Impact of vaccination with Cervarix™ on subsequent HPV-16/18 infection and cervical disease in women 15–25 years of age

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Abstract

Cervical cancer of both squamous and adenocarcinoma types is considered virtually 100% attributable to human papillomavirus (HPV) infection. HPV-16 and -18 are the predominant types worldwide accounting for over 70% of all cervical cancer. Persistent oncogenic HPV infection has been confirmed as one key determinant in the development of cervical precancer (cervical intraepithelial neoplasia [CIN] 2+) and cervical cancer. The impact of prophylactic HPV vaccination on the reduction of virological and cytohistological outcomes related to HPV-16 and -18 has been evaluated in clinical trials with the HPV-16/18 AS04-adjuvanted cervical cancer vaccine (Cervarix™) through a Phase IIb study with a long-term follow-up of efficacy up to 5.5 years, and a large Phase III trial in women 15–25 years of age. These individual studies include populations with different underlying risk factors, each of which shows high efficacy against both HPV-16/18 persistent infections and CIN2+. When the two studies are combined and the respective populations are evaluated, vaccine efficacy against HPV-16 and -18-related CIN2+ remains at 100%. As this vaccine is used over time in universal prophylactic HPV-16/18 vaccination of girls and women, reductions in cervical cancers at both the individual and public health levels will be appreciated.

Introduction

Oncogenic human papillomavirus (HPV) has been identified in nearly all cervical cancers worldwide [1]. In particular, HPV types 16 and 18 are clearly established as the two most commonly found oncogenic types in both squamous cell carcinomas (SCC) and adenocarcinomas. Among SCC, HPV-16 accounts for 55% and HPV-18 another 13%, whereas among adenocarcinomas, while HPV-16 still accounts for about half, HPV-18 is responsible for 30–40% of cases [2]. Worldwide, HPV-16 and -18 together account for 70% or more of all cervical cancers [3].

Persistent infections caused by oncogenic HPV types such as 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 progress to precancers and, over the long term, invasive cancer [4], [5], [6], [7], [8], [9], [10], [11]. Infection with HPV-16 was found to be more likely to persist than other high-risk types and to result in CIN3 or cancer in 20% of those infected within 10 years [12], [13], [14]. This aggressive oncogenesis is reflected in the very high positive predictive value of HPV-16 for cervical cancer [15]. HPV-18 is the second most aggressive oncogenic type with both a short-term and long-term increased risk of CIN2 and CIN3+, respectively [12], [13], [14]. Taken together, persistent HPV-16 and -18 infections are considered the most aggressive since they confer a preferential risk for both squamous cell and adenocarcinomas of the cervix and hence are a surrogate marker for HPV vaccine efficacy evaluation.

Detection of high-grade precancers (CIN2/3 and adenocarcinoma in situ) has evolved as the primary aim of many cervical cancer screening programs because of the high success rate of detecting and treating cervical cancers. Hence, these high-grade precancers are a surrogate marker for cancer prevention and vaccine efficacy evaluation [16].

In the clinical arena, where treatment only exists for visible lesions and not persistent infection, routine testing for cytologic abnormalities is followed by diagnostic histologic sampling. The impact of the vaccine will be seen both in the reduction of abnormal screening tests as well as in the reduction of women needing follow-up diagnostic sampling. For instance, in developed countries with screening programs, HPV-16 and -18 account for 41–57% of high-grade squamous intraepithelial lesions (HSIL), 15–32% of low-grade squamous intraepithelial lesions (LSIL), and 8–19% of atypical squamous cells of undetermined significance (ASC-US) [3]. Despite the higher prevalence of HPV-16 and -18 in any type of invasive cervical cancer than in other precursor cervical lesions, the absolute numbers of women with detected HPV-16/18-related cervical lesions in developed countries are an order of magnitude larger than those with HVP-16/18-related invasive cervical cancer.

A simple exercise to appreciate the current magnitude of detected HPV-16/18-related cytology and CIN disease can be demonstrated with data from a large country such as the US, where screening is organized on an opportunistic basis. Every year, approximately 55 million women in the USA are screened for cervical cancer by cytology, resulting in approximately 1.1 million cases of HPV-16/18-related cervical abnormalities. The absolute numbers contributing to the different cervical disease states are: about 70% of 11,000 (i.e. 7700) cases of cancer; about 50% of 550,000 (i.e. 275,000) cases of HSIL; about 25% of 1.6 million (i.e. 400,000) cases of LSIL; and about 15% of 2.7 million (i.e. 405,000) cases of ASC-US detection [8], [17]. These 1.1 million HPV-16/18-related lesions, representing a maximum number of lesions, require frequent follow-up or treatment, are clinically and economically important, and could, theoretically, be fully preventable by vaccination under the following assumptions: complete population coverage, 100% vaccine efficacy, and lifetime duration of vaccine efficacy [17].

The purpose of this article is to delineate the extent to which a promising new cervical cancer vaccine, Cervarix™, could eventually reduce the burden of cervical lesions and invasive cancer attributed to persistent HPV-16 and -18 infections in two different target populations: young women unexposed to HPV infection, and a cohort of women both exposed and unexposed to HPV infections. Clinical trials with Cervarix™ have demonstrated that the cervical cancer vaccine is highly efficacious in preventing HPV-16/18 infections and associated cytohistological abnormalities [18], [19], [20]. The potential impact of Cervarix™ on the prevention of precancers and invasive cancers detected through cervical screening is best described by combining all available trial data for Cervarix™ using the scientifically more rigorous definition of persistent HPV attribution to the CIN lesion (see Jenkins D., this issue, page 18–25).

Section snippets

Target populations

These clinical trials are designed to reflect the varied natural patterns of exposure to genital infection with oncogenic HPV and use detectable virological and clinicopathological endpoints. The design of each Cervarix™ trial aims to assess the impact of vaccination on age groups which represent the varying HPV exposure status expected of different groups in the whole population of women from 10 years of age onwards in many countries. Evaluations in clinical trials include women with a variety

Implications

In a broad sense, from the public health perspective, HPV vaccination will impact both the incidence of cervical cancer and the modalities and interval frequencies used to screen for cervical cancer. It is expected that new screening technologies, including molecular HPV testing as well as automated cytology processing, will be evaluated with the goal of screening at less frequent intervals throughout a woman's life. As the prevalence of HPV-related disease decreases in the general female

Conclusions

Virus-like particle vaccines directed against HPV-16 and -18 are highly efficacious in preventing HPV-16/18-related infection and disease. A vaccine such as Cervarix™ should reduce cervical cancer rates over the long term because of its efficacy in both unexposed women and populations of women with and without previous HPV exposure.

Conflict of interest statement

DMH received clinical trial support for and speaking honoraria about HPV vaccines from both Merck and Co. and GlaxoSmithKline, Inc.

Acknowledgments

Thank you to all the investigators, staff and women enrolled globally in the Phase IIb primary efficacy trial, the extended follow-up study (NTC00120848) and the Phase III PATRICIA trial (NCT 001122681). Thank you also to Susan Wieting and Meridian HealthComms Ltd for logistical support.

References (32)

  • TjalmaW.A. et al.

    Role of human papillomavirus in the carcinogenesis of squamous cell carcinoma and adenocarcinoma of the cervix

    Best Pract. Res. Clin. Obstet. Gynaecol.

    (2005)
  • UmezakiK. et al.

    Distribution of epithelial-specific antigen in uterine cervix with endocervical glandular dysplasia

    Gynecol. Oncol.

    (1997)
  • KyrgiouM. et al.

    Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis.

    Lancet

    (2006)
  • MuñozN. et al.

    Epidemiologic classification of human papillomavirus types associated with cervical cancer.

    N. Engl. J. Med.

    (2003)
  • SmithJ.S. et al.

    Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update

    Int. J. Cancer

    (2007)
  • DalsteinV. et al.

    Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study

    Int. J. Cancer

    (2003)
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