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

抗逆转录病毒治疗(ART)被推荐给所有艾滋病毒携带者(PLWH)--无论他们的CD4 细胞计数--提高存活率，减少传播。这种“包治百病”的方法总体上使PLWH受益，但 还增加了暴露免疫重建炎症综合症(IRIS)和死亡的风险，尤其是 适用于全球30-40%的晚期艾滋病毒感染者(CD4200细胞/微克L)。 2017年，世界卫生组织(WHO)建议晚期艾滋病毒感染者 筛查机会性感染(OIS)，并给予结核病(TB)和隐球菌抗原预防 (峭壁)。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并没有得到始终如一的实施。让问题变得更加复杂的是，为CD4检测提供资金 由于抗逆转录病毒治疗的启动不再需要进行CD4检测，利益攸关方已经减少了这一比例。因此， 通过CD4检测和OI筛查识别晚期艾滋病毒患者，并经常采取预防措施 在现实中是不会发生的。因此，接受抗逆转录病毒治疗后的早期死亡率仍然很高。 在2017年世卫组织关于OI筛查和预防的初步建议发布后， 出现了几种针对OIS的新的医疗保健诊断和治疗方法： Visitect关怀点CD_4检测提供了CD_4计数200个/µL的直观结果，具有 静脉血的敏感性为92%，特异性为89%； 半定量CRAG侧向流动分析(CRAG-SQ LFA)可以检测出可能患有ROG滴度的人 尽管有标准的护理和抗真菌治疗，但仍有传播感染和脑膜炎/死亡的风险； Fujifilm SILVAMP TB LAM是一种新的医疗点TB LAM尿检方法，其敏感性为70%，特异性为91%； 异烟肼(INH)+利福喷丁治疗潜伏期肺结核1个月的疗效不逊于9个月的异烟肼。 这项提议的目的是提高晚期艾滋病毒患者的存活率。我们会 在24家乌干达诊所实施2x2析因整群随机试验，以：(目标1)确定存活率 一种新的护理点式CD4检测与标准的流式细胞术检测相比在慢性阻塞性肺疾病患者中的益处 晚期艾滋病毒疾病；以及(目标2)确定增强的诊断OI筛查和 晚期艾滋病毒感染者的预防策略。增强型OI筛查与预防 战略将包括Fujifilm TB LAM，CRAG-SQ LFA，以及加强结核病预防(1个月) 异烟肼+利福喷丁)，以及转诊高滴度血浆CRAG+到医院。生存和留住护理 将在6个月后进行评估。最后，(目标3)我们将评估CD4的成本和成本效益 检测战略(在目标1中描述)和OI筛查和预防战略(在目标2中描述)。 这项试验的结果将有可能影响国际艾滋病毒治疗指南的最佳 管理晚期艾滋病毒感染者，以便在全球范围内减少与艾滋病毒有关的死亡率。

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.