Elsevier

The Lancet Oncology

Volume 13, Issue 1, January 2012, Pages 89-99
The Lancet Oncology

Articles
Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial

https://doi.org/10.1016/S1470-2045(11)70286-8Get rights and content

Summary

Background

Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults).

Methods

Healthy women aged 15–25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681.

Findings

Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5–100) in the TVC-naive and 45·7% (22·9–62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9–98·7) in the TVC-naive and 45·6% (28·8–58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15–17 year age group and progressively decreased in the 18–20 year and 21–25 year age groups. Vaccine efficacy against all AIS was 100% (31·0–100) and 76·9% (16·0–95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination.

Interpretation

PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer.

Funding

GlaxoSmithKline Biologicals.

Introduction

Nearly a decade ago, a proof-of-principle report1 on the high efficacy of a prophylactic monovalent human papillomavirus (HPV) vaccine against HPV-16 was heralded as the possible “beginning of the end” for cervical cancer,2 the major disease associated with oncogenic HPV infection. Comprehensive reports describing excellent vaccine efficacy against precursors of cervical cancer were subsequently published for the HPV-16/18 AS04-adjuvanted vaccine (Cervarix, GlaxoSmithKline Biologicals)3, 4, 5 and the HPV-6/-11/-16/-18 vaccine (Gardasil, Merck),6, 7, 8 which are now licensed in many countries.

Licensure studies focused primarily on prevention of cervical intraepithelial neoplasia grade 2 or greater (CIN2+; defined as CIN2, CIN3, adenocarcinoma in situ [AIS], or invasive cervical cancer [ICC]) as the primary endpoint, since regulatory agencies considered CIN2+ to be an acceptable surrogate endpoint for ICC. However, it was recognised at the time that CIN2+ had limitations, including potential lack of reproducibility9 and the fact that a large proportion of CIN2 cases spontaneously regress.10 CIN3 is the immediate precursor of ICC,11 and CIN3+ is generally considered to be a more predictive endpoint than CIN2+. Moreover, the prevalence of different HPV types in CIN3 lesions is more similar to that in ICC than in CIN2 lesions.12 However, the lower incidence of CIN3+ means that its use as an endpoint requires a large sample size with a long follow-up period to ensure sufficient statistical power to make firm conclusions regarding efficacy.

The PApilloma TRIal against Cancer In young Adults (PATRICIA) is the largest trial of HPV-16/18 vaccine efficacy so far. Results from event-driven analyses showed high vaccine efficacy against CIN2+ lesions associated with HPV-16 and HPV-18 infections, and protection against non-vaccine HPV types (HPV-31, HPV-33, and HPV-45).3, 4 However, information on CIN3+ endpoints was limited because of the follow-up time accrued. Here, we report end-of-study results at month 48 with roughly 68 000 person-years of follow-up, most notably vaccine efficacy against all CIN3+ and AIS lesions irrespective of HPV DNA.

Section snippets

Methods

Detailed methods of the double-blind, randomised, controlled PATRICIA trial, including full inclusion and exclusion criteria, trial locations, and dates, has been reported previously.3, 4 Briefly, healthy women aged 15–25 years, from 14 countries in Asia Pacific, Europe, Latin America, and North America, and with no more than six lifetime sexual partners were included in the trial irrespective of their baseline HPV DNA status, HPV-16/18 serostatus, or cytology. The exclusion criterion of no

Results

The first study participant was enrolled in May, 2004, and the last study visit took place in November, 2009. Participant disposition is shown in figure 2. In the TVC, mean and median follow-up times were 43·7 months (SD 11·7) and 47·4 months (range 0–62; 3·6 and 4·0 years), respectively. The number of person-years of follow-up was 42 942 in the TVC-naive, and 68 032 in the TVC. Demographic and baseline data are shown in the webappendix p 2.

The vaccine had efficacy against 6-month and 12-month

Discussion

The most important finding of the PATRICIA end-of-study analysis reported here was the high vaccine efficacy for HPV-16/18 vaccine against CIN3+ and AIS irrespective of HPV DNA in the lesion in women who were HPV naive at baseline. This represents the estimate of efficacy against the most stringent ICC precursor lesions in a cohort that approximates adolescents before sexual debut. The overall effect of the vaccine against CIN3+ is derived from protection against lesions associated with vaccine

References (28)

  • SM Garland et al.

    Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases

    N Engl J Med

    (2007)
  • Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions

    N Engl J Med

    (2007)
  • N Muñoz et al.

    Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women

    J Natl Cancer Inst

    (2010)
  • JD Carreon et al.

    CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples

    Int J Gynecol Pathol

    (2007)
  • Cited by (0)

    For the HPV PATRICIA Study Group see webappendix p 11

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