ArticlesOverall 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
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.
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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)
- 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
Lancet
(2007) - 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
Lancet
(2009) - et al.
The carcinogenicity of human papillomavirus types reflects viral evolution
Virology
(2005) - et al.
Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional survey
Lancet Oncol
(2010) - et al.
Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study
Lancet
(2011) - et al.
Trends in mortality from cervical cancer in the Nordic countries: association with organised screening programmes
Lancet
(1987) - et al.
Cervical cancer incidence can increase despite HPV vaccination
Lancet Infect Dis
(2010) - et al.
A controlled trial of a human papillomavirus type 16 vaccine
N Engl J Med
(2002) The beginning of the end for cervical cancer?
N Engl J Med
(2002)Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6·4 years
Lancet
(2009)
Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases
N Engl J Med
Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions
N Engl J Med
Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women
J Natl Cancer Inst
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
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For the HPV PATRICIA Study Group see webappendix p 11