retinal Findings and Characteristics in AIDS Patients With Systemic Mycobacterium avium-intracellulare Complex and Toxoplasmic Encephalitis

BACKGROUND AND OBJECTIVE The purpose of this study was to evaluate the incidence and characteristics of retinal and choroidal manifestations of toxoplasmosis and/or Mycobacterium avium-intracellulare complex (MAC) in patients with acquired immunodeficiency syndrome (AIDS). PATIENTS AND METHODS The authors analyzed their prospectively collected data and found 120 patients with new retinal lesions (group A) that were diagnosed 3 months or longer following the diagnosis of MAC and/or toxoplasmic encephalitis. The authors also performed a point prevalence study of retinal/choroidal findings in 25 consecutive AIDS patients (group B) without known eye disease who had been recently treated for toxoplasmic encephalitis and/or disseminated MAC infections. In addition, the characteristics of retinochoroidal toxoplasmosis scars in 5 AIDS patients were studied and compared with the characteristics of scars in 18 immunocompetent patients. RESULTS In this study the incidence of ocular manifestations of MAC was zero (95% confidence interval [CI] 0.0% to 3.8%). Two of 25 patients (8%) (95% CI 1% to 26%) in group A and 2 of 11 patients (18.1%) (95% CI 3.3% to 51.8%) in group B had toxoplasmic retinochoroiditis. CONCLUSION In AIDS patients, ocular manifestations of toxoplasmosis are more common than ocular MAC. In addition, when compared with immunocompetent patients, AIDS patients tend to have retinochoroidal scars with less retinal pigment epithelium hyperplasia (1.8+ vs 3+) (P = .03).

Clinical versus fundus photographic evaluation of the status of cytomegalovirus retinitis in AIDS patients.

Purpose: To evaluate the accuracy of clinical examinations and serial fundus photographic readings in determining the response of cytomegalovirus retinitis to antiviral therapy in patients with acquired immune deficiency syndrome. Methods: Fifty two consecutive patients with cytomegalovirus retinitis who were prospectively evaluated over a 30-month period for a minimum of 6 months (or until death) were included in this study. There was a total of 708 patient visits. The clinical evaluations included indirect ophthalmoscopy, fundus drawings, 60° fundus photographs, and a comparison of the photographs with those of the previous visit. The fundus photographs were reevaluated in a blinded fashion. Cytomegalovirus retinitis was classified as active (progression of border since last examination), intermediate (border activity without progression), healed (no activity since last visit), or normal (no retinitis). Results: Using the photographic data as the measure of cytomegalovirus retinitis activity, the sensitivity and specificity of clinical assessments were determined. The sensitivity and specificity of clinical versus photographic evaluations varied with retinitis status. In healed retinitis the sensitivity of the clinical examination was 98%, and the specificity was 83%. In cases of border opacification without progression the sensitivity was 80%, and the specificity was 96%. In cases of clinically active retinitis the sensitivity was 63% with a specificity of 100%. Clinical detection of active retinitis and border opacification without progression was reduced when potential problems were present that made visualization of the retinitis border difficult, such as smoldering retinitis, progressive retinal destruction without border opacification, poor media, or fundus pigmentation. Conclusions: Progressive retinal destruction and visual loss can occur in patients with cytomegalovirus retinitis despite antiviral therapy. Examining the patient through indirect ophthalmoscopy only can result in failure to detect subtle changes.

Fluorophotometry in patients with human immunodeficiency virus with and without cytomegalovirus retinitis

OBJECTIVE To study the aqueous humor dynamics in subjects with human immunodeficiency virus (HIV) with and without cytomegalovirus (CMV) retinitis. DESIGN Prospective cross-sectional study. PARTICIPANTS Fourteen HIV-positive subjects (27 eyes, 19 with CMV retinitis and 8 without CMV retinitis), and a control group of 9 HIV-negative subjects (17 eyes). TESTING Fluorophotometry. MAIN OUTCOME MEASURES Aqueous flow rates as measured by fluorophotometry and intraocular pressure (IOP). RESULTS Analysis of variance of the mean corrected aqueous flow rate revealed that both HIV-positive groups had significantly lower aqueous flow rates than did the control group (P < 0.03). No difference in mean aqueous flow rates was found between the HIV-positive eyes with or without CMV retinitis. Comparison of mean IOP revealed that HIV-positive eyes with CMV retinitis had significantly lower IOP than did the HIV-positive eyes without CMV retinitis (P = 0.03) and HIV-negative subjects (P = 0.002). There was no correlation between aqueous flow rate and IOP in HIV-positive subjects (P > 0.5). CONCLUSION The lack of correlation between the aqueous flow rate and IOP suggests that there may be some disassociation between these parameters in HIV-positive patients. Further studies are needed to better understand the mechanism of aqueous formation and in the management of disorders affecting IOP in this population.