Comparison of Three Regimens for Treatment of Mild to Moderate Pneumocystis carinii Pneumonia in Patients with AIDS: A Double-Blind, Randomized Trial of Oral Trimethoprim-Sulfamethoxazole, Dapsone-Trimethoprim, and Clindamycin-Primaquine

*For additional members of the ACTG 108 study group, see the Appendix. In 1994, 15 440 cases of Pneumocystis carinii pneumonia occurring in the United States were reported to the Centers for Disease Control and Prevention [1]. Thus, despite the advent of prophylactic agents to prevent this infection, the need for effective and nontoxic therapeutic regimens remains. Increased physician and patient awareness, along with improved methods of diagnosis, have made earlier institution of ambulatory therapy with oral medications a feasible alternative to hospitalization for inpatient treatment in many instances. Previous studies [2-8] suggest that the efficacy of trimethoprim-sulfamethoxazole, available since 1968, is equivalent or superior to that of all alternative therapies for P. carinii pneumonia. However, rates of treatment-limiting toxicity ranging from 20% to 57% in patients with the acquired immunodeficiency syndrome (AIDS) who receive this regimen [2, 3, 5, 7, 8] have necessitated a continued search for better-tolerated regimens. In one study [9], the combination of dapsone and trimethoprim was successfully used to treat 15 patients with a first episode of P. carinii pneumonia. In a subsequent randomized trial [5], this combination was compared with trimethoprim-sulfamethoxazole in 60 patients with arterial oxygen pressures of 60 mm Hg or greater. In this latter study, the efficacy of dapsone-trimethoprim was similar to that of trimethoprim-sulfamethoxazole (93% compared with 90%), but dapsone-trimethoprim was associated with a lower frequency of major toxicities (30% compared with 57%). The combination of clindamycin with primaquine has shown excellent activity against P. carinii in in vitro studies and in an experimental rat model [10]. Successful use of this regimen in the treatment of P. carinii pneumonia, generally with intravenous administration of clindamycin for all or part of therapy, has been described since 1989 [11-15]. In one study of 60 patients with an alveolar-arterial oxygen difference (PAO2-PaO2) of 40 mm Hg or less [15], the administration of intravenous or oral clindamycin and oral primaquine was associated with therapeutic success in 92% of patients and with doselimiting toxicity in 15% of patients. A randomized trial [16] compared intravenous clindamycin and oral primaquine with intravenous or oral trimethoprim-sulfamethoxazole in 49 patients with a first episode of P. carinii pneumonia and an arterial oxygen pressure of 50 mm Hg or greater; 90% of patients in each group were classified as having successful therapy, and dose-limiting toxicity occurred in 18% and 20% of patients, respectively. Thus, although dapsone-trimethoprim and clindamycin-primaquine have gained widespread use in the treatment of P. carinii pneumonia, their relative efficacies have not yet been validated in a large controlled trial, and their toxicity profiles have not been directly compared. To guide the clinician in selecting the optimal oral therapy for patients with AIDS and mild to moderate P. carinii pneumonia, we compared the toxicities and efficacies of trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine in a randomized, doubleblind multicenter trial. Methods Beginning in May 1991, patients were enrolled at 24 centers participating in the AIDS Clinical Trials Group (ACTG) of the National Institutes of Allergy and Infectious Diseases (NIAID). Each site's institutional review board approved the study (ACTG trial 108), and all participants gave informed consent before the study drug was administered. Patients Eligible patients had human immunodeficiency virus (HIV) infection, were older than 13 years of age, weighed 35 to 100 kg, and had symptoms or signs of P. carinii pneumonia, such as cough, shortness of breath, or an abnormal chest radiograph. Enrollment was limited to patients whose room air PAO2-PaO2 was 45 mm Hg or greater. Morphologic confirmation of the diagnosis by visualization of P. carinii in induced sputum, bronchoscopic lavage, or transbronchial biopsy specimens was required within 10 days of study entry. Treatment of P. carinii pneumonia lasting no more than 24 hours was permitted before randomization. Exclusion criteria were concurrent pulmonary pathologic conditions that could obscure the evaluation of response to therapy; the third trimester of pregnancy; receipt of systemic corticosteroids within 7 days of study entry; deficiency of glucose-6-phosphate-dehydrogenase (G6PD) or nicotinamide adenine dinucleotide methemoglobin reductase; hemoglobin M abnormality; previous enrollment in the study; inability to receive oral therapy; and serum creatinine level greater than 152.5 mol/L, hemoglobin level less than 80 g/L, absolute neutrophil count less than 0.75 109/L, platelet count less than 50 109/L, or alanine aminotransferase levels greater than 7.5 times the upper limit of normal. Randomization and Dosing Patients were assigned to treatment on the basis of a permuted block randomization. Randomization was stratified by treatment center and by the use of antipneumocystis prophylaxis within 30 days and was accomplished by computerized linkage to a central data management center. Active study drug and placebo assignments were implemented by each site's pharmacist, who labeled the bottles in a blinded manner. The Burroughs Wellcome Company (Research Triangle Park, North Carolina), the Jacobus Pharmaceutical Company (Princeton, New Jersey), the Upjohn Company (Kalamazoo, Michigan), and Sterling-Winthrop Pharmaceuticals (New York, New York) provided the study drug. The dosages of the study drugs were as follows: dapsone, 100 mg daily; clindamycin, 600 mg three times daily; and primaquine base, 30 mg daily. The dosages of trimethoprim and sulfamethoxazole were based on patient weight: Patients weighing 51 to 80 kg received two double-strength trimethoprim-sulfamethoxazole tablets (320:1600 mg) three times daily or trimethoprim (300 mg) three times daily with dapsone once daily. Patients weighing 36 to 50 kg received 240:1200 mg of trimethoprim-sulfamethoxazole (1.5 double-strength tablets) three times daily or 200 mg of trimethoprim three times daily with dapsone once daily. Patients weighing 81 to 99 kg received 400:2000 mg of trimethoprim-sulfamethoxazole (2.5 double-strength tablets) three times daily or 400 mg of trimethoprim three times daily with dapsone once daily. To maintain a doubleblind status, all patients received one active regimen and one placebo regimen. Patients with a PAO2-PaO2 of 35 to 45 mm Hg received adjunctive prednisone, 40 mg twice daily for 5 days, then 40 mg daily for 5 days, then 20 mg daily until antipneumocystis therapy was discontinued [17]. Patients with a history of intolerance to trimethoprim-sulfamethoxazole were enrolled beginning in September 1992 and were randomly assigned to one of the other treatment arms. Therapy was administered for 21 1 days. For patients with dose-limiting toxicity, the protocol specified either double-blind crossover to an alternative regimen (according to a second randomized list) or the substitution of intravenous pentamidine (3 to 4 mg/kg of body weight daily). Antipneumocystis therapy could be terminated if the patient had received therapy for at least 14 days and if clinical signs and symptoms had remitted. Patients meeting criteria for therapeutic failure (see below) were to receive intravenous pentamidine to complete therapy. We did not permit concurrent therapy with zidovudine, ganciclovir, colony-stimulating factors, rifampin, rifabutin, folinic acid, investigational agents other than triazole antifungal agents, and other medications potentially effective against P. carinii (such as pyrimethamine and sulfadiazine). Clinical and Laboratory Assessments At baseline, physical examination, venipuncture (for complete blood count with differential; reticulocyte count; and determination of creatinine, aminotransferase, and lactic acid dehydrogenase levels), measurement of room air arterial blood gas, and chest radiography were done. Physical examination and venipuncture were repeated on days 0, 3, 7, 10, 14, and 21 of therapy; arterial blood gas determination was repeated on days 7 and 21; and chest radiography was repeated on day 7. Serum methemoglobin levels were measured on days 3, 7, and 10 of therapy. Physical examination, venipuncture, and chest radiograph were repeated 2 weeks after therapy was completed. Survival status and recurrence of P. carinii pneumonia were determined 60 days after completion of therapy. Secondary antipneumocystis prophylaxis was advised for all patients who completed the study, and each patient's primary physician chose the medication. We used a battery of instruments to assess the effect of treatment on patient-reported health status. Physical function was measured using the Duke Activity Status Index [18], a 12-item index weighted on the basis of known metabolic costs of each activity. Energy, pain, and general health perceptions were measured using scales from the Medical Outcomes Study [19], supplemented by four additional general health items [20]. Disability was measured by the number of days spent in bed or the decrease in the number of usual activities the patient could perform [21]. Severity of pulmonary (cough, dyspnea, and chest tightness) and other symptoms (fever, pain, nausea, rash, and dizziness) was assessed using a questionnaire that required approximately 5 minutes to complete and was available in English and Spanish [22]. Definitions of End Points Therapeutic failure at day 7 was defined by one of the following: 1) increase in PAO2-PaO2 of greater than 20 mm Hg over baseline without remission of baseline signs and symptoms; 2) change in antipneumocystis therapy for reasons other than toxicity; 3) intubation; and 4) death. Therapeutic failure at day 21 was defined by any of the above variables or by therapeutic failure at day 7. We used neither persistence of fe