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

描述(申请人提供)：艾滋病毒感染者在高效抗逆转录病毒疗法(HAART)时代提高了存活率，但仍有更高的死于其他严重疾病的风险，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来识别，SCCA可能是HIV感染者死亡的一个可预防的原因。SCCA与艾滋病定义的恶性肿瘤宫颈癌有许多生物学上的相似之处，包括与高危人类乳头瘤病毒(HPV)感染的因果关系，以及在HIV感染人群中这两种癌症的发病率增加。过去的研究和初步数据表明，尽管使用了HAART，但SCCA的发生率仍在增加，而且HAART对肛门癌前病变的影响尚不清楚。与其他可能的混杂因素相比，使用HAART的相对影响尚不清楚，这些因素包括艾滋病毒感染时间、最低CD4计数和HPV相关因素。这项建议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。这项建议的具体目的是：1)检验长期的晚期免疫抑制与SCCA的发生有关的假说；2)检验HAART幼稚、人口学研究不足的人群中肛门异型增生和高危HPV感染患病率增加的假说，并确定高危HPV病毒载量是否与肛门异型增生和晚期免疫抑制的级别独立相关；3)测量基线免疫抑制以及HAART启动后的免疫应答在进展为高度肛门异型增生和高危HPV病毒载量方面的相对影响。第一个具体目标将通过使用一个独特的、全国性的退伍军人卫生管理局艾滋病毒登记册进行回溯性队列研究来实现。第二个目标将通过一项横断面研究来实现，评估一个HAART-幼稚的艾滋病毒感染队列，第三个目标将通过前瞻性地跟踪该队列的成员来实现。研究计划、教学培训和出色的指导环境将使首席调查员在临床研究的开发和执行方面获得新的技能并完善现有技能，使她能够发展成为艾滋病毒相关恶性肿瘤的流行病学、预防和护理方面的独立调查员。

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.