Faculty Bibliography

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 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 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 occuring at less-than-or-equal-to 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

To determine the efficacy and safety of albendazole for treatment of intestinal microsporidosis due to Enterocytozoon bieneusi, 29 patients with AIDS were studied. All had chronic diarrhea, weight loss, and evidence of malabsorption. After 1 month of treatment with albendazole (400 mg orally twice a day), the mean number of bowel movements decreased from 7.0 to 3.8 stools/day (P < .0001) and the mean weight gain was 0.56 kg (P = .259). Albendazole at this dose did not clear E. bieneusi on follow-up small-bowel biopsies, but ultrastructural studies revealed an apparent decrease in parasite burden in 2 patients and an increased proportion of dividing plasmodia in 5 patients. There were no significant adverse events associated with this dose of albendazole. A formal double-blind placebo-controlled study using higher doses has recently been approved and will soon be underway (AIDS Clinical Trial Group protocol 207)

To determine the pharmacokinetics (pk) as well as evaluate the safety and efficacy of foscarnet (FOS) treatment at a dose of 90 mg/kg IV q12h in upper and lower gastrointestinal (GI) cytomegalovirus (CMV) infection 10 patients with the Acquired Immunodeficiency Syndrome (AIDS) were studied. Plasma FOS concentrations were measured by ion-pair reversed-phase liquid chromatography on days 1 and 20. Safety was evaluated by monitoring clinical/laboratory variables and adverse events. Efficacy was measured by histopathological examination of biopsies and endoscopic grading which were performed at baseline, week 3 and week 6. If resolution occurred at week 3, FOS was discontinued. Five patients with upper GI CMV disease and 5 with lower GI CMV disease were enrolled into study. Median age was 43.5 years and median CD4 count was 26.5 cells/mm3. On day 1, mean peak and trough plasma FOS levels were 621 +/- 130 and 37 +/- 20 micromolar, while on day 20, levels were 687 +/- 141 and 48 +/- 14 micromolar, respectively. FOS was discontinued in 1 patient after he developed hypokalemia and an increased serum creatinine. Another patient's 24 hour creatinine clearance decreased below 50 mg/ml after three weeks, but he completed therapy. Mild edema was noted in 2/10 patients (20%), but resolved. Eight of 10 patients (80%) required 6 weeks for full resolution. Nine of 10 patients (90%) responded histopathologically (P=.0067) and 9/10 (90%) responded endoscopically (P=.0004). In conclusion, the peak concentrations of twice daily administration of FOS were higher than those necessary to inhibit CMV. There was no difference in the pk between days 1 and 20. This regimen appears to be safe and effective in the treatment of gastrointestinal CMV disease in AIDS patients

This prospective, randomized, multicenter, controlled trial was designed to evaluate the efficacy and safety of intravenous ganciclovir for the treatment of peripheral cytomegalovirus (CMV) retinitis in patients with AIDS. Patients were randomly assigned to receive either immediate treatment, intravenous ganciclovir, 5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily for 14 weeks, or deferred treatment. Patients randomized to deferred treatment whose retinitis progressed were offered ganciclovir. Of the 22 patients randomized to deferred treatment who were included in the final analysis, 20 were found to have progressive CMV retinitis compared with 10 of the 13 randomized to immediate treatment. The median time to progression in the deferred treatment group, as determined by a masked fundus photography reading center, was 13.5 days compared with 49.5 days in the immediate treatment group (mean +/- SD, 19.3 +/- 4.1 vs. 66.4 +/- 14.0; P = .001, log rank test). These data indicate that ganciclovir delays the progression of CMV peripheral retinitis in persons with AIDS

Ten patients with AIDS and progressive cytomegalovirus disease were treated with ganciclovir and foscarnet concurrently. The patients had received ganciclovir and foscarnet monotherapy a median of 330 days before receiving combination therapy for a median of 80 days. Nine of the 10 patients responded to the combination. No electrolyte abnormalities were noted during combination therapy, but rates of neutropenia (relative rate, combination vs. ganciclovir, 1.99; P = .229) and thrombocytopenia (relative rate, combination vs. ganciclovir, 1.53; P = .616) were higher with combination therapy than with either drug alone. The relative rate of anemia was significantly increased with combination therapy compared with monotherapy (relative rate, combination vs. ganciclovir, 2.69; P = .025). These data suggest that combination ganciclovir and foscarnet therapy after failure of either alone appears to be as effective as standard therapy with single agents. The rate of anemia with combination therapy was significantly greater than either agent alone, but no significant difference was noted among the other parameters of toxicity studied

This compassionate-use study examined the efficacy of foscarnet in patients with AIDS and cytomegalovirus (CMV) gastrointestinal disease who had failed ganciclovir induction. Nineteen male homosexuals with AIDS and biopsy-proven CMV gastrointestinal disease who had twice failed standard ganciclovir induction (defined as progression of clinical CMV disease) were studied. Foscarnet 60 mg/kg every 8 h was administered intravenously for 14 days, then maintenance was utilized at 90 or 120 mg/kg every day with 1 L normal saline daily. Endpoints included endoscopic appearance, blinded histopathologic analysis of biopsies for CMV inclusions, and changes in symptoms by 50% from baseline. Patients were evaluated before and 2-3 wk after foscarnet. Histopathologic improvement was seen in 67%, whereas 74% improved clinically after a median duration of 7.5 days (1-12). Among the nine with esophageal disease, six patients (68%) had a clinical response and six of eight (75%) had a pathologic response. Among the 10 with colonic disease, eight patients (80%) had a clinical response and six (60%) had a pathologic response. Reversible elevations in creatinine were seen in two of 17 (12%). Three patients with esophageal disease developed strictures late in therapy requiring dilation. Median survival after foscarnet induction was 5.0 months. Foscarnet appears to induce remission of CMV gastrointestinal disease in 67% of patients when ganciclovir induction has failed. Reversible nephrotoxicity occurred in 12%. Strictures may be a late complication of CMV esophagitis

The efficacy and safety of ganciclovir therapy for cytomegalovirus (CMV) colitis in patients with AIDS was examined in a double-blind, placebo-controlled study. Sixty-two patients at four university medical centers were enrolled. All had biopsy-proven CMV colitis with diarrhea, fever, and weight loss. Other pathogens were excluded. Ganciclovir (5 mg/kg) or placebo was administered every 12 h for 14 days. A significant reduction in CMV-positive colonic and urine cultures was seen with ganciclovir (P = .034 and P < .001, respectively) compared with placebo. Colonoscopy scores were improved significantly more with ganciclovir than with placebo (P = .042). New extracolonic CMV disease developed in 7 (23%) of 30 placebo patients and in 3 (9%) of 32 ganciclovir patients in only 14 days (P = .026). Ganciclovir-treated patients maintained body weight, while placebo patients had a mean loss of 1.5 kg. Overall, ganciclovir appears of some benefit in treating CMV colitis in patients with AIDS