Elsevier

The Lancet Oncology

Volume 12, Issue 9, September 2011, Pages 862-870
The Lancet Oncology

Articles
Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial

https://doi.org/10.1016/S1470-2045(11)70213-3Get rights and content

Summary

Background

Anal cancer remains rare (incidence of about 1·5 per 100 000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18).

Methods

Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18–25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1:1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0·5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov, number NCT00128661.

Findings

All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62·0%, 95% CI 47·1–73·1) compared with the cervix (76·4%, 67·0–83·5; p for interaction by anatomical site 0·031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83·6% (66·7–92·8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87·9%, 77·4–94·0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article.

Interpretation

The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment.

Funding

National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals.

Introduction

Anal cancer remains rare, with an annual age-standardised incidence in the general population of about 1·5 per 100 000 for women;1 but rates have roughly doubled in recent decades in many countries, including the USA and several European nations.2, 3, 4, 5 The absolute burden of anal cancer is higher for women than men,3, 4, 5 yet, anal cancer disproportionately affects HIV-positive individuals and men who have sex with men, even if they are HIV-negative.6, 7

Human papillomavirus (HPV) causes most anal cancers, with an estimated 75–80% of HPV-associated anal cancers caused by HPV types 16 or 18.8, 9 For other HPV-associated extracervical cancers, including cancers of the oropharynx, vagina, vulva, and penis,9 variable proportions are caused by HPV infection but, when HPV is present, HPV 16 is the predominant type implicated (75–95% of the HPV-associated cancers).9

Two vaccines prevent infection with HPV 16 and HPV 18: the bivalent HPV 16 and HPV 18 vaccine (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium)10 and the quadrivalent HPV 6, 11, 16, and 18 vaccine (Gardasil, Merck, Whitehouse Station, NJ, USA).11 In women, vaccine efficacy has been shown against cervical precancer (both vaccines)10, 11 and vaginal and vulvar HPV infections and related diseases (quadrivalent only).12 For men, vaccine efficacy has been shown against penile, perianal, perineal HPV infections as a combined endpoint (quadrivalent only).13 To our knowledge, direct evidence for efficacy against anal HPV infection has only been shown in one unpublished trial14 of the quadrivalent vaccine in about 600 men who have sex with men. The bivalent vaccine has not been assessed at extracervical sites.

We assessed the efficacy of the bivalent HPV vaccine to decrease anal HPV infection using data nested in a community-based randomised trial of cervical vaccine efficacy in young adult women.

Section snippets

Patients

Women included in this study were participants in a double-blind, randomised clinical trial initially designed to assess the efficacy of a bivalent HPV vaccine against persistent type-specific infection with HPV 16, HPV 18, or both (from here on referred to as HPV 16/18) and associated precancerous lesions at the cervix.15, 16 The study enrolled women residing in Guanacaste and selected areas of Puntarenas, Costa Rica, identified via a census, between June 28, 2004, and Dec 21, 2005. Main

Results

Of the 7466 women randomly assigned to HPV or control vaccines, 6352 attended the 4-year study visit (figure). 384 of women were virgins and therefore not eligible for anal specimen collection. Another 1744 women refused anal specimen collection. After exclusion of 14 missing anal HPV results because of inadequate specimen volume, the full analytical cohort consisted of 4210 women. Median follow-up time was 54·2 months (4·5 years) and was similar between groups (HPV 54·2 months [range

Discussion

A randomised analysis of data from our community-based HPV vaccine trial in Costa Rica shows that the bivalent HPV vaccine is efficacious against prevalent anal HPV 16/18 infections in young women measured 4 years after vaccination. We also show, to our knowledge for the first time, evidence of cross-protection against a composite endpoint of HPV types 31/33/45 at an extragenital site; providing confirmation that the protection afforded by the bivalent HPV vaccine goes beyond the HPV types

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