γ-Herpesvirus Load as Surrogate Marker of Early Death in HIV-1 Lymphoma Patients Submitted to High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) is a feasible procedure for human immunodeficiency virus-1 (HIV-1) lymphoma patients, whose underlying disease and intrinsic HIV-1- and ASCT-associated immunodeficiency might increase the risk for γ-herpesvirus load persistence and/or reactivation. We evaluated this hypothesis by investigating the levels of Epstein-Barr virus (EBV)- and Kaposi sarcoma-associated herpesvirus (KSHV)-DNA levels in the peripheral blood of 22 HIV-1-associated lymphoma patients during ASCT, highlighting their relationship with γ-herpesvirus lymphoma status, immunological parameters, and clinical events. EBV-DNA was detected in the pre-treatment plasma and peripheral blood mononuclear cells (PBMCs) of 12 (median 12135 copies/mL) and 18 patients (median 417 copies/106 PBMCs), respectively; the values in the two compartments were correlated (r = 0.77, p = 0.0001). Only EBV-positive lymphomas showed detectable levels of plasma EBV-DNA. After debulking chemotherapy, plasma EBV-DNA was associated with lymphoma chemosensitivity (p = 0.03) and a significant higher mortality risk by multivariate Cox analysis adjusted for EBV-lymphoma status (HR, 10.46, 95% CI, 1.11–98.32, p = 0.04). After infusion, EBV-DNA was detectable in five EBV-positive lymphoma patients who died within six months. KSHV-DNA load was positive in only one patient, who died from primary effusion lymphoma. Fluctuations in levels of KSHV-DNA reflected the patient’s therapy and evolution of his underlying lymphoma. Other γ-herpesvirus-associated malignancies, such as multicentric Castleman disease and Kaposi sarcoma, or end-organ complications after salvage treatment were not found. Overall, these findings suggest a prognostic and predictive value of EBV-DNA and KSHV-DNA, the monitoring of which could be a simple, complementary tool for the management of γ-herpesvirus-positive lymphomas in HIV-1 patients submitted to ASCT.自体造血干细胞移植（Autologous stem cell transplantation, ASCT）是人类免疫缺陷病毒1型（Human Immunodeficiency Virus-1, HIV-1）淋巴瘤患者的可行治疗方案，此类患者的基础疾病、自身HIV-1相关及ASCT相关免疫功能低下，可能会增加γ疱疹病毒（γ-herpesvirus）载量持续存在或再激活的风险。本研究针对该假说展开验证：通过检测22例HIV-1相关淋巴瘤患者在ASCT期间的外周血样本中EB病毒（Epstein-Barr virus, EBV）与卡波西肉瘤相关疱疹病毒（Kaposi sarcoma-associated herpesvirus, KSHV）的DNA载量，阐明其与γ疱疹病毒相关性淋巴瘤状态、免疫学参数及临床事件的关联。 预处理阶段，12例患者的血浆中可检测到EBV-DNA（中位载量12135拷贝/mL），18例患者的外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）中可检测到EBV-DNA（中位载量417拷贝/10⁶ PBMCs）；两个样本中的EBV-DNA水平呈显著正相关（r=0.77，p=0.0001）。仅EBV阳性淋巴瘤患者的血浆中可检测到EBV-DNA。 经减瘤化疗后，校正EBV淋巴瘤状态的多因素Cox分析（multivariate Cox analysis）结果显示，血浆EBV-DNA水平与淋巴瘤化疗敏感性显著相关（p=0.03），且与更高的死亡风险独立相关（风险比HR=10.46，95%置信区间CI：1.11~98.32，p=0.04）。 输注造血干细胞后，5例EBV阳性淋巴瘤患者的外周血中可检测到EBV-DNA，且均在6个月内死亡。仅1例患者的KSHV-DNA载量呈阳性，该患者最终死于原发性渗出性淋巴瘤（primary effusion lymphoma），其KSHV-DNA载量波动与治疗方案及基础淋巴瘤的病情演变高度吻合。 本研究未发现其他γ疱疹病毒相关恶性肿瘤（如多中心Castleman病（multicentric Castleman disease）、卡波西肉瘤），也未观察到挽救治疗后的终末器官并发症。 综上，本研究结果提示EBV-DNA与KSHV-DNA具有预后及预测价值，对二者进行监测可作为接受ASCT的HIV-1患者中γ疱疹病毒阳性淋巴瘤管理的简便、有效补充手段。