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Enhanced Antifungal Therapy to Improve Survival in Early Disseminated Cryptococcal Infection

加强抗真菌治疗可提高早期播散性隐球菌感染的生存率

基本信息

批准号：
10621009
负责人：
Radha Rajasingham
金额：
$ 67.69万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-21 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621009
关键词：
Acquired Immunodeficiency Syndrome Adult Africa Africa South of the Sahara Amphotericin Amphotericin B Antifungal Agents Antifungal Therapy Antigens Blood CD4 Lymphocyte Count Cause of Death Cells Central Nervous System Infections Cessation of life Clinical Trials Cost Analysis Country Cryptococcal Meningitis Cryptococcosis Cryptococcus Data Data Reporting Development Disease Dose Enrollment Excess Mortality Fluconazole Flucytosine Guidelines HIV HIV therapy Hospital Costs Incidence Income Infection International Liposomes Meningitis Neurocognitive Neurologic Neurological outcome Outcome Participant Performance Persons Phase Plasma Prevention Prospective, cohort study Public Health Randomized Recommendation Regimen Testing Uganda Work World Health Organization antiretroviral therapy brain parenchyma comparative effectiveness trial cost cost effective cost effective intervention cost-effectiveness evaluation disability effective therapy efficacy evaluation efficacy testing high risk improved mortality phase III trial prevent randomized trial randomized, clinical trials recruit safety and feasibility screening standard of care survival outcome treatment guidelines

项目摘要

Abstract Cryptococcal meningitis is the most common adult neuroinfection in sub-Saharan Africa and causes ~15% of AIDS-related mortality globally. In the weeks prior to onset of meningitis, cryptococcal antigen (CrAg) is detectable in the blood, and is a predictor of meningitis and death. CrAg screening in plasma is an effective public health strategy to identify persons with CD4<200 cells/mcL at high risk of meningitis and death. In a randomized trial of 2000 persons with HIV, CrAg screening and preemptive fluconazole treatment yielded a 28% survival benefit over standard-of-care. As a result, the World Health Organization and U.S. guidelines recommend CrAg screening. Yet despite the survival benefit seen with CrAg screening and preemptive therapy, 25% of initially asymptomatic CrAg+ persons treated with fluconazole still die, even with HIV therapy. From 4 prospective cohort studies of CrAg+ persons in Africa, we have determined that as plasma CrAg titer increases, mortality increases, despite fluconazole therapy. Among asymptomatic CrAg+ persons, disseminated cryptococcosis is the most commonly identified cause of death. We posit that subclinical disseminated early neuroinfection in the brain parenchyma accompanies high CrAg titers, and fluconazole is inadequate therapy. More effective treatment is critically needed to reduce mortality in CrAg+ persons. For symptomatic cryptococcal meningitis, amphotericin B is the most effective antifungal; fluconazole alone is inadequate. Recent randomized trial data reported single dose of liposomal amphotericin (AmBisome) 10 mg /kg with flucytosine (5FC) and fluconazole is as effective and less toxic than the traditional 7-day amphotericin + 5FC for meningitis. We hypothesize that AmBisome (10mg/kg x1), when combined with fluconazole, will be more effective than fluconazole monotherapy for asymptomatic CrAg+ persons. We have enrolled 244 CrAg+ persons in the initial phase II of a phase II/III randomized trial to demonstrate safety and feasibility of this enhanced regimen in Uganda, and now we seek to complete the phase III trial in order to test efficacy. The objective of this application is to assess the efficacy of AmBisome plus fluconazole to prevent cryptococcal meningitis and death. We will complete a randomized clinical trial of 600 CrAg+ persons (i.e. 356 more participants) to determine if preemptive therapy with AmBisome (10mg/kg x1) plus fluconazole for CrAg+ persons will improve cryptococcal meningitis-free 6-month survival compared with the current standard of fluconazole monotherapy (Aim 1). In Aim 2, we will determine if neurocognitive outcomes in CrAg+ persons preemptively treated with AmBisome with fluconazole are superior to outcomes with fluconazole monotherapy. Finally, in Aim 3 we will evaluate the cost and cost-effectiveness of AmBisome with fluconazole preemptive treatment in CrAg+ persons. Findings from this trial will impact U.S. and international HIV guidelines on the optimal prevention of cryptococcal meningitis, in order to reduce mortality in persons living with HIV.

摘要