Elsevier

Vaccine

Volume 24, Supplement 3, 21 August 2006, Pages S78-S89
Vaccine

Chapter 9: Clinical applications of HPV testing: A summary of meta-analyses

https://doi.org/10.1016/j.vaccine.2006.05.117Get rights and content

Abstract

Background

More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods.

Material and methods

A summary is given from recently published meta-analyses on three possible clinical applications of human papillomavirus (HPV)-DNA testing: triage of women with equivocal or low-grade cytological abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer.

Results

Consistent evidence is available indicating that HPV-triage with the Hybrid Capture-2 assay (HC2) is more accurate (significantly higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. When triaging women with low-grade squamous intraepithelial lesions (LSIL), a reflex HC2 test does not show a significantly higher sensitivity, but a significantly lower specificity compared to a repeat Pap smear. After treatment of cervical lesions, HPV testing easily detects (with higher sensitivity and not lower specificity) residual or recurrent CIN than follow-up cytology. Primary screening with HC2 generally detects 23% (95% confidence interval, CI: 13–23%) more CIN-2, CIN-3, or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASCUS) or LSIL, but is 6% (95% CI: 4–8%) less specific. By combined HPV and cytology screening, a further 4% (95% CI: 3–5%) more CIN-3 lesions can be identified but at the expense of a 7% (95% CI: 5–9%) loss in specificity, in comparison with isolated HC2 screening.

Conclusions

Sufficient evidence exists to recommend HPV testing in triage of women with atypical cytology and in surveillance after treatment of CIN lesions. In the United States, recently reviewed knowledge has resulted in the approval of combined cytology and HC2 primary screening in women older than 30 years. However, in Europe, cytology-based screening still remains the standard screening method. The European screening policy will be reviewed based on the longitudinal results of randomised population trials which are currently underway.

Introduction

The recognition of the strong causal relationship between persistent infection of the genital tract with high-risk HPV types and occurrence of cervical cancer [1] has resulted in the development of a series of HPV-DNA or -RNA detection systems. Detection of high-risk HPV-DNA is considered to be potentially useful in three clinical applications: first as a primary screening test, solely or in combination with a Pap smear to detect cervical cancer precursors; further as a triage test to select women showing minor cytological lesions in their Pap smears needing referral for diagnosis and treatment and, finally, as a follow-up test for women treated for high-grade intraepithelial lesion with local ablative or excisional therapy to predict cure or failure of treatment.

In this chapter, we will summarise and update recently conducted meta-analyses and systematic reviews which synthesise current knowledge on the performance of HPV-DNA testing in each of these three clinical applications.

Section snippets

Triage of cases with minor cytological abnormalities

A first meta-analysis [2], [3] addressed the cross-sectional accuracy of HPV-DNA testing to triage women with an index smear showing atypical squamous cells of unspecified significance (ASCUS) or atypical glandular cells of unspecified significance (AGUS) where the purpose is to detect cervical intraepithelial neoplasia of grade II or worse (CIN-2+) confirmed by histology. Studies were included if the HC2 assay (cocktail of probes for 13 high-risk HPV types) was applied to women with a prior

Absolute accuracy

We retrieved 20 studies, where the accuracy of HC2 for triage of women with findings of ASCUS could be assessed (see Table 1, a1–a20). On average, in 9.7% (95% CI: 7.7–11.7%) and 4.3% (95% CI: 2.7–5.9%) of cases, underlying CIN-2+ or CIN-3+ was found (Table 2). The variation of the accuracy of HC2 triage in detecting these high-grade CIN is displayed in the forest plots in Fig. 1. Overall, HC2 had a sensitivity of 92.5% (95% CI: 90.1–94.9%) and 95.6% (95% CI: 92.8–98.4%) for detecting

Discussion

From this updated review, we can conclude that for the detection of underlying high-grade CIN, virological testing is more sensitive than the cytological examination of a Pap smear, in whatever clinical application. However, the absolute and relative specificity clearly differs from one application to the other. The studies we have pooled had essentially a cross-sectional design. To translate this pooled knowledge into clinical recommendations, we must take into account the natural history of

Disclosed potential conflicts of interest

MA: Travel Grants (GlaxoSmithKline)

PS: Research Grants (Digene Corporation, Roche)

CJLM: Consultant (Digene Corporation, GlaxoSmithKline)

JD: Consultant (Merck and Co., Inc., Sanofi-Pasteur MSD)

Acknowledgements

We received financial support from (1) the European Commission (Directorate of SANCO), Luxembourg, Grand-Duché du Luxembourg, through the European Cancer Network; (2) the DWTC/SSTC (Federal Services for Scientific, Cultural and Technical Affairs of the Federal Government, Belgium) and (3) the Gynaecological Cancer Cochrane Review Collaboration (Bath, UK). We are grateful to Bernadette Claus and Ine Vanmarsenille (of the Scientific Institute of Public Health, Brussels, Belgium) for their

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