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

• 批准号: 10673693
• 负责人: Radha Rajasingham
• 金额: $ 63.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/10673693
• 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; Cost Analysis; 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

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“包治百病”的方法总体上有利于 PLWH，但是 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 （岩）。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， 它在撒哈拉以南非洲地区并没有得到一致实施。 CD4 测试的资金使问题变得更加复杂 由于 ART 启动不再需要 CD4 测试，利益相关者已减少了这一数量。最后， 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 现实中不会发生。因此，开始 ART 后的早期死亡率仍然很高。 继 2017 年世界卫生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 侧流检测 (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。我们将 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 晚期艾滋病毒疾病； （目标 2）确定增强的 OI 诊断筛查对生存的益处， 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 + 利福喷丁），并将血浆 CrAg+ 转诊至医院。生存和保留护理 将在6个月时进行评估。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。