Clare Gilham

Urine high‐risk human papillomavirus testing as an alternative to routine cervical screening: A comparative diagnostic accuracy study of two urine collection devices using a randomised study design trial

AbstractObjectiveTo evaluate the sensitivity of human papillomavirus (HPV) tested urine to detect high‐grade cervical precancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) using two urine collection devices.DesignRandomised controlled trial.SettingSt Mary's Hospital, Manchester, UK.PopulationColposcopy attendees with abnormal cervical screening; a total of 480 participants were randomised. Matched urine and cervical samples were available for 235 and 230 participants using a first‐void urine (FVU)‐collection device and standard pot, respectively.MethodsUrine was self‐collected and mixed with preservative – randomised 1:1 to FVU‐collection device (Novosanis Colli‐pee® 10 mL with urine conservation medium [UCM]) or standard pot. Matched clinician‐collected cervical samples were taken before colposcopy. HPV testing used Roche cobas® 8800. A questionnaire evaluated urine self‐sampling acceptability.Main outcome measuresThe primary outcome measured sensitivity of HPV‐tested urine (FVU‐collection device and standard pot) for CIN2+ detection. Secondary outcomes compared HPV‐tested cervical and urine samples for CIN2+ and evaluated the acceptability of urine self‐sampling.ResultsUrine HPV test sensitivity for CIN2+ was higher with the FVU‐collection device (90.3%, 95% CI 83.7%–94.9%, 112/124) than the standard pot (73.4%, 95% CI 64.7%–80.9%, 91/124, p = 0.0005). The relative sensitivity of FVU‐device‐collected urine was 0.92 (95% CI 0.87–0.97, pMcN = 0.004) compared with cervical, considering that all women were referred after a positive cervical HPV test. Urine‐based sampling was acceptable to colposcopy attendees.ConclusionsTesting of FVU‐device‐collected urine for HPV was superior to standard‐pot‐collected urine in colposcopy attendees and has promising sensitivity for CIN2+ detection. General population HPV testing of FVU‐device‐collected urine will establish its clinical performance and acceptability as an alternative to routine cervical screening.

Long‐term prediction by DNA methylation of high‐grade cervical intraepithelial neoplasia: Results of the ARTISTIC cohort

AbstractMethylation markers have shown potential for triaging high‐risk HPV‐positive (hrHPV+) women to identify those at increased risk of invasive cervical cancer (ICC). Our aim was to assess the performance of the S5 DNA methylation classifier for predicting incident high‐grade cervical intraepithelial neoplasia (CIN) and ICC among hrHPV+ women in the ARTISTIC screening trial cohort. The S5 classifier, comprising target regions of tumour suppressor gene EPB41L3 and L1 and L2 regions of HPV16, HPV18, HPV31, and HPV33, was assayed by pyrosequencing in archived hrHPV+ liquid‐based samples from 343 women with high‐grade disease (139 CIN2, 186 CIN3, and 18 ICC) compared to 800 hrHPV+ controls. S5 DNA methylation correlated directly with increasing severity of disease and inversely with lead time to diagnosis. S5 could discriminate between hrHPV+ women who developed CIN3 or ICC and hrHPV+ controls (p <.0001) using samples taken on average 5 years before diagnosis. This relationship was independent of cytology at baseline. The S5 test showed much higher sensitivity than HPV16/18 genotyping for identifying prevalent CIN3 (93% vs. 61%, p = .01) but lower specificity (50% vs. 66%, p <.0001). The S5 classifier identified most women at high risk of developing precancer and missed very few prevalent advanced lesions thus appearing to be an objective test for triage of hrHPV+ women. The combination of methylation of host and HPV genes enables S5 to combine the predictive power of methylation with HPV genotyping to identify hrHPV‐positive women who are at highest risk of developing CIN3 and ICC in the future.

Implications for women testing positive for human papillomavirus

Triaging women with human papillomavirus infection and normal cytology or low‐grade dyskaryosis: evidence from 10‐year follow up of the ARTISTIC trial cohort

ObjectivesTo estimate long‐term cervical intraepithelial neoplasia grade 3 (CIN3) risks associated with different triage strategies for human papillomavirus positive (HPV+) women with a view to reducing unnecessary referrals.DesignThe ARTISTIC trial cohort was recruited in Manchester in 2001–03 and was followed up for CIN3 and cancer notification through national registration until December 2015.ResultsThe 10‐year cumulative risk of CIN3+ was much higher for women with HPV16/18 infection (19.4%, 95% CI 15.8–23.8% with borderline/low‐grade cytology and 10.7%, 95% CI 8.3–13.9% with normal cytology) than for those with other HPV types (7.3%, 95% CI 5.4–9.7% with borderline/low‐grade cytology and 3.2%, 95% CI 2.2–4.5% with normal cytology). Among the 379 women with normal to low‐grade cytology and new HPV infection, the 10‐year cumulative CIN3+ risk was 2.9% (95% CI 1.6–5.2%).ConclusionsThe CIN3 risk is confined to women with persistent type‐specific HPV so partial genotyping test assays identifying HPV16/18 as a minimum are essential for efficient risk stratification. Immediate referral to colposcopy for HPV+ women with borderline or low‐grade cytology and referral after a year if still HPV+ with normal cytology may be unnecessary. Low‐grade lesions can safely be retested to identify those with persistent HPV. Recall intervals of 1 year for HPV16/18 and 2 years for other high‐risk HPVs are justified for women with normal cytology and might also be considered for women with borderline/low‐grade cytology. The minimal risk of invasive cancer that has progressed beyond stage 1A must be weighed against the advantages for patients and the NHS of reducing the number of referrals to colposcopy.Tweetable abstractCervical screening would be better for women and cheaper for the NHS if women with HPV and normal to low‐grade cytology were retested after a year or two when many infections will have cleared.

Diagnostic accuracy of cervical cancer screening and screening–triage strategies among women living with HIV-1 in Burkina Faso and South Africa: A cohort study

Background Cervical cancer screening strategies using visual inspection or cytology may have suboptimal diagnostic accuracy for detection of precancer in women living with HIV (WLHIV). The optimal screen and screen–triage strategy, age to initiate, and frequency of screening for WLHIV remain unclear. This study evaluated the sensitivity, specificity, and positive predictive value of different cervical cancer strategies in WLHIV in Africa. Methods and findings WLHIV aged 25–50 years attending HIV treatment centres in Burkina Faso (BF) and South Africa (SA) from 5 December 2011 to 30 October 2012 were enrolled in a prospective evaluation study of visual inspection using acetic acid (VIA) or visual inspection using Lugol’s iodine (VILI), high-risk human papillomavirus DNA test (Hybrid Capture 2 [HC2] or careHPV), and cytology for histology-verified high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) at baseline and endline, a median 16 months later. Among 1,238 women (BF: 615; SA: 623), median age was 36 and 34 years (p < 0.001), 28.6% and 49.6% ever had prior cervical cancer screening (p < 0.001), and 69.9% and 64.2% were taking ART at enrolment (p = 0.045) in BF and SA, respectively. CIN2+ prevalence was 5.8% and 22.4% in BF and SA (p < 0.001), respectively. VIA had low sensitivity for CIN2+ (44.7%, 95% confidence interval [CI] 36.9%–52.7%) and CIN3+ (56.1%, 95% CI 43.3%–68.3%) in both countries, with specificity for ≤CIN1 of 78.7% (95% CI 76.0%–81.3%). HC2 had sensitivity of 88.8% (95% CI 82.9%–93.2%) for CIN2+ and 86.4% (95% CI 75.7%–93.6%) for CIN3+. Specificity for ≤CIN1 was 55.4% (95% CI 52.2%–58.6%), and screen positivity was 51.3%. Specificity was higher with a restricted genotype (HPV16/18/31/33/35/45/52/58) approach (73.5%, 95% CI 70.6%–76.2%), with lower screen positivity (33.7%), although there was lower sensitivity for CIN3+ (77.3%, 95% CI 65.3%–86.7%). In BF, HC2 was more sensitive for CIN2+/CIN3+ compared to VIA/VILI (relative sensitivity for CIN2+ = 1.72, 95% CI 1.28–2.32; CIN3+: 1.18, 95% CI 0.94–1.49). Triage of HC2-positive women with VIA/VILI reduced the number of colposcopy referrals, but with loss in sensitivity for CIN2+ (58.1%) but not for CIN3+ (84.6%). In SA, cytology high-grade squamous intraepithelial lesion or greater (HSIL+) had best combination of sensitivity (CIN2+: 70.1%, 95% CI 61.3%–77.9%; CIN3+: 80.8%, 95% CI 67.5%–90.4%) and specificity (81.6%, 95% CI 77.6%–85.1%). HC2 had similar sensitivity for CIN3+ (83.0%, 95% CI 70.2%–91.9%) but lower specificity compared to HSIL+ (42.7%, 95% CI 38.4%–47.1%; relative specificity = 0.57, 95% CI 0.52–0.63), resulting in almost twice as many referrals. Compared to HC2, triage of HC2-positive women with HSIL+ resulted in a 40% reduction in colposcopy referrals but was associated with some loss in sensitivity. CIN2+ incidence over a median 16 months was highest among VIA baseline screen-negative women (2.2%, 95% CI 1.3%–3.7%) and women who were baseline double-negative with HC2 and VIA (2.1%, 95% CI 1.3%–3.5%) and lowest among HC2 baseline screen-negative women (0.5%, 95% CI 0.1%–1.8%). Limitations of our study are that WLHIV included in the study may not reflect a contemporary cohort of WLHIV initiating ART in the universal ART era and that we did not evaluate HPV tests available in study settings today. Conclusions In this cohort study among WLHIV in Africa, a human papillomavirus (HPV) test targeting 14 high-risk (HR) types had higher sensitivity to detect CIN2+ compared to visual inspection but had low specificity, although a restricted genotype approach targeting 8 HR types decreased the number of unnecessary colposcopy referrals. Cytology HSIL+ had optimal performance for CIN2+/CIN3+ detection in SA. Triage of HPV-positive women with HSIL+ maintained high specificity but with some loss in sensitivity compared to HC2 alone.

The Use of First‐Void Urine to Screen Women Aged 60–79 for HPV in the UK: The Catch‐Up Screen Study

ABSTRACT Objective Almost half the deaths from cervical cancer in the UK are among women aged over 65 who were already above the upper age of screening when primary HPV screening was introduced in the UK in 2019. Our aim is to test the feasibility of a national catch‐up HPV testing programme. Design This first phase of the Catch‐Up Screen study involved randomizing over 3000 invited participants to receive a urine HPV test and a follow‐up telephone call or text message. Setting GP practices in Hull and Manchester, UK. Population Women aged 60–79 who have not undergone primary HPV screening. Methods Eligible women were selected from GP practice records, and 3074 were invited to provide an at‐home first‐void urine sample for HPV testing. Main Outcome Measures Uptake of at‐home urine screening according to screening history, area‐level index of deprivation, and randomised follow‐up method. Results Overall, 59% (1816) of invited women returned a urine sample for HPV testing. Response varied by screening history and index of area‐level deprivation, but 39% of those who declined their last invited NHS screen responded favorably and took part in Catch‐Up Screen. Telephone reminders yielded a 5% absolute increase in response compared to the text message arm ( p  = 0.007). Conclusions An at‐home first‐void urine sample is a viable method for a national catch‐up HPV test and has the potential to address decreasing national coverage among older women being invited for their last screen.