Philip C. Johnson

Safety and Efficacy of Liposomal Amphotericin B Compared with Conventional Amphotericin B for Induction Therapy of Histoplasmosis in Patients with AIDS

Context Amphotericin B is the preferred initial treatment for moderate to severe disseminated histoplasmosis. Because amphotericin B has many serious side effects, alternative treatments are needed. Contribution This double-blind, multicenter trial compared liposomal amphotericin B with regular amphotericin B in patients with disseminated histoplasmosis and AIDS. Liposomal amphotericin B had a higher treatment response (88% vs. 64%) and lower mortality rates (2% vs. 13%). It also had fewer infusion-related side effects (25% vs. 63%) and less nephrotoxicity (9% vs. 37%). Implications Although expensive, liposomal amphotericin B is better than regular amphotericin B for treating severe disseminated histoplasmosis. The Editors In endemic areas, 5% to 20% of HIV-infected persons develop disseminated histoplasmosis (1-3). Amphotericin B is the therapeutic agent of choice for induction therapy of moderate to severe disseminated histoplasmosis (1), whereas noncomparative studies show that itraconazole (4) and fluconazole (5, 6) are effective for induction and consolidation treatment of milder disease. Treatment of severe disease with amphotericin B, however, has not produced optimal results (3). Liposomal amphotericin B achieves high concentrations in the reticuloendothelial system (7) and is less nephrotoxic. It achieves higher blood concentrations and exhibits reduced clearance compared with deoxycholate amphotericin B and other lipid preparations (8). In addition, it achieves the highest concentrations in the brains of rabbits (9). Central nervous system involvement indicates poor outcome in patients with AIDS and disseminated histoplasmosis (2, 10). We compared the safety and efficacy of liposomal amphotericin B with deoxycholate amphotericin B for treatment of moderate to severe disseminated histoplasmosis in persons with AIDS. Methods Study Design After we obtained informed consent, patients with AIDS and moderate to severe disseminated histoplasmosis were randomly assigned in a 2:1 ratio (liposomal amphotericin Bamphotericin B) in this multicenter double-blind trial. Randomization blocks of size 3 were used, and the research pharmacist at each site randomly assigned patients using the closed-envelope (security) technique. Disseminated histoplasmosis was diagnosed by culture of Histoplasma capsulatum, by histopathologic examination, or by urine or serum antigen levels determined by enzyme immunoassay (11, 12). Patients were excluded from the trial if they had a serum creatinine level greater than twice the upper limit of normal; had other uncontrolled opportunistic infections or malignant disease; or had been treated for 3 or more days with ketoconazole, itraconazole, fluconazole, or amphotericin B. Medication Administration Patients received daily doses of liposomal amphotericin B (AmBisome, Fujisawa Healthcare, Deerfield, Illinois), 3.0 mg/kg of body weight, or amphotericin B, 0.7 mg/kg, for 2 weeks. Medication was administered in a blinded fashion by intravenous infusion over 2 hours. Patients in whom induction therapy was successful received itraconazole for 10 weeks as consolidation therapy. Premedication was not allowed before the first dose. For later doses, premedication could be used and infusion times could be modified depending on side effects. Monitoring Before random assignment, a history and physical examination was performed and hematologic and serum chemistry values, serum and urine samples for detecting H. capsulatum antigen levels, quantitative lysis centrifugation blood cultures, and a chest radiograph were obtained. Samples were drawn for blood cultures and serum and urine antigen testing for H. capsulatum on days 4, 7, and 14 and at weeks 4, 8, and 12 (or when a patient withdrew from the study). Samples were analyzed at the Histoplasmosis Reference Laboratory in Indianapolis, Indiana. Response Criteria Clinical and mycologic successes were the primary efficacy end points. A successful clinical response to induction therapy was defined as a maximum daily temperature lower than 37.8 C for 72 hours; no increase in severity of signs, symptoms, or laboratory abnormalities attributable to histoplasmosis; and the resolution of at least one of the signs or symptoms of histoplasmosis that qualified the patient for enrollment in the trial. A clinical success could be declared after as few as 7 days of induction therapy, at which time itraconazole therapy could be started. A successful clinical outcome after consolidation therapy was defined as resolution or reduction in clinical severity of symptoms and signs attributed to histoplasmosis compared with baseline. Survival was compared for the two treatments. Early discontinuation of induction therapy due to drug toxicity was the primary end point for safety. Secondary end points were time to defervescence; mycologic efficacy, defined as rate of blood culture conversion; change in H. capsulatum antigen levels in urine and serum at week 2; and rates of acute infusion toxicities and nephrotoxicity (increase in serum creatinine level to more than twice the baseline level). Statistical Analysis The accrual target was 75 patients. Positive baseline blood cultures were estimated at 80%. The response rate for both therapies was expected to be 70%. Outcome analysis was performed on an intention-to-treat basis. Treatment groups were compared by using the KruskalWallis test for ordered measurements (13) and the Fisher exact test for categorized measurements with corresponding exact 95% CIs (14). MantelHaenszel methods were used in a post hoc analysis to assess the impact of enrolling-site differences on clinical outcome (15). The KaplanMeier method was used in survival and defervescence analyses, and the treatment groups were compared by using the log-rank test (16). We used StatXact 4 for Windows (Cytel Software, Cambridge, Massachusetts) for efficacy comparisons that involved exact methods. We used SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina) for all other analyses. Role of the Funding Source This study was supported by a research grant from the National Institute of Allergy and Infectious Diseases (NIAID) and the National Center for Research Resources, and by Gilead Sciences, Inc. The NIAID assisted in the collection, analysis, and interpretation of the data and in the decision to submit the paper for publication. The National Center for Research Resources assisted with data collection at sites with a General Clinical Research Center. Gilead Sciences, Inc. had no direct role in the conduct of this study. Results Eighty-one patients were enrolled by 21 sites. Flow of patients through the study is shown in Figure 1. Of 55 patients randomly assigned to receive liposomal amphotericin B, 2 withdrew consent before receiving the study medication and were ineligible for the efficacy and safety analyses and 2 were excluded from the efficacy analysis because they did not have disseminated histoplasmosis. Of 26 patients randomly assigned to receive amphotericin B, 1 died and 1 withdrew consent before receiving any medication. These 2 patients were excluded from the efficacy and safety analyses. Another 2 patients did not have histoplasmosis and were excluded from the efficacy analysis. Overall, 73 patients were evaluated for efficacy and 77 patients were evaluated for safety in an intention-to-treat analysis. Figure 1. Flow of patients through the study. The two treatment groups did not differ significantly in any baseline characteristics tested, including clinical features of severe disease (Table). The median age of patients was 33 years (range, 16 to 68 years), and approximately 88% of the 73 patients were men. Fifty-two percent were African American, 32% were white, 15% were Hispanic, and 1% were Asian. Baseline blood cultures were positive in 74% of patients. Table. Characteristics of Patients with Progressive Disseminated Histoplasmosis and AIDS, according to Treatment Group The overall clinical efficacy of induction therapy differed between groups. Clinical success was achieved in 45 of 51 patients (88% [95% CI, 77% to 96%]) treated with liposomal amphotericin B compared with 14 of 22 patients in the other treatment group (64% [CI, 42% to 83%]) (P = 0.014). The difference between groups was 24 percentage points (CI, 1 to 52 percentage points). Twenty-eight of 51 patients (55% [CI, 40% to 69%]) treated with liposomal amphotericin B and 7 of 22 patients (32% [CI, 14% to 55%]) treated with amphotericin B successfully completed therapy before 14 days (difference, 23 percentage points [CI, 2 to 48 percentage points]). The median time to defervescence was 3 days for both therapies (Figure 2, top). By day 14, however, patients receiving liposomal amphotericin B were less likely to have fever than those receiving amphotericin B (13% vs. 36%; P = 0.09 [log-rank test]). Figure 2. KaplanMeier analysis. Top P Bottom P Among the 57 patients receiving itraconazole for consolidation therapy, 89% had a clinical response. Consolidation therapy was successful in 38 of 43 patients (88% [CI, 76% to 96%]) treated with liposomal amphotericin B and 13 of 14 patients (93% [CI, 66% to 99%]) treated with amphotericin B (difference, 5 percentage points [CI, 25 to 35 percentage points]) (P > 0.2). There was no significant difference in time to negative cultures (P > 0.2). After 2 weeks of therapy, 89% of all patients had negative cultures, regardless of type of treatment. Of the 54 patients with a baseline blood culture positive for H. capsulatum, 74% responded to induction therapy and received consolidation therapy. There was no statistically significant difference in negative cultures between the two groups at the end of consolidation therapy. Histoplasma capsulatum antigen clearance was also similar between the treatment groups. To control for potential investigator bias in outcome responses, data for 42 patients from eight sites were evaluated by using MantelHa

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THE APPLICATION OF RADIOISOTOPES TO THE STUDY OF CEREBRAL BLOOD FLOW, COMPARISON OF THREE METHODS.

Several new radioisotope techniques have been described as being useful for estimating cerebral flow’-’ but as yet, none of these techniques have been confirmed in the literature by investigators other than the originator of one new method. Because of the importance of cerebral flow and the relative difficulty of measuring it with nonradioisotope methods, we have thought it advisable to attempt a comparison of these relatively

The Application of Radioisotopes To the Study of Cerebral Blood Flow Using Externally Placed Detectors

in biological systems since 1927 when Blumgart and Yens used radium to measure velocity of vascular flow.1 Radioisotope techniques were extended in 1945 to the estimation of erythrocyte dilution curves by Nylin and in 1949 to the clearance of intramuscularly injected radioactivity by Kety.2. 3 Veall et al. were the first to devise quantitative flow formulas for the measurement of cardiac output by the use of a detector placed on the chest wall.4 Except for the heart and lower extremities, radioisotope methods for measuring vascular flow have not appeared until recently. The importance of cerebral flow and its relative isolation from other circulations should make