Mariam El-Zein

Cervical cancer screening of HPV vaccinated populations: Cytology, molecular testing, both or none.

Cervical cancer control includes primary prevention through vaccination to prevent human papillomavirus (HPV) infection and secondary prevention through screening to detect and treat cervical precancerous lesions. This review summarizes the evidence for the population impact of vaccines against oncogenic HPV types in reducing the prevalence of cervical precancerous lesions. We examine the gradual shift in screening technology from cervical cytology alone to cytology and HPV cotesting, and finally to the recognition that HPV testing can serve alone as the new screening paradigm, particularly in the initial post-vaccination era. We should expect an impact on screening performance and practices, as cohorts of HPV-vaccinated girls and adolescents reach cervical cancer screening age. In preparation for changes in the screening paradigm for the vaccination era, we propose that policymaking on cervical cancer screening should mirror current practices with other cancers as benchmarks. Cervical precancerous lesions will become a very rare condition following the widespread implementation of HPV vaccines with broader coverage in the number of preventable oncogenic types. Irrespective of screening technology, the false positive results will far outnumber the true positive ones, a tipping point that will herald a new period when the harms from cervical cancer screening will outweigh its benefits. We present a conceptual framework to guide decision making when we reach this point within 25-30 years.

Assessment of mediators of racial disparities in cervical cancer survival in the United States.

Cervical cancer (CC) morbidity and mortality have decreased in the United States, but they remain high among black women. We assessed racial disparities in CC mortality, accounting for socioeconomic status (SES). We linked data from the 1988 to 2007 Surveillance Epidemiology and End Results (SEER) database to the US Census. Additional SES information was obtained through linkage with Area Resource Files. We used the Kaplan–Meier method for estimating probabilities following CC diagnosis and Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CC mortality by race. The models were incrementally adjusted for marital status, registry, period, stage, age at diagnosis, histology, treatment, household income, poverty and unemployment rates. We stratified the analyses by disease stage and American state. A total of 44,554 women with CC were identified. Compared to white women, black women had a higher risk of dying from CC; crude and adjusted HRs were 1.41 (CI: 1.34–1.48) and 1.09 (CI: 1.03–1.15), respectively. Corresponding estimates for Hispanic women were 0.85 (CI: 0.80–0.89) and 0.75 (CI: 0.71–0.80). Black women diagnosed at late disease stages had a higher risk of CC death, whereas Hispanic women diagnosed at early and late stages had significantly lower risks. Black CC patients in California experienced poorer survival relative to white women. Conversely, longer CC survival was seen among Hispanic women in California, Georgia and Utah. While crude estimates indicated an increased CC death risk among black women, risks diminished upon adjustment for clinical and sociodemographic characteristics.

Estimating HPV DNA Deposition Between Sexual Partners Using HPV Concordance, Y Chromosome DNA Detection, and Self-reported Sexual Behaviors

Background Detection of human papillomavirus (HPV) DNA in genital samples may not always represent true infections but may be depositions from infected sexual partners. We examined whether sexual risk factors and a biomarker (Y chromosome DNA) were associated with genital HPV partner concordance and estimated the fraction of HPV detections potentially attributable to partner deposition. Methods The HITCH study enrolled young women attending a university or college in Montréal, Canada, and their male partners, from 2005 to 2010. We tested baseline genital samples for Y chromosome DNA and HPV DNA using polymerase chain reaction. Results Type-specific HPV concordance was 42.4% in partnerships where at least one partner was HPV DNA positive. Y chromosome DNA predicted type-specific HPV concordance in univariate analyses, but in multivariable models the independent predictors of concordance were days since last vaginal sex (26.5% higher concordance 0-1 vs 8-14 days after last vaginal sex) and condom use (22.6% higher concordance in never vs always users). We estimated that 14.1% (95% confidence interval [CI], 6.3-21.9%) of HPV DNA detections in genital samples were attributable to vaginal sex in the past week. Conclusions A substantial proportion of HPV DNA detections may be depositions due to recent unprotected vaginal sex.

Cervical Infection with Cutaneous Beta and Mucosal Alpha Papillomaviruses

Background: Alpha-human papillomavirus (α-HPV) plays a causal role in cervical cancer, but little is known about the epidemiology of genital Beta-human papillomavirus (β-HPV) infection. Methods: We used Luminex and PCR hybridization to detect β- and α-HPVs prevalence at enrollment and 12-month follow-up in cervical samples from 505 women enrolled in the Ludwig-McGill cohort study. We compared epidemiologic correlates of both β- and α-HPVs and compared genotypes between these genera with respect to co-occurrence and association with cervical cytologic abnormalities. Results: Infection with β-HPV types was more prevalent than that with α-HPV types at both visits (cumulative prevalences: 27.3% vs. 21.6%, respectively, P = 0.034). β-HPVs were mostly transient; however, only 1.98% women retained their original positivity at 12 months, whereas persistence was higher for α-HPVs (5.15%; P = 0.007). Age, parity, and sexual activity variables were predictors of α-HPV but not of β-HPV. α- and β-HPV types occurred independently. Increased risk of cervical abnormalities was restricted to women infected with α-9 or α-6 HPV types. We found no epidemiologic correlates for β-HPV infections. Conclusions: Detection of β-HPV types in the cervix tends to occur as random and transient episodes not explained via the sexual-transmission correlates that characterize infections by α-HPVs. Impact: Although it is plausible that β-HPVs may play a direct or indirect carcinogenic role, the lack of epidemiologic correlates for detection episodes of these viruses and lack of association with cervical lesions speak against their ancillary role as sexually transmitted agents in cervical carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(8); 1312–20. ©2017 AACR.

Determinants of cervical cancer screening accuracy for visual inspection with acetic acid (VIA) and lugol's iodine (VILI) performed by nurse and physician

Background Visual inspection with acetic acid (VIA) and Lugol’s iodine (VILI) are used to screen women for cervical cancer in low-resource settings. Little is known about correlates of their diagnostic accuracy by healthcare provider. We examined determinants of VIA and VILI screening accuracy by examiner in a cross-sectional screening study of 1528 women aged 30 years or older in a suburb of Kinshasa, Democratic Republic of Congo. Methods We used a logistic regression model for sensitivity and specificity to estimate the diagnostic accuracy of VIA and VILI, independently performed by nurse and physician, as a function of sociodemographic and reproductive health characteristics. Results Nurses rated tests as positive more often than physicians (36.3% vs 30.2% for VIA, 26.2% vs 25.2% for VILI). Women’s age was the most important determinant of performance. It was inversely associated with sensitivity (nurse’s VIA: p<0.001, nurse’s VILI: p = 0.018, physician’s VIA: p = 0.005, physician’s VILI: p = 0.006) but positively associated with specificity (all four combinations: p<0.001). Increasing parity adversely affected sensitivity and specificity, but the effects on sensitivity were significant for nurses only. The screening performance of physician’s assessment was significantly better than the nurse’s (difference in sensitivity: VIA = 13%, VILI = 16%; difference in specificity: VIA = 6%, VILI = 1%). Conclusions Age and parity influence the performance of visual tests for cervical cancer screening. Proper training of local healthcare providers in the conduct of these tests should take into account these factors for improved performance of VIA and VILI in detecting cervical precancerous lesions among women in limited-resource settings.

Design, methods, and research goals of the HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) cohort study (Preprint)

Background Human papillomavirus (HPV) epidemiological research has generally been individual based, typically focusing on women, with couple-based research mostly consisting of cross-sectional assessment of prevalent HPV infection in both partners. Objective The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study was set up to investigate the transmissibility of HPV among young, recently formed couples in Montreal, Canada. This paper provides an overview of the HITCH cohort study design and procedures as well as a narrative summary of the most important findings. Methods HITCH is a longitudinal investigation of HPV transmission in recently formed heterosexual partnerships initiated within 6-month pre-enrollment, a time at which considerable transmission is believed to occur. A total of 549 newly formed dyads were recruited (2005-2011) from postsecondary institutions, including 502 young women and their male partners. An additional 46 males were enrolled at follow-up, as some women enrolled a subsequent partner at follow-up. Women aged 18-24 years were followed for 24 months for acquisition of HPV types not present at enrollment, whereas men returned for a single follow-up visit at month 4, for a sum total of 3361 clinic visits. The last follow-up visit occurred in January 2014. Extensive sociodemographic, sexual behavioral, and medical history data were collected every 2-4 months using computer-assisted, self-administered questionnaires. Furthermore, participants provided genital, blood, oral, and hand specimens for HPV assessment. Results Although in its early analysis stage, HITCH has produced important publications. Findings from HITCH have increased the available knowledge about the natural history of HPV transmission and its determinants, provided further evidence regarding oral-oral and oral-genital routes of HPV transmission, and supplied empirically valid epidemiological parameters of HPV transmission to assist mathematical modelers in health economic assessments. In addition, HITCH data were made available to several multistudy collaborations evaluating new HPV detection assays and evidence for-or-against HPV type replacement following the introduction of HPV vaccination. Conclusions HITCH will continue to offer a unique resource for research on HPV transmission. International Registered Report Identifier (IRRID) RR1-10.2196/11284

Validation of a new HPV self-sampling device for cervical cancer screening: The Cervical and Self-Sample In Screening (CASSIS) study

OBJECTIVE We compared the self-sampling performance of the newly designed HerSwab™ device with a physician-collected cervical sample and another self-sample using the cobas® PCR Female swab for the detection of cervical intraepithelial neoplasia (CIN) and cancer. METHODS Women referred for colposcopy at McGill University affiliated hospital clinics collected two consecutive self-samples, one with HerSwab™ and one with cobas® swab, after receiving instructions. The order of sampling was randomized. The colposcopist then collected a cervical sample and conducted a colposcopic examination. Samples were tested for human papillomavirus (HPV) DNA. Sensitivity and specificity to detect CIN2+ and respective 95% confidence intervals (CI) were calculated to compare sampling approaches. The HPV testing agreement between samples was measured using the Kappa statistic. RESULTS Of 1217 women enrolled, 1076 had complete results for HPV and cytology; 148 (13.8%) had CIN1, 147 (13.7%) had CIN2/3, and 5 (0.5%) had cancer. There was very good agreement between methods for HPV detection (HerSwab™ versus physician: kappa=0.84; cobas® swabs versus physician: kappa=0.81; HerSwab™ versus cobas® swabs: kappa=0.87). The sensitivity of HPV detection for CIN2+ was 87.6% (95%CI: 79.8-93.2) with self-sampling using HerSwab™, 88.6% (95%CI: 80.9-94.0) with self-sampling using the cobas® swab, and 92.4% (95%CI: 85.5-96.7) with physician sampling. Corresponding estimates of specificity were 58.1% (95%CI: 54.1-62.1), 55.0% (95%CI: 50.9-59.0) and 58.7% (95%CI: 54.6-62.6). Cytology (ASC-US or more severe) done on the physician-collected specimen was 80.2% (95%CI: 70.8-87.6) sensitive and 61.4% (95%CI: 57.2-65.5) specific for CIN2+. CONCLUSIONS The HerSwab™ had good agreement with physician sampling in detecting HPV, and adequate performance in detecting high-grade lesions among women referred to colposcopy for abnormal cytology.

Y Chromosome DNA in Womenʼs Vaginal Samples as a Biomarker of Recent Vaginal Sex and Condom Use With Male Partners in the HPV Infection and Transmission Among Couples Through Heterosexual Activity Cohort Study

Background Y chromosome DNA from male epithelial and sperm cells was detected in vaginal samples after unprotected sex in experimental studies. We assessed the strength of this association in an observational setting to examine the utility of Y chromosome DNA as a biomarker of recent sexual behaviors in epidemiological studies. Methods The HPV (human papillomavirus) Infection and Transmission Among Couples Through Heterosexual Activity cohort study enrolled 502 women attending a university or college in Montréal, Canada, and their male partners from 2005 to 2010. Participants completed self-administered questionnaires. We used real-time polymerase chain reaction to test womens baseline vaginal samples for Y chromosome DNA and assessed which sexual behaviors were independent predictors of Y chromosome DNA positivity and quantity with logistic and negative binomial regression. Results Y chromosome DNA positivity decreased from 77% in women in partnerships reporting vaginal sex 0 to 1 day ago to 13% in women in partnerships reporting last vaginal sex of 15 or more days ago (adjusted odds ratio, 0.09; 95% confidence interval, 0.02–0.36). The mean proportion of exfoliated vaginal sample cells with Y chromosome DNA was much lower for women who reported always using condoms (0.01%) than for women who reported never using condoms (2.07%) (adjusted ratio, 26.8; 95% confidence interval, 8.9–80.5). No association was found with reported oral/digital sex frequency or concurrency of partnerships. Conclusions Y chromosome DNA quantity is strongly associated with days since last vaginal sex and lack of condom use in observational settings. Y chromosome DNA quantity may prove useful as a correlate of recent vaginal sex in observational studies lacking data on sexual behavior, such as surveillance studies of human papillomavirus infection prevalence.

Mobile Screening Units for the Early Detection of Cancer: A Systematic Review

Mobile screening units (MSUs) provide cancer screening services outside of fixed clinical sites, thereby increasing access to early detection services. We conducted a systematic review of the performance of MSUs for the early detection of cancer. Databases (MEDLINE, EMBASE, Cochrane Library, WHO Global Health Library, Web of Science, PsycINFO) were searched up to July 2015. Studies describing screening for breast, cervical, and colon cancer using MSUs were included. Data were collected for operational aspects including the performance of exams, screening tests used, and outcomes of case detection. Of 268 identified studies, 78 were included. Studies investigated screening for cancers including breast (n = 55), cervical (n = 12), colon (n = 1), and multiphasic screening for multiple cancers (n = 10). The median number of screening exams performed per intervention was 1,767 (interquartile range 5,656–38,233). Programs operated in 20 countries, mostly in North America (36%) and Europe (36%); 52% served mixed rural/urban regions, while 35% and 13% served rural or urban regions, respectfully. We conclude that MSUs have served to expand access to screening in diverse contexts. However, further research on the implementation of MSUs in low-resource settings and health economic research on cost-effectiveness of MSUs compared with fixed clinics to inform policymakers is needed. Cancer Epidemiol Biomarkers Prev; 26(12); 1679–94. ©2017 AACR.