Date Published: September 19, 2017
Publisher: Public Library of Science
Author(s): Karen Canfell, Michael Caruana, Val Gebski, Jessica Darlington-Brown, Stella Heley, Julia Brotherton, Dorota Gertig, Chloe J. Jennett, Annabelle Farnsworth, Jeffrey Tan, C. David Wrede, Philip E. Castle, Marion Saville, Silvia de Sanjosé
Abstract: BackgroundUsing primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplastic lesions and invasive cancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) compared to cytology, but no evaluation has been conducted in a population previously offered HPV vaccination. We aimed to assess colposcopy referral and CIN2+ detection rates for HPV-screened versus cytology-screened women in Australia’s HPV-vaccinated population (by 2014, resident women ≤33 years had been age-eligible for HPV vaccination, with 3-dose uptake across age cohorts being about 50%–77%).Methods and findingsCompass is an open-label randomised trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening. In the first phase, consenting women aged 25–64 years presenting for routine screening at 47 primary practices in Victoria, Australia, provided a cervical sample and were randomised at a central laboratory at a 1:2:2 allocation to (i) image-read LBC screening with HPV triage of low-grade cytology (‘LBC screening’), (ii) HPV screening with those HPV16/18 positive referred to colposcopy and with LBC triage for other oncogenic (OHR) types (‘HPV+LBC triage’), or (iii) HPV screening with those HPV16/18 positive referred to colposcopy and with dual-stained cytology triage for OHR types (‘HPV+DS triage’). A total of 5,006 eligible women were recruited from 29 October 2013 to 7 November 2014 (recruitment rate 58%); of these, 22% were in the group age-eligible for vaccination. Data on 4,995 participants were analysed after 11 withdrawals; 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. No serious trial-related adverse events were reported. The main outcomes were colposcopy referral and detected CIN2+ rates at baseline screening, assessed on an intention-to-treat basis after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes (dataset closed 31 August 2016). Analysis was adjusted for whether women had been age-eligible for HPV vaccination or not. For the LBC-screened group, the overall referral and detected CIN2+ rates were 27/995 (2.7% [95% CI 1.8%–3.9%]) and 1/995 (0.1% [95% CI 0.0%–0.6%]), respectively; for HPV+LBC triage, these were 75/1,992 (3.8% [95% CI 3.0%–4.7%]) and 20/1,992 (1.0% [95% CI 0.6%–1.5%]); and for HPV+DS triage, these were 79/2,008 (3.9% [95% CI 3.1%–4.9%]) and 24/2,008 (1.2% [95% CI 0.8%–1.6%]) (p = 0.09 for difference in referral rate in LBC versus all HPV-screened women; p = 0.003 for difference in CIN2+ detection rate in LBC versus all HPV-screened women, with p = 0.62 between HPV screening groups). Limitations include that the study population involved a relatively low risk group in a previously well-screened and treated population, that individual women’s vaccination status was unknown, and that long-term follow-up data on disease detection in screen-negative women are not yet available.ConclusionsIn this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. It had been predicted that increased disease detection might be associated with a transient increase in colposcopy referral rates in the first round of HPV screening, possibly dampened by HPV vaccine effect; in this study, although the point estimates for referral rates in women in each HPV-screened group were 41%–44% higher than in cytology-screened women, the difference in referral rate between cytology- and HPV-screened women was not significant. These findings provide initial support for the implementation of primary HPV screening in vaccinated populations.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12613001207707
Partial Text: A number of countries are currently considering a transition to primary human papillomavirus (HPV) testing for cervical screening, underpinned by evidence from a number of large-scale randomised trials and longitudinal cohort studies, which, taken together, show improved early detection of high-grade precancerous disease (cervical intraepithelial neoplasia grade 2 or 3 [CIN2/3]), lower cumulative incidence of CIN3 and invasive cervical cancer in HPV negative compared to cytology negative women, and, following treatment of detected CIN2/3, subsequent improved long-term protection against CIN3 and invasive cervical cancer in HPV-screened women compared to those screened with cytology [1–9]. However, no prior trials of primary HPV screening compared to cytology screening have been conducted in a population with substantial uptake of HPV vaccination.
Of an estimated 8,595 eligible women presenting for cervical screening from 29 October 2013 to 7 November 2014, a total of 5,303 participants were initially recruited, but 297 women were subsequently found to be ineligible (according to trial inclusion/exclusion criteria) when the sample was received at the laboratory and were not randomised. Data on 4,995 participants were analysed after 11 women subsequently withdrew (Fig 1); a total of 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 were assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 were assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. The final estimated recruitment rate as a proportion of all women having cervical screening over the recruitment period at participating centres was 58% (range 25%–95% across centres). The randomisation allocation for eligible participants in each vaccine age-eligibility stratum is given in Table 1.
Compass is, to our knowledge, the first randomized trial of cervical screening conducted in an extensively HPV-vaccinated population and one of the first trials of HPV screening using a partial genotyping strategy in which women with the highest risk HPV infections (HPV16 and HPV18) are directly referred to colposcopy. In the current study, we have demonstrated acceptably high rates of trial participation and, by implication, high rates of acceptability of primary HPV screening at longer intervals. In this first analysis, we found an increased detection rate of high-grade precancerous disease (CIN2+) in the first round of screening for HPV-screened compared to cytology-screened women, and for the first time, to our knowledge, we have demonstrated that this increased detection rate is also seen in a population for whom the younger cohort had been offered HPV vaccination, with high levels of vaccine uptake.