Ping Bai

An Evaluation of Novel, Lower-Cost Molecular Screening Tests for Human Papillomavirus in Rural China

New, lower-cost tests that target high-risk human papillomavirus (HR-HPV) have been developed for cervical cancer screening in lower-resource settings but large, population-based screening studies are lacking. Women ages 25 to 65 years and living in rural China (n = 7,543) self-collected a cervicovaginal specimen, had 2 cervical specimens collected by a clinician, and underwent visual inspection after acetic acid (VIA). The self- and one clinician-collected specimens underwent HR-HPV DNA testing by careHPV (QIAGEN) and Hybrid Capture 2 (HC2; QIAGEN) and the other clinician-collected specimen was tested for HPV16, 18, and 45 E6 using OncoE6 (Arbor Vita Corporation). Women who screened positive for any test and a random sample of those negative on all tests underwent colposcopic evaluation. The percent test positive was 1.8% for HPV E6 oncoprotein, between 14% and 18% for HR-HPV DNA testing, and 7.3% for VIA. The sensitivity for cervical intraepithelial neoplasia grade 3 or more severe (CIN3+; n = 99) was 53.5% for OncoE6, 97.0% for both careHPV and HC2 testing of the clinician-collected specimen, 83.8% for careHPV testing and 90.9% for HC2 testing of the self-collected specimen, and 50.5% for VIA. OncoE6 had the greatest positive predictive value (PPV), at 40.8% for CIN3+, compared with the other tests, which had a PPV of less than 10%. OncoE6 tested 70.3% positive for HPV16, 18, or 45-positive CIN3+ and tested negative for all HPV16-, 18-, or 45-negative CIN3+ (P < 0.0001). HPV E6 oncoprotein detection is useful for identifying women who have cervical precancer and cancer. Cancer Prev Res; 6(9); 938–48. ©2013 AACR.

Lower cost strategies for triage of human papillomavirus DNA-positive women.

Using human papillomavirus (HPV) testing for cervical cancer screening in lower‐resource settings (LRS) will result in a significant number of screen‐positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV‐positive women in LRS. This was a population‐based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self‐collected and two clinician‐collected specimens. The self‐collected and one clinician‐collected specimen were tested by two HPV DNA tests—careHPV™ and Hybrid Capture 2; the other clinician‐collected specimen was tested for HPV16/18/45 E6 protein. CareHPV™‐positive specimens were tested for HPV16/18/45 DNA. HPV DNA‐positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA‐positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA‐positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.

Effectiveness of novel, lower cost molecular human papillomavirus-based tests for cervical cancer screening in rural china.

This study examined the efficacy of the OncoE6™ Cervical Test, careHPV™ and visual inspection with acetic acid (VIA) in identifying women at risk for cervical cancer and their capability to detect incident cervical precancer and cancer at 1‐year follow‐up. In a population of 7,543 women living in rural China, women provided a self‐collected and two clinician‐collected specimens and underwent VIA. All screen positive women for any of the tests, a ∼10% random sample of test‐negative women that underwent colposcopy at baseline, and an additional ∼10% random sample of test‐negative women who did not undergo colposcopy at baseline (n = 3,290) were recruited. 2,904 women were rescreened 1 year later using the same tests, colposcopic referral criteria, and procedures. Sensitivities of baseline tests to detect 1‐year cumulative cervical intraepithelial neoplasia Grade 3 or cancer (CIN3+) were 96.5% and 81.6% for careHPV™ on clinician‐collected and self‐collected specimens, respectively, and 54.4% for OncoE6™ test. The OncoE6™ test was very specific (99.1%) and had the greatest positive predictive value (PPV; 47.7%) for CIN3+. Baseline and 1‐year follow‐up cervical specimens testing HPV DNA positive was sensitive (88.0%) but poorly predictive (5.5–6.0%) of incident CIN2+, whereas testing repeat HPV16, 18 and 45 E6 positive identified only 24.0% of incident CIN2+ but had a predictive value of 33.3%. This study highlights the different utility of HPV DNA and E6 tests, the former as a screening and the latter as a diagnostic test, for detection of cervical precancer and cancer.

The concordance of HPV DNA detection by Hybrid Capture 2 and careHPV on clinician- and self-collected specimens

BACKGROUND careHPV is a new, lower-cost DNA test for human papillomavirus (HPV). There are limited analytic comparisons of careHPV against a referent HPV DNA test like Hybrid Capture 2 (HC2). OBJECTIVE To assess the test agreement between careHPV and HC2 on self- and clinician-collected specimens. STUDY DESIGN In a population of 7541 women living in rural China, women provided a self-collected (sc) and two clinician-collected (cc) specimens and underwent visual inspection after acetic acid (VIA). The sc specimen and one cc specimen were tested by careHPV and HC2; a random subset of specimens was tested for HPV genotypes. RESULTS The percent positive on cc specimens and sc specimens was 14.69% and 14.97% for careHPV, respectively, and 15.05% and 18.53% for HC2, respectively; HC2 testing of sc specimens was more likely to test positive than other combinations of tests and specimens (p<0.0001 for all comparisons). The agreement between different tests on the same specimens (kappa=0.787 and 0.691 for cc and sc specimens, respectively) was better than the same test on different specimens (kappa=0.653 and 0.649 for HC2 and careHPV, respectively). Disagreement between the same test on different specimens increased with increasing participant age (ptrend=0.0001 for HC2 and 0.002 for careHPV). HC2-positive/careHPV-negative specimens were more likely to test positive for non-carcinogenic HPV genotype than test HPV negative whereas the converse was true for HC2-negative/careHPV-positive specimens. DISCUSSION The agreement for HPV DNA detection between careHPV and HC2 was good to very good.

The Influence of Human Papillomavirus Genotypes on Visual Screening and Diagnosis of Cervical Precancer and Cancer

Objective To examine the influence of human papillomavirus (HPV) genotypes on the sensitivity of visual inspection with acetic acid (VIA) for screening, and colposcopy for diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+). Materials and Methods Women aged 25 to 65 years from China (n = 7,541) were screened with 6 tests (careHPV and Hybrid Capture 2 on self- and clinician-collected specimens; HPV-16, HPV-18, HPV-45 E6 detection; and VIA). Biopsies from women with a diagnosis of CIN2+ underwent testing for 25 HPV genotypes using SPF10/LiPA. Human papillomavirus genotyping results were classified according to broad categories of cancer risk. Results Among the 143 women with a diagnosis of CIN2+, the percentage who were HPV16 positive increased with increasing severity of diagnosis: 33.3% for CIN2 (n = 39), 69.1% for CIN3 (n = 94), and 90% for cancer (n = 10). There was a higher percentage of HPV-16 in women with abnormal colposcopic impression (p = .007) and positive VIA (p = .02) than normal colposcopy and negative VIA, respectively. Colposcopy and VIA were more sensitive to detect CIN2+ among HPV-16– and/or HPV-18–positive women than HPV-16–/HPV-18–negative women (67.4% vs 43.1%, p = .008, for colposcopy; and 53.3% vs 37.3%, p = .08, for VIA). Conclusions Human papillomavirus type 16 is related to more clear visual acetowhite changes in the epithelium. Therefore, we should expect a reduction of the performance of VIA for cervical cancer screening to identify women with CIN2+, and reduction of the performance of colposcopy to diagnose CIN2+, in vaccinated populations.

Clinical determinants of a positive visual inspection after treatment with acetic acid for cervical cancer screening

To examine the determinants of a positive visual inspection after acetic acid (VIA), including the relationship of testing positive for high‐risk human papillomavirus (HR‐HPV), which is the necessary cause of cervical cancer.

Optimal Positive Cutoff Points for careHPV Testing of Clinician- and Self-Collected Specimens in Primary Cervical Cancer Screening: an Analysis from Rural China

ABSTRACT careHPV, a lower-cost DNA test for human papillomavirus (HPV), is being considered for cervical cancer screening in low- and middle-income countries. However, not a single large-scaled study exists to investigate the optimal positive cutoff point of careHPV test. We pooled data for 9,785 women participating in two individual studies conducted from 2007 to 2011 in rural China. Woman underwent multiple screening tests, including careHPV on clinician-collected specimens (careHPV-C) and self-collected specimens (careHPV-S), and Hybrid Capture 2 on clinician-collected specimens (HC2-C) as a reference standard. The primary endpoint was cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) (n = 127), and secondary endpoint was CIN2+ (n = 213). The area under the curves (AUCs) for HC2-C and careHPV-C were similar (0.954 versus 0.948, P = 0.166), and better than careHPV-S (0.878; P < 0.001 versus both). The optimal positive cutoff points for HC2-C, careHPV-C, and careHPV-S were 1.40, 1.74, and 0.85, respectively. At the same cutoff point, careHPV-C was not significantly less sensitive and more specific for CIN3+ than HC2-C, and careHPV-S was significantly less sensitive for CIN3+ than careHPV-C and HC2-C. Raising the cutoff point of careHPV-C from 1.0 to 2.0 could result in nonsignificantly lower sensitivity but significantly higher specificity. Similar results were observed using CIN2+ endpoint. careHPV using either clinician- or self-collected specimens performed well in detecting cervical precancer and cancer. We found that the optimal cutoff points of careHPV were 2.0 on clinician-collected specimens and 1.0 on self-collected specimens.