Marc Arbyn, MD, MSc, DrTMH; Lan Xu, MSc; Freija Verdoodt, PhD; Jack Cuzick, PhD; Anne Szarewski, MD, PhD (†); Jerome L. Belinson, MD; Nicolas Wentzensen, MD, PhD; Julia C. Gage, PhD, MPH; Michelle J. Khan, MD, MPH
Acknowledgment: The authors thank the following researchers for contributing requested unpublished data: Maria Benevolo (Pathology Department, Regina Elena National Cancer Institute, Rome, Italy) (41), Sonia Andersson (Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden) (31), Ming Guo (Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas) (33), Philippe Halfon (Virological Laboratory and Infectious Diseases, Laboratory Alphabio, Marseille, France) (34), Lee-Wen Huang (Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan) (54), Shihai Huang (Abbott Molecular, Des Plaines, Illinois) (35), François Coutlée (Département de Microbiologie et Infectiologie and de Gynécologie-Obstétrique et Pathologie, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada) (36), Jean Monsonego (Institute of the Cervix, Paris, France) (38), Angela Pista (National Institute of Health, Lisbon, Portugal) (39), Aris Spathis (Department of Cytopathology, University General Hospital ATTIKON, School of Medicine, National and Kapodistrian University of Athens, Chaidari, Greece) (42), and Marc H. Stoler (University of Virginia Health System, Charlottesville, Virginia) (43). Additional unpublished data were provided by the following coauthors: Jerome Belinson (Preventive Oncology International, Cleveland, Ohio) (28), Julia Gage (Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland) (32), Jack Cuzick (Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom) (44), and Nicolas Wentzensen (Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland) (46).
Financial Support: Drs. Arbyn and Verdoodt and Ms. Xu were supported by the Belgian Foundation Against Cancer, Brussels, Belgium; the European Commission through the COHEAHR Network (grant no. 603019), coordinated by the Free University of Amsterdam (Amsterdam, the Netherlands), funded by the 7th Framework Programme of DG Research (Brussels, Belgium); the Joint Action CANCON, which has received funding from the European Union in the framework of the Health Programme (2008-13); and the Medizinische Hochschule of Hannover (Hannover, Germany). Dr. Khan was supported by training grant 5T32AI065388-05 from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, institutional grant UL1 RR024131 through the National Institutes of Health/National Center for Research Resources University of California San Francisco–Clinical and Translational Science Institute Strategic Opportunities Support program, and mentored career development award K12 HS023009 through the Agency for Healthcare Research and Quality.
Disclosures: Dr. Cuzick reports grants from Qiagen, BD, Abbott, Hologic, Trovagene, Genera, and Cepheid; personal fees from Merck; and nonfinancial support from BD, Abbott, Hologic, Trovagene, and Cepheid during the conduct of the study. Dr. Belinson reports grants from Hologic and nonfinancial support from BGI Shenzhen during the conduct of the study. Dr. Wentzensen reports that he is an employee of the National Cancer Institute, which has received cervical cancer screening assays in-kind or at reduced cost from BD, Cepheid, Hologic, and Roche. Dr. Gage reports receiving human papillomavirus tests for research at no cost from Roche and BD. Dr. Khan reports travel reimbursement from Cepheid and the American Society for Colposcopy and Cervical Pathology outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2735.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available in Supplement 1. Statistical code: See the Methods and the study protocol. Data set: Available from Dr. Arbyn (e-mail, email@example.com).
Requests for Single Reprints: Marc Arbyn, MD, MSc, DrTMH, Coordinator of the Unit of Cancer Epidemiology, Belgian Cancer Centre, Scientific Institute of Public Health, J. Wytsmanstreet 14, B1050 Brussels, Belgium; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Arbyn and Verdoodt and Ms. Xu: Unit of Cancer Epidemiology/Belgian Cancer Centre, Scientific Institute of Public Health, J Wytsmanstreet 14, B1050 Brussels, Belgium.
Dr. Cuzick: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Dr. Belinson: Cleveland Clinic, Women's Health Institute, 9500 Euclid Avenue, A81, Cleveland, OH 44118.
Drs. Wentzensen and Gage: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 609 Medical Center Drive, Bethesda, MD 20892.
Dr. Khan: Department of Obstetrics and Gynecology, Kaiser Permanente Northern California, 2500 Merced Street, San Leandro, CA 94577.
Author Contributions: Conception and design: M. Arbyn, A. Szarewski, J.C. Gage, M.J. Khan.
Analysis and interpretation of the data: M. Arbyn, L. Xu, F. Verdoodt, J. Cuzick, J.L. Belinson, N. Wentzensen, J.C. Gage, M.J. Khan.
Drafting of the article: M. Arbyn, L. Xu, F. Verdoodt, J. Cuzick, J.C. Gage, M.J. Khan.
Critical revision of the article for important intellectual content: L. Xu, F. Verdoodt, J. Cuzick, J.L. Belinson, N. Wentzensen, J.C. Gage, M.J. Khan.
Final approval of the article: M. Arbyn, L. Xu, F. Verdoodt, J. Cuzick, J.L. Belinson, N. Wentzensen, J.C. Gage, M.J. Khan.
Provision of study materials or patients: M. Arbyn, L. Xu, A. Szarewski, J.C. Gage, M.J. Khan.
Statistical expertise: M. Arbyn, L. Xu, F. Verdoodt, J. Cuzick, N. Wentzensen.
Obtaining of funding: M. Arbyn.
Administrative, technical, or logistic support: M. Arbyn.
Collection and assembly of data: M. Arbyn, L. Xu, F. Verdoodt, A. Szarewski, J.L. Belinson, N. Wentzensen, J.C. Gage, M.J. Khan.
Arbyn M, Xu L, Verdoodt F, Cuzick J, Szarewski A, Belinson JL, et al. Genotyping for Human Papillomavirus Types 16 and 18 in Women With Minor Cervical Lesions: A Systematic Review and Meta-analysis. Ann Intern Med. 2017;166:118-127. doi: 10.7326/M15-2735
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Published: Ann Intern Med. 2017;166(2):118-127.
Published at www.annals.org on 15 November 2016
High-risk human papillomavirus (hrHPV) testing to triage women with minor cervical lesions generates many referrals.
To evaluate the accuracy of genotyping for HPV types 16 and 18 and its utility as a second triage step after hrHPV testing in women with minor cervical lesions.
Searches of 4 bibliographic databases, without language restrictions, from 1 January 1999 to 1 February 2016.
Studies involving women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) who were triaged with tests for hrHPV and HPV 16/18 to find cervical intraepithelial neoplasia (grade ≥2 [CIN2+] or grade ≥3 [CIN3+]).
Independent study selection, extraction of data, and quality assessment by 2 reviewers.
Twenty-four moderate- to good-quality studies involving 8587 women with ASC-US and 5284 with LSIL were found. The pooled sensitivity of HPV 16/18 genotyping for CIN3+ was about 70% for women with either ASC-US or LSIL. The pooled specificity (with a threshold of grade <2 CIN) was 83% (95% CI, 80% to 86%) for women with ASC-US and 76% (CI, 74% to 79%) for those with LSIL. The average risk for CIN3+ was 17% and 19% in HPV 16/18–positive women with ASC-US and LSIL, respectively, and was 5% in hrHPV-positive but HPV 16/18–negative women with either ASC-US or LSIL.
Methodological and technical heterogeneity among studies; insufficient data to assess accuracy of separate assays.
Testing for HPV 16/18 to triage women with minor abnormal cytology is poorly sensitive but may be useful as a second triage test after hrHPV testing, with direct referral if the woman is positive for HPV 16/18. Whether colposcopy or repeated testing is recommended for hrHPV-positive but HPV 16/18–negative women depends on local decision thresholds that can be derived from pretest–posttest probability plots.
7th Framework Programme of the European Commission.
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