HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial

Summary

Background

Testing for human papillomavirus (HPV) DNA is reportedly more sensitive than cytology for the detection of high-grade cervical intraepithelial neoplasia (CIN). The effectiveness of HPV testing in primary cervical screening was assessed in the ARTISTIC trial, which was done over two screening rounds approximately 3 years apart (2001–03 and 2004–07) by comparing liquid-based cytology (LBC) combined with HPV testing against LBC alone.

Methods

Women aged 20–64 years who were undergoing routine screening as part of the English National Health Service Cervical Screening Programme in Greater Manchester were randomly assigned (between July, 2001, and September, 2003) in a ratio of 3:1 to either combined LBC and HPV testing in which the results were revealed and acted on, or to combined LBC and HPV testing where the HPV result was concealed from the patient and investigator. The primary outcome was the detection rate of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in the second screening round, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821.

Findings

There were 24 510 eligible women at entry (18 386 in the revealed group, 6124 in the concealed group). In the first round of screening 233 women (1·27%) in the revealed group had CIN3+, compared with 80 (1·31%) women in the concealed group (odds ratio [OR] 0·97, 95% CI 0·75–1·25; p>0·2). There was an unexpectedly large drop in the proportion of women with CIN3+ between the first and second rounds of screening in both groups, at 0·25% (29 of 11 676) in the revealed group and 0·47% (18 of 3866 women) in the concealed group (OR 0·53, 95% CI 0·30–0·96; p=0·042). For both rounds combined, the proportion of women with CIN3+ were 1·51% (revealed) and 1·77% (concealed) (OR 0·85, 95% CI 0·67–1·08; p>0·2).

Interpretation

LBC combined with HPV testing resulted in a significantly lower detection rate of CIN3+ in the second round of screening compared with LBC screening alone, but the effect was small. Over the two screening rounds combined, co-testing did not detect a higher rate of CIN3+ or CIN2+ than LBC alone. Potential changes in screening methodology should be assessed over at least two screening rounds.

Funding

National Institute of Health Research Health Technology Assessment Programme.

Introduction

In primary cervical screening, human papillomavirus (HPV) testing is more sensitive than cytology for the detection of high-grade cervical intraepithelial neoplasia (CIN), although it has been shown to be less specific, especially in younger women.¹ HPV testing is approved in the USA for primary screening when co-testing with cytology, and is also approved for the triage of women with atypical cells of undetermined significance (ASCUS) cytology, as it has a high negative predictive value and greater sensitivity than repeat cytology.2, 3 Randomised trials comparing conventional cytology plus HPV testing with cytology alone in Sweden⁴ and the Netherlands⁵ recently reported increased detection of high-grade CIN in the initial (prevalence) round, reduced incidence in the subsequent round, and no difference when the two rounds were combined. Liquid-based cytology (LBC) has replaced conventional Papanicolaou cytology as the platform for cervical cytology in the UK, and is replacing conventional cytology in a number of other developed countries. Advantages of LBC include more rapid screening of slides, a substantial reduction in unsatisfactory cervical samples requiring repeat testing,⁶ and a cellular residue suitable for HPV testing. ARTISTIC is the first randomised trial to report a comparison of LBC plus HPV testing against LBC testing alone in primary screening. The aim of the study was to determine whether combined testing would result in a reduced incidence of high-grade disease in the second screening round compared with LBC alone.