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

Abstract

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.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that EAJ has received advisory board fees from Merck, and funding through his institution to conduct epidemiological HPV studies for GlaxoSmithKline. He has received lecture fees from Merck, Sanofi Pasteur MSD, and GlaxoSmithKline. SMG has received advisory board fees and grant support from Commonwealth Serum Laboratories and GlaxoSmithKline, and lecture fees from Merck and Sanofi Pasteur MSD. She has received funding through her institutions to conduct HPV vaccine studies for GlaxoSmithKline. DGF has received consultancy fees and funding through his institution to conduct HPV vaccine studies for GlaxoSmithKline, and lecture fees, advisory board fees, and consulting from Merck. GP has received lecture fees from Merck and Sanofi Pasteur MSD and is now an employee of Merck. KAA has received consultancy and advisory board fees from Merck, and has received funding through his institution to conduct HPV vaccine studies for GlaxoSmithKline, Roche, and the National Institute for Allergy and Infectious Diseases, and for non-vaccine clinical trials for Gen-Probe. WKH has received advisory board and lecture fees from Merck. He has received advisory board fee from GlaxoSmithKline. In addition, EAJ, SMG, DGF JP, KA, and WKH have received funding through their institutions to conduct HPV vaccine studies for Merck. HLS, MKJ, GP, and RMH and are employees of Merck and potentially own stock or stock options in the company.

Figures

Fig 1 Study design for assessing effect of quadrivalent HPV vaccine on incidence of subsequent HPV related disease among women who had undergone surgery for cervical disease or who were diagnosed with vulvar or vaginal disease. Subsequent disease was measured from 60 days after surgery or diagnosis

Fig 2 Participant flow through study

Fig 3 Incidence of HPV related disease detected ≥60 days after cervical surgery or diagnosis of vulvar or vaginal disease among women who did not receive quadrivalent HPV vaccine (that is, placebo recipients)

Fig 4 Time to detection of any HPV related disease (A) or vulvar or vaginal disease (B) after cervical surgery; and of any HPV related disease (C) or any cervical disease (D) after diagnosis of vulvar or vaginal disease. Case counting began 60 days after surgery or diagnosis