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

项目总结 霍奇金淋巴瘤(HL)在南非PLWH的转归比HIV(-)患者的要差， 尽管在临床试验中结果是有利的。晚期疾病和一致的EBV相关性 在PLWH中得到了很好的认可。在S.A.，在诊断时，一些PLWH的临床情况很差 他们没有得到治疗。诊断延迟会导致报告延迟，因为HL的诊断需要手术 活组织检查以进行明确的病理评估。在这方面，S.A.的资源和基础设施是有限的。 为了更好地理解PLWH在标准护理环境下的不同结果，我们提出了一项前瞻性研究 S.A.中HIV(+)和HIV(-)HL的观察研究(目标1)。运动状态(PS)、器官功能、临床 将对分期、肿瘤组织亚型、EBV相关性和突变情况进行评估 化疗方案，治疗反应，死亡原因，由微创确定 对同意的参与者进行尸检。由于结核病是南卡罗来纳州PLWH的主要死亡原因， 其症状类似于HL，HL患者以前经常接受经验性治疗并反复进行结核病检测 进行切除活组织检查。高感染率再加上免疫抑制化疗可能会 在治疗期间导致PLWH中的结核病进展，并可能导致最终死亡。因此，目标1将 也主要关注结核病的贡献。这项研究的结果将有助于更好地理解 PS、器官功能和TB在PLWH患者HL预后中的作用以及EBV的各个方面 关联性和突变特征。 EB病毒在HIV(+)HL中的近乎均匀的相关性可能有助于通过非侵入性的 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 建议开发一种诊断算法(AIM 2A)，用于发现有HL和无HL的PLWH队列 恶毒。EBV DNA将与其他血浆标志物一起进行评估，以提高特异性。最优的 将使用标记的组合来开发一种算法，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。在那些被诊断为HL或其他淋巴瘤的人中，PS 器官功能将被重新评估。经历这些指标明显下降的参与者，到 如果他们没有接受标准的化疗，将被认为是潜在的“拯救生命”的诊断 该算法可应用于临床。我们注意到，实施分子技术所需的大部分基础设施 技术在S.A.可用，我们的南非合作者在引入 向全国推广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