An Enhanced Package of Care to Reduce Mortality in Persons with Advanced HIV Disease

加强一揽子护理以降低晚期艾滋病毒患者的死亡率

基本信息

批准号：
10473887
负责人：
Radha Rajasingham
金额：
$ 62.64万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-23 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473887
关键词：
Africa South of the Sahara Antifungal Therapy Antigens Biological Assay Blood CD4 Lymphocyte Count Caring Cells Cessation of life Clinic Clinical Clinical Trials Cluster randomized trial Coupled Cryptococcal Meningitis Cryptococcus Data Diagnostic Disease Flow Cytometry Fluconazole Funding Guidelines HIV Health Health Personnel Hospital Costs Hospitals Infection Inflammatory International Meningitis Opportunistic Infections Performance Persons Plasma Prophylactic treatment Randomized Recommendation Retrospective cohort Risk Scotland Serum Specificity Syndrome Testing Time Tuberculosis Uganda Venous Visual World Health Organization antiretroviral therapy care seeking cost cost effectiveness cost-effectiveness evaluation diagnostic screening high risk high risk population immune reconstitution improved isoniazid lateral flow assay mortality novel point of care point-of-care diagnostics randomized trial rifapentine screening screening guidelines standard of care transmission process treatment guidelines tuberculosis treatment urinary

项目摘要

Antiretroviral therapy (ART) is recommended for all people living with HIV (PLWH) – regardless of their CD4 cell count – to improve survival and reduce transmission. This “treat-all” approach benefits PLWH overall, but also confers a risk of unmasking immune reconstitution inflammatory syndrome (IRIS) and death, particularly for the 30-40% of people who present with advanced HIV disease (CD4 count <200 cells/µL) worldwide. In 2017, the World Health Organization (WHO) recommended that persons with advanced HIV disease be screened for opportunistic infections (OIs) and given prophylaxis for tuberculosis (TB) and cryptococcal antigen (CrAg). However, because this screening and prophylaxis package has never been validated in a clinical trial, it is not consistently implemented in sub-Saharan Africa. Compounding the problem, funding for CD4 testing has been reduced by stakeholders as CD4 testing is no longer needed for ART initiation. Consequently, identification of persons with advanced HIV disease via CD4 testing and OI screening and prophylaxis often does not occur in reality. As a result, early mortality after ART initiation remains high. Subsequent to the release of the initial 2017 WHO recommendations for OI screening and prophylaxis, several novel point-of-care diagnostics and treatments for OIs have emerged: ● Visitect point-of-care CD4 assay provides a visual result of CD4 count >200 of <200 cells/µL, with a sensitivity of 92% and specificity of 89% in venous blood; ● Semi-quantitative CrAg lateral flow assay (CrAg-SQ LFA) can detect persons with CrAg titers who likely have disseminated infection and are at risk of meningitis/death despite standard of care antifungal therapy; ● Fujifilm SILVAMP TB LAM, a new point-of-care TB urinary test, has 70% sensitivity and 91% specificity; ● Isoniazid (INH) + Rifapentine given for one month for latent TB treatment is non-inferior to 9 months of INH. The objective of this proposal is to improve survival in persons with advanced HIV disease. We will implement a 2x2 factorial, cluster-randomized trial in 24 Ugandan clinics to: (Aim 1) determine the survival benefit of a novel point-of-care CD4 test compared with standard flow cytometry CD4 testing in persons with advanced HIV disease; and (Aim 2) determine the survival benefit of an enhanced diagnostic OI screening and prophylaxis strategy in persons with advanced HIV disease. The enhanced OI screening and prophylaxis strategy will include point-of-care FujiFilm TB LAM, CrAg-SQ LFA, with enhanced prophylaxis for TB (1 month of INH + rifapentine), and referral of plasma CrAg+ with high titers to hospital. Survival and retention-in-care will be assessed at 6 months. Lastly, (Aim 3) we will evaluate the cost and cost-effectiveness of the CD4 testing strategies (described in Aim 1) and OI screening and prophylaxis strategies (described in Aim 2). Findings from this trial will have the potential to impact international HIV treatment guidelines on optimal management of persons with advanced HIV disease in order to reduce HIV-related mortality globally.

建议所有 HIV 感染者 (PLWH) 接受抗逆转录病毒治疗 (ART)——无论其 CD4 水平如何细胞计数——提高存活率并减少传播。这种“治疗所有”的方法总体上有利于感染者。还带来暴露免疫重建炎症综合征 (IRIS) 和死亡的风险，特别是全球 30-40% 的晚期 HIV 患者（CD4 计数 <200 个细胞/μL）。 2017年，世界卫生组织（WHO）建议晚期艾滋病毒患者筛查机会性感染 (OIs) 并预防结核病 (TB) 和隐球菌抗原（CrAg）。然而，由于这种筛查和预防方案从未在临床试验中得到验证，撒哈拉以南非洲地区并没有得到一致实施，CD4 测试的资金也使问题变得更加复杂。由于 ART 启动审查不再需要 CD4 测试，因此已被利益相关者减少。经常通过 CD4 检测和 OI 筛查和预防来识别患有晚期 HIV 疾病的人现实中并没有发生，因此，开始 ART 后的早期死亡率仍然很高。继 2017 年世卫组织首次发布成骨不全筛查和预防建议后，一些针对成骨不全症的新型护理点诊断和治疗方法已经出现： ● Visitect 护理点 CD4 检测可提供 CD4 计数 >200 或 <200 个细胞/μL 的直观结果，静脉血的敏感性为 92%，特异性为 89%； ● 半定量 CrAg 侧向层析检测 (CrAg-SQ LFA) 可以检测出具有 CrAg 滴度的人，这些人可能患有以下疾病：尽管进行了标准护理抗真菌治疗，但仍存在播散性感染，并且有脑膜炎/死亡的风险； ● Fujifilm SILVAMP TB LAM 是一种新型床旁结核尿检测，灵敏度为 70%，特异性为 91%； ● 异烟肼(INH) + 利福喷丁治疗潜伏性结核病1个月不劣于9个月的INH。该提案的目的是提高晚期艾滋病毒患者的生存率。在 24 家乌干达诊所实施 2x2 析因、整群随机试验，以：（目标 1）确定生存率与标准流式细胞术 CD4 检测相比，新型护理点 CD4 检测对患有以下疾病的患者的益处晚期 HIV 疾病；以及（目标 2）确定强化诊断性 OI 筛查的生存益处；晚期艾滋病毒患者的预防策略加强 OI 筛查和预防。该策略将包括床旁 FujiFilm TB LAM、CrAg-SQ LFA，并加强结核病预防（1 个月 INH + 利福喷汀），以及转诊高滴度血浆 CrAg+ 至医院的生存和留院治疗。最后，（目标 3）我们将评估 CD4 的成本和成本效益。检测策略（目标 1 中描述）以及成骨不全筛查和预防策略（目标 2 中描述）。该试验的结果将有可能影响国际艾滋病毒最佳治疗指南对晚期艾滋病毒患者进行管理，以降低全球艾滋病毒相关死亡率。