(PQ4) Anal HPV infection and anal HSIL among HIV-infected MSM aged 50+ years

 描述(申请人提供)：美国的艾滋病毒感染人口正在老龄化，居住在美国的一半以上的人年龄在50岁或以上。不幸的是，抗逆转录病毒疗法 并没有完全恢复健康。肛门癌在感染艾滋病毒的男男性行为者(MSM)中最常见，感染HIV的男男性行为者感染HPV-16的风险最高，这是80%-90%的肛门癌的病因，以及肛门高级别鳞状上皮内病变(HSIL)，肛门癌的先兆。在普通人群中，肛门癌也是一种年龄更高的癌症，60岁或以上的男性被诊断为肛门癌的可能性是所有年龄段的男性的3倍。关于年龄与HPV感染/HSIL与HIV感染之间的关系，人们知之甚少。因此，50岁以上感染艾滋病毒和未感染艾滋病毒的MSM构成了一个理想的人群，在这个人群中回答了一个挑衅性的问题：PQ4：衰老和艾滋病毒感染的生物学如何在各种癌症的发展中相互作用？年龄导致癌症风险增加的机制尚不清楚。与年轻人相比，老龄化人口有证据表明炎症增加，这可能导致HPV持续感染和HSIL清除减少。慢性炎症在艾滋病毒感染者中也很常见。我们建议进行一项研究，评估年龄组(50-59岁、60-69岁、70岁以上)、HPV和HIV感染之间的相互作用。我们将进行一项横断面研究，以确定这些老年人群中肛门HPV/HSIL的患病率，并研究它们与衰老生物标记物包括炎症生物标记物的相关性。然后，我们将每隔6个月跟踪观察肛门HPV-16DNA阳性但没有被诊断为HSIL的男性，评估他们HPV-16的持久性和HSIL的发生率。我们将同样跟踪观察肛门HPV-16DNA阴性和HSIL阴性的男性的肛门HPV-16感染的发生率和/或再激活情况。在每个预期队列中，我们将评估研究结果与衰老生物学生物标记物之间的关系。具体目的：1)确定50岁以上男男性接触者HPV感染和HSIL感染的年龄分布及其与炎症和衰老生物标志物的关系。2)研究HPV-16感染与未感染的50岁以上男男性接触者中HPV-16感染持续时间及HSIL发生率，探讨HPV-16感染与HSIL发病的关系。3)研究新发现的HPV-16感染和HSIL在50岁以上无HPV16感染和HSIL的50岁以上MSM人群中新发现的肛门HPV-16感染和HSIL的发生率及其与炎症和衰老生物标志物的关系。这项研究将首次提供有关老年HIV感染者中HPV感染/HSIL的有效ART的数据，并确定衰老生物学在该人群肛门癌发病机制中的作用。这一结果将有助于我们了解在HIV感染和未感染人群中肛门癌的发病机制。

 DESCRIPTION (provided by applicant):The HIV-infected population in the US is aging and more than half living in the US are 50 years of age or older. Unfortunately, antiretroviral therapy has not restored full health. Anal cancer occurs most frequently among HIV-infected men who have sex with men (MSM) and HIV-infected MSM are at the highest risk of anal HPV-16 infection, the causative agent in 80- 90% of anal cancers , and anal high-grade squamous intraepithelial lesions (HSIL), the precursor to anal cancer. Anal cancer is also a cancer of more advanced age in the general population and men aged 60 years or older are 3 times more likely to be diagnosed with anal cancer compared with men of all ages. Little is known about the relationship between age and HPV infection/HSIL and HIV infection. HIV-infected and uninfected MSM aged 50+ therefore constitute an ideal population in which to address the provocative question "PQ4: How do the biology of aging and HIV infection interact in the development of various cancers?" The mechanisms by which age contributes to increased risk of cancer are not known. The aging population has evidence for increased inflammation compared with younger people, and these may contribute to persistent HPV infection and reduced clearance of HSIL. Chronic Inflammation is also commonly found in HIV-infected individuals. We propose to conduct a study evaluating the interplay between age group (50-59, 60-69, 70+), HPV and HIV infection. We will perform a cross-sectional study to establish the prevalence of anal HPV/HSIL in these older age groups, and study their association with biomarkers of aging including biomarkers of inflammation. We will then follow men every six months for 3 years who are anal HPV-16 DNA-positive but who have no diagnosis of HSIL evaluating them for persistence of HPV-16 and incident HSIL. We will similarly follow men who are anal HPV-16 DNA-negative and HSIL- negative for incidence and/or reactivation of anal HPV-16 infection. In each prospective cohort we will evaluate the relationship between study outcomes and the biomarkers of the biology of aging. Specific Aims: 1) To determine the age-specific prevalence of anal HPV infection and anal HSIL and their association with biomarkers of inflammation and aging HIV-infected and uninfected MSM aged 50+ years. 2) To determine the persistence of anal HPV-16 infection and incidence of anal HSIL in a cohort of HIV-infected and uninfected MSM aged 50+ years with prevalent anal HPV-16 infection at baseline but no anal HSIL, and their relationship to biomarkers of inflammation and aging. 3) To determine the incidence of newly detectable anal HPV-16 infection and anal HSIL in a cohort of HIV-infected and uninfected MSM aged 50+ years without anal HPV 16 infection and HSIL at baseline, and their relationship to biomarkers of inflammation and aging. This study will provide the first data on HPV infection/HSIL among older HIV-infected individuals on effective ART and determine the role of the biology of aging in the pathogenesis of anal cancer in this population. The results wil inform our understanding of the pathogenesis of anal cancer in both HIV-infected and uninfected populations.