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.

Public Health Relevance

HIV(+) women have significantly elevated incidence of cervical pre-cancer and cancer, and at each clinical visit nearly a third have abnormal Pap tests. Most of these abnormal Pap tests do not, however, reflect clinically relevant disease (i.e., a lesion that requires treatment). Thus, most cervical colposcopy and 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/NIH. Encouragingly, a new era of molecular screening has begun with several promising, commercially available, cervical cancer screening assays that have good sensitivity, specificity, positive (PPV) and negative predictive value (NPV), alone or as an adjunct to Pap in HIV(-) women. The proposed study will for the first time assess the molecular methods most likely to be useful in HIV(+) women, using specimens/data from the Women's Interagency HIV Study (WIHS) and affiliated colposcopy clinics. If as predicted the accuracy of cervical cancer screening is significantly improved through the use of one or more of these molecular assays it could change clinical practice in HIV(+) women.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA174634-02
Application #
8657423
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Dominguez, Geraldina
Project Start
2013-05-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$660,318
Indirect Cost
$189,411
Name
Albert Einstein College of Medicine
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
D?Souza, Gypsyamber; Burk, Robert D; Palefsky, Joel M et al. (2014) Cervical human papillomavirus testing to triage borderline abnormal pap tests in HIV-coinfected women. AIDS 28:1696-8
Xue, Xiaonan; Kim, Mimi Y; Castle, Philip E et al. (2014) A new method to address verification bias in studies of clinical screening tests: cervical cancer screening assays as an example. J Clin Epidemiol 67:343-53