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.     

Long Term Results of Follow-up After HPV Self-sampling with Devices Qvintip and HerSwab in Women Non-attending Cervical Screening Programme

BackgroundWe are presenting the results of the Slovenian human papillomaviruses (HPV) self-sampling pilot study in colposcopy population of National Cervical Cancer Screening Programme ZORA for the first time. One-year and four-year follow-up results are presented for two different self-sampling devices.Participants and methodsA total of 209 women were enrolled in the study at colposcopy clinic. Prior to the gynaecological examination, all women performed self-collected vaginal swab at the clinic; 111 using Qvintip and 98 using HerSwab self-sampling device. After self-sampling, two cervical smears were taken by a clinician; first for conventional cytology and second for HPV test. After that, all women underwent colposcopy and a cervical biopsy if needed. We compared sensitivity, specificity, and predictive values of cytology (at the cut-off atypical squamous cells of undetermined significance or more [ASC-US+]) and HPV test (on self- and clinician-taken samples) for the detection of cervical intraepithelial neoplasia grade 2 or more (CIN2+) after one and four years of follow-up. Hybrid Capture 2 (HC2) assay was used for all HPV testing.ResultsThe mean age of 209 women was 37.6 years and HPV positivity rate 67.0% (140/209), 36.9 years and 70.3% (78/111) in the Qvintip group and 38.4 years and 63.3% (62/98) in the HerSwab group, respectively. Overall, percent agreement between self and clinician-taken samples was 81.8% (kappa 0.534) in the Qvintip and 77.1% (kappa 0.456) in the HerSwab group. In the Qvintip group, the longitudinal sensitivity, specificity, positive and negative predictive values were 71.8%, 75.0%, 83.6%, 60.0% for cytology; 83.1%, 51.3%, 75.6% and 62.5% for HPV test of self-taken samples and 94.4%, 57.5%, 79.8% and 85.2% for HPV test on clinician-taken samples. In the HerSwab group, the corresponding results were 71.7%, 46.7%, 61.3%, 58.3% for cytology; 75.0%, 47.7%, 62.9% and 61.8% for HPV test on self-taken samples and 94.3%, 44.4%, 66.7% and 87.0% for clinician-taken samples, respectively.ConclusionsThe results confirm that HPV self-sampling is not as accurate as clinician sampling when HC2 is used. All HPV tests showed a higher sensitivity in detecting CIN2+ compared to cytology. Due to non-inferior longitudinal sensitivity of HPV self-sampling compared to cytology, HPV self-sampling might be an option for non-attenders to the National Cancer Screening Programme.Key words: HPV self-sampling, cytology, high-grade intraepithelial lesion     

Lower cost strategies for triage of human papillomavirus DNA‐positive women

Using human papillomavirus (HPV) testing for cervical cancer screening in lower‐resource settings (LRS) will result in a significant number of screen‐positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV‐positive women in LRS. This was a population‐based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self‐collected and two clinician‐collected specimens. The self‐collected and one clinician‐collected specimen were tested by two HPV DNA tests—careHPV? and Hybrid Capture 2; the other clinician‐collected specimen was tested for HPV16/18/45 E6 protein. CareHPV?‐positive specimens were tested for HPV16/18/45 DNA. HPV DNA‐positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA‐positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA‐positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.     

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+.     

Experience with high-risk human papillomavirus testing on vaginal brush-based self-samples of non-attendees of the cervical screening program

We evaluated the effect of offering brush-based vaginal self-sampling for high-risk human papillomavirus (hrHPV) testing to non-attendees of the cervical screening program on response rate, compliance to follow-up and cervical intraepithelial neoplasia grade 2 or 3 (CIN2+/CIN3+) yield. In addition, concordance of hrHPV test results between physician-taken cervical scrapes and vaginal self-samples was determined. A total of 26,409 nonattending women were randomly assigned to receive a vaginal brush device for hrHPV testing by Hybrid Capture-2 method (i.e., self-sampling group, n = 26,145) or a reinvitation for regular cytology-based screening (i.e., recall control group, n = 264). hrHPV-positive self-sampling responders were invited for a physician-taken scrape for cytology and blinded hrHPV testing. If cytology was abnormal, women were referred for colposcopy. Response rate in the self-sampling group was significantly increased compared to the recall control group (30.8% versus 6.5%; p < 0.001). The concordance rate between hrHPV detection in self-samples and corresponding physician-taken cervical scrape samples was 68.8%. Amongst women with CIN3+ and CIN2+, the concordance rates in hrHPV positivity between both samples were 95.5% and 93.8%, respectively. Adherence at baseline to cytology triage of hrHPV-positive self-sampling women (89.1%) and colposcopy referral of those with abnormal cytology (95.8%) was high. The CIN2+/CIN3+/carcinoma yields were 1.5%, 1.0% and 0.1%, respectively, in self-sampling responders. In conclusion, offering hrHPV testing on self-sampled vaginal material with a brush device to non-attendees significantly increases the attendance to the regular screening program, yields hrHPV test results that are in very good concordance with those of physician-taken scrapes in women with CIN2+/CIN3+, and is effective in detecting CIN2+/CIN3+.     

Is HPV DNA testing specificity comparable to that of cytological testing in primary cervical cancer screening? Results of a meta‐analysis of randomized controlled trials

Human‐papillomavirus (HPV) DNA testing has been proposed as an alternative to primary cervical cancer screening using cytological testing. Review of the evidence shows that available data are conflicting for some aspects. The overall goal of the study is to update the performance of HPV DNA as stand‐alone testing in primary cervical cancer screening, focusing particularly on the aspects related to the specificity profile of the HPV DNA testing in respect to cytology. We performed a meta‐analysis of randomized controlled clinical trials. Eight articles were included in the meta‐analysis. Three outcomes have been investigated: relative detection, relative specificity, and relative positive predictive value (PPV) of HPV DNA testing versus cytology. Overall evaluation of relative detection showed a significantly higher detection of CIN2+ and CIN3+ for HPV DNA testing versus cytology. Meta‐analyses that considered all age groups showed a relative specificity that favored the cytology in detecting both CIN2+ and CIN3+ lesions whereas, in the ≥30 years' group, specificity of HPV DNA and cytology tests was similar in detecting both CIN2+ and CIN3+ lesions. Results of the pooled analysis on relative PPV showed a not significantly lower PPV of HPV DNA test over cytology. A main key finding of the study is that in women aged ≥30, has been found an almost overlapping specificity between the two screening tests in detecting CIN2 and above‐grade lesions. Therefore, primary screening of cervical cancer by HPV DNA testing appears to offer the right balance between maximum detection of CIN2+ and adequate specificity, if performed in the age group ≥30 years.     

Comparative performance evaluation of different HPV tests and triaging strategies using self-samples and feasibility assessment of thermal ablation in ‘colposcopy and treat’ approach: A population-based study in rural China

Human papillomavirus (HPV) test, self-sampling and thermal ablation for cervical intraepithelial neoplasia (CIN) have been developed separately to increase screening coverage and treatment compliance of cervical cancer screening programmes. A large-scale study in rural China screened 9,526 women with their combinations to explore the optimal cervical cancer-screening cascade in the real-world. Participants received careHPV and polymerase chain reaction (PCR) HPV tests on self-collected samples. Women positive on either HPV test underwent colposcopy, biopsy and thermal ablation in a single visit. Samples positive on either HPV test were retested for genotyping. Absolute and relative performance of HPV tests, triage strategies, ‘colposcopy and thermal ablation’ approach were statistically evaluated. PCR HPV test detected 33.3% more CIN grade two or worse (CIN2+) at a cost of 28.1% more colposcopies compared to careHPV. Sensitivities of PCR HPV and careHPV tests to detect CIN2+ were 96.7 and 72.5%. Specificities for the same disease outcome were 82.1 and 86.0%. Triaging HPV-positive women with HPV16/18 genotyping considerably improved the positive predictive value for CIN2+ (4.8–5.0 to 18.2–19.2%). Ninety-six women positive on HPV and having abnormal colposcopy were eligible for thermal ablation and all accepted same-day treatment, contributing to 64.6% being treated appropriately (CIN1+ on histopathology), which reached up to 84.8% among women positive on HPV 16/18 triage. No serious side-effects/complications were reported. The combination of PCR HPV test followed by HPV 16/18 triaging on self-collected samples and colposcopy of triage positive women followed by immediate thermal ablation might be the appropriate screening cascade for rural China.     

HPV self-sampling as an alternative strategy in non-attenders for cervical screening - a randomised controlled trial

Background:

A randomised trial to ascertain whether women who do not attend for cervical screening are more likely to respond to the opportunity to collect a self-sample for human papillomavirus (HPV) testing, or to a further invitation to attend for cervical screening.

Methods:

The study was carried out in a Primary Care Trust (PCT) in London between June 2009 and December 2009. In total, 3000 women were randomly selected from persistent non-responders (i.e., who had not responded to at least two invitations to attend for screening). The women were randomised on a 1 : 1 basis to either receive an HPV self-sampling kit or a further invitation to attend for cervical cytology. The main outcome measures were (1) percentage of women attending for cervical cytology compared with those returning a self-sample HPV test or attending for cytology subsequent to receiving the kit and (2) percentage of those testing positive for HPV who attended further investigation.

Results:

The total response in the self-sampling group for screening was 10.2%. Of the 1500 women in the control group sent a further invitation for cervical screening, 4.5% attended for cytology screening. This difference is highly statistically significant (P<0.0001). Of the 8 women who tested positive for HPV, 7 attended for a cervical smear and had a concurrent colposcopy. Three of these (43%) had high-grade disease (defined as CIN 2+), with one found to have an invasive cancer (stage 1b) and one CIN 3.

Conclusions:

The value of this intervention relies on the detection of high-grade CIN and early stage cancer with a good prognosis. The relatively high yield of abnormalities found is consistent with that expected among a hard to reach and relatively high-risk group of women. Our study suggests that self-sampling could increase participation among non-responders in England, but further work is needed to ascertain whether the low response rate seen here is likely to be representative of the rest of the country. Other studies are needed to investigate the response to self-sampling in different demographic and geographic settings.     

Acceptability and Concordance of Self- Versus Clinician- Sampling for HPV Testing among Rural South Indian Women

Background: Despite being largely preventable, HPV-related cervical cancers continues to be the second highest cause of cancer deaths among Indian women. HPV testing using self-sampled samples may offer an opportunity to expand cervical cancer screening in India where there is currently a shortage of providers and facilities for cervical cancer screening. The study examines acceptability and concordance of self vs. clinician collected samples for HPV-relted cervical cancer screening among rural South Indian women. Methods: Between May and August 2017, eight mobile screening clinics were conducted among 120 eligible women in rural villages in Mysore District, India. Women over the age of 30 underwent informed consent process and then self-sampled a sample for cervicovaginal HPV DNA testing. Next, the women underwent clinical exam where the clinician collected a cervicovaginal HPV DNA sample. Following the clinical exam, all participants answered an interviewer-administered questionnaire to assess their history of cervical cancer screening and acceptability of self- and clinician-sampling methods. To assess diagnostic accuracy, concordance of self- and clinician-sampled HPV DNA specimens was calculated in addition to five measures of acceptability (feeling of caring, privacy, embarrassment, genital discomfort, and genital pain). Results: Study participants had a median age 39 years, about four-in-ten (41.7%) had a secondary education or above, the vast majority (87.5%) were married and only 3.4% reported having screened for cervical cancer. For all measures of participant acceptability, self-sampling was rated significantly higher than clinician-sampling. Cohen’s kappa was 0.73 (95% CI: 0.34, 1.00), indicating substantial agreement between self- and clinician-sampling. Conclusion: This study demonstrates that HPV self-sampling for cervical cancer screening is feasible and acceptable in a community setting among South Indian rural women. Concordance between self-sampling and clinician-sampling was adequate for screening in community settings.