Dennis M. Causey

Cytomegalovirus Retinitis and Response to Therapy with Ganciclovir

A 15-month prospective study of 109 patients with the acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) was conducted. Cytomegalovirus (CMV) retinitis developed in 18 of these patients; they were treated with ganciclovir. Five other patients with CMV retinitis who were not part of the prospective study were also treated with ganciclovir. CMV retinitis frequently involved the peripheral retina. All 23 patients treated with ganciclovir showed clinical regression of retinitis, although breakthrough recurrence of CMV retinitis occurred in seven patients (30.4%) while on maintenance therapy with ganciclovir. During treatment, neutropenia (less than 1000 leukocytes/mm3) developed in three patients (13%). Ganciclovir is an effective means of therapy for CMV retinitis, but it must be given chronically to prevent reactivation. Breakthrough recurrences while on maintenance therapy are not uncommon, but can be successfully treated with more aggressive treatment with ganciclovir. In addition, the prognosis for survival of AIDS patients being treated with ganciclovir is improved when compared with that of untreated patients.

A pilot study of low-dose zidovudine in human immunodeficiency virus infection.

BACKGROUND Zidovudine delays the progression of human immunodeficiency virus (HIV) infection but is associated with hematologic toxicity at high doses. Regimens are needed that preserve or enhance efficacy and reduce toxicity. Acyclovir has been reported to potentiate the effect of zidovudine on HIV in vitro. METHODS We conducted a Phase II open-label, dose-escalating trial to evaluate the clinical and antiviral effects of zidovudine at low (300 mg daily, 28 subjects), medium (600 mg, 24 subjects), and high (1500 mg, 15 subjects) doses, either with or without acyclovir (4.8 g) by random assignment. The subjects had the acquired immunodeficiency syndrome (AIDS)-related complex, but not AIDS. All of them had either HIV p24 antigenemia or plasma viremia and CD4-lymphocyte counts of 200 to 500 per cubic millimeter when they began treatment. RESULTS Performance scores and fatigue improved the most in the low- and medium-dose zidovudine groups (both P less than or equal to 0.025). Those assigned to low-dose zidovudine gained the most weight and had the greatest improvement in the mean CD4-lymphocyte count (from 321 per cubic millimeter at base line to 412 per cubic millimeter after 12 weeks, P = 0.01). The proportion of subjects in whom HIV antigenemia resolved, the decrease in the level of antigenemia, and the reduction in the plasma virus titers were similar at all three doses. Subjects assigned to receive the low or medium dose who subsequently crossed over to the 1500-mg dose (n = 19) did not have an increase in CD4-cell counts or a decline in levels of HIV antigen, but they did have dose-related toxicity. The addition of acyclovir to zidovudine was well tolerated, but it did not enhance any of zidovudines antiretroviral effects. CONCLUSIONS In this pilot study a very low dose of zidovudine (300 mg) had clinical and virologic effects similar to those of higher daily doses (600 and 1500 mg). The minimal effective dose of zidovudine for the treatment of HIV infection has yet to be determined, and further studies of very low daily doses are warranted.

Prevalence, Pathophysiology, and Treatment of Rhegmatogenous Retinal Detachment in Treated Cytomegalovirus Retinitis

Seventeen patients with the acquired immune deficiency syndrome and cytomegalovirus retinitis were treated with the antiviral drug ganciclovir (9-[1,3-dihydroxy-2-propoxy-methyl]-guanine, DHPG). Eight eyes of five patients developed rhegmatogenous retinal detachment after initiation of treatment. Multiple breaks in areas of peripheral, healed, atrophic retina accounted for the detachments. All seven eyes that underwent surgery had extensive retinal detachments that were reattached with vitrectomy and silicone oil. Retinotomy and retinal tacks were necessary in two cases that were complicated by severe proliferative vitreoretinopathy. In the fellow eye of one patient, laser treatment was used prophylactically to wall off a peripheral patch of healed retinitis. Endoretinal biopsies and culture were taken in five eyes; evidence of persistent cytomegalovirus was seen in two cases despite concurrent and clinically effective antiviral therapy.

A Clinical, Histopathologic, and Electron Microscopic Study of Pneumocystis carinii Choroiditis

We studied the clinical and histopathologic features of Pneumocystis carinii choroiditis in three patients with acquired immunodeficiency syndrome. In two cases, a provisional diagnosis of disseminated P. carinii infection was made by ophthalmologic examination. The characteristic fundus changes in this infection consisted of numerous slightly elevated, plaque-like, yellow-white lesions located in the choroid and unassociated with signs of intraocular inflammation. The diagnosis was confirmed by postmortem examination of the eyes and other organs. Histopathologically, the globes showed many choroidal infiltrates that were eosinophilic, acellular, vacuolated, and frothy. Several such infiltrates were noted within the choroidal vessels and choriocapillaries. Gomoris methenamine silver stain demonstrated many cystic and crescentic organisms. Electron microscopy disclosed thick-walled cystic organisms and large numbers of trophozoites.

Phase II dose-ranging trial of foscarnet salvage therapy for cytomegalovirus retinitis in AIDS patients intolerant of or resistant to ganciclovir (ACTG protocol 093)

Objective:To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. Methods:Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60mg/kg every 8h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. Results:A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occuring at ≤2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. Conclusion:In patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.

Bull's Eye Retinopathy and Clofazimine

Excerpt To the Editors:Clofazimine, a red phenazine dye used to treat dapsone-resistant leprosy, has now become part of the standard multidrug regimen for the treatment of patients with the acquire...

Pharmacodynamic relationship of pharmacokinetic parameters of maintenance doses of foscarnet and clinical outcome of cytomegalovirus retinitis.

The pharmacodynamic relationship between a range of foscarnet exposure measurements obtained from studying nine patients receiving ongoing maintenance therapy for cytomegalovirus retinitis and a range of efficacy values (days to retinitis progression) obtained by independent examination of serial retinal photographs from the same nine patients was analyzed. In the resulting proportional hazards models, the foscarnet area under the concentration-time curve approached statistical significance (P = 0.11) as a predictor of decreased risk of retinitis progression.

Phase II Dose-Ranging Trial of Foscarnet Salvage Therapy for Cytomegalovirus Retinitis in AIDS Patients Intolerant of or Resistant to Ganciclovir (ACTG Protocol 093): AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases

OBJECTIVE To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. METHODS Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90 mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. RESULTS A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occurring at < or = 2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. CONCLUSION In patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.