Dose-escalation, phase 1/11 study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS

Objective: To assess the safety, tolerance and activity of increasing doses of azithromycin in combination with pyrimethamine for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS. Design: A phase 1/11 dose-escalation study of oral azithromycin in combination with pyrimethamine. Setting: Eight clinical sites in the United States. Patients: Forty-two adult HIV-infected patients with confirmed or presumed acute TE. Methods: Patients were enrolled into three successive cohorts receiving azithromycin 900, 1200 and 1500mg a day with pyrimethamine as induction therapy. The induction period was 6 weeks followed by 24 weeks of maintenance therapy. Main outcome measures: Patient response was evaluated clinically and radiologically. Results: Of the 30 evaluable patients, 20 (67%) responded to therapy during the induction period. Ten experienced disease progression. Of the 15 patients who received maintenance therapy, seven (47%) relapsed. Six patients discontinued treatment during the induction period as a result of reversible toxicities. Treatment-terminating adverse events occurred most frequently among the patients receiving the 1500 mg dose. Conclusion: The combination of azithromycin (900-1200 mg a day) and pyrimethamine may be useful as an alternative therapy for TE among patients intolerant of sulfonamides and clindamycin, but maintenance therapy with this combination was associated with a high relapse rate. The combination was safe, but low-grade adverse events were common.