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

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，而不是 与HPV.11引起的其他5种癌症密切相关，这项研究的目的是评估 HPV16 E6标记用于识别PLWH亚群中患HPV-OPC风险最高的人群，以及其头部和 宫颈癌筛查将是最有效的。为了做到这一点，我们将对HPV16进行自然历史研究 E6抗体标志物。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 中年男性和艾滋病毒感染额外增加了高达4倍的风险。使用田纳西州艾滋病中心 研究(TN-CFAR)生物库，来自40岁以上艾滋病毒携带者(N=3,261)的库存血液样本将进行检测 HPV16E6抗体。所有HPV16E6阳性和HPV16E6血清阴性的子集(1：2比例)将被邀请 参加由Vanderbilt Ingram每年(总共4次)进行的全面头颈部癌症筛查检查 癌症中心(VICC)头颈外科医生。癌症筛查检查将包括：目视检查口腔和 扁桃体触诊、超声成像、喉镜检查、详细问卷调查和生物素采集。E6 血清阳性的男性将在以下方面与E6血清阴性的男性进行比较：a)HPV-OPC风险升高的标志物和b) 人乳头瘤病毒OPC的研究进展。具体目的是：(1)估计老年男性中HPV16E6抗体的流行率 40+艾滋病毒携带者；(2)确定HPV16E6血清阳性与HPV-OPC风险标志物的关系；(3) 评估发生HPV-OPC的风险：a)HPV-OPC和/或癌前标志物；b)HPV16E6血清状态的HPV-OPC。我们 假设携带HPV16E6抗体的男性更有可能存在与HPV-OPC相关的已知危险因素 发展[性行为，持续的口腔HPV感染]，将比男性更有可能发展为HPV-OPC 未检测到HPV16E6抗体。这些努力可能有助于为定制的口腔健康筛查指南提供证据 致PLWH。考虑到HPV-OPC对PLWH的影响不成比例，这项工作特别有影响力。

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. These efforts could help to generate evidence for oral health screening guidelines tailored to PLWH. This work is particularly impactful given that HPV-OPC disproportionately affects PLWH.