Elsevier

Vaccine

Volume 30, Supplement 5, 20 November 2012, Pages F88-F99
Vaccine

Review
Evidence Regarding Human Papillomavirus Testing in Secondary Prevention of Cervical Cancer

https://doi.org/10.1016/j.vaccine.2012.06.095Get rights and content

Abstract

More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. A summary is given from recent meta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV) testing: triage of women with equivocal or low-grade cytologic 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. Consistent evidence is available indicating that HPV-triage with the Hybrid Capture® 2 assay (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. Several other tests show at least similar accuracy but mRNA testing with the APTIMA® (Gen-Probe Inc., San Diego, CA, USA) test is similarly sensitive but more specific compared to HC2. In triage of low-grade squamous intraepithelial lesions (LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology. The APTIMA® test is more specific than HC2 without showing a loss in sensitivity. Identification of DNA of HPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women at highest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower than full-range high-risk HPV (hrHPV) testing. After conservative treatment of cervical pre-cancer, HPV testing picks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-grade CIN than follow-up cytology. Primary screening for hrHPV generally detects more CIN2, CIN3 or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL, but is less specific. Combined HPV and cytology screening provides a further small gain in sensitivity at the expense of a considerable loss in specificity if positive by either test is referred to colposcopy, in comparison with HPV testing only. Randomised trials and follow-up of cohort studies consistently demonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30 years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologically negative. The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV) versus only HPV-negative women is small. HC2, GP5+/6+ PCR (polymerase chain reaction), cobas® 4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, Des Plaines, IL, USA) can be considered as clinically validated for use in primary screening. The loss in specificity associated with primary HPV-based screening can be compensated by appropriate algorithms involving reflex cytology and/or HPV genotyping for HPV16 or 18. There exists a substantial evidence base to support that HPV testing is advantageous both in triage of women with equivocal abnormal cytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 years or older. However, the possible advantages offered by HPV-based screening require a well organised program with good compliance with screening and triage policies.

This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and Related Diseases” Vaccine Volume 30, Supplement 5, 2012.

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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