HPV16 E6 Antibody Detection as an Early Marker of Oropharyngeal Cancer Among Men Living with HIV

项目摘要/摘要 艾滋病毒携带者(PLWH)由于有效的治疗而延长了预期寿命。这导致了一种 非艾滋病定义癌症(NADCs)，特别是由人类乳头瘤病毒(HPV)引起的癌症发病率增加。 在美国普通人群中，与HPV相关的恶性肿瘤增长最快的是HPV引起的口咽癌 (HPV-OPC)，一种在过去几十年中发病率增加了200%以上的头颈部疾病1，2 PLWH患HPV-OPC的可能性是普通人群的1.5到4倍。3他们也更有可能 患HPV-OPC的年龄较小(51岁对60岁)，癌症预后较差。5与宫颈癌不同， 高效筛查的引入显著降低了子宫颈癌的发病率和死亡率 对于癌症，目前还没有早期检测HPV-OPC的方法。早期发现的一个主要障碍是无法 鉴于OPC的癌前病变尚未确定，确定HPV-OPC风险最高的PLWH。 最近，HPV16E6抗体阳性已被确定为一个有希望的早期生物标志物。我们之前的工作 研究小组发现，HPV16E6抗体存在于高达90%的HPV-OPC患者中，并且出现时间超过10年 7-9此外，我们已经证明HPV16E6抗体对HPV-OPC10具有高度特异性，并且 与HPV.11引起的其他5种癌症没有很强的相关性，这项研究的目的是评估 HPV16E6标记用于识别PLWH亚群中患HPV-OPC风险最高的人群以及 而宫颈癌筛查将是最有效的。为了实现这一目标，我们将进行一项关于 HPV16E6抗体标记物。这项研究将重点关注40岁以上的艾滋病毒携带者，因为大约85%的HPV-OPC病例 发生在中年男性，艾滋病毒感染额外增加了高达4倍的风险。使用田纳西中心 艾滋病研究(TN-CFAR)生物库，来自40岁以上艾滋病毒携带者(N=3,261)的血液样本将被储存 检测HPV16 E6抗体。所有HPV16 E6血清阳性和HPV16 E6血清阴性的子集(1：2比例)将 受邀参加一年一次(共4次)的头颈癌综合筛查检查 范德比尔特·英格拉姆癌症中心(VICC)头颈外科医生。癌症筛查访问将包括：目视检查 扁桃体的口腔和触诊，超声成像，喉镜检查，详细的问卷调查和生物显微镜检查 收集。E6血清阳性男子与E6血清阴性男子将在以下方面进行比较：a)HPV-OPC升高的标志物 风险和b)HPV-OPC的发展。具体目标是：(1)估计人群中HPV16 E6抗体的流行率 40岁以上男性HIV感染者；(2)确定HPV16E6血清阳性与HPV-OPC标志物的关系 风险；(3)估计发生以下疾病的风险：a)HPV-OPC和/或HPV-OPC的癌前标志物；b)HPV16 E6感染的HPV-OPC 血清状态。我们假设携带HPV16E6抗体的男性更有可能存在已知的风险因素 与HPV-OPC的发展相关[性行为，持续的口腔HPV感染]，并将更有可能 发生HPV-OPC的男性要比无HPV16E6抗体的男性多。新冠肺炎大流行阻止了这一领域的招募 因此，本补编旨在克服这些障碍，使研究能够按计划进行。

Project Summary/Abstract People living with HIV (PLWH) have an increased life expectancy due to effective therapies. This has resulted in an increased incidence of non-AIDS defining cancers (NADCs), in particular, cancers caused by human papillomavirus (HPV). The most rapidly increasing HPV-related malignancy in the general US population is HPV-driven oropharyngeal cancer (HPV-OPC), a type of head and neck that has increased in incidence by more than 200% over the past few decades.1, 2 PLWH are 1.5 to 4 times more likely to develop HPV-OPC than the general population.3 They are also more likely to develop HPV-OPC at younger ages (51 versus 60)4 and have a less favorable cancer prognoses.5 Unlike cervical cancer, where the introduction of highly effective screening has significantly reduced the incidence and mortality of cervical cancer, there are no methods for early detection of HPV-OPC. A major barrier for early detection has been the inability to identify PLWH at highest risk for HPV-OPC given that a precancerous precursor lesion for OPC has yet to be identified. Recently, HPV16 E6 antibody positivity has been identified as a promising early biomarker. Previous work from our group showed that HPV16 E6 antibodies are present in up to 90% of HPV-OPC patients6 and appear more than 10 years prior to diagnosis.7-9 Additionally, we have shown that HPV16 E6 antibodies are highly specific for HPV-OPC10 and are not strongly associated with the 5 other cancers caused by HPV.11 The objective of this study is to evaluate the ability of the HPV16 E6 marker to identify a sub-population of PLWH at highest risk for developing HPV-OPC and for which head and neck cancer screening would be most effective. To accomplish this, we will conduct a natural history study of the HPV16 E6 antibody marker. This study will focus on men aged 40+ living with HIV given that ~85% of HPV-OPC cases occur in middle aged men and HIV infection additionally elevates risk by up to 4-fold. Using the Tennessee Center for AIDS Research (TN-CFAR) Biorepository, banked blood samples from men aged 40+ living with HIV (N=3,261) will be tested for HPV16 E6 antibodies. All HPV16 E6 seropositives and a subset of HPV16 E6 seronegatives (1:2 ratio) will be invited to participate in yearly (4 total) comprehensive head and neck cancer screening exams performed by a Vanderbilt Ingram Cancer Center (VICC) head and neck surgeon. Cancer screening visits will include: visual inspection of the mouth and palpation of tonsils, ultrasound imaging, laryngoscope exam, a detailed questionnaire and biospecimen collection. E6 seropositive men will be compared to E6 seronegative men in terms of: a) markers of elevated HPV-OPC risk and b) development of HPV-OPC. The specific aims are: (1) Estimate the prevalence of HPV16 E6 antibodies among men aged 40+ living with HIV; (2) Determine the association between HPV16 E6 seropositivity and markers of HPV-OPC risk; (3) Estimate the risk of developing: a) precancerous markers of HPV-OPC and/or; b) HPV-OPC by HPV16 E6 serostatus. We hypothesize that men with HPV16 E6 antibodies will be more likely to have known risk factors associated with HPV-OPC development [sexual behavior, persistent oral HPV infection] and will be more likely to develop HPV-OPC than men without HPV16 E6 antibodies. The COVID-19 pandemic has prevented recruitment into this study; thus, this supplement is aimed at overcoming these barriers to allow the study to proceed as planned.