hrHPV-positive Women Research Articles

Reducing unnecessary referrals for colposcopy in hrHPV-positive women within the Dutch cervical cancer screening programme: A modelling study

BackgroundWith the implementation of primary high-risk human papillomavirus (hrHPV) screening in the Netherlands, an increase was observed in the number of unnecessary referrals (≤Cervical Intraepithelial Neoplasia (CIN) 1) to colposcopy. We aimed to investigate which alternative triage strategies safely reduce unnecessary referrals in HPV-based cervical cancer screening programmes. MethodsMicrosimulation model MISCAN was used to simulate an unvaccinated cohort of ten million 30-year old Dutch women. We calculated unnecessary referrals, cervical cancer incidence, mortality, costs and QALYs for 24 triage strategies. Condition for direct referral (atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), conditional on HPV-genotype 16/18/other high risk (OHR)), type of triage test (cytology alone or combined with hrHPV) and time to triage test (6 or 12 months) was varied. ResultsThe 24 triage strategies had varying effects on the number of unnecessary referrals ranging from −72% to +35%. Adjusting conditions for referral to ‘HPV16/18+ and ASC-US+’ and ‘HPVOHR+ and HSIL+’ and extending the interval between tests to 12 months resulted in a reduction in unnecessary referrals of 40% (incidence +0%, mortality −1%). Reduction in unnecessary referrals without genotyping was achieved by adjusting conditions for direct referral to LSIL (12 months to repeat test) (unnecessary referrals −37%, incidence +2%, mortality +0%). ConclusionsTo reduce the number of unnecessary referrals without increasing incidence and mortality by more than 2% in the Dutch cervical cancer screening programme, genotyping for HPV16 or HPV16/18 should be implemented with 12 months to repeat testing.

Effectiveness of High-risk Human Papillomavirus Testing for Cervical Cancer Screening in China

Evidence is needed regarding the introduction of high-risk human papillomavirus (hrHPV) testing into China's national cervical cancer screening program. To evaluate hrHPV testing as a new screening modality for the national program. This population-based, multicenter, open-label, randomized clinical trial took place across 20 primary health care centers in urban and rural areas across China. At least 3000 women aged 35 to 64 years per site were invited to participate, for a total of 60 732 women evaluated. At baseline, women were randomly assigned to cytology, hrHPV testing, or visual inspection with acetic acid and Lugol iodine (VIA/VILI) (rural only). Women who tested positive for hrHPV were randomized into cytology-triage, VIA/VILI-triage (rural only), or direct colposcopy arms. Regarding primary or triaging tests, women with cytological abnormalities or who tested positive with VIA/VILI were referred to colposcopy. After 24 months, combined screening of cytology, hrHPV testing, and VIA/VILI was performed, and all women with positive results were referred to colposcopy. The primary outcomes were cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+ yields. The secondary outcome was colposcopy referral rate. A total of 60 732 women were included in this study, with median (interquartile range) age of 47 (41-52) years. Among urban women, 8955 were randomized to cytology and 18 176 to hrHPV genotyping; among rural women, 11 136 were randomized to VIA/VILI, 7080 to cytology, and 15 385 to hrHPV testing. Participants who tested positive for hrHPV with direct colposcopy had higher risk ratios for disease yields at baseline (urban hrHPV vs cytology, CIN2+ 2.2 [95% CI, 1.6-3.2] and CIN3+ 2.0 [95% CI, 1.2-3.3]; rural hrHPV vs cytology, 2.6 [95% CI, 1.9-4.0] and 2.7 [95% CI, 2.0-3.6]; rural hrHPV vs VIA/VILI, 2.0 [95% CI, 1.6-2.3] and 2.3 [95% CI, 1.8-3.1]). At 24 months, baseline-negative women in the hrHPV arm had significantly lower risk ratios than those with cytology, or VIA/VILI for CIN2+ (0.3 [95% CI, 0.2-0.5], 0.3 [95% CI, 0.2-0.6]) and CIN3+ (0.3 [95% CI, 0.1-0.6], 0.4 [95% CI, 0.2-0.8]) in rural sites. The colposcopy referral rate for hrHPV-positive rural women was reduced to 2.8% by cytology triage, with significantly higher CIN2+ yields than cytology (2.1 [95% CI, 1.3-2.6]) or VIA/VILI arm (1.6 [95% CI, 1.03-2.1]). Genotyping for hrHPV with cytology triage significantly reduced the colposcopy referral rate compared with cytology (0.8 [95% CI, 0.7-0.9]) for urban women. In this randomized clinical trial, testing for hrHPV was an effective primary screening method in primary health care centers. Incorporating hrHPV testing (polymerase chain reaction-based for urban areas, hybrid capture-based for rural areas) into China's national screening program is reasonable. Chinese Clinical Trial Registry Identifier: ChiCTR1900022530.

Therapeutic Efficacy of a Coriolus versicolor-Based Vaginal Gel in Women with Cervical Uterine High-Risk HPV Infection: A Retrospective Observational Study.

A Coriolus versicolor-based vaginal gel is available for treating women with cervical uterine high-risk human papillomavirus (HPV) infection through re-epithelizing and re-balancing microbiota actions. A longitudinal retrospective observational study was performed to evaluate efficacy and safety of the gel. Women treated with Coriolus versicolor-based vaginal gel were compared with women not treated with the gel. Both groups were monitored for HPV infection by an HPV DNA test, Pap smear (cytology) and colposcopy at baseline and after 6months. Overall, 183 high-risk HPV positive women were enrolled (97 treated and 86 controls). After 6months, the HPV DNA test became negative in 67.0% versus 37.2% of treated and controls, respectively (p < 0.0001). Furthermore, 76.1% versus 40.8% registered a colposcopy improvement (p = 0.0005) and 60.4% versus 40.8% showed a remission (p = 0.05), for treated versus controls, respectively. Regarding to cytology, 78.5% of treated versus 37.7% of controls registered an improvement, while 70.8% of treated versus 34.8% of controls had a remission (p < 0.0001 for both variables). At multivariate analyses adjusted for age, smoking habit, and use of estroprogestinic pill, compared to controls, women treated with the gel showed a significantly higher likelihood to experience the clearence of HPV DNA (OR 4.81; 95% 2.43-9.53), and remission at colposcopy (OR 2.30; 95% 1.00-5.31), and cytology (OR 5.13; 95% 2.40-10.96) at 6months. No adverse event was reported during the follow-up. The use of a Coriolus versicolor-based vaginal gel in high-risk HPV patients is safe and effective based on all examined tests.

Distribution of cervical lesions in high-risk HPV (hr-HPV) positive women with ASC-US: a retrospective single-center study in China

BackgroundTo investigate distributions of cervical lesions and factors associated with the severity of the cervical lesions in high-risk HPV (hr-HPV) positive women with atypical squamous cells of undetermined significance (ASC-US) cytology.MethodsClinical information of 250,000 women who underwent HPV and cytological test was collected from January 2012 to January 2019. The association between the severity of the cervical lesions and hr-HPV genotypes, hr-HPV viral load, and ages, were analyzed in hr-HPV-positive/ASC-US women.Results3459 hr-HPV-positive/ASC-US women were enrolled in this study. Overall, 43.51% of women with ASC-US had normal histological results, 34.35% had high-grade squamous intraepithelial lesion (HSIL), and 1.30% had cervical cancer. The rate of HSIL or worse (HSIL+) in women with single HPV16 infection (63.09%) was the highest, followed by HPV33 (57.50%), HPV51 (36.11%), HPV58 (36.11%), HPV52 (28.28%), HPV18 (26.37%), HPV66 (19.35%), HPV39 (18.92%), HPV53 (15.00%), and HPV56 (8.51%). Detection rate of HSIL+ in low, intermediate and high viral-load groups were 15.87% (n = 30), 34.91% (n = 74) and 40.68% (n = 214) (Cochran-Armitage Trend test χ2 = 35.03, p < 0.0001). Compared with the 51–60-year-old group (21.65%), the women in ≤ 30 (40.52%), 31–40 (39.67%), and 41–50 (34.22%) year-old groups had significantly higher risk of HSIL+. The women in ≤ 51–60 (2.68%) and > 60 (3.41%) year-old groups were at increased risk for cervical cancer, compared with the ≤ 30-year-old group (0.61%).ConclusionsASC-US women with HPV 16/18/33/51/52/58 single infection and multiple infections, as well as high HPV viral loads, have high risk of HSIL+.

Primary HPV screening for cervical cancer: Results after two screening rounds in a regional screening program in Finland.

Since 2012, cervical cancer screening has been conducted with a primary high-risk human papillomavirus (hrHPV) test and conventional cytology triage in the city of Tampere, Finland. The women who were screened with the hrHPV test in 2012 were invited to participate in the second screening round in 2017. The aim of the present report was to compare the number of colposcopy referrals and the number of histological high-grade squamous intraepithelial lesion (HSIL)+ (cervical intraepithelial neoplasia [CIN2+]) lesions between the first and second screening rounds of women of a specific age group who were screened twice with the hrHPV test. The primary hrHPV test used was the RealTime hrHPV PCR assay by Abbott. Women with a positive hrHPV test and cytology triage equal to or worse than low-grade squamous intraepithelial lesion or atypical glandular cells, favor neoplasia, were directly referred to colposcopy, whereas hrHPV-positive women with a negative or equivocal cytology triage were re-screened after approximately 12-16months. hrHPV-negative women were scheduled for re-screening after 5years. The present report focuses on the cohort of women who were screened twice with the hrHPV test, who were 35-55years old in 2012, and 40-60years old in 2017. In all, 8076 women were invited for HPV screening in 2012 and 8331 women were invited for the second round 5years later, with attendance rates of 70% and 71%, respectively. Of the women who were screened in 2012, 4571 (69%) belonged to the 35- to 55-year age cohort. In 2017, 4807 (73%) of the women aged 40-60years participated in the screening. In this cohort, 185 (4.0%) colposcopies were performed in the first screening round, compared with 139 (2.9%) in the second round, and the colposcopy rate was 29% smaller in the second round (P=.002). The number of histological HSIL+ cases was 38 (0.8%) during the first screening round and 29 (0.6%) during the second round (P=.220). In the setting of routine organized cervical cancer screening, the initially high colposcopy rate associated with primary HPV screening seems to level off at the second screening round in women who were screened twice with an hrHPV test.

Effective methylation triage of HPV positive women with abnormal cytology in a middle-income country.

The S5-methylation test, an alternative to cytology and HPV16/18 genotyping to triage high-risk HPV-positive (hrHPV+) women, has not been widely validated in low-middle-income countries (LMICs). We compared S5 to HPV16/18 and cytology to detect cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) and CIN3+ in hrHPV+ women selected from a randomized pragmatic trial of 2661 Colombian women with an earlier-borderline abnormal cytology. We included all hrHPV+ CIN2 and CIN3+ cases (n = 183) age matched to 183 <CIN2 hrHPV+. Baseline specimens were HPV-genotyped and tested by S5-methylation, blinded to cytology, histology and initial HPV results. We evaluated the test performance of predefined S5-classifier (cut-point 0.8) and a post hoc classifier at a different cut-point (3.1). S5 sensitivity for CIN2+ was 82% (95% confidence interval [CI] 76.4-87.5) and for CIN3+ 77.08% (95% CI 65.19-88.97). S5 sensitivity was higher than HPV16/18 sensitivity (48.1%, 95% CI 40.85-55.33) or cytology (31.21%, 95% CI 24.50-37.93) but with lower specificity (35%, 95% CI 28.1-42). At cut-point 3.1, S5 sensitivity for CIN2+ (55.2%, 95% CI 48-62.4) or CIN3+ (64.6%, 95% CI 51.0-78.1) was also superior to HPV16/18 (P < .05) or cytology (P < .0001). At this cut-point S5 specificity (76%, 95% CI 69.8-82.1 for <CIN2) was higher than HPV16/18 (67.21%, 95% CI 60.41-74.01, P = .0062) and similar to cytology (75.57%, 95% CI 69.34-81.79, P = 1). HPV16/18 plus cytology sensitivity was similar to S5 for CIN3+, however, false-positive rate was higher (50.27% vs. 24.04%). High sensitivity is crucial in LMICs, S5-methylation exceeded HPV16/18 or cytology sensitivity with comparable specificity for CIN2+ and CIN3+ in hrHPV-positive Colombian women. Furthermore, S5 triage had comparable sensitivity and significantly fewer false positives than cytology and HPV16/18 combination.

Attendance at early recall and colposcopy in routine cervical screening with human papillomavirus testing.

Attendance at early recall and colposcopy is crucial to attaining the benefits of primary high-risk human papillomavirus (HR-HPV)-based screening. Within the English HPV pilot, we analysed deprivation- and age-related patterns of attendance at colposcopy and 12- and 24-month early recall of HR-HPV positive women screened in 2013 to 2015 (N = 36 466). We fitted logistic regression models for adjusted odds ratios (OR). Despite high overall attendance, area deprivation had a small but significant impact at both early recalls, for example, attendance at 24 months was 86.3% and 83.0% in less vs more deprived areas, respectively (ORadj : 0.76; 95% CI: 0.67-0.87). Older women (≥30 years) were more likely to attend early recall than younger women (<30 years), for example, attendance at 24 months was 86.1% vs 82.3%, respectively (ORadj : 1.32, 95% CI: 1.16-1.51). Most women attended colposcopy following a baseline referral, with 96.9% attendance among more deprived and 97.8% among less deprived areas (ORadj : 0.70; 95% CI: 0.55-0.88). Differences in colposcopy attendance by deprivation level at 12 and 24 months were of approximately the same magnitude. In conclusion, attendance at early recall and colposcopy was reassuringly high. Although there were statistically significant differences by deprivation and age group, these were small in absolute terms.

Can DNA methylation tests improve the accuracy of cervical screening?

In this issue of BJOG, Kremer and colleagues present a comprehensive review on the role of hypermethylation of host cell genes in cervical carcinogenesis and discuss the complexity of the literature surrounding different human DNA methylation tests (BJOG 2020 xxxx). The authors further discuss possible clinical applications within established cervical screening programmes ranging from triage of high-risk HPV (hrHPV) positive women at screening, to selection of women for treatment, and more accurate exit strategies.

Abstract LB-165: Risk factor prediction models for triage of HR-HPV positive women: The Estampa study

Abstract Background: Cervical cancer remains an important public health problem worldwide, being the 4th most common cancer in women globally. HPV testing has been proposed for primary cervical cancer screening, given its higher sensitivity compared to cytology to detect cervical cancer precursors. However, HPV testing may lead to costly and unnecessary increases in follow-ups and/or treatments for transiently HPV positive women. Thus, triage methods are needed for HR-HPV positive women to determine optimal management. This study aims to construct and validate a risk prediction model for cervical pre-cancer based on demographics, clinical, and lifestyle characteristics among HR-HPV positive women. Methods: This analysis from the Multicentric study of cervical cancer screening and triage with HPV testing (ESTAMPA) included HR-HPV positive women aged 30-65 recruited on nine countries in Latin America from 2012 to 2019 (n=4565). The outcomes were: (1) cervical intraepithelial neoplasia grade 2 or more severe disease (CIN2+), and (2) CIN grade 3 or more severe disease (CIN3+) before final pathology review. Covariates included demographic characteristics and cervical cancer risk factors. Univariate logistic regression models were used to assess potential predictors of CIN2+ and CIN3+, controlling for the effect of the country of residence, using a multilevel approach. A multivariate logistic regression model was used to predict outcomes. After computing the probability of CIN2+ and CIN3+ among participants, we categorized these probabilities in deciles, to set the scale boundaries. Receiver-operating curves (ROC) and the Area under the Curves (AUC) were constructed. Sensitivity, specificity and predictive values were used to summarize the performance of the scoring system. Results: The prevalence of CIN2+ and CIN3+ in the study population were 14.7% and 9.7%, respectively. Age at recruitment, history of last Pap test, number of pregnancies, use of oral contraceptives, cigarette use and age at first sexual intercourse were significantly associated (p&amp;lt;0.05) with having CIN2+ and CIN3+. The AUC for the risk factor prediction model was 0.66 for CIN2+ and 0.69 for CIN3+. The optimal cutpoint selected by the Youden's statistic was the 5th decile for CIN2+ and 6th decile for CIN3+. This optimal point was for women with probabilities of CIN2+ greater than 13% and greater than 10% for CIN3+. Thus, in these deciles the number of referrals to colposcopy decreased from 100% to 60% for CIN2+ (100% to 49% for CIN3+), and the sensitivity and specificity obtained in this decile was 80% and 43% for CIN2+, respectively (73% and 54% for CIN3+). Conclusions: Our risk prediction model demonstrated a close to acceptable discrimination. This risk prediction model has the potential to reduce the number of HR-HPV positive women who are referred to colposcopy or treatment unnecessarily, reducing the burden for the patient and the healthcare system. Further analyses after pathology review are underway. Citation Format: Marievelisse Soto-Salgado, Maribel Almonte, Ana Patricia Ortiz, Erick L. Suarez, Luis R. Pericchi, Armando Baena, Rolando Herrero. Risk factor prediction models for triage of HR-HPV positive women: The Estampa study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-165.

Abstract 267: microRNA expression analysis in hrHPV positive FFPE tissues for the detection of cervical disease

Abstract Cervical cancer ranks first in cancer mortality among women of low-middle income countries where 80% of the 570,000 cases and 311,000 worldwide deaths estimated for 2018 occurred. Persistent infections with high-risk HPV (hrHPV) genotypes can lead to cervical high-grade lesions (Cervical Intraepithelial Neoplasia grade 2 or more severe disease, CIN-II+), that if left untreated progress to cancer. hrHPV test has high sensitivity but because many women infected with hrHPV genotypes will clear the infection spontaneously, it has low specificity to detect CIN-II+. MicroRNAs (miRNAs) are small RNAs that regulate gene expression and show differential profiles in cervical intraepithelial lesions. Our aim was to identify miRNAs differentially expressed in CIN-II+ and to evaluate their potential use as biomarkers to distinguish low from high-grade lesions in hrHPV positive women. Methods We compared the miRNAs expression pattern between Formalin-Fixed Paraffin-Embedded (FFPE) tissues from hrHPV positive women with low-grade lesions (n=10) and women with high-grade lesions (n=10) of Medellin, Colombia, using the QIAseq miRNA Library Kit (Qiagen) and sequencing reagents and protocols from Illumina. The miRNAs with low coefficient of variation and high fold change were further validated by RT-PCR (miR-133a-3p, 143-3p, 143-5p, 29a-3p and 30b-5p) using miRCURY LNA miRNA PCR kit (Qiagen) and SNORD44 as housekeeping gene. Receiver Operating Characteristic (ROC) analyses with 95% confidence interval of the area under the curve were used to evaluate the diagnostic accuracy of the 5 miRNA and their combinations and the maxim Youden index to determine the optimal specificity and sensitivity. Results The differential miRNAs expression analysis identified 25 miRNAs overexpressed in high- versus low-grade lesions. The relative expression by RT-PCR of 5 of those miRNAs was higher in high-grade when compared to low-grade, and the levels of miR-143-3p, 143-5p and 30b-5p increased with disease progression (from healthy, CIN-I, CIN-II, CIN-III+). ROC analyses showed that miR-143-5p and the combination with miR-133a-3p exhibits the highest AUC 79% (95% CI: 65-93). However, the highest sensitivity is given by miR-29a-3p, 87.50% (95% CI: 67.64 - 97.34), and the highest specificity is given by miR-30b-5p, 95.45% (95% CI: 77.16-99-88), with cut-offs of &amp;gt;1,157 and &amp;gt;3,345 respectively. In conclusion, we identified 25 candidate miRNAs biomarkers and validated 5 of them with good diagnostic performance to distinguish high-grade from low-grade cervical lesions. Further validation on a larger cohort of samples is needed to confirm the potential role of these microRNAs to triage HPV positive women. Citation Format: Martha I. Gonzalez, Jone Garai, Jovanny Zabaleta, Gloria I. Sanchez. microRNA expression analysis in hrHPV positive FFPE tissues for the detection of cervical disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 267.

The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review.

This paper briefly reviews the role of hypermethylation of host cell genes in cervical carcinogenesis and discusses potential clinical applications of methylation analysis in the management of high‐risk HPV (hrHPV) ‐positive women. We argue that methylation assays can be used: 1. for primary triage of hrHPV‐positive women to detect cervical cancer and advanced cervical intraepithelial neoplasia (CIN); 2. as secondary triage for women with minor cytological abnormalities to identify those with the highest risk of CIN3 or worse; 3. as exit test for women leaving the screening programme to identify cervical cancer and advanced CIN; and 4. to support management of CIN.Tweetable abstractThis paper discusses potential clinical applications of DNA methylation analysis in the management of women with a high‐risk HPV infection.

Reflex cytology for triage of high-risk human papillomavirus positive self-sampled material in cervical cancer screening: a prospective cohort study.

ObjectiveHigh‐risk human papillomavirus (HrHPV)‐positive women detected by self‐sampling require an extra visit at the general practitioner for additional cytology testing, but the loss to follow up within this triage is substantial. The aim of this study was to evaluate the clinical utility of reflex cytology on hrHPV‐positive self‐samples for immediate stratification of women who need referral for colposcopy.DesignA prospective cohort study.SettingTwo Dutch cervical cancer‐screening laboratories.Population1014 screenees who tested hrHPV‐positive on self‐samples between 1 December 2018 and 1 August 2019.MethodsSelf‐samples were directly used for cytological analysis. Cytological and histological outcomes during follow up were obtained from the Dutch Pathology Registry (PALGA).Main outcome measuresTest performance of reflex cytology on self‐samples was determined for different thresholds and compared with physician‐taken cytology and histological outcomes.ResultsReflex cytology on self‐samples for detecting abnormal cytology showed a sensitivity of 26.4% (95% CI 21.8–31.3) and specificity of 90.5% (95% CI 87.7–92.8). Of all ≥CIN2 cases, 29.4% (95% CI 22.5–37.1) were detected with reflex cytology on self‐samples. The positive predictive value for detection of ≥CIN2 was higher with cytology on self‐collected samples than on physician‐collected samples. Of women who were lost to follow up, 12.9% were found to have abnormal cytology on their self‐sampled material.ConclusionCytology testing is achievable on hrHPV‐positive self‐samples, could decrease the loss to follow up in screening and is easily implementable in the current clinical practice. Of all hrHPV‐positive women with abnormal cytology on additional physician‐collected samples, 26.4% could have been directly referred for colposcopy if triage with reflex cytology on self‐sampled material had been performed.Tweetable abstractReflex cytology for triage of hrHPV+ self‐samples is of added value for direct referral of women for colposcopy.

Benefit of double-reading cytology smears as a triage strategy among high-risk human papillomavirus-positive women in Mexico.

The goal of this study was to determine whether the detection of histologically confirmed cases of cervical high-grade squamous intraepithelial lesions or worse (HSIL+) can be increased by having each liquid-based cytology (LBC) slide read by 2 cytotechnologists as part of routine screening. Over 36,212 women aged 30 to 64years participated in the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage (FRIDA) Study in Mexico between 2013 and 2016. For each participant, 2 cervical samples were collected at the same clinic visit, one to test for high-risk human papillomavirus (hrHPV) and the other for LBC, which was used to triage those with a hrHPV positive result. LBC slides were evaluated by 7 cytotechnologists, with each slide read independently by 2 blinded cytotechnologists. All women with atypical cells of undetermined significance or a worse result were referred to colposcopy for further evaluation and diagnosis. Three pathologists evaluated the biopsy specimens to confirm the final HSIL+ diagnosis. The HSIL+ detection rates for the single versus double reading were estimated and compared. A total of 3,914 women with a positive hrHPV result were triaged with LBC. The first and second cytology readings resulted in 43 HSIL+ cases detected; the double-reading strategy detected 9 additional HSIL+ cases, resulting in a total of 52 HSIL+ cases. The HSIL+ detection rate increased from 10.99/1000 with a single reading to 13.29/1000 with the double-reading strategy (P=.004). A 20.9% increase in HSIL+ cases detected was achieved with a double reading of the LBC slides in this sample of hrHPV-positive women.

The Performance of Immunocytochemistry Staining as Triaging Tests for High-Risk HPV-Positive Women: A 24-Month Prospective Study.

It is urgent to develop an accurate approach to improve the predictive performance of hrHPV-based screening. The aim is to evaluate the performance of p16/Ki-67 and p16/MCM2 staining to triage high-risk human papillomavirus- (hrHPV-) positive women. Cervical specimens were collected from eligible women and tested for hrHPV genotyping, cytology, p16/Ki-67, and p16/MCM2 staining at baseline. Women were invited to participate in follow-up screening by cytology and hrHPV testing at 24 months. Positive women received colposcopy and biopsies. Histopathological diagnoses were the gold standard. 485 women came back for the follow-up screening. The positive rate of p16/Ki-67 was 20.2% and of p16/MCM2 was 27.2%. The positive rates of p16/Ki-67 ( P < 0.001) and p16/MCM2 (P=0.021) were increased by the severity of histopathology findings. Among hrHPV-positive women, the sensitivity, specificity, PPV, and NPV for p16/Ki-67 were 90.9%, 67.0%, 16.5%, and 99.0%, and for p16/MCM2 were 81.8%, 43.1%, 9.4%, and 97.1%. The sensitivity of cytology for triaging hrHPV-positive women were lower than p16/Ki-67 (P=0.012) and p16/MCM2 (P=0.065). The cocktail staining did not add sensitivity to p16/Ki-67 or p16/MCM2 staining alone (P > 0.05), however, cutting down the specificity of p16/Ki-67 staining alone with statistical significance (67.0% vs. 40.2%, P < 0.001). The risk of CIN2+ within 24 months for hrHPV-positive but triaging negative women at baseline was 0.5 (0.1–2.7), 0.7 (0.1–4.1), and 2.4 (1.1–5.0) for p16/Ki-67, p16/MCM2, and cytology, respectively. As an objective and accurate immunocytochemical staining, the p16/Ki-67 and p16/MCM2 dual staining performed better than cytology to triage positive hrHPV. On condition that high-quality cytology is unavailable, immunocytochemical staining by p16/Ki-67 or p16/MCM2 is an option for triaging hrHPV-positive women. The combination of p16/Ki-67 and p16/MCM2 could not improve the accuracy in detecting CIN2+.

Risk of cervical lesions in high-risk HPV positive women with normal cytology: a retrospective single-center study in China

BackgroundTo investigate high-risk HPV (hr-HPV) genotype distributions and the association between hr-HPV infection with severity of the cervical lesions in women with normal cytology.MethodsIn this cross-sectional study, the result of the hr-HPV test and biopsy of colposcopy of women with normal cytology from January 2012 to January 2019 were analyzed. The detection rate of high-grade squamous intraepithelial lesion (HSIL) and cervical cancer were calculated among different hr-HPV genotypes, viral load group, and age groups.ResultsFive thousand eight hundred eighty women were enrolled in this study. Overall, 59.97% had normal histological results, 19.32% had HSIL, and 1.07% had cervical cancer. The detection rate of HSIL or worse (HSIL+) in women with single HPV16(34.00%), HPV31(27.50%), HPV33(25.58%), and HPV52(20.88%) infection were higher significantly than single HPV18 (15.59%) infection, respectively. The HSIL+ detection rate between HPV16 single infection and multiple infections (excluding HPV18) was no significant difference (34% vs 35.47%, P = 0.638), contrary to HPV18(12.59% vs 21.67%, P = 0.022). In women without HPV16/18 infections, HSIL+ detection rates for single, double, and triple or more hr-HPV infections were 12.28, 20.31, and 37.50%, the risk of detection of HSIL+ significantly increasing. With the hr-HPV DNA load increases, the risk of detection of HSIL+ (χ2 = 91.01, P < 0.0001) and invasive cervical cancer (χ2 = 5.757, P = 0.016) increase. In age < 30, 31–40, 41–50, 51–60, > 60 group, HSIL+ detection rate were 24.80%、22.10%、19.59%、14.29, and 12.61%, respectively.ConclusionWomen who have normal cytology with HPV 16/18/31/33/52/58 infections, multiple HPV infections and high viral load, have a higher detection rate of HSIL+.

Comparison Study of Self-Sampled and Physician-Sampled Specimens for High-Risk Human Papillomavirus Test and Cytology

Objective: The objective of this study was to calculate the positive rate and overall concordance rate of high-risk human papillomavirus (hrHPV) test and cytology using self-sampled and physician-sampled cervicovaginal tests and to compare both specimens. Methods: In collaboration with 3 private hospitals in Sapporo city, 300 women visiting these organizations were enrolled in the study by previously signing an informed consent. From these women, both types of samples (self-obtained and physician-sampled) were obtained at the same time. HrHPV test and cytology were performed on both specimens, and the positive rate and overall concordance rate were calculated to compare both specimens. Results: HrHPV-positive women were 13.7% in physician-sampled specimens and 14.7% in self-sampled specimens, with an overall concordance rate of 96.3% (95% confidence interval [CI]: 94–98%). On the other hand, the positive rate of the cases higher than or equal to atypical squamous cells of undetermined significance (ASCUS) on cytology was different between both groups, that is, 12.3% in physician-obtained and 5.3% in self-sampled specimens; the overall concordance rate was 90.7% (95% CI: 87–94%), indicating an apparent decrease in the positive rate of cytology in self-obtained specimens. Conclusion: HrHPV test and cytology were performed on parallel samples obtained by the patients with a self-sampling tool and by the physician. The positive rate of cytology was considerably different between these specimens, while almost equivalent results were obtained for hrHPV test in both specimens. It was concluded that hrHPV test may be safely and accurately performed on self-obtained cervicovaginal samples by the help of a self-sampling device in the Japanese population as a first screening tool, with equivalent results to physician-obtained specimens.

Dietary Antioxidant Intake and Human Papillomavirus Infection: Evidence from a Cross-Sectional Study in Italy.

Several lines of evidence suggested that antioxidants might play a protective role against high-risk human papillomavirus (hrHPV) infection and cervical cancer. However, the effect of combined intake of antioxidants has not been investigated thus far. The current cross-sectional study aimed to understand the relationship between dietary antioxidant intake and the risk of high-risk HPV (hrHPV) infection among 251 Italian women with normal cervical cytology. Women were tested for hrHPV using the Digene HC2 HPV DNA Test. Dietary antioxidant intakes were assessed using a semi-quantitative food frequency questionnaire, and a Composite Dietary Antioxidant Index (CDAI) was constructed on the basis of zinc, selenium, manganese, vitamin A, vitamin C, vitamin E, carotenoid, and flavonoid intake. Logistic regression analysis was used to assess odds ratio (OR) and 95% confidence interval (95% CI) for the associations of antioxidant intakes or CDAI with hrHPV status, adjusting for age, smoking status, body mass index, parity, educational level, marital status, and use of multivitamins and oral contraceptives. We first observed that hrHPV-positive women (n = 84) reported lower intake of zinc, manganese, and vitamins A and C than non-infected women. Specifically, we found a negative association between dietary intake of zinc and hrHPV-positive status when all antioxidants were considered simultaneously (OR = 0.46; 95% CI = 0.27–0.80; p = 0.006). With respect to cumulative dietary antioxidant intake, we demonstrated that women with high CDAI (third tertile) had lower odds of being hrHPV-positive than those with low CDAI (first tertile) (OR = 0.39; 95% CI = 0.18–0.85; p = 0.018). To our knowledge, this is the first study demonstrating that a diet based on the combined intake of nutrients with antioxidant properties might reduce the risk of hrHPV infection. However, further research is needed to understand whether dietary antioxidant intake is associated with hrHPV infection or its persistence.

FHIT and C-MYC expression in cervical histology and cytology as biomarkers for detecting high-grade intraepithelial neoplasia in human papillomavirus-positive women.

BACKGROUND: The current cervical cancer screening strategies based on Papanicolaou (Pap) and Human papillomavirus (HPV) tests receive great achievement but still exhibit many limitations in clinical practice. Exploring new biomarkers as stratified management method in HPV primary screening is becoming the tendency of current research.METHODS: Immunocytochemistry (ICC) of FHIT and C-MYC were performed on exfoliated cervical cells from 197 eligible high-risk HPV positive women. Mann-Whitney U test, Pearson Chi-Square test, logistic regression analysis and receiver operating characteristic (ROC) curves were used to assess the diagnostic efficiency.RESULTS: ICC staining intensity of FHIT and C-MYC in high-grade cervical intraepithelial neoplasia (CIN) specimens was significantly different from low-grade CIN and normal specimens. Compared with Pap test, ROC analysis of ICC in detecting high-grade CIN resulted in a larger area under the curve (AUC) (0.805 and 0.814 vs 0.723, 0.001). FHIT achieved higher sensitivity than Pap test (79.41% vs 66.67%, 0.04). Logistic regression analysis of the combination of two biomarkers led to higher AUC value, specificity and PPV than any single biomarker.CONCLUSIONS: The utility of FHIT and C-MYC ICC analysis in cervical exfoliated cells of HPV-positive women displayed superior diagnostic potential and may improve clinical performance of cervical cancer screening.

High-risk human papillomavirus prevalence in self-collected cervicovaginal specimens from human immunodeficiency virus (HIV)-negative women and women living with HIV living in Botswana.

The prevalence of high-risk human papillomavirus (hrHPV) is poorly described overall and in women living with HIV (WLWH) and HIV-negative women living in Botswana, a high HIV and cervical cancer-burden country. We conducted a pilot study of self-collection and high-risk HPV testing for cervical screening, from which data on HPV prevalence was available. From five health facilities in the Kweneng East District, 1,022 women aged 30-49 years were enrolled to self-collect their cervicovaginal specimen for hrHPV testing by the Xpert HPV Test (Cepheid, Sunnyvale, CA, USA). Crude and age group-adjusted hrHPV prevalence by HIV status were calculated, and the relationship of hrHPV risk groups HPV16>HPV18/45>other hrHPV types) to the presence and severity of visible lesions. Of the 1,022 women enrolled, 1,019 (99.7%), 570 WLWH and 449 HIV-negative women, had hrHPV testing results. Crude hrHPV prevalences were 25.2% (95%CI = 21.2-29.4%) for HIV-negative women and 40.4% (95%CI = 36.3-44.5%) for WLWH. Age group-adjusted hrHPV prevalences were 23.7% (95%CI = 19.9-27.9%) for HIV-negative women and 41.3% (95%CI = 37.2-45.4%) for WLWH. Age group-adjusted prevalences of HPV16 (p<0.001), HPV18/45 (p<0.001), HPV31/33/35/52/58 (p<0.001), and HPV39/56/66/68 (p = 0.011) were greater among WLWH than HIV-negative women. Riskier hrHPV groups were more likely to have visible abnormalities (ptrend = 0.004) and visible abnormalities not eligible for cryotherapy (ptrend = 0.030). hrHPV infection was common among all women in the study living in Botswana, to a greater extent in WLWH than their HIV-negative counterparts. Strategies to triage hrHPV-positive women will be needed to avoid over-treating many women with benign hrHPV infections.

Type-specific Distribution of Cervical hrHPV Infection and the Association with Cytological and Histological Results in a Large Population-based Cervical Cancer Screening Program: Baseline and 3-year Longitudinal Data.

Objectives: This study aimed to describe the study design, and to analyze the type-specific distribution of cervical high-risk human papillomavirus (hrHPV) infection and its association with cytological and histological results in a large population-based screening program in Buji Street, Shenzhen, China.Methods: A total of 10,186 women aged 21-70 years were co-tested by Cobas4800 HPV assay and liquid-based cytology. Women were referred to colposcopy by virtue of being HPV16/18-positive, Other hrHPV-positive/ cytology ≥ASCUS, or HPV-negative/ cytology ≥LSIL. Three-year histological follow-up data were recorded.Results: The overall prevalence of hrHPV infection was 11.1%; among them, the highest type was Other hrHPV (8.9%), followed by HPV16 (1.6%) and HPV18 (0.6%). Moreover, the prevalence of hrHPV and that of HPV16 increased with cytological severity (Ptrend <0.001). In the baseline phase, 106 women had cervical intraepithelial neoplasia 2/3 (CIN2/3) and six had cervical cancers. During 3-year follow-up, 12 cases of CIN2/3 and no cancers were identified. For HPV16-positive women with normal cytology, the baseline risks of CIN2/3 or worse (CIN2+/CIN3+) were 15.5% (7.0-23.9%) and 4.2% (1.4-8.5%) respectively. For Other hrHPV-positive women with normal cytology, the cumulative 3-year risks of CIN2+/CIN3+ were 3.1% (1.0-5.2%) and 0.7% (0.3-2.1%) respectively. Strikingly, 75.8% (322/425) of abnormal cytology and 50.9% (29/57) HSIL cytology were attributed to Other hrHPV infection in HPV-positive women. Similarly, Other hrHPV infection led to large proportions of CIN2 (62.7%) and CIN3+ (43.9%) over 3-year follow-up.Conclusions: The co-testing modality is a feasible, effective and safe option for cervical cancer screening in urban population. Great importance should also be attached to 'genotypes excluding HPV16/18' and separate detection of each genotype when considering screening and vaccination strategy.