Hodgkin Lymphoma in PLWH in South Africa: TB, EBV, and Tumor Molecular Markers

项目摘要 南非PLWH患者的霍奇金淋巴瘤（HL）结局（S.A.）比HIV（-）患者差， 尽管在临床试验中结果比较有利。晚期疾病与一致的EB病毒相关性 在PLWH中得到了很好的认可。在SA，在诊断时，一些艾滋病毒携带者的临床状况很差， 他们没有得到治疗。诊断延迟导致晚期表现，因为HL诊断需要手术 活检以进行明确的病理学评估。资源和基础设施在S.A.在这方面是有限的。 为了更好地了解标准治疗环境中PLWH的不同结果，我们提出了一个前瞻性的 S.A.中HIV（+）和HIV（-）HL的观察性研究(Aim 1）。体力状态（PS）、器官功能、临床 分期、肿瘤组织学亚型、EBV相关性和突变景观都将被评估， 化疗方案，对治疗的反应和死亡原因，由微创 在知情同意的参与者中进行尸检。由于结核病是南非艾滋病毒携带者死亡的主要原因，的 症状类似HL，HL患者通常根据经验进行治疗，并在治疗前反复进行TB检测。 进行切除活检。高合并感染率加上免疫抑制化疗可能 导致PLWH在治疗期间结核病进展，并可能导致最终死亡率。目标1将 也主要关注结核病的贡献。这项研究的结果将导致更好地了解 PS、器官功能和TB在PLWH的HL预后中的作用，以及EBV 关联和突变特征。 HIV（+）HL中EBV的几乎一致的相关性可能有助于通过非侵入性方法识别PLWH中的HL。 血浆EBV检测可以识别需要紧急切除活检的患者。为了探索这种可能性，我们 建议在PLWH伴HL和不伴HL的发现队列中开发诊断算法（Aim 2A） 恶性肿瘤将沿着其他血浆标志物评估EBV DNA，以增加特异性。最优 标记物的组合将用于开发一种算法，该算法将在高风险的验证队列中进行测试。 PLWH（目标2B）。将获得基线PS和器官功能，并进行为期一年的严格随访，以确保 淋巴瘤患者的准确分类。在被诊断为HL或其他淋巴瘤的患者中，PS 器官功能将被重新评估这些指标明显下降的参与者， 点，他们没有接受标准化疗，将被认为是潜在的“挽救生命”，如果诊断 该算法可以应用于临床。我们注意到实施分子所需的大部分基础设施 技术可在S.A.获得，我们的南非合作者有着引入 先进的结核病分子诊断技术。 1

PROJECT SUMMARY Hodgkin lymphoma (HL) outcomes in PLWH in South Africa (S.A.) are inferior to those in HIV(-) patients, although outcomes compare favorably in clinical trials. Advanced stage disease and consistent EBV-association are well recognized in PLWH. In S.A., at the time of diagnosis, some PLWH are in such poor clinical condition that they are not treated. Diagnostic delays contribute to late presentations, as HL diagnoses require surgical biopsies for a definitive pathologic evaluation. Resources and infrastructure in S.A. are limited in this regard. To better understand disparate outcomes in PLWH in standard-of-care settings, we propose a prospective observational study of HIV(+) and HIV(-) HL in S.A. (Aim 1). Performance status (PS), organ function, clinical stage, tumor histological subtype, EBV association, and mutational landscape will all be assessed, as will chemotherapy regimen, response to treatment, and cause of death, as determined by a minimally invasive autopsy in consenting participants. Since tuberculosis (TB) is the leading cause of death in PLWH in S.A., the symptoms of which mimic HL, HL patients are often empirically treated and repeatedly tested for TB before excisional biopsies are pursued. A high co-infection rate coupled with immunosuppressive chemotherapy may lead to TB progression in PLWH during therapy, and may contribute to ultimate mortality. Therefore, Aim 1 will also have a major focus on the contributions of TB. The results of this study will lead to a better understanding of the roles that PS, organ function and TB have in HL prognosis in PLWH, as well as aspects of the EBV association and the mutational features. The near uniform association of EBV in HIV(+) HL may aid in the recognition of HL in PLWH via a non-invasive plasma EBV test that can identify patients needing urgent excisional biopsy. To explore this possibility, we propose to develop a diagnostic algorithm (Aim 2A) in a discovery cohort of PLWH with HL and without malignancy. EBV DNA will be assessed along with additional plasma markers to increase specificity. The optimal combination of markers will be used to develop an algorithm that will be tested in a validation cohort of high risk PLWH (Aim 2B). Baseline PS and organ function will be obtained, and a rigorous yearlong follow-up will ensure accurate classification of persons with lymphoma. In those who are diagnosed with HL or other lymphoma, PS and organ function will be re-assessed. Participants who experience a marked decline in these measures, to the point that they do not receive standard chemotherapy, will be considered potential “lives saved” if the diagnostic algorithm could be applied clinically. We note that much of the infrastructure needed to implement the molecular techniques is available in S.A., and that our South African collaborators have a track record of introducing sophisticated molecular diagnostics for TB to the entire country. 1