Evaluation of CRAG screening with enhanced antifungal therapy for asymptomatic CRAG-positive persons

对无症状 CRAG 阳性者进行强化抗真菌治疗的 CRAG 筛查评估

• 批准号: 10341089
• 负责人: Radha Rajasingham
• 金额: $ 16.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341089
• 关键词: AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Adherence; Adult; Africa South of the Sahara; Amphotericin; Amphotericin B; Antifungal Agents; Antifungal Therapy; Antigens; Biometry; Blood; CD4 Lymphocyte Count; Caring; Cause of Death; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Cost Effectiveness Analysis; Counseling; Country; Cryptococcal Meningitis; Cryptococcus; Custom; Data; Decision Analysis; Diagnostic; Disease; Dose; Evaluation; Expert Opinion; Failure; Fluconazole; Future; Goals; Guidelines; HIV; HIV therapy; Infection; Inferior; International; K-Series Research Career Programs; Liposomes; Medicine; Meningitis; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Minnesota; Morbidity - disease rate; Patients; Persons; Plasma; Policies; Prevention; Public Health; Recommendation; Research; Research Methodology; Research Personnel; Resource Allocation; Resources; South Africa; Symptoms; Testing; Therapeutic; Time; Training; Translating; Uganda; Universities; Validation; advanced disease; aggressive therapy; antiretroviral therapy; base; career; clinical care; cost effective; cost effective intervention; cost effectiveness; cost-effectiveness evaluation; cost-effectiveness ratio; effective intervention; effective therapy; effectiveness evaluation; experience; improved; improved outcome; incremental cost-effectiveness; individualized medicine; innovation; interest; lateral flow assay; models and simulation; mortality; multidisciplinary; novel; point of care; prevent; professor; randomized trial; screening; screening guidelines; skills; standard of care; therapy outcome; treatment guidelines; treatment strategy

Dr. Rajasingham is an Assistant Professor in the Division of Infectious Diseases & International Medicine at the University of Minnesota. Her long-term goal is to become an independent investigator with expertise in evaluating the effectiveness and cost-effectiveness of innovative diagnostics and therapeutics related to the prevention and management of AIDS-related opportunistic infections. She is particularly interested in using cost-effectiveness analysis alongside clinical trials, in order to translate effective interventions into policy. Training: This K23 award will provide the mentored clinical research experience and didactic training in decision analysis and simulation modeling necessary to establish her independent research career. With the mentorship of an interdisciplinary team with expertise in decision analysis, biostatistics, and HIV international clinical trials, she will: 1) acquire advanced training in decision analysis and simulation modeling, 2) acquire expertise in HIV international clinical research methodology, and 3) develop multidisciplinary collaborative and networking skills. Research: Cryptococcus is a leading cause of AIDS-related morbidity and mortality worldwide. Cryptococcal antigen (CRAG) can be detected in the blood weeks to months prior to the onset of meningitis and is an independent predictor of mortality. A public health strategy to reduce mortality is to screen for CRAG in the plasma of people entering HIV care with a CD4 count <100 cells/mcL. Those who are asymptomatic CRAG+ can be treated preemptively with fluconazole antifungal therapy to prevent meningitis or death while receiving HIV therapy. Despite the survival benefit associated with this WHO-recommended CRAG screening and treatment strategy, ~30% of asymptomatic CRAG+ persons die despite standard of care treatment with fluconazole. Those with high CRAG titers (>1:160) are 3 times more likely to die than are those with low CRAG titers (<1:80) in blood. I hypothesize that customized antifungal therapy based on CRAG titers will improve survival, whereby patients with high titers (>1:160) require more aggressive antifungal therapy. The overall objective of this proposal is to identify a more clinically effective yet economically feasible treatment strategy for asymptomatic CRAG+ persons. The aims of this proposal are to: 1) determine if enhanced antifungal therapy improves 6-month survival for asymptomatic persons with high CRAG titers; 2) determine the cost-effectiveness of enhanced antifungal therapy for HIV-infected CRAG+ persons, stratified by CRAG titer; and 3) validate a novel semi-quantitative CRAG lateral flow assay to rapidly detect high CRAG titers (>1:160). The proposed study seeks to improve the international standard of clinical care for HIV-infected persons with advanced disease, and to generate evidence that will inform international HIV care guidelines. The findings and the training in decision analysis that Dr. Rajasingham will obtain will inform future proposals to evaluate cost-effective strategies to reduce AIDS-related deaths across sub-Saharan Africa.

Rajasingham 博士是传染病与国际医学部的助理教授 明尼苏达大学。她的长期目标是成为一名具有专业知识的独立调查员 评估与以下疾病相关的创新诊断和治疗方法的有效性和成本效益 预防和管理与艾滋病相关的机会性感染。她特别感兴趣的是使用 成本效益分析和临床试验，以便将有效的干预措施转化为政策。 培训：该 K23 奖项将提供指导性临床研究经验和教学培训 决策分析和模拟建模对于建立她的独立研究生涯至关重要。随着 拥有决策分析、生物统计学和艾滋病毒国际专业知识的跨学科团队的指导 临床试验期间，她将：1) 获得决策分析和模拟建模方面的高级培训，2) 获得 HIV国际临床研究方法方面的专业知识，以及3）发展多学科协作和 网络技能。 研究：隐球菌是全世界艾滋病相关发病率和死亡率的主要原因。 脑膜炎发病前数周至数月可在血液中检测到隐球菌抗原 (CRAG) 是死亡率的独立预测因子。降低死亡率的公共卫生策略是筛查 CRAG 进入 HIV 护理人员血浆中 CD4 计数 <100 个细胞/mcL。无症状者 CRAG+ 可以先用氟康唑抗真菌疗法进行治疗，以预防脑膜炎或死亡 接受艾滋病毒治疗。尽管 WHO 推荐的 CRAG 筛查具有生存获益 和治疗策略，尽管接受标准护理治疗，仍有约 30% 的无症状 CRAG+ 患者死亡 氟康唑。 CRAG 滴度高 (>1:160) 的人死亡的可能性是 CRAG 滴度低的人的 3 倍 血液中的滴度（<1:80）。我假设基于 CRAG 滴度的定制抗真菌治疗将会改善 生存率，高滴度 (>1:160) 的患者需要更积极的抗真菌治疗。 该提案的总体目标是确定一种临床上更有效且经济上可行的方法 无症状 CRAG+ 患者的治疗策略。该提案的目的是： 1) 确定是否 加强抗真菌治疗可提高 CRAG 滴度高的无症状患者的 6 个月生存率； 2） 确定 HIV 感染 CRAG+ 人群强化抗真菌治疗的成本效益，按以下因素分层 CRAG滴度； 3) 验证一种新型半定量 CRAG 侧流测定法，以快速检测高 CRAG 滴度（>1:160）。拟议的研究旨在提高艾滋病毒感染者临床护理的国际标准 患有晚期疾病的人，并产生可为国际艾滋病毒护理指南提供信息的证据。 Rajasingham 博士将获得的调查结果和决策分析培训将为未来的提案提供信息 评估减少撒哈拉以南非洲地区与艾滋病相关死亡的成本效益策略。

项目成果

Cryptococcosis in pregnancy and the postpartum period: Case series and systematic review with recommendations for management.

妊娠期和产后期的隐球菌病：病例系列和系统评价以及管理建议。

• DOI: 10.1093/mmy/myz084
• 发表时间: 2020
• 期刊: Medical mycology
• 影响因子: 2.9
• 作者: Pastick,KatelynA;Nalintya,Elizabeth;Tugume,Lillian;Ssebambulidde,Kenneth;Stephens,Nicole;Evans,EmilyE;Ndyetukira,JaneFrances;Nuwagira,Edwin;Skipper,Caleb;Muzoora,Conrad;Meya,DavidB;Rhein,Joshua;Boulware,DavidR;Rajasingham,R
• 通讯作者: Rajasingham,R

Sterile Cerebrospinal Fluid Culture at Cryptococcal Meningitis Diagnosis Is Associated with High Mortality.

• DOI: 10.3390/jof9010046
• 发表时间: 2022-12-28
• 期刊: Journal of fungi (Basel, Switzerland)

Effect of Coronavirus Disease 2019 Lockdowns on Identification of Advanced Human Immunodeficiency Virus Disease in Outpatient Clinics in Uganda.

2019 年冠状病毒病封锁对乌干达门诊晚期人类免疫缺陷病毒病鉴定的影响。

• DOI: 10.1093/cid/ciad087
• 发表时间: 2023
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Nalintya,Elizabeth;Sekar,Preethiya;Kavuma,Paul;Kigozi,Joanita;Ssuna,Martin;Kirumira,Paul;Naluyima,Rose;Namuli,Teopista;Musa,FredTurya;Skipper,CalebP;Hullsiek,KathyHuppler;Ellis,Jayne;Boulware,DavidR;Meya,DavidB;Rajasingham
• 通讯作者: Rajasingham

An updated systematic review of HIV-associated cryptococcal meningitis treatment strategies.

HIV 相关隐球菌性脑膜炎治疗策略的最新系统评价。

• DOI: 10.1111/hiv.13412
• 发表时间: 2023
• 期刊: HIV medicine
• 影响因子: 3
• 作者: Shapiro,AdrienneE;Tenforde,MarkW;Chiller,TomM;Ford,Nathan;Rajasingham,Radha
• 通讯作者: Rajasingham,Radha

Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19.

• DOI: 10.1093/ofid/ofaa500
• 发表时间: 2020-11
• 期刊: Open forum infectious diseases
• 影响因子: 4.2
• 作者: Lofgren SM;Nicol MR;Bangdiwala AS;Pastick KA;Okafor EC;Skipper CP;Pullen MF;Engen NW;Abassi M;Williams DA;Nascene AA;Axelrod ML;Lother SA;MacKenzie LJ;Drobot G;Marten N;Cheng MP;Zarychanski R;Schwartz IS;Silverman M;Chagla Z;Kelly LE;McDonald EG;Lee TC;Hullsiek KH;Boulware DR;Rajasingham R
• 通讯作者: Rajasingham R