Molecular Methods to Improve Cervical Cancer Screening in HIV+ Women

描述(由申请人提供)：艾滋病毒(+)妇女的宫颈癌前期(即CIN-2/CIN-3)和癌症的发病率显著增加，在每次临床就诊时，近三分之一(25%-35%)的巴氏试验异常(即ASC-US+)。然而，这些异常的PAP大多不能反映临床相关疾病(即CIN-2+)。因此，大多数宫颈阴道镜检查/活组织检查都是不必要的，给医疗保健系统带来了巨大的费用，并增加了艾滋病毒(+)妇女出血、疼痛、感染和焦虑的风险--这些被美国疾病控制和预防中心/疾病预防控制中心定义为“伤害”。令人鼓舞的是，分子筛查的新时代已经开始，几种有希望的、商业上可用的宫颈癌筛查试验具有良好的灵敏度、特异度、阳性(PPV)、阴性预测价值(NPV)，无论是单独的还是作为Pap的辅助， 在HIV(-)女性中。然而，目前尚不清楚这些检测方法(如下所列)是否对HIV(+)女性有用--这些患者非常需要更准确的宫颈癌筛查。因此，这项拟议的研究将首次确定在HIV(+)妇女中有前景的分子宫颈癌筛查方法的敏感性/特异性/PPV/NPV。它将涉及1050名受试者，包括N=400名新的艾滋病毒(+)患者参加妇女机构间艾滋病毒研究(WIHS)，这是美国最大的艾滋病毒(+)女性队列，以及N=650名艾滋病毒(+)女性，她们将通过WIHS附属的阴道镜诊所单独登记。阴道镜检查患者通常是因为巴氏试验异常而转诊的，因此，他们的数据可以作为巴氏试验的辅助手段来研究新的分析方法(目标1)。然而，我们也希望研究在HIV(+)妇女中每个单独的分子检测的敏感性/特异性/PPV/NPV，以及评估这些检测相互结合(目标2)。通过调整抽样比例(例如，对PAP异常的女性进行过抽样)，我们可以结合来自WIHS新兵和阴道镜患者的数据，准确地估计在几倍大的初选中将获得的结果 筛选人口(见C.3)--成本效益高的设计。拟议的分子检测包括(I)FDA批准的两种致癌HPV脱氧核糖核酸检测，即眼镜蛇HPV检测和杂交捕获2(HC2)，(Ii)E6活性/增殖的细胞标志物(p16/ki-67细胞学；CINTEC+)，(Iii)S期异常诱导的细胞标志物(MCM2/TOP2A细胞学；BD ProExC)，(Iv)一次性HPVE6/E7癌基因的表达(保护HPV-Proofer)，以及(V)提供&GT；40个个体HPV半定量结果的“内部”HPVDNA聚合酶链式反应。所有的PAP和组织学都将由一个专家病理小组进行审查，所有的分析都将集中进行。如果像预测的那样，通过使用一种或多种有希望的分子检测来提高宫颈癌筛查的准确性，可能会改变HIV(+)女性的临床实践。

DESCRIPTION (provided by applicant): HIV(+) women have significantly elevated incidence of cervical pre-cancer (i.e., CIN-2/CIN-3) and cancer, and at each clinical visit nearly a third (25%-35%) have abnormal Pap tests (i.e., ASC-US+). Most of these abnormal Paps do not, however, reflect clinically relevant disease (i.e., CIN-2+). Thus, most cervical colposcopy/biopsy are conducted unnecessarily at great expense to the health care system, as well as risk of bleeding, pain, infection, and anxiety among HIV(+) women - which are defined as "harms" by USPHS/CDC. Encouragingly, a new era of molecular screening has begun with several promising, commercially available, cervical cancer screening assays with good sensitivity, specificity, positive (PPV), negative predictive value (NPV), either alone or as an adjunct to Pap, in HIV(-) women. However, it is unknown if these assays (listed below) are useful in HIV(+) women - patients in great need of more accurate cervical cancer screening. Therefore, the proposed study will for the first time determine the sensitivity/specificity/PPV/NPV of promising molecular cervical cancer screening methods in HIV(+) women. It will involve 1,050 subjects, including N=400 new HIV(+) enrollees in the Women's Interagency HIV Study (WIHS), the largest cohort of HIV(+) women in the US, and N=650 HIV(+) women who will be separately enrolled through WIHS-affiliated colposcopy clinics. Colposcopy patients are typically referred because of an abnormal Pap and, thus, their data can be used to study new assays as an adjunct to Pap tests (Aim 1). However, we also wish to study the sensitivity/specificity/PPV/NPV of each individual molecular assay in HIV(+) women, as well as assess these assays in combination with one another (Aim 2). By adjusting for sampling fractions (e.g., oversampling of women with abnormal Paps), we can combine data from the new WIHS recruits and colposcopy patients to accurately estimate the results that would be obtained in a several-fold larger primary screening population (see C.3.) - a cost effective design. The proposed molecular assays include (i) two FDA-approved DNA tests for oncogenic HPV namely, the cobas HPV Test and Hybrid Capture 2 (HC2), (ii) cellular markers of E6 activity / proliferation (p16/ki-67 cytology; CINtec+), (iii) cellular markers of aberrant S-phase induction (MCM2/Top2A cytology; BD ProExC), (iv) oncHPV E6/E7 oncogene mRNA expression (PreTect HPV-Proofer), and (v) an "in-house"HPV DNA PCR that provides semi-quantitative results for >40 individual HPV types. All Paps and histology will be reviewed by an expert pathology panel, and all assays will be centrally conducted. If as predicted the accuracy of cervical cancer screening is improved through the use of one or more of these promising molecular assays it could change clinical practice in HIV(+) women.