Peter Frame

A Randomized Trial Comparing Fluconazole with Clotrimazole Troches for the Prevention of Fungal Infections in Patients with Advanced Human Immunodeficiency Virus Infection

Background Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated. Methods We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. Results After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the cl...

A Randomized Trial of Three Antipneumocystis Agents in Patients with Advanced Human Immunodeficiency Virus Infection

BACKGROUND We evaluated the effectiveness of three treatment strategies for the prevention of a first episode of Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus (HIV). METHODS In an open-label trial, 843 patients with HIV infection and fewer than 200 CD4+ cells per cubic millimeter received zidovudine plus one of three randomly assigned prophylactic agents, beginning with trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine and followed by a defined sequence of other drugs to be used in cases of intolerance. RESULTS The estimated 36-month cumulative risks of P. carinii pneumonia were 18 percent, 17 percent, and 21 percent in the trimethoprim-sulfamethoxazole, dapsone, and aerosolized-pentamidine groups, respectively (P = 0.22). The difference in risk among treatment strategies was negligible in patients entering the study with 100 or more CD4+ lymphocytes per cubic millimeter. In those entering with fewer than 100 CD4+ cells per cubic millimeter, the risk was 33 percent with aerosolized pentamidine, as compared with 19 percent with trimethoprim-sulfamethoxazole and 22 percent with dapsone (P = 0.04). The lowest failure rates occurred in patients receiving trimethoprim-sulfamethoxazole, and failures were more common with 50 mg of dapsone than with 100 mg. Toxoplasmosis developed in less than 3 percent of patients. Of the patients assigned to the two systemic therapies, only 23 percent were receiving their assigned drug and dose when they completed the study. The median survival was approximately 39 months in all three groups, and the mortality attributable to P. carinii pneumonia was only 1 percent. CONCLUSIONS In patients with advanced HIV infection, the three treatment strategies we examined have similar effectiveness in preventing P. carinii pneumonia. Strategies that start with trimethoprim-sulfamethoxazole or with high-dose dapsone, rather than aerosolized pentamidine, are superior in patients with fewer than 100 CD4+ lymphocytes per cubic millimeter.

Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

BACKGROUND Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

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 sites 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 sites 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 patients 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

A randomized trial of interferon alpha therapy for HIV type 1 infection.

The immunologic and virologic efficacy and safety of interferon a (IFN-alpha) administered in combination with zidovudine (ZDV) and zalcitabine (ddC) was evaluated in HIV-infected subjects with CD4+ cell counts between 300 and 500 cells/ml and no more than 14 weeks of prior antiretroviral therapy. A total of 256 subjects enrolled in an open-label, randomized controlled trial. Subjects were randomized equally into treatment groups. All subjects received ZDV and ddC, while half also receive IFN-alpha (3 MU subcutaneously every 24 hr). At 48 weeks the median average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA for the two-drug group was -0.68 versus -0.75 log10 copies/ml for the IFN-alpha group (p = 0.046). Mean HIV-1 RNA changes from baseline to 48 weeks for these groups were -0.65 and -1.12 log10 copies/ml, respectively (p = 0.010). The median AAUCMB for CD4+ cell count for the two-drug group was 28 versus -1 cells/mm3 for the IFN-alpha group (p = 0.011). Neutropenia, anemia, and drug intolerance were more common in the IFN-alpha group. This study demonstrates that IFN-alpha inhibits HIV-1 replication but attenuates the CD4+ cell response to dual therapy with ZDV and ddC.

Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced HIV infection.

We compared the occurrences of several types of infections in HIV-infected patients participating in a randomized clinical trial of three treatment strategies given for the primary prevention of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis. In a phase III open label trial, 842 patients with HIV infection and fewer than 200 CD4+ cells/mm(3) received zidovudine (standard dose) plus one of three randomly assigned prophylactic agents: trimethoprim-sulfamethoxazole (TMP-SMZ), or dapsone (DAP), or aerosolized pentamidine (AP). Patients developing intolerance to treatment were crossed over to another predefined prophylactic therapy. Patients were monitored for infections every other week for 8 weeks and then monthly until the study was completed. Primary statistical models were proportional hazards models adapted to recurrent end points. In an intent-to-treat analysis, compared with AP and DAP, TMP-SMZ significantly reduced the risk of any bacterial infection (combining all distinct types) (p = 0.02 and p = 0.01, respectively). When considering distinct types separately, compared with AP, TMP-SMZ significantly reduced the risk of infectious diarrhea (p = 0.04); compared with DAP, AP and TMP-SMZ significantly reduced the risk of sinusitis/otitis media (p = 0.03 and p = 0.04, respectively); compared with AP and DAP, TMP-SMZ significantly reduced the risk of a second occurrence of pneumonia (p = 0.04 and 0.02, respectively). For any bacterial infection, infection rates per 100 patient-years of follow-up were 31, 39, and 38 for TMP-SMZ, DAP, and AP, respectively. In patients with advanced HIV infection not taking highly active antiretroviral therapy, the treatment strategy that initiates prophylaxis with TMP-SMZ is superior to those initiating with AP or DAP for preventing any bacterial infection, with most of the advantage manifested through infectious diarrhea, sinusitis/otitis media, and pneumonia.