Susan D. Mellow

A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS

OBJECTIVE To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.

Randomized, Double-Masked Study of Cyclosporine Compared to Prednisolone in the Treatment of Endogenous Uveitis

Fifty-six patients with bilateral sight-threatening noninfectious intermediate or posterior uveitis participated in a randomized double-masked study of the use of cyclosporine vs prednisolone in their treatment. Applying the end-point definitions, visual acuity or vitreal haze improved in only 13 of 28 (46%) patients in each group. The macular edema resolved in seven of 15 patients of the cyclosporine-treated group, and in ten of 16 patients of the prednisolone-treated group (P = .376). Patients whose therapies failed both cyclosporine and prednisolone trials were treated with both drugs, which resulted in additional patient improvements. Secondary effects were observed in both therapeutic alternatives, the most notable being alterations in serum creatinine concentration and hypertension with the dosage of cyclosporine used.

Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration

Therapy for severe uveitis is frequently long-term immunosuppression using systemic corticosteroids and cytotoxic agents, but side effects make long-term therapy difficult. A long-term (>4 year) Phase I/II single armed interventional study using intravenous anti-IL-2 receptor alpha treatments (daclizumab) and a short-term Phase II study evaluating the use of a subcutaneous daclizumab formulation were conducted. Patients were tapered off their systemic immunosuppressive therapy and received daclizumab infusions or subcutaneous injections at intervals varying from 2 to 6 weeks. In the long-term study, seven of ten enrolled patients were tapered from their original immunosuppressive medications and maintained exclusively on repeated daclizumab infusions for control of their uveitis for over 4 years. No patient was permanently removed from therapy for an adverse event ascribed to the medication. The use of 6-week infusion intervals led to recurrence of uveitis, while 2- to 4-week intervals did not. Only one patient developed measurable anti-daclizumab antibodies but this disappeared when subcutaneous therapy was begun. In the short-term study, four of the five patients receiving the subcutaneous formulation met the study endpoints for success within the first 12 weeks. All five were successful by 26 weeks. These studies provide preliminary evidence that regularly administered long-term daclizumab therapy can be given in lieu of standard immunosuppression for years to treat severe uveitis and that subcutaneously administered daclizumab appeared to be a clinically viable treatment strategy. These studies suggest that anti-IL-2 receptor blockade could be useful in the treatment of Th1-mediated autoimmune conditions.

Liver injury from cyclosporine A

To assess the incidence of cyclosporine A-induced hepatotoxicity, we retrospectively analyzed liver biochemical test results in 59 patients with endogenous uveitis who received cyclosporine A. All patients had normal liver tests before treatment and had at least six determinations during a 6- to 36-month course of therapy with cyclosporine A at a dose of 2–10 mg/kg/day. Thirty-four (58%) patients developed at least one abnormality of liver tests, and 19 (32%) had a prolonged pattern of abnormalities. The usual abnormalities consisted of a mild, transient increase in alkaline phosphatase levels occasionally accompanied by slight elevations in serum bilirubin and aminotransferase activities. Peak alkaline phosphatase levels ranged from 125 to 243 units/liter and persisted for seven days to 48 months. Thus, biochemical evidence of mild cholestatic liver injury was common in patients receiving cyclosporine A. These abnormalities are usually self-limited and asymptomatic but may cause diagnostic difficulty if a preexisting liver disease is present.

Increased survival of a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis who received sodium phosphonoformate (Foscarnet)

PURPOSE To evaluate the impact of foscarnet on the longevity of persons with human immunodeficiency virus, type 1 (HIV-1) infection and cytomegalovirus (CMV) retinitis. PATIENTS AND METHODS A cohort of 24 patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis received sodium phosphonoformate (foscarnet) as part of a controlled efficacy trial at the National Institutes of Health. Foscarnet was continued for as long as it was tolerated. Antiretroviral therapy was given to the patients as tolerated. Long-term follow-up was available on all patients. RESULTS Seventeen patients received zidovudine during or after receiving foscarnet, 2 patients received dideoxyinosine, 2 patients zidovudine and dideoxyinosine, and 3 patients received no specific antiretroviral agent. Patients received foscarnet for a mean of 6.2 months (median, 4 months; range, 10 days to 22 months). Ten patients required a change to ganciclovir therapy at some time after receiving foscarnet. The median time from the diagnosis of CMV retinitis until death was 13.5 months (range, 3 to 34 months). Patients lived longer than untreated or ganciclovir-treated historical controls with AIDS and CMV retinitis. There was no difference in the survival of patients treated with foscarnet at the time of diagnosis and those patients treated with foscarnet only after progression of their CMV retinitis. CONCLUSIONS These data suggest that foscarnet may prolong the survival of persons with AIDS and CMV retinitis and should be the initial treatment of choice in these patients.

Clinical, radiographic, and electrophysiologic findings in patients with achiasma or hypochiasma

Objective : To report the clinical, electrophysiologic, and radiographic analysis of four patients presenting with nystagmus and diagnosed with achiasma or hypochiasma and summarize all 11 patients reported with this syndrome. Methods : Each patient underwent complete ophthalmologic examination, fundus photography, ocular motor recordings (OMR), visual evoked potentials (VEP), visual field testing (VFT), and magnetic resonance imaging (MRI) of the optic pathways. Results : Reduced vision, strabismus, optic nerve dysplasia, congenital nystagmus (CN), and see-saw nystagmus were present in all patients. One of these four patients had congenital hy-drocephalus and three of the four patients had amblyopia. Monocular VFT was full in the older patients tested. OMR showed dysconjugate vertical, multiplanar ocular oscillations with CN slow phases, well-developed foveation periods, and occasional spontaneous uniocular saccades. VEPs showed crossed asymmetry and increased latency consistent with uncrossed optic pathways and optic nerve dysplasia. Specific MRI studies showed no chiasm in three patients and a hypoplastic chiasm in one. Conclusions : These patients further elucidate the spectrum of human achiasma/hypochiasma. Careful intraocular and ocular motor evaluation found optic nerve anomalies and see-saw nystagmus in all patients. Patients with congenital optic nerve hypoplasia/dysplasia with or without other midline neurologic defects should be carefully evaluated for the clinical presence of see-saw nys-tagmus (SSN). The occurrence of the conditions CN, SSN, and optic nerve anomaly strongly suggests achiasma/hypochiasma. Electrophy-siologic and radiographic evaluations should be considered in these patients.