HPV Disease in the Era of HPV Vaccines

总体描述（由申请人提供）：人乳头瘤病毒（HPV）仍然是美国和全球的主要公共卫生问题。从青春期到成年期，女性特别容易受到HPV的医疗后果的影响;不仅是宫颈癌及其前期病变，而且还有不必要的和潜在有害的假阳性筛查测试和诊断结果的干预。我们提出的计划项目的总体目标是提供关于HPV感染的科学知识，这将导致以证据为基础的策略，用于预防女性HPV相关癌症。我们计划通过开展三个跨学科的研究项目来实现这一目标，这些项目将相互协同，并利用我们团队在HPV感染和相关癌前病变和癌症的分子流行病学研究方面的经验。每个项目将由一名高级研究员和一名初级研究员共同指导，其中一名研究员具有临床专业知识，另一名研究员具有实验室或流行病学专业知识。这种监督结构确保了临床研究的高标准，同时鼓励通过思想的交叉交流进行发现。这些项目将得到三个核心的支持：实验室， 生物统计学/流行病学和管理。我们的目标集中在重要的未解决的科学和临床问题，包括30至50岁女性的再激活与新的高危（HR）HPV感染的风险（项目1），由不同HR-HPV基因型引起的CIN 2病变的自然史和潜在后果（项目2），以及表观遗传变化在CIN 2的持续性，进展和消退中的作用（项目3）。这些研究结果将有助于改善HR-HPV相关癌前病变和良性病变妇女的管理策略，适当使用预防性HPV疫苗和HR-HPV诊断检测，并开发新型去甲基化治疗方法。 项目1： 标题：中年女性HPV感染的自然史 项目负责人：Winer，R 项目1描述（由申请人提供）：虽然现在对性活跃的年轻女性HPV感染的获得和早期自然史了解很多，但对中年女性HPV感染知之甚少。特别是，从新的性伴侣获得新的高危（HR）HPV感染的风险尚未确定，并且在青春期或年轻成年期获得的HR HPV感染的重新激活频率未知。此外，与新发感染和再激活感染相关的细胞学异常风险尚不明确。我们将招募1,000名年龄在30到50岁之间的女性，她们是华盛顿大学的教职员工或学生，并在两年的时间里对她们进行两年一次的临床随访。每次访视时，执业护士将进行面对面的医疗和性行为访谈（辅以双周在线性行为日记） 并收集子宫颈样本作巴氏试验、人类乳头瘤病毒基因分型及病毒载量测试。将在入组和退出访视时采集用于HPV抗体检测的血清。女性还将在每次访视时自行收集阴道样本进行HPV DNA检测，并将选择200名女性的子集在第6个月至第12个月访视之间进行每月自我收集。这项纵向研究的具体目的是：1）确定中年女性中新获得和再激活的类型特异性HR HPV感染的发生率和决定因素; 2）确定200名女性中再激活的概率和决定因素（有既往感染的血清学证据，最近没有新的性伴侣），随后每月阴道自我采集HPV检测6个月;和3）比较与新获得的与再活化的类型特异性HR HPV感染相关的异常细胞学（意义不明或更大的非典型鳞状细胞[ASC-US+]）的概率。该项目的研究结果将为临床医生/患者的相互作用以及预防性疫苗实施和中年妇女人群宫颈癌筛查指南的制定提供信息。

DESCRIPTION OF THE OVERALL PROGRAM (provided by applicant): Human papillomavirus (HPV) continues to be a major public health problem both in the US and worldwide. From adolescence through adulthood, females are especially vulnerable to the medical consequences of HPV; not only cervical cancer and its precursor lesions but also unnecessary and potentially harmful interventions for false positive screening tests and diagnostic findings. The overall objective of our proposed program project is to provide scientific knowledge on HPV infections that will lead to evidence-based strategies for age-appropriate prevention of HPV-related cancers in women. We plan to accomplish this goal by undertaking three interdisciplinary research projects that will synergistically build on each other, and on our team's experience with molecular epidemiology studies of HPV infection and related precancerous lesions and cancers. Each project will be co-directed by one senior and one junior investigator, with one investigator having clinical expertise and the other having laboratory or epidemiological expertise. This oversight structure ensures high standards in the conduct of the clinical research while encouraging discovery through cross-fertilization of ideas. The projects will be supported by three cores: laboratory, biostatistics/epidemiology, and administration. Our aims focus on important unresolved scientific and clinical issues including the risk of reactivating versus new high-risk (HR) HPV infection in women 30 to 50 years of age (project 1), the natural history and potential consequences of CIN2 lesions caused by different HR-HPV genotypes (project 2), and the role of epigenetic changes in the persistence, progression, and regression of CIN2 (project 3). Finding from these studies will contribute to improved management strategies for women with HR-HPV-related precancerous and benign lesions, appropriate use of prophylactic HPV vaccines and HR-HPV diagnostic tests, and to the development of novel demethylating treatments. PROJECT 1: Title: Natural History of HPV Infections in Mid-Adult Women Project Leader: Winer, R PROJECT 1 DESCRIPTION (provided by applicant): While much is now known about the acquisition and early natural history of HPV infections in sexually active young women, little is known about HPV infections in mid-adult women. In particular, the risk of acquiring new high-risk (HR) HPV infections from new sex partners is undefined and the frequency of reactivating HR HPV infections that were acquired in adolescence or young adulthood is unknown. Furthermore, the risk of abnormal cytology associated with new versus reactivated infections is undefined. We will enroll 1,000 women between the ages of 30 to 50 who are faculty, staff, or students at the University of Washington and follow them with bi-annual clinical visits for two years. At each visit, a nurse practitioner will conduct a face-to-face medical and sexual behavior interview (supplemented with bi-weekly online sexual behavior diaries) and collect cervical specimens for Pap testing and for HPV genotyping and viral load testing. Serum for HPV antibody testing will be collected at the enrollment and exit visits. Women will also self-collect vaginal samples for HPV DNA testing at each visit, and a subset of 200 women will be selected to do monthly self collections between the month 6 and month 12 visits. The specific aims of this longitudinal study are to 1) define rates and determinants of newly acquired and reactivated type-specific HR HPV infections in mid-adult women; 2) define the probability and determinants of reactivation in a subset of 200 women (with serologic evidence of prior infection and no recent new sex partners) followed with monthly vaginal self-collections for HPV testing for 6 months; and 3) compare the probability of abnormal cytology (atypical squamous cells of undetermined significance or greater [ASC-US+]) associated with newly acquired versus re-activated type-specific HR HPV infections. Findings from this project will inform clinician/patient interactions and development of prophylactic vaccine implementation and cervical cancer screening guidelines in populations of mid-adult women.