Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data

Objectives To determine the effect of human papillomavirus (HPV) quadrivalent vaccine on the risk of developing subsequent disease after an excisional procedure for cervical intraepithelial neoplasia or diagnosis of genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia. Design Retrospective analysis of data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants Among 17 622 women aged 15–26 years who underwent 1:1 randomisation to vaccine or placebo, 2054 received cervical surgery or were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia. Intervention Three doses of quadrivalent HPV vaccine or placebo at day 1, month 2, and month 6. Main outcome measures Incidence of HPV related disease from 60 days after treatment or diagnosis, expressed as the number of women with an end point per 100 person years at risk. Results A total of 587 vaccine and 763 placebo recipients underwent cervical surgery. The incidence of any subsequent HPV related disease was 6.6 and 12.2 in vaccine and placebo recipients respectively (46.2% reduction (95% confidence interval 22.5% to 63.2%) with vaccination). Vaccination was associated with a significant reduction in risk of any subsequent high grade disease of the cervix by 64.9% (20.1% to 86.3%). A total of 229 vaccine recipients and 475 placebo recipients were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia, and the incidence of any subsequent HPV related disease was 20.1 and 31.0 in vaccine and placebo recipients respectively (35.2% reduction (13.8% to 51.8%)). Conclusions Previous vaccination with quadrivalent HPV vaccine among women who had surgical treatment for HPV related disease significantly reduced the incidence of subsequent HPV related disease, including high grade disease. Trial registrations NCT00092521 and NCT00092534

[1]  Henry C Kitchener,et al.  Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial , 2007, The Lancet.

[2]  Susun Bellew,et al.  Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women , 2010 .

[3]  F. X. Bosch,et al.  Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions , 2007 .

[4]  P. Langley,et al.  The costs of treating external genital warts in England and Wales: a treatment pattern analysis , 2004, International journal of STD & AIDS.

[5]  Charlotte Paul,et al.  Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. , 2008, The Lancet. Oncology.

[6]  C. Wheeler,et al.  The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. , 2009, The Journal of infectious diseases.

[7]  Cosette M Wheeler,et al.  Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. , 2005, The Lancet. Oncology.

[8]  C. Wheeler,et al.  Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials , 2007, The Lancet.

[9]  Joakim Dillner,et al.  Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. , 2010, Journal of the National Cancer Institute.

[10]  J. T. Cox,et al.  American Cancer Society Guideline for Human Papillomavirus (HPV) Vaccine Use to Prevent Cervical Cancer and Its Precursors , 2007, CA: a cancer journal for clinicians.

[11]  F. Z. Zarama Márquez,et al.  [Risk factors for cervical cancer]. , 2003, Ginecologia y obstetricia de Mexico.

[12]  C. Wheeler,et al.  Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection , 2009, Human vaccines.

[13]  M. Lehtinen,et al.  Is smoking an independent risk factor for invasive cervical cancer? A nested case-control study within Nordic biobanks. , 2008, American journal of epidemiology.

[14]  S. Franceschi,et al.  Human Papillomavirus Genotype Distribution in Low-Grade Cervical Lesions: Comparison by Geographic Region and with Cervical Cancer , 2005, Cancer Epidemiology Biomarkers & Prevention.

[15]  N. Muñoz,et al.  Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-blind trial , 2009, The Lancet.

[16]  Charles M Kodner,et al.  Management of genital warts. , 2004, American family physician.

[17]  Daron G Ferris,et al.  Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. , 2007, The New England journal of medicine.

[18]  C. Wheeler,et al.  Impact of an HPV6/11/16/18 L1 virus‐like particle vaccine on progression to cervical intraepithelial neoplasia in seropositive women with HPV16/18 infection , 2011, International journal of cancer.

[19]  Edson Duarte Moreira Júnior,et al.  Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. , 2007, The New England journal of medicine.

[20]  R. Maw,et al.  An international survey of patients with genital warts: perceptions regarding treatment and impact on lifestyle , 1998, International journal of STD & AIDS.

[21]  I. Chan,et al.  Exact power and sample size for vaccine efficacy studies , 1998 .

[22]  Diane Solomon,et al.  2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. , 2007, American journal of obstetrics and gynecology.

[23]  B Romanowski,et al.  Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women , 2009, The Lancet.

[24]  K. Ault.  Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials , 2007, The Lancet.

[25]  S. Kjaer,et al.  A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD. , 2010, Vaccine.

[26]  C. Wheeler,et al.  Efficacy of Human Papillomavirus-16 Vaccine to Prevent Cervical Intraepithelial Neoplasia: A Randomized Controlled Trial , 2006, Obstetrics and gynecology.

[27]  H. Jessen,et al.  HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. , 2011, The New England journal of medicine.

[28]  D. N. Catotti,et al.  The psychosocial impact of human papillomavirus infection: implications for health care providers , 1996, International journal of STD & AIDS.

[29]  M. Henry.  The Bethesda System 2001: an update of new terminology for gynecologic cytology. , 2003, Clinics in laboratory medicine.

[30]  E. Unger,et al.  Post-licensure monitoring of HPV vaccine in the United States. , 2010, Vaccine.

[31]  R. Railkar,et al.  Natural history of genital warts: analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. , 2009, The Journal of infectious diseases.

[32]  A. Moscicki,et al.  External genital warts: diagnosis, treatment, and prevention. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[33]  End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age , 2011, British Journal of Cancer.

[34]  N. Weiss,et al.  Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. , 2009, Vaccine.

[35]  E. Dasbach,et al.  The health and economic burden of genital warts in a set of private health plans in the United States. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[36]  C. Lacey.  Therapy for genital human papillomavirus-related disease. , 2005, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[37]  S. Garland,et al.  Pregnancy and Infant Outcomes in the Clinical Trials of a Human Papillomavirus Type 6/11/16/18 Vaccine: A Combined Analysis of Five Randomized Controlled Trials , 2009, Obstetrics and gynecology.

[38]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[39]  S. Garland,et al.  Human Papillomavirus Infections and Vulvar Disease Development , 2009, Cancer Epidemiology Biomarkers & Prevention.

[40]  C. Wheeler,et al.  Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. , 2006, Vaccine.

[41]  L. Shulman.  Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection. , 2007, The Journal of infectious diseases.

[42]  S. Wacholder,et al.  Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. , 2005, The Journal of infectious diseases.

[43]  M. Stoler,et al.  The Distribution of Low and High-risk HPV Types in Vulvar and Vaginal Intraepithelial Neoplasia (VIN and VaIN) , 2006, The American journal of surgical pathology.

[44]  M. Lehtinen,et al.  Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. , 2007, Vaccine.