ReviewEvidence Regarding Human Papillomavirus Testing in Secondary Prevention of Cervical Cancer
Highlights
► In triage of LSIL, methods more specific than general hrHPV DNA tests may be preferred. ► To predict failure of treatment of high-grade cervical precancer, HPV tests are more sensitive than and as specific as cytology. ► In screening, a negative hrHPV DNA test is associated with a low future risk of precancer and cancer. ► HPV-screening followed by cytology triage of HPV+ women (30 years or older) is more effective than cytology-based screening.
Introduction
The recognition of the strong causal relationship between persistent cervical infection with high-risk human papillomavirus (HPV) types and occurrence of cervical cancer [1] has led to the development of a series of HPV DNA or RNA tests. Detection of high-risk (hr) HPV DNA is considered to be potentially useful in three clinical applications: (1) as a triage test to select women, whose cytology is equivocal or mildly abnormal, needing referral for diagnosis and treatment; (2) as a follow-up test for women treated for high-grade cervical intraepithelial neoplasia (CIN) with local ablative or excisional therapy to predict cure or failure of treatment; and (3) as a primary screening test, solely or in combination with cervical cytology to detect cervical precancer and to rule it out in the predominantly healthy population.
In this chapter, we will update and extend previously conducted meta-analyses and systematic reviews which synthesize current knowledge on the performance of HPV testing in each of these three clinical applications. In particular, attention is given on the evidence regarding HPV-based primary screening as a new paradigm of cervical cancer prevention and on the identification of HPV assays, which fulfil minimal requirements, allowing use in primary cervical cancer screening.
Section snippets
Material and methods
For the purpose of this paper, previous meta-analyses on the absolute and relative performance of HPV- and cytology-based testing of cervical specimens were extended and updated [2]. New HPV-related assays, in addition to the Hybrid Capture® 2 (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2), were evaluated as well, including both other HPV DNA assays and E6/E7 mRNA essays. Three major clinical applications were distinguished: (1) triage of women with a cervical cytology of
ASC-US
In the 39 retrieved studies (web table liststudies.xls-ASCUStriage), the pooled sensitivity of HC2 was 90.4% (95% confidence interval [CI]: 88.1–92.3%) and 93.7% (95% CI: 90.4–95.9%), whereas the pooled specificity was 58.3% (95% CI: 53.6–62.9%) and 52.3% (95% CI: 45.7–58.7%) for predicting presence or absence of CIN2+ or CIN3+, respectively (Table 1). In 10 of the 39 studies, a repeat smear was also taken. In these 10 studies, the pooled sensitivity of HC2 was significantly higher than that of
Discussion
In this paper, a large body of data from clinical trials has been synthesised. Systematic assessment of the evidence base is an essential step for developing practice guidelines.
Conclusions
The evidence base supports the notion that hrHPV tests can provide an advantage in triage of women with equivocal cytologic lesions and in the follow-up after treatment of cervical precancer. However, in triage of LSIL, more specific tests are preferred. HPV DNA or RNA genotyping for a limited number of HPV types allow identification of women at highest risk, but women testing negative for these tests still will need further testing.
The evidence base indicates that hrHPV DNA testing with a
Disclosed potential conflicts of interest
MA: See acknowledgements.
GR, AA, GO, GK, RS, JP: Have disclosed no potential conflicts of interest.
CJLMM: Scientific advisory board (Qiagen), speakers office (GSK, Roche), research grant (Abbott), shares minority (Self-Screen B.V)
MP: Advisory Board (Roche); Consultant (Abbott); Research Grants (Abbott, Roche); Speakers Bureau (Abbott, Roche); Travel Grants (Abbott, Roche).
PN: Has received lecture fees from Abbott Laboratories.
Acknowledgements
We acknowledge and thank the following authors who have provided additional non-published data which were used in the meta-analyses: S. Andersson, S. Belinson, J. Cage, F. Coutlée, K. Cuschieri, J. Cuzick, M. Fröberg, M. Guo, P. Halfon, S. Hibbits, M.Z. Huang, S. Huang, S. Kulasingam, A. Lytwyn, J. Monsonego, M. Nasioutziki, P. Naucler, A. Pista, R. Pretorius, R. Sankaranarayanan, S. Ratnam, M. Reuschenbach, G. Ronco, M. Stoler, K. Syrjanen, A. Szarewski and N. Wentzensen. L. Houthuys is
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