Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25–65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56–1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43–1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14–65) and intervention 43 (95% CI: 25–73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1–0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.     

Human papillomavirus testing versus cytology in primary cervical cancer screening: End‐of‐study and extended follow‐up results from the Canadian cervical cancer screening trial

The Canadian Cervical Cancer Screening Trial was a randomized controlled trial comparing the performance of human papillomavirus (HPV) testing and Papanicolaou cytology to detect cervical intraepithelial neoplasia of grades 2 or worse (CIN2+) among women aged 30–69 years attending routine cervical cancer screening in Montreal and St. John's, Canada (n = 10,154). We examined screening and prognostic values of enrollment cytologic and HPV testing results. Extended follow‐up data were available for St. John's participants (n = 5,754; 501,682.6 person‐months). HPV testing detected more CIN2+ than cytology during protocol‐defined (82.9 vs. 44.4%) and extended (54.2 vs. 19.3%) follow‐up periods, respectively. Three‐year risks ranged from 0.87% (95% CI: 0.37–2.05) for HPV‐/Pap‐ women to 35.77% (95% CI: 25.88–48.04) for HPV+/Pap+ women. Genotype‐specific risks ranged from 0.90% (95% CI: 0.40–2.01) to 43.84% (95% CI: 32.42–57.24) among HPV? and HPV16+ women, respectively, exceeding those associated with Pap+ or HPV+ results taken individually or jointly. Ten‐year risks ranged from 1.15% (95% CI: 0.60–2.19) for HPV?/Pap? women to 26.05% (95% CI: 15.34–42.13) for HPV+/Pap+ women and genotype‐specific risks ranged from 1.13% (95% CI: 0.59–2.14) to 32.78% (95% CI: 21.15–48.51) among women testing HPV? and HPV16+, respectively. Abnormal cytology stratified risks most meaningfully for HPV+ women. Primary HPV testing every 3 years provided a similar or greater level of reassurance against disease risks as currently recommended screening strategies. HPV‐based cervical screening may allow for greater disease detection than cytology‐based screening and permit safe extensions of screening intervals; genotype‐specific testing could provide further improvement in the positive predictive value of such screening.     

A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: extended follow up in the ARTISTIC trial

Background

The additional sensitivity of HPV testing compared with cytology could permit extended cervical screening intervals. We wished to determine, through a further (third) round of screening in the ARTISTIC trial, the protection provided by a negative baseline HPV screen compared with that of cytology over a 6 year period.

Methods

Cumulative rates of CIN2 or worse (CIN2+) and CIN3 or worse (CIN3+) were correlated with baseline HPV status and cytology. HPV was detected using the Hybrid Capture 2 (Qiagen) assay for high risk types and genotyped using the Linear Array (Roche) and Papillocheck (Greiner) assays. LBC was performed using ThinPrep (Hologic).

Findings

Round 3 included 8,873 women of whom 6,337 had been screened in both rounds 1 and 2 and 2,536 had not been screened since round 1. The median duration of follow-up was 72.7 months. The cumulative rate of CIN2+ over three rounds was 3.88% (95%CI 3.59%, 4.17%) overall; 2.39% in round 1, 0.78% in round 2 and 0.74% in round 3. Cumulative rates by baseline status were 20.53% (95%CI 19.04%, 22.08%) for abnormal cytology, 20.12% (95%CI 18.68%, 21.61%) for HPV detection, 1.41% (95%CI 1.19%, 1.65%) for negative cytology and 0.87% (95%CI 0.70%, 1.06%) for a negative HPV test. In HPV negative women aged over 50 the cumulative rate was 0.16% (95%CI 0.07%, 0.34%). Women who were HPV positive/cytology negative at entry had a cumulative CIN2+ rate of 7.73% (95%CI 6.29%, 9.36%) over 6 years, twice the overall rate.

Interpretation

A negative HPV test was significantly more protective than normal cytology over three rounds. The findings of this extension of ARTISTIC suggest that the screening interval could be extended to 6 years if HPV testing replaced cytology as the primary screening test.     

Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial �C the HPV FOCAL Study

Background:

Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented.

Methods:

The three arms are: Control arm – liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm – hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm – hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years.

Results:

A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+.

Conclusion:

After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.     

Long‐term HPV type‐specific risks for ASCUS and LSIL: A 14‐year follow‐up of a randomized primary HPV screening trial

Human papillomavirus (HPV) infections result in a significant burden of low‐grade cervical lesions. Between 1997 and 2000, our randomized trial of primary HPV screening enrolled 12,527 women participating in population‐based screening. Women between 32 and 38 years of age (median: 34, interquartile range: 33–37) were randomized to HPV and cytology double testing (intervention arm, n = 6,257 enrolled, n = 5,888 followed‐up) or to cytology, with samples frozen for future HPV testing (control arm, n = 6,270 enrolled, n = 5,795 followed‐up). We estimated the HPV type‐specific, long‐term absolute risks (AR), and population attributable proportions (PAR) for cytological diagnoses of atypical squamous cells of undetermined significance (ASCUS) or low‐grade squamous intraepithelial lesion (LSIL) and for histopathologically diagnosed cervical intraepithelial neoplasia grade 1 (CIN1). The women were followed using comprehensive, nationwide register‐based follow‐up. During a mean follow‐up time of 11.07 years, 886 ASCUS and LSIL lesions were detected, 448 in the intervention arm and 438 in the control arm. Poisson regression estimated the incidence rate ratios (IRRs) of low‐grade lesions by HPV type. The IRRs were strongly dependent on follow‐up time. The IRRs for ASCUS/LSIL associated with high‐risk HPV positivity were 18.6 (95% CI: 14.9–23.4) during the first screening round, 4.1 (95% CI: 2.8–6.2) during the second, 2.6 (95% CI: 1.7–4.1) during the third, and 1.1 (95% CI: 0.7–1.8) for >9 years of follow‐up, with similar declines seen for the individual types. Type 16 contributed consistently to the greatest proportion of ASCUS, LSIL, and CIN1 risk in the population (first screening round PAR: ASCUS: 15.5% (95% CI: 9.7–21.9), LSIL: 14.7% (95% CI: 8.0–20.9), and CIN1: 13.4% (95% CI: 3.2–22.5)), followed by type 31 [8.4% (95% CI: 4.2–12.5) for ASCUS to 17.3% (95% CI: 6.8–26.6) for CIN1]. In summary, most ASCUS/LSIL lesions associated with HPV infection are caused by new HPV infections and most lesions are found during the first screening round.     

Human papillomavirus testing and cervical cytology in primary screening for cervical cancer among women in rural China: Comparison of sensitivity,specificity, and frequency of referral

The causal relationship between persistent high‐risk human papillomavirus infection and cervical cancer is widely accepted. HR‐HPV DNA testing, alone or in combination with Pap smear testing, may have a role in primary screening. The screening results (VIA, VILI, Pap, and HR‐HPV DNA) of 9,057 women in rural China were analyzed to determine the screening performance for the detection of CIN3+. All screening strategies had comparable AUCs (0.9). Cotesting strategies had the overall highest sensitivity for CIN3+ (99.4%), followed by HR‐HPV DNA testing alone (96.3%), Pap alone (80.2%), and reflex testing (75.4%). Reflex testing had the highest specificity (96.7%), followed by Pap alone (93.3%), HR‐HPV DNA testing alone (85.5%), and both cotesting strategies (LSIL: 84.8%, HSIL: 84.8%). Of the single‐test strategies, HR‐HPV DNA testing had a higher sensitivity (96.3% vs. 80.2%) compared with Pap testing. The specificity of the Pap test was higher (93.3% vs. 85.5%) and it had a lower percent referred for colposcopy (7.8% vs. 15.8%) than HR‐HPV DNA testing. HR‐HPV DNA testing with a 10.0 cutoff point (relative light units/cutoff ratio) had a sensitivity (85.2%) and specificity (90.6%) estimate comparable to Pap testing. A single‐test primary screening strategy with adequate performance would permit less frequent screening and be most appropriate. Of the primary screening strategies investigated in this setting in China, the performance of HR‐HPV DNA testing with an increased cutoff‐point might best meet these criteria.     

High‐risk human papillomavirus DNA load in a population‐based cervical screening cohort in relation to the detection of high‐grade cervical intraepithelial neoplasia and cervical cancer

In a population‐based cervical screening cohort, we determined the value of type‐specific viral load assessment for the detection of high‐grade cervical intraepithelial neoplasia and cervical cancer (≥CIN2). Viral load was determined by type‐specific real‐time PCR in women with single HPV16,‐18,‐31 and ‐33 infections, as determined by GP5+/6+‐PCR. Study endpoints were the detection of cumulative ≥CIN2 or ≥CIN3 within 18 months of follow‐up. High viral loads of HPV16,‐31, and ‐33 were predictive for ≥CIN2 (relative risk of 1.6 (95% CI: 1.3–1.9), 1.7 (95% CI: 1.1–2.7) and 1.9 (95% CI: 1.1–3.1) per 10‐fold change in viral load, respectively). For HPV18, the relative risk was of similar magnitude (1.5, 95% CI: 0.7–3.1), though not significant (p = 0.3). Subsequently, we determined the sensitivities of viral load for ≥CIN2 and ≥CIN3 in HPV DNA‐positive women using viral load thresholds previously defined in a cross‐sectional study. These thresholds were based on the 25th, 33rd and 50th percentiles of type‐specific HPV16,‐18,‐31 or ‐33 viral load values found in women with normal cytology. For all types, combined sensitivities for ≥CIN2 were 93.5%, 88.8% and 77.7% for the 25th, 33rd and 50th percentile thresholds, respectively. Response‐operator‐characteristics (ROC) curve analysis showed that viral load testing on HPV DNA‐positive women in addition to or instead of cytology may result in an increased sensitivity for ≥CIN2, but at the cost of a marked decrease in specificity in relation to cytology. Similar results were obtained when using ≥CIN3 as endpoint. In conclusion, in a cervical screening setting viral load assessment of HPV16, 18, 31 and 33 has no additive value to stratify high‐risk HPV GP5+/6+‐PCR‐positive women for risk of ≥CIN2 or ≥CIN3. © 2008 Wiley‐Liss, Inc.     

Stratifying HPV‐positive women for CIN3+ risk after one and two rounds of HPV‐based screening

A main challenge of human papilloma (HPV)‐based screening for cervical cancer is to adequately identify HPV‐positive women at highest risk of cervical intraepithelial neoplasia grade 3 or worse, CIN3+. The prognostic value of currently used adjunct markers (HPV16/18 genotyping and reflex cytology) may change after multiple rounds of HPV‐based screening because of a change in the proportion of HPV‐positive women with incident infections. To this end, we re‐analyzed results from the POBASCAM trial (Population Based Screening Study Amsterdam). Women were randomized to HPV/cytology cotesting (intervention group) or to cytology‐only (HPV blinded; control group) at enrolment. Our analytical population consisted of women with an HPV‐positive result at the second round, 5 years after enrolment (n = 381 intervention, n = 392 control). Nine‐year CIN3+ risks were estimated by Kaplan–Meier. HPV‐positive women were stratified by risk markers: HPV16/18 genotyping, reflex cytology and preceding HPV results. When comparing one to two rounds of HPV‐based screening, the prognostic value of an abnormal cytology result did not change (40.0% vs. 42.3%, p = 0.5617), but diminished for an HPV16/18 positive result (25.4% vs. 38.0%, p = 0.0132). HPV16/18 genotyping was nondiscriminative in women with incident HPV infections (HPV16/18 positive 10.0% vs. negative 12.1%, p = 0.3193). Women from the intervention group were more likely to have incident infections compared to women from the control group (incident screen‐positive results 75.6% vs. 64.6%, p = 0.001) Our results indicate that at a second round of HPV‐based screening, risk differentiation by cytology remained strong, but was diminished for HPV 16/18 genotyping because of a larger proportion of incident infections.     

Good performance of p16/ki‐67 dual‐stained cytology for surveillance of women treated for high‐grade CIN

Women treated for high‐grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high‐risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki‐67 dual‐stained cytology (p16/Ki‐67) for posttreatment monitoring. Three hundred and twenty‐three women treated for high‐grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki‐67 dual‐staining was performed on residual liquid‐based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki‐67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki‐67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71–1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68–0.99). Specificity of p16/Ki‐67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19–1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12–1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki‐67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92–1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19–1.38). Thus, when considered in combination with hrHPV, p16/Ki‐67 might be an attractive approach for surveillance of women treated for high‐grade CIN.     

Quadrivalent HPV vaccine effectiveness against high‐grade cervical lesions by age at vaccination: A population‐based study

Human papillomavirus (HPV) types 16/18, included in HPV vaccines, contribute to the majority of cervical cancer, and a substantial proportion of cervical intraepithelial neoplasia (CIN) grades 2/3 or worse (CIN2+/CIN3+) including adenocarcinoma in situ or worse. The aim of this study was to quantify the effect of quadrivalent HPV (qHPV) vaccination on incidence of CIN2+ and CIN3+. A nationwide cohort of girls and young women resident in Sweden 2006–2013 and aged 13–29 (n = 1,333,691) was followed for vaccination and histologically confirmed high‐grade cervical lesions. Data were collected using the Swedish nationwide healthcare registers. Poisson regression was used to calculate incidence rate ratios (IRRs) and vaccine effectiveness [(1‐IRR)x100%] comparing fully vaccinated with unvaccinated individuals. IRRs were adjusted for attained age and parental education, and stratified on vaccination initiation age. Effectiveness against CIN2+ was 75% (IRR = 0.25, 95%CI = 0.18–0.35) for those initiating vaccination before age 17, and 46% (IRR = 0.54, 95%CI = 0.46–0.64) and 22% (IRR = 0.78, 95%CI = 0.65–0.93) for those initiating vaccination at ages 17–19, and at ages 20–29, respectively. Vaccine effectiveness against CIN3+ was similar to vaccine effectiveness against CIN2+. Results were robust for both women participating to the organized screening program and for women at prescreening ages. We show high effectiveness of qHPV vaccination on CIN2+ and CIN3+ lesions, with greater effectiveness observed in girls younger at vaccination initiation. Continued monitoring of impact of HPV vaccination in the population is needed in order to evaluate both long‐term vaccine effectiveness and to evaluate whether the vaccination program achieves anticipated effects in prevention of invasive cervical cancer.     

Comparing the performance of FAM19A4 methylation analysis,cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high‐risk HPV‐positive women of a gynecologic outpatient population (COMETH study)

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high‐grade cervical intraepithelial neoplasia and cervical cancer (≥CIN3) in high‐risk HPV (hrHPV)‐positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥CIN3 detection in hrHPV‐positive women participating in a prospective observational multi‐center cohort study. The study population comprised hrHPV‐positive women aged 18–66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy‐directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation‐specific PCR (qMSP). Sensitivities and specificities for ≥CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV‐positive women, the sensitivities for ≥CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥30 years (n = 287), ≥CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2–96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0–94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8–68.4) compared to 47.6% (95%CI: 41.1–54.1)]. In conclusion, among hrHPV‐positive women from an outpatient population aged ≥30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥CIN3.     

Immunodeficiency and the risk of cervical intraepithelial neoplasia 2/3 and cervical cancer: A nested case‐control study in the Swiss HIV cohort study

HIV‐infected women are at increased risk of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC), but it has been difficult to disentangle the influences of heavy exposure to HPV infection, inadequate screening and immunodeficiency. A case‐control study including 364 CIN2/3 and 20 ICC cases matched to 1,147 controls was nested in the Swiss HIV Cohort Study (1985–2013). CIN2/3 risk was significantly associated with low CD4+ cell counts, whether measured as nadir [odds ratio (OR) per 100‐cell/μL decrease = 1.15, 95% CI: 1.08, 1.22], or at CIN2/3 diagnosis (1.10, 95% CI: 1.04, 1.16). An association was evident even for nadir CD4+ 200–349 versus ≥350 cells/μL (OR = 1.57, 95% CI: 1.09, 2.25). After adjustment for nadir CD4+, a protective effect of >2‐year cART use was seen against CIN2/3 (OR versus never cART use = 0.64, 95% CI: 0.42, 0.98). Despite low study power, similar associations were seen for ICC, notably with nadir CD4+ (OR for 50 vs. >350 cells/μL= 11.10, 95% CI: 1.24, 100). HPV16‐L1 antibodies were significantly associated with CIN2/3, but HPV16‐E6 antibodies were nearly exclusively detected in ICC. In conclusion, worsening immunodeficiency, even at only moderately decreased CD4+ cell counts, is a significant risk factor for CIN2/3 and cervical cancer.     

Short-time repeat high-risk HPV testing by self-sampling for screening of cervical cancer

Background:

Testing for high-risk human papillomavirus (HPV) in primary screening for cervical cancer is considered more sensitive, but less specific, in comparison with Pap-smear cytology. Women with persistent HPV infections have a higher risk of developing cervical intraepithelial neoplasia 2+ (CIN2+) lesions. This study was performed to evaluate the gain in specificity for detection of histologically confirmed CIN2+ lesions achieved by short-time repeat testing for high-risk HPV in women aged 30–65 years, with the primary sample for HPV analysis taken by self-sampling.

Methods:

A total of 8000 women in Uppsala County, aged 30–65 years, who had not attended organised screening for 6 years or longer, were offered self-sampling of vaginal fluid at home and the samples sent for HPV typing. Of these, 8% (669) were not possible to contact or had performed hysterectomy. Women positive for high-risk HPV in the self-sampling test were invited for a follow-up HPV test and a cervical biopsy on average 3 months after the initial HPV test.

Results:

In all, 39% (2850/7331) of invited women chose to perform self-sampling of vaginal fluid at home. High-risk HPV infection was found in 6.6% (188) of the women. In all, 89% of the women testing HPV positive performed a follow-up examination, on average 2.7 months, after the first test and 59% of these women were HPV positive in the follow-up test. The prevalence of CIN2+ lesions in women with an initial HPV-positive test was 23% (95% CI 18–30%) and in women with two consecutive HPV-positive tests was 41% (95% CI 31–51%). In women with two positive HPV tests, the prevalence of CIN2+ lesions varied from 49% in women at age 30–39 years to 24% in women at age 50–65 years. Short-time repeat HPV testing increased the specificity for detection of CIN2+ lesions from about 94.2% to 97.8%. The most prevalent HPV types were HPV16 (32%), followed by HPV18/45 (19%) and HPV 33/52/58 (19%).

Conclusion:

The short-time persistence of high-risk HPV infection in this age group was about 60%. Repeat testing for high-risk HPV using self-sampling of vaginal fluid can be used to increase the specificity in the screening for cervical cancer in women aged 30–65 years.     

Effectiveness of novel,lower cost molecular human papillomavirus‐based tests for cervical cancer screening in rural china

This study examined the efficacy of the OncoE6? Cervical Test, careHPV? and visual inspection with acetic acid (VIA) in identifying women at risk for cervical cancer and their capability to detect incident cervical precancer and cancer at 1‐year follow‐up. In a population of 7,543 women living in rural China, women provided a self‐collected and two clinician‐collected specimens and underwent VIA. All screen positive women for any of the tests, a ～10% random sample of test‐negative women that underwent colposcopy at baseline, and an additional ～10% random sample of test‐negative women who did not undergo colposcopy at baseline (n = 3,290) were recruited. 2,904 women were rescreened 1 year later using the same tests, colposcopic referral criteria, and procedures. Sensitivities of baseline tests to detect 1‐year cumulative cervical intraepithelial neoplasia Grade 3 or cancer (CIN3+) were 96.5% and 81.6% for careHPV? on clinician‐collected and self‐collected specimens, respectively, and 54.4% for OncoE6? test. The OncoE6? test was very specific (99.1%) and had the greatest positive predictive value (PPV; 47.7%) for CIN3+. Baseline and 1‐year follow‐up cervical specimens testing HPV DNA positive was sensitive (88.0%) but poorly predictive (5.5–6.0%) of incident CIN2+, whereas testing repeat HPV16, 18 and 45 E6 positive identified only 24.0% of incident CIN2+ but had a predictive value of 33.3%. This study highlights the different utility of HPV DNA and E6 tests, the former as a screening and the latter as a diagnostic test, for detection of cervical precancer and cancer.     

Randomised study of HPV prevalence and detection of CIN2+ in vaginal self-sampling compared to cervical specimens collected by medical personnel

We conducted a randomised study to compare vaginal self-sampling with assisted sampling by medical personnel on the cervix for HPV testing in primary screening. The first aim was to determine if the HPV prevalence is independent of sampling location (vagina versus cervix) and the person performing the sampling. The second aim was to evaluate if the two sampling strategies differed in the detection rate of CIN2+. In total, 19,523 women were randomised into two groups, with 9926 invited to perform self-sampling (SS arm) using the Rover VIBA-brush and 9597 offered assisted sampling using the cytobrush (AS arm). All samples were applied to the indicating FTA elute card and analysed for high-risk HPV using the hpVIR real-time PCR assay. The outcome for the first aim was HPV prevalence and for the second aim the number of CIN2+ based on histology. In the SS arm, 52.7% of invited women participated in the study, as compared to 34.2% in the AS arm. All samples contained sufficient amount of nuclear DNA for a valid HPV result, with vaginal samples having a higher DNA amount than cervical samples (p < 4.62 × 10⁻¹¹). HPV prevalence was 4.6% in the SS arm and 4.1% in the AS arm (p = 5.5 × 10⁻²), and the distribution of HPV types similar between arms. There was no difference in the prevalence of CIN2+ per 1000 women screened between arms (p = 0.86). The results show that vaginal self-sampling is an equivalent alternative to sampling by medical personnel for HPV typing and identification of CIN2+.     

The HPV test has similar sensitivity but more overdiagnosis than the Pap test—A randomised health services study on cervical cancer screening in Finland

We compared test sensitivity (in terms of prevented cancers) and overdiagnosis (in terms of non‐progressive pre‐invasive lesions) between the human papillomavirus test (HPV test, Hybrid Capture 2) and the traditional Pap test in routine screening for cervical cancer. The design was a randomised (1:1) health services study in Finland with intake between 2003 and 2007. We estimated sensitivity by the incidence method within one screening round. Overdiagnosis was based on the rate of cervical intraepithelial Grade 3 (CIN3) lesions diagnosed at screen and during the following interval. Out of 203,788 randomised women 132,298 attended (65% in both study arms) and 600,753 person‐years accumulated among attenders up to the end of 2010. In all attenders, 34 invasive cervical cancers and 288 CIN3 lesions were diagnosed at screen or during the following interval. The interval cancer incidence was 2.5/10⁵ person‐years (sensitivity 0.87) and 1.4 (sensitivity 0.93) in the HPV arm and Pap test arm, respectively. The rate of CIN3 lesions was 57.1 and 38.8, respectively. In conclusion, sensitivity of HPV testing was similar to that of Pap testing but caused more overdiagnosis. Therefore, implementation of HPV testing needs to be reconsidered especially in countries with well organised programmes.     

A cohort study of cervical screening using partial HPV typing and cytology triage

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk‐stratification (“triage”) of HPV‐positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3‐year or 18‐month CIN3+ risks. We typed ～9,000 archived specimens, taken at enrollment (2007–2011) into the NCI‐Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+‐woman KPNC screening population. Based on 3‐year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups (“high‐grade,” ASC‐US/LSIL, NILM). For the resultant 15 HPV group‐cytology combinations, 3‐year CIN3+ risks ranged 1,000‐fold from 60.6% to 0.06%. To guide management, we compared the risks to established “benchmark” risk/management thresholds in this same population (e.g., LSIL predicted 3‐year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3‐year risk thresholds (supplemented by 18‐month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow‐up to permit HPV “clearance”; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV‐positive women using partial HPV typing and cytology.     

A randomized trial comparing conventional cytology to liquid‐based cytology and computer assistance

Liquid‐based cytology (LBC) has replaced conventional cytology (CC) for cervical cancer screening in some countries. However, it remains unclear whether LBC is superior to CC. A randomized controlled trial was conducted between August 2007 and March 2009 in Germany to compare LBC, alone and in combination with computer‐assisted imaging technology (CAS), to CC in the detection of histologically confirmed cervical intraepithelial neoplasia (CIN). The main outcome measures were detection rates, relative sensitivities, positive predictive values (PPVs) and relative PPVs comparing LBC without and with CAS to CC. Primary histological outcome was CIN2 or higher. Included were 20,627 women participating in opportunistic cervical cancer screening at 20 gynecologic practices. The practices were randomized weekly to use LBC (n = 11,331) or CC (n = 9,296). Patients with positive findings were invited to expert colposcopy. The relative sensitivity of LBC versus CC using the CIN2+ cut‐off was 2.74 (95% confidence interval [CI] 1.66–4.53). The relative sensitivity of LBC/CAS versus CC for CIN2+ was 3.17 (95% CI 1.94–5.19). The PPV of LBC and CC for CIN2+ was 48% and 38%, respectively. The PPV ratio did not differ significantly from unity. Differences between LBC and CC were smaller in some sensitivity and subgroup analyses; however, relative sensitivity of LBC remained increased. LBC without and with CAS compared with CC under the field conditions of an opportunistic screening system had a significantly higher sensitivity for the detection of CIN without deterioration of PPVs. Additional use of CAS did not further improve sensitivity of LBC. © 2012 Wiley Periodicals, Inc.     

Comparative performance of novel self‐sampling methods in detecting high‐risk human papillomavirus in 30,130 women not attending cervical screening

We determined whether the participation rate for a brush‐based cervicovaginal self‐sampling device is noninferior to the participation rate for a lavage‐based one for testing for hrHPV (high‐risk human papillomavirus). Additionally, positivity rates for hrHPV, the detection rates for cervical intraepithelial neoplasia grades 2 and 3 or worse (CIN2+/3+), and user comfort were compared. A total of 35,477 non‐responders of the regular cervical screening program aged 33–63 years were invited to participate. Eligible women (n = 30,130) were randomly assigned to receive either a brush‐based or a lavage‐based device, and a questionnaire for reporting user convenience. Self‐sampling responders testing hrHPV‐positive were invited for a physician‐taken sample for cytology; triage‐positive women were referred for colposcopy. A total of 5,218 women participated in the brush‐based sampling group (34.6%) and 4809 women in the lavage‐based group (31.9%), i.e. an absolute difference of 2.7% (95%CI 1.8–4.2). The hrHPV‐positivity rates in the two groups were identical (8.3%, relative risk (RR) 0.99, 95%CI 0.87–1.13). The detection of CIN2+ and CIN3+ in the brush group (2.0% for CIN2+; 1.3% for CIN3+) was similar to that in the lavage group (1.9% for CIN2+; 1.0% for CIN3+) with a cumulative RR of 1.01, 95%CI 0.83–1.24 for CIN2+ and 1.25, 95%CI 0.92–1.70 for CIN3+. The two self‐sampling devices performed similarly in user comfort. In conclusion, offering a brush‐based device to non‐responders is noninferior to offering a lavage‐based device in terms of participation. The two self‐sampling methods are equally effective in detecting hrHPV, CIN2+/CIN3+ and are both well accepted.     

HPV self‐sampling or the Pap‐smear: A randomized study among cervical screening nonattenders from lower socioeconomic groups in France

Today in France, low attendance to cervical screening by Papanicolaou cytology (Pap‐smear) is a major contributor to the 3,000 new cervical cancer cases and 1,000 deaths that occur from this disease every year. Nonattenders are mostly from lower socioeconomic groups and testing of self‐obtained samples for high‐risk Human Papilloma virus (HPV) types has been proposed as a method to increase screening participation in these groups. In 2011, we conducted a randomized study of women aged 35–69 from very low‐income populations around Marseille who had not responded to an initial invitation for a free Pap‐smear. After randomization, one group received a second invitation for a free Pap‐smear and the other group was offered a free self‐sampling kit for HPV testing. Participation rates were significantly different between the two groups with only 2.0% of women attending for a Pap‐smear while 18.3% of women returned a self‐sample for HPV testing (p ≤ 0.001). The detection rate of high‐grade lesions (≥CIN2) was 0.2‰ in the Pap‐smear group and 1.25‰ in the self‐sampling group (p = 0.01). Offering self‐sampling increased participation rates while the use of HPV testing increased the detection of cervical lesions (≥CIN2) in comparison to the group of women receiving a second invitation for a Pap‐smear. However, low compliance to follow‐up in the self‐sampling group reduces the effectiveness of this screening approach in nonattenders women and must be carefully managed.