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: 10322279
• 负责人: Radha Rajasingham
• 金额: $ 66.23万
• 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/10322279
• 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

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.

抗逆转录病毒疗法（ART）被推荐给所有艾滋病毒感染者（PLWH）-无论他们的CD 4 细胞计数-提高存活率和减少传播。这种“全方位治疗”的方法使PLWH总体受益，但 也有暴露免疫重建炎症综合征（IRIS）和死亡的风险， 全球30-40%的晚期艾滋病患者（CD 4计数<200个细胞/微升）。 2017年，世界卫生组织（世卫组织）建议，艾滋病晚期患者应 筛查机会性感染（OI），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， 在撒哈拉以南非洲，这一方案没有得到一贯执行。使问题更加复杂的是，为CD 4检测提供资金 由于开始抗逆转录病毒治疗不再需要CD 4检测，因此，委员会认为， 通过CD 4检测和OI筛查和预防来识别晚期艾滋病毒感染者， 在现实中是不会发生的。因此，开始ART后的早期死亡率仍然很高。 继2017年世卫组织发布关于OI筛查和预防的初步建议后， 已经出现了几种新的用于OI的即时诊断和治疗： ● Visitect床旁CD 4检测提供CD 4计数>200或<200个细胞/微升的目视结果， 静脉血检测的敏感性为92%，特异性为89%; ●半定量CrAg侧流检测（CrAg-SQ LFA）可以检测出CrAg滴度可能有以下情况的人： 播散性感染，尽管接受了标准抗真菌治疗，仍有脑膜炎/死亡的风险; ● Fujifilm SILVAMP TB LAM是一种新的即时结核病尿液检测方法，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INH治疗9个月。 该提案的目的是提高艾滋病毒晚期患者的生存率。我们将 在24个乌干达诊所实施一项2x2析因随机分组试验，以：（目的1）确定 与标准流式细胞术CD 4检测相比，一种新型床旁CD 4检测在患有 晚期HIV疾病;以及（目标2）确定增强诊断性OI筛查的生存益处， 艾滋病毒晚期患者的预防策略。强化OI筛查和预防 策略将包括即时治疗的FujiFilm TB LAM、CrAg-SQ LFA，以及增强的结核病预防（1个月 INH +利福喷丁），并将具有高滴度的血浆CrAg+转诊至医院。存活率和继续护理 将在6个月时进行评估。最后，（目标3）我们将评估CD 4的成本和成本效益 检测策略（如目标1所述）和OI筛查和预防策略（如目标2所述）。 这项试验的结果将有可能影响国际艾滋病毒治疗指南， 艾滋病毒/艾滋病晚期患者的管理，以降低全球艾滋病毒相关死亡率。