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

项目概要/摘要 艾滋病毒感染者（PLWH）由于有效的治疗而延长了预期寿命。这导致 非艾滋病定义的癌症（NADC）的发病率增加，特别是由人乳头瘤病毒（HPV）引起的癌症。 在美国普通人群中，HPV相关恶性肿瘤增长最快的是HPV驱动的口咽癌 （HPV-OPC），这是一种头颈部疾病，在过去几十年中发病率增加了200%以上。 PLWH发生HPV-OPC的可能性是普通人群的1.5至4倍。 在较年轻的年龄（51岁对60岁）4发展HPV-OPC，并且具有较不利的癌症预后。5与宫颈癌不同， 采用高效筛查显著降低了宫颈癌的发病率和死亡率， 在癌症中，没有用于早期检测HPV-OPC的方法。早期发现的一个主要障碍是 鉴于尚未确定OPC的癌前前驱病变，确定PLWH中HPV-OPC的最高风险。 最近，HPV 16 E6抗体阳性已被确定为有希望的早期生物标志物。我们以前的工作 HPV 16 E6抗体存在于高达90%的HPV-OPC患者6中，并且出现时间超过10年 7 -9此外，我们已经证明HPV 16 E6抗体对HPV-OPC 10具有高度特异性， 与HPV引起的其他5种癌症没有很强的相关性。11本研究的目的是评估 HPV 16 E6标记物，以鉴定处于发展HPV-OPC最高风险的PLWH亚群， 颈部癌症筛查是最有效的。为了实现这一目标，我们将进行自然历史研究， HPV 16 E6抗体标记物。这项研究将重点关注40岁以上的男性艾滋病毒感染者，因为约85%的HPV-OPC病例 发生在中年男子和艾滋病毒感染额外增加风险高达4倍。使用田纳西中心 艾滋病研究（TN-CFAR）生物储存库，来自40岁以上男性艾滋病毒感染者（N= 3，261）的库存血液样本将在 检测了HPV 16 E6抗体所有HPV 16 E6血清阳性和HPV 16 E6血清阴性亚组（1：2比例）将在 邀请参加每年（共4次）全面的头颈部癌症筛查检查， 范德比尔特英格拉姆癌症中心（VICC）头颈外科医生。癌症筛查访视将包括： 口腔和扁桃体触诊，超声成像，喉镜检查，详细的问卷调查和生物标本 收藏.将E6血清阳性男性与E6血清阴性男性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。本研究的具体目的是：（1）检测人群中HPV 16 E6抗体的阳性率， 40岁以上男性HIV感染者;（2）确定HPV 16 E6血清阳性与HPV-OPC标志物之间的关系 风险;（3）评估发生以下的风险：a）HPV-OPC的癌前标志物和/或; B）HPV 16 E6引起的HPV-OPC 血清状态我们推测，携带HPV 16 E6抗体的男性更有可能存在已知的危险因素， 与HPV-OPC发展[性行为，持续性口腔HPV感染]相关，并且更有可能 HPV 16 E6抗体阳性的男性比HPV 16 E6抗体阴性的男性更易发生HPV-OPC。2019冠状病毒病大流行阻止了这一领域的招聘 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.