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Clinical Performance of Human Papillomavirus Testing and Visual Inspection With Acetic Acid in Primary, Combination, and Sequential Cervical Cancer Screening in China

Wang, Margaret Z. MD*†‡; Feng, Rui-mei PhD§¶; Wang, Shaoming PhD§¶; Duan, Xian-zhi MD; Li, Dong PhD; Zhang, Xun MD¶**; Mu, Rong MD††; Qiao, Youlin PhD§¶; Smith, Jennifer S. PhD‡‡§§

doi: 10.1097/OLQ.0000000000001026
Original Studies

Background World Health Organization guidelines recommend screening with human papillomavirus (HPV) testing followed by either treatment of all HPV-positives, or by visual inspection (VIA) for triage to treatment, citing insufficient evidence to recommend either strategy over the other.

Methods We assessed VIA and HPV testing individually, in combination (HPV-VIA cotesting), and as triage models. Three thousand women were screened in Inner Mongolia, China, concurrently with HPV testing and VIA in a real population setting. Screen-positive women underwent colposcopy, and biopsy, if indicated. Accuracy of screening algorithms for cervical intraepithelial neoplasia grade 2 or higher (CIN-2+) was calculated after controlling for verification bias. HPV testing followed by VIA triage for CIN-2+ detection was compared with Hybrid Capture 2 viral loads triage, measured in relative light units/cutoff.

Results CIN-2+ prevalence was 1.0%. Corrected sensitivity, false negative rate, and specificity for CIN-2+, respectively, for primary HPV testing were 89.7%, 10.3%, and 83.3%; 44.8%, 55.2%, and 92·3% for VIA; 93.1%, 6.9%, and 80.2% for HPV-VIA cotesting; and 41.4%, 58.6, and 95.4% for HPV with VIA triage scenarios. Using relative light units/cutoff of 5 or greater to triage HPV-positive women had twice the sensitivity as VIA triage, with comparable specificity for CIN-2+.

Conclusions When VIA performs relatively poorly and HPV testing is available, adding VIA to sequential (ie, HPV followed by VIA triage) or primary (HPV-VIA cotesting) screening does not significantly improve CIN-2+ detection beyond primary HPV screening alone. Sequential screening (ie, HPV followed by VIA triage) reduces sensitivity too low for population-based screening programs. The HPV viral loads could offer an alternative low-resource country triage strategy.

Sequential algorithms of primary human papillomavirus with visual inspection (VIA) triage did not have better clinical performance than primary human papillomavirus or primary VIA alone in low-resource settings where VIA sensitivity is relatively low.

From the *Pritzker School of Medicine, University of Chicago, Chicago, IL;

UJMT Fogarty Consortium, NIH Fogarty International Center, Bethesda, MD;

Department of Psychiatry, University of Texas at Southwestern, Dallas, TX;

§Department of Epidemiology, National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences (CAMS);

Peking Union Medical College (PUMC);

Department of Gynecology, Beijing Tongren Hospital, Capital Medical Center;

**Department of Pathology, National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences (CAMS), Beijing;

††Department of Pathology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia Province, China;

‡‡Department of Epidemiology, Gillings School of Global Public Health, and

§§UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, NC

Acknowledgments: This work was supported by the National Institutes of Health Office of the Director, Fogarty International Center, Office of AIDS Research, National Cancer Center, National Heart, Blood, and Lung Institute, and the NIH Office of Research for Women's Health through the Fogarty Global Health Fellows Program Consortium comprised of the University of North Carolina, John Hopkins, Morehouse and Tulane (R25TW009340).

This demonstration project was supported by funds provided by the Central Governmental of the People's Republic of China to Inner Mongolia Autonomous Region People's Hospital. The funding agency did not have any role in the conduct of the study, data analysis, or preparation of the manuscript.

Conflict of Interests: J.S.S. has received research grants, supply donations and consultancies; served on paid advisory boards; and/or been a paid speaker for Arbor Vita, Qiagen, BD Diagnostics, Hologic Corporation and Trovagene in the past 5 years. Y.Q. served as a paid consultant for GSK and MSD. The other authors declare no competing conflicts of interest.

Author Contributions: J.S.S. jointly conceived study, gave input on data analysis and writing of the article. Y.L.Q. provided input on data analysis and writing of the article. M.Z.W. conducted literature search, data interpretation, designed tables/figures, and writing of the article. R.M.F. performed data analysis, revised data, and contributed to the article revisions. S.M.W. designed and cleaned the database and commented on the article. X.Z.D. designed protocol, performed HPV testing and VIA and commented on manuscript. D.L. provided input into data analysis and commented on the article. X.Z. performed reading of pathology slides and commented on the article. M.R. performed reading of pathology slides and commented on the article.

Correspondence: Jennifer S. Smith, PhD, MPH, Gillings School of Global Public Health University of North Carolina at Chapel Hill 2101 McGavran-Greenberg Hall, CB 7435 Chapel Hill, NC 27599-7435. E-mail:

Received for publication December 2, 2018, and accepted May 22, 2019.

Online date: June 17, 2019

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