Elsevier

The Lancet

Volume 369, Issue 9576, 2–8 June 2007, Pages 1861-1868
The Lancet

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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

https://doi.org/10.1016/S0140-6736(07)60852-6Get rights and content

Summary

Background

Cervical cancer and its obligate precursors, cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3), and adenocarcinona in situ (AIS), are caused by oncogenic human papillomavirus (HPV). In this combined analysis of four clinical trials we assessed the effect of prophylactic HPV vaccination on these diseases.

Methods

20 583 women aged 16–26 years were randomised to receive quadrivalent HPV6/11/16/18 vaccine (n=9087), its HPV16 vaccine component (n=1204), or placebo (n=10 292). They underwent periodic Papanicolaou testing, with colposcopy or biopsy for detected abnormalities. The primary composite endpoint was the combined incidence of HPV16/18-related CIN2/3, AIS, or cervical cancer. These trials are registered at ClinicalTrials.gov, numbers NCT00365378, NCT00365716, NCT00092521, and NCT00092534.

Findings

Mean follow-up was 3·0 years (SD 0·66) after first dose. In women negative for HPV16 or HPV18 infection during the vaccination regimen (n=17 129, per protocol), vaccine efficacy was 99% for the primary endpoint (95% CI 93–100), meeting the statistical criterion for success. In an intention-to-treat analysis of all randomised women (including those who were HPV16/18 naive or HPV16/18-infected at day 1), efficacy was 44% (95% CI 31–55); all but one case in vaccine recipients occurred in women infected with HPV16 or HPV18 before vaccination. In a second intention-to-treat analysis we noted an 18% reduction (95% CI 7–29) in the overall rate of CIN2/3 or AIS due to any HPV type.

Interpretation

Administration of HPV vaccine to HPV-naive women, and women who are already sexually active, could substantially reduce the incidence of HPV16/18-related cervical precancers and cervical cancer.

Introduction

Cervical cancer, the second leading cause of death from cancer in women worldwide,1 is caused by infection with oncogenic types of human papillomavirus (HPV). The main histological types are adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma, which are preceded by dysplastic lesions (cervical intraepithelial neoplasia grades 2 and 3 [CIN2/3], and adenocarcinoma in situ [AIS], respectively). Although screening programmes using the Papanicolaou (Pap) test have led to substantial declines in mortality caused by cervical cancer in developed countries, about 230 000 women per year die from cervical cancer worldwide.1 Even in developed countries, cervical cancer remains the second leading cancer in women younger than 45 years.1

HPV16 and HPV18 are responsible for about 70% of all invasive cervical cancers.2 Two vaccines targeting these types have been developed.3, 4, 5 One of them, a quadrivalent HPV vaccine that also targets HPV6 and HPV11 (the types that cause 90% of genital warts), has been licensed in several countries.4, 5

Although the most important public-health effect of prophylactic HPV vaccines is prevention of cervical cancer, phase III clinical trials to demonstrate this endpoint are neither feasible nor ethical. Thus, WHO and the Vaccines and Related Biologic Products Advisory Committee to the US Food and Drug Administration recommended that phase III trials for HPV vaccines be designed to show efficacy against CIN2/3 and AIS with high precision as a condition of licensure, since these lesions are the obligate and immediate precursors to invasive cancer.6, 7 The committee also recommended that trials of such vaccines should enrol participants irrespective of baseline HPV status or Pap test results, so that trial results would indicate the efficacy and safety of the vaccine in a general population that includes women who have already been infected with HPV.

To accommodate these requirements, four similarly designed efficacy trials of HPV16 and quadrivalent HPV vaccine were done.4, 5, 8, 9 A combined analysis of the four studies was prespecified to maximise the precision of vaccine efficacy with respect to CIN2/3 and AIS related to HPV16 and HPV18. These trials did not exclude women with serological evidence of previous infection with HPV, DNA evidence of ongoing HPV infection, abnormal cytology, or cervical neoplasia at enrolment. As HPV vaccines are meant to be prophylactic, the primary efficacy evaluations were done in women who were naive to the relevant HPV-types before vaccination. Supplementary analyses were done to assess the effect of the vaccine on the general study population with respect to disease associated with HPV16/18, and for disease due to any HPV type.

Section snippets

Study designs

20 583 women (the majority aged 16–23 years; two aged 15 years and 79 aged 24–26 years) from the Americas, Europe, and Asia-Pacific were enrolled in one of four double-blind, placebo-controlled, randomised trials between October, 1998, and May, 2003 (table 1). Recruitment was done mainly at university student health and urban clinics through advertisements approved by the local institutional review boards, and by word of mouth. Some radio or television advertisements and educational seminars

Results

The four studies enrolled a total of 20 583 women. The proportions of women with specific baseline characteristics were similar between the two vaccination groups (table 2). Of the randomised women, 17 129 (83%) were included in one or both of the type-specific per-protocol populations for HPV16/18-related endpoints. The most common reason for exclusion from the per-protocol populations was detection of antibodies to HPV16 or HPV18 at day 1, detection of HPV16 or HPV18 DNA between day 1 and

Discussion

Our findings showed that prophylactic administration of a monovalent HPV16 or quadrivalent HPV6/11/16/18 L1 virus-like-particle vaccine was highly efficacious in preventing HPV16/18-related CIN2/3 and AIS, leading to an inference of prophylactic effectiveness of the vaccines against HPV16 and HPV-18-related cervical cancer. In all studies, vaccination was well tolerated.4, 5, 9

The confidence with which these efficacy results can be extrapolated to prevention of cervical cancer relates to the

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