Molecular Methods to Improve Cervical Cancer Screening in HIV+ Women

改善艾滋病毒女性宫颈癌筛查的分子方法

• 批准号: 9122798
• 负责人: HOWARD D STRICKLER
• 金额: $ 58.21万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122798
• 关键词: Anxiety; Atypical Squamous Cell; Biological Assay; Biopsy; Centers for Disease Control and Prevention (U.S.); Cervical; Cervical Cancer Screening; Cervical Intraepithelial Neoplasia; Clinic; Clinical; Colposcopy; Cytology; DNA; Data; Detection; Diagnosis; Disease; Enrollment; FDA approved; HIV; Healthcare Systems; Hemorrhage; Histologic; Histology; Housing; Human Papillomavirus; Hybrids; Incidence; Individual; Infection; Lesion; MCM2 gene; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Methods; Molecular; Oncogenes; Oncogenic; Pain; Pap smear; Pathology; Patients; Population; Predictive Value; Recruitment Activity; Risk; S Phase; Sampling; Sensitivity and Specificity; Specificity; Specimen; Testing; Time; United States National Institutes of Health; United States Public Health Service; Viral; Visit; Woman; clinical practice; clinically relevant; cohort; cost effective; cost effectiveness; design; improved; mRNA Expression; monolayer; public health relevance; screening

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.

描述（由申请人提供）：HIV（+）女性宫颈癌前病变（即，CIN-2/CIN-3）和癌症，并且在每次临床访问时，近三分之一（25%-35%）具有异常的巴氏试验（即，ASC-US+）。然而，这些异常Paps中的大多数并不反映临床相关疾病（即，CIN-2+）。因此，大多数宫颈阴道镜检查/活检都是不必要的，对卫生保健系统造成了巨大的费用，以及艾滋病毒（+）妇女的出血，疼痛，感染和焦虑的风险-这被USPHS/CDC定义为“危害”。 令人鼓舞的是，分子筛查的新时代已经开始，几种有前途的、市售的宫颈癌筛查测定具有良好的灵敏度、特异性、阳性（PPV）、阴性预测值（NPV），单独或作为Pap的辅助， 在HIV阴性的女性中。然而，目前尚不清楚这些检测方法（如下所列）是否适用于HIV（+）女性患者，这些患者非常需要更准确的宫颈癌筛查。 因此，拟议的研究将首次确定HIV（+）妇女中有前途的分子宫颈癌筛查方法的灵敏度/特异性/PPV/NPV。它将涉及1，050名受试者，其中包括N=400名新入组女性机构间艾滋病毒研究（WIHS）的艾滋病毒（+）受试者，该研究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附属阴道镜诊所单独入组。阴道镜检查患者通常是因为异常的巴氏涂片而被转诊的，因此，他们的数据可以用于研究新的检测方法，作为巴氏涂片检测的辅助方法（目的1）。然而，我们还希望研究HIV（+）女性中每种分子检测的灵敏度/特异性/PPV/NPV，并评估这些检测的相互组合（目的2）。通过调整采样分数（例如，Pap异常妇女的过度抽样），我们可以将来自新WIHS招募者和阴道镜检查患者的数据联合收割机结合起来，以准确估计在几倍大的主要研究中获得的结果。 筛选人群（见C.3.）- 一个成本有效的设计。 所提出的分子测定包括（i）两种FDA批准的致癌HPV的DNA测试，即cobas HPV测试和杂交捕获2（HC 2），（ii）E6活性/增殖的细胞标志物（p16/ki-67细胞学; CINtec+），（iii）异常S期诱导的细胞标志物（MCM 2/Top 2A细胞学; BD ProExC），（iv）oncHPV E6/E7癌基因mRNA表达（PreTect HPV-Proximate），和（v）“内部“HPV DNA PCR，其提供>40种单独HPV类型的半定量结果。所有Paps和组织学将由专家病理学小组进行审查，所有试验将集中进行。 如果像预测的那样，通过使用一种或多种这些有前途的分子检测来提高宫颈癌筛查的准确性，它可能会改变艾滋病毒（+）妇女的临床实践。