The Epidemiologic Effects of HAART on HIV-related Anal Cancer and Anal Dysplasia

描述（由申请人提供）：艾滋病毒感染者在高效抗逆转录病毒疗法（HAART）时代的生存率有所提高，但仍然有较高的其他严重疾病死亡风险，如肛门鳞状细胞癌（SCCA）和其他非艾滋病定义的恶性肿瘤。由于SCCA前体病变很容易通过细胞学筛查识别，SCCA可能是hiv感染者中可预防的死亡原因。SCCA与定义艾滋病的恶性宫颈癌在生物学上有许多相似之处，包括与高危人乳头瘤病毒（HPV）感染的因果关系，以及这两种癌症在艾滋病毒感染人群中的发病率增加。过去的研究和初步数据表明，尽管使用了HAART，但SCCA的发病率仍在增加，并且HAART对肛门癌前驱病变的影响尚不清楚。与其他可能的混杂因素（包括HIV感染时间长短、CD4最低计数和hpv相关因素）相比，HAART使用的相对影响尚不清楚。本提案的目标是评估自广泛引入HAART以来SCCA发病率的变化，并确定导致这些变化的相关因素。该建议的具体目的是：1)验证长期、晚期免疫抑制与SCCA发展相关的假设；2)检验在HAART治疗未成熟、人口统计学研究不足的人群中肛门发育不良和高危HPV感染的患病率增加的假设，并确定高危HPV病毒载量是否与肛门发育不良的程度和晚期免疫抑制独立相关；3)测量基线免疫抑制的相对影响，以及随后HAART启动的免疫应答对高级肛门发育不良和高危HPV病毒载量的进展。第一个具体目标将通过使用独特的全国退伍军人卫生管理局艾滋病毒登记处进行回顾性队列研究来实现。第二个目标将通过评估haart初始hiv感染队列的横断面研究来解决，第三个目标将通过前瞻性跟踪该队列的成员来实现。研究计划、教学培训和优秀的指导环境，将使首席研究员获得新的技能，并在临床研究的开发和执行中完善现有技能，使她能够发展成为艾滋病毒相关恶性肿瘤流行病学、预防和护理方面的独立研究者。

DESCRIPTION (provided by applicant): HIV-infected individuals have improved survival in the highly active antiretroviral therapy (HAART) era, but continue to have a higher risk of mortality from other serious illnesses such as squamous cell cancer of the anus (SCCA) and other non-AIDS defining malignancies. Because SCCA precursor lesions are readily identifiable using cytologic screening, SCCA may be a preventable cause of death among HIV-infected individuals. SCCA shares many biologic similarities with the AIDS-defining malignancy cervical cancer, including a causal relationship with high-risk human papillomavirus (HPV) infection and an increased incidence of both cancers in HIV-infected populations. Past research and preliminary data indicate that the incidence of SCCA is increasing in spite of HAART utilization, and that the effect of HAART on anal cancer precursor lesions is unclear. The relative influence of HAART use compared to other possibly confounding factors including length of HIV infection, nadir CD4 count, and HPV-related factors are unknown. The goals of this proposal are to assess the changes in the incidence of SCCA since the wide-spread introduction of HAART and identify relevant factors responsible for those changes. The specific aims for this proposal are: 1) To test the hypothesis that prolonged, advanced immunosuppression is associated with the development of SCCA; 2) To test the hypothesis that the prevalences of anal dysplasia, and high-risk HPV infection in a HAART naive, demographically understudied population is increased, and to determine if high-risk HPV viral load is independently associated with grade of anal dysplasia and advanced immunosuppression; 3) To measure the relative effect of baseline immunosuppression, and subsequent immunologic response to HAART initiation on the progression to high-grade anal dysplasia and high-risk HPV viral loads. The first specific aim will be accomplished with a retrospective cohort study using a unique, national, Veteran's Health Administration HIV registry. The 2nd aim will be addressed through a cross-sectional study evaluating a HAART-naive HIV-infected cohort and the 3rd aim will be accomplished by prospectively following the members of that cohort. The research plan, didactic training and outstanding mentoring environment, will allow the principal investigator to acquire new skills as well as refine existing skills in the development and execution of clinical studies, allowing her to develop into an independent investigator in the epidemiology, prevention and care of HIV-related malignancies.