Oral HPV Research Among Latin Americans Living with HIV (ORAL - H² Study)

摘要 口咽癌（OPC）主要由HPV 16和其他致癌HPV类型引起， 对男性和艾滋病毒感染者（PLWH）的影响尤为严重。没有可靠的方法来检测OPC 癌前病变的二级预防。评估9vHPV疫苗预防OPC有效性的试验 我们的团队正在进行：NCI资助的U 54赠款，口腔和宫颈癌，HPV和艾滋病毒在 美洲[ROCCHHA]在HIV感染男性中进行的试验201和在HIV未感染者中进行的默克v503-049试验 男人虽然HPV疫苗接种是一种有希望的一级预防OPC的方法，但疫苗接种可能不是一种有效的方法。 由于大多数国家在其国家方案中排除了男性， 艾滋病毒/艾滋病感染者疫苗接种政策。预防OPC和识别PLWH最高风险的其他方法 迫切需要进行监测，特别是考虑到OPC发病率在 美国和拉丁美洲。为预防战略提供信息，确定可改变的风险因素， 需要测量的生物标志物来识别那些处于最高风险的人。HPV相关OPC的发展是多方面的， 阶乘性行为导致口腔致癌HPV感染是必要的步骤。无论 解剖部位的感染，只有一部分感染持续和进展为癌症。多重交互作用 影响病毒持久性的因素。我们是为数不多的几个团体进行了大的口腔HPV自然 历史研究有助于这一文学。我们和其他研究的结果表明，年龄较大，贫穷， 口腔健康，免疫失调，如发生在PLWH，和异常的DNA甲基化影响口腔 HPV持久性。使这一情况更加严重的是，艾滋病毒携带者活到了更老的年龄，导致终身免疫。 可能加速生物衰老的功能障碍，增加获得或重新激活多种 感染，如EBV，并最终导致降低致癌病毒控制。社会因素加剧了这一点 由于艾滋病毒携带者对牙科保健和其他服务的利用率较低， 感染，随后的慢性口腔炎症，牙周病和牙齿脱落，这些因素可能 促进口腔HPV致癌作用，并与HPV-OPC风险独立相关。我们 作为我们ROCCHHA补助金的一部分，在PLWH中进行了两项大型研究， 在一年两次的研究访视中采集漱口液样本，我们将利用这些样本来研究口腔HPV自然史。的目标 本申请旨在确定PLWH中致癌性口腔HPV感染的自然史。中央 拉丁美洲艾滋病毒感染者口腔HPV研究（口腔H2）的假设是， 在PLWH中，生物学年龄、牙齿健康和病毒因素与持续性口腔 致癌性HPV。我们将评估口腔HPV 16和致癌HPV感染，评估与病毒相关的因素， 持久性，并确定生物标志物和行为因素的最佳组合，预测口腔 致癌HPV持续存在。

ABSTRACT Oropharyngeal cancer (OPC) is predominantly caused by HPV 16 and other oncogenic HPV types and disproportionately impacts men and people living with HIV (PLWH). There is no reliable method to detect OPC pre-cancerous lesions for secondary prevention. Trials assessing efficacy of the 9vHPV vaccine to prevent OPC are ongoing by our team: NCI-funded U54 grant, Research on Oral and Cervical Cancer, HPV and HIV in the Americas [ROCCHHA] Trial 201 among men with HIV, and the Merck v503-049 trial among HIV-uninfected men. While HPV vaccination is a promising approach for the primary prevention of OPC, vaccination may not be available to those in greatest need as most countries exclude males in their national programs and may not have policies for PLWH vaccination. Additional methods to prevent OPC and identify PLWH at highest risk for surveillance are urgently needed, particularly given that OPC incidence rates are significantly increasing in the US and Latin America. To inform prevention strategies, the identification of modifiable risk factors and easily measured biomarkers identifying those at highest risk is needed. Development of HPV-related OPC is multi- factorial. Sexual behavior leading to an oral oncogenic HPV infection is a necessary step. Regardless of anatomic site of infection, only a proportion of infections persist and progress to cancer. Multiple interplaying factors influence viral persistence. We are among the few groups that have conducted large oral HPV natural history studies contributing to this literature. Results from ours and other studies indicate that older age, poor oral health, immune dysregulation, such as occurs among PLWH, and aberrant DNA methylation influence oral HPV persistence. Exacerbating this is the fact that PLWH are living to older ages which results in lifelong immune dysfunction that may accelerate biological aging, increase risk of acquiring or reactivating a multitude of infections such as EBV, and ultimately lead to reduced oncogenic viral control. Social factors compound this scenario as PLWH have lower utilization of dental care and other services resulting in prolonged untreated oral infections, subsequent chronic oral inflammation, periodontal disease, and tooth loss, factors that potentially promote oral HPV carcinogenesis, and have independently been associated with HPV-OPC risk. We are conducting two large studies as part of our ROCCHHA grant among PLWH that obtain clinical data and oral gargle specimens at bi-annual study visits, which we will leverage to study oral HPV natural history. The goal of this application is to define the natural history of oncogenic oral HPV infection among PLWH. The central hypothesis of the Oral HPV Research Among Latin Americans Living with HIV (ORAL H2) Study is that among PLWH advanced biological age, dental health, and viral factors are associated with persistent oral oncogenic HPV. We will estimate oral HPV 16 and oncogenic HPV infection, assess factors associated with viral persistence, and determine the optimal combination of biomarkers and behavioral factors that predict oral oncogenic HPV persistence.