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Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15–26 Years of Age

Garland, Suzanne M., MD; Joura, Elmar A., MD; Ault, Kevin A., MD; Bosch, F. Xavier, MD, PhD; Brown, Darron R., MD; Castellsagué, Xavier, MD; Ferenczy, Alex, MD; Ferris, Daron G., MD; Giuliano, Anna R., PhD; Hernandez-Avila, Mauricio, MD; Huh, Warner K., MD; Iversen, Ole-Erik, MD, PhD; Kjaer, Susanne K., MD; Kurman, Robert J., MD; Luna, Joaquin, MD; Monsonego, Joseph, MD; Muñoz, Nubia, MD; Paavonen, Jorma, MD; Pitisuttihum, Punnee, MD; Ronnett, Brigitte M., MD; Steben, Marc, MD; Stoler, Mark H., MD; Wheeler, Cosette M., PhD; Wiley, Dorothy J., PhD, MPH; Perez, Gonzalo, MD; Saah, Alfred J., MD; Luxembourg, Alain, MD, PhD; Li, Se, PhD; DiNubile, Mark J., MD; Wagner, Monika, PhD; Velicer, Christine, PhD

doi: 10.1097/AOG.0000000000002736
Cancer: Original Research: PDF Only

OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15–26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59).

METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15–26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods.

RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs.

CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00092521 and NCT00092534.

Most low-grade and high-grade squamous vulvar and vaginal intraepithelial lesions in young women are associated with common human papillomavirus genotypes.

Department of Microbiology Infectious Diseases, the Royal Women's Hospital, Department of Microbiology, the Royal Children's Hospital, Infection and Immunity, Murdoch Children's Research Institute, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; the Department of Gynecology and Obstetrics, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; the Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas; Institut Catala d’Oncologia, IDIBELL, CIBER-ESP, RTICC, L’Hospitalet de Llobregat, Barcelona, Spain; the Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; the Department of Pathology, SMBD Jewish General Hospital and McGill University, Montréal, Québec, Canada; the Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia; the Center for Infection Research in Cancer, Moffitt Cancer Center, Tampa, Florida; the National Institute of Public Health, Cuernavaca, Morelos, Mexico; the Division of Gynecologic Oncology, University of Alabama, Birmingham, Alabama; the Department of Clinical Science, University of Bergen/Haukeland University Hospital, Bergen, Norway; the Danish Cancer Society Research Center, Copenhagen, Denmark and Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Johns Hopkins University School of Medicine, Baltimore, Maryland; the Department of Obstetrics and Gynecology, Clinica Colsanitas, Fundacion Universitaria Sanitas, Bogota, Colombia; Institut du col, Paris, France; the National Institute of Cancer, Bogotá, Colombia; the Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland; the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Direction des Risques Biologiques et de la Santé au Travail, Institut National de Santé Publique du Québec, Montréal, Québec, Canada; Robert E. Fechner Laboratory of Surgical Pathology, University of Virginia Health System, Charlottesville, Virginia; the Departments of Pathology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; UCLA School of Nursing, Los Angeles, California; Merck & Co, Inc., Kenilworth, New Jersey; Universidad del Rosario, Bogota, Colombia; and Analytica LASÉR, Montréal, Québec, Canada.

Corresponding author: Suzanne M. Garland, MD, Royal Women's Hospital, Locked Bag 300, Cnr Grattan St & Flemington Road, Parkville VIC 3052, Australia; email: suzanne.garland@thewomens.org.au.

The research in the current study and the parent studies adhered to Good Publication Practice (GPP3) and was sponsored and funded by Merck & Co, Inc., Kenilworth, New Jersey, the manufacturer of Gardasil and Gardasil9.

Financial Disclosure All academic authors have been investigators for Merck & Co, Inc., Kenilworth, New Jersey. Dr. Garland reports having received funding through her institution to perform human papillomavirus (HPV) vaccine studies for Merck & Co, Inc., CSL Limited, and GlaxoSmithKline; received payment for board membership on the Merck Global Advisory Board; and received honoraria for lectures including services on a speakers’ bureau conducted during her personal time; she also serves as co-chair of the PATRICIA publication steering committee. Dr. Joura reports having received grant support paid to his institution from Merck & Co, Inc. and GlaxoSmithKline; advisory board fees from Merck & Co, Inc. and Sanofi Pasteur MSD, and lecture fees from Sanofi Pasteur MSD, Merck & Co, Inc., GlaxoSmithKline, and Roche. Dr. Ault has received grants to his institution from Merck & Co, Inc. and the National Institutes of Health and advisory committee fees from the American College of Obstetricians and Gynecologists. He also serves on the editorial board for the National Cancer Institute. Dr. Bosch has received institutional research and educational grants from Sanofi Pasteur MSD and GlaxoSmithKline and personal travel grant and speakers’ honorarium from Sanofi Pasteur MSD and GlaxoSmithKline. Dr. Brown has served on an advisory board at Merck & Co, Inc. and has lectured on the quadrivalent HPV vaccine (honoraria received from Merck & Co, Inc. are donated to charities). His laboratory has received research funding from Merck & Co, Inc. Indiana University and Merck &Co, Inc. have an agreement that pays the university based on certain landmarks related to vaccine development. Dr. Brown receives a portion of these funds as income. Dr. Castellsagué received institutional research and educational grants from Sanofi Pasteur MSD, Merck & Co, Inc., GlaxoSmithKline, and Genticel and occasional personal travel grants and speakers' honoraria from Sanofi Pasteur MSD and Vianex. Dr. Castellsagué's family has given permission that he may be listed as a coauthor in this article. Dr. Ferenczy is a member of the Pathology Panel for Merck & Co, Inc. randomized controlled vaccine trials. Dr. Ferris has received grants to his institution and lecture fees from Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc., and advisory board and consultant fees from Merck & Co, Inc. Dr. Giuliano has received grant support and advisory board member fees to her institution from Merck & Co, Inc. Dr. Huh has received honoraria for advisory board participation with Merck & Co, Inc. Dr. Iversen has received compensation from Merck & Co, Inc. and GlaxoSmithKline to conduct vaccine clinical trials as well as scientific advisory board fees from Merck & Co, Inc. Dr. Kjaer has received scientific advisory board and speakers' fees from Sanofi Pasteur MSD and Merck & Co, Inc. and unrestricted research grants through her institution from Merck & Co, Inc. and scientific advisory board fees from Becton Dickinson. Dr. Kurman is a member of the Pathology Panel for Merck & Co, Inc. randomized controlled vaccine trials. Dr. Monsonego has received an honorarium as a member of the scientific advisory board of Sanofi Pasteur MSD, Merck & Co, Inc., Roche Diagnostics, Genprobe, and Genticel and compensation from Merck & Co, Inc. and GlaxoSmithKline to conduct vaccine trials. Dr. Muñoz has received an honorarium from Merck & Co, Inc. for being a member of the HPV Global Advisory Board. Dr. Paavonen has received research funding from Merck & Co, Inc. and GlaxoSmithKline through his institution. Dr. Pitisuttihum has received research funding from Merck & Co, Inc. through her institution. Dr. Ronnett has consulted for Merck & Co, Inc. as a member of the Pathology Panel for Merck & Co, Inc. randomized controlled vaccine trials. Dr. Steben has received grants and personal fees from Merck & Co, Inc., BD Diagnostics, Hologic/Gen-Probe, Roche Diagnostics, and Valeant as well as personal fees from Cepheid, Inovio, and Paladin. Dr. Stoler has served or is serving as a consultant in clinical trial design and as an expert pathologist for HPV vaccine and diagnostic trials for Roche, Ventana Medical Systems, Hologic/Gen-Probe, Becton Dickinson, Cepheid, Qiagen, Inovio, and Merck & Co, Inc. Dr. Wheeler has received equipment and reagents for HPV genotyping from Roche Molecular Systems and contracts for HPV vaccine studies from GlaxoSmithKline and Merck & Co, Inc. through her institution, the University of New Mexico. Dr. Wagner is a senior consultant with Analytica LASER, contracted to participate in the analysis, design, and reporting of study findings. Dr. Wiley has received an honorarium as a member of the speakers' bureau and has received industry-sponsored grant support for research from Merck & Co, Inc. Drs. Perez, Saah, Luxembourg, Li, and Velicer are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. and hold stock and stock options in the company. Dr. DiNubile was an employee of Merck Sharp & Dohme Corp and held stock and stock options in the company for most of the time this article was in preparation; he continues to hold stock options in the company through 2018 and now is an employee of BioAegis Therapeutics, North Brunswick, New Jersey, where his involvement with the article has continued. The other authors did not report any potential conflicts of interest.

Presented in part at EUROGIN 2016, June 15–18, 2016, Salzburg, Austria; AOGIN 2016, August 12–14, 2016, Singapore; EUROGIN 2017, October 8–11, 2017, Amsterdam, The Netherlands; and ISSVD 2017, September 13–15, 2017, Mendoza, Argentina.

The authors thank Jane Liao, Weifeng Xu, and Xingshu Zhu of Merck & Co, Inc. for statistical support; Adrienne Jackson and Karyn Davis of Merck & Co, Inc. for logistic support; and Elizabeth Suarez for analytical support while interning at Merck & Co, Inc. Medical writing and editorial assistance were provided by Emily Cullinan of The Lockwood Group, Stamford, Connecticut, and funded by Merck & Co, Inc.

Xavier Castellsagué is deceased.

Each author has indicated that he or she has met the journal's requirements for authorship.

Received February 05, 2018

Received in revised form April 25, 2018

Accepted May 03, 2018

© 2018 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.