hrHPV-positive Women Research Articles

Risk stratification for cervical neoplasia using extended high-risk HPV genotyping in women with ASC-US cytology: A large retrospective study from China.

Extended high-risk human papillomavirus (hrHPV) genotype testing (hrHPVGT) has emerged as a new strategy to help optimize the efficiency of hrHPV triage. Women with an atypical squamous cells of undetermined significance (ASC-US) cervical Papanicolaou test result who underwent hrHPVGT between October 2017 and May 2021 at the Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China, were studied. For hrHPVGT, a proprietary multiplex real-time polymerase chain reaction assay was used. hrHPVGT and viral load test results in selected patients were correlated with histopathologic follow-up findings available within 6months. In total, 17,235 women with ASC-US cytology who had hrHPVGT results were identified in the Obstetrics and Gynecology Hospital of Fudan University database. The hrHPV-positive rate was 61.8%, and the most prevalent hrHPV genotypes were type 52 (HPV52) (16%), HPV16 (11.3%), HPV58 (10.2%), and HPV53 (8.4%). Single hrHPV genotypes were detected in 65.9% of women with hrHPV-positive results, and multiple genotypes were detected in 34.1%. Histopathologic cervical findings within 6months were available in 5627 hrHPV-positive women and 2223 hrHPV-negative women. High-grade cervical intraepithelial lesions or cervical cancer (cervical intraepithelial neoplasia 2 or greater [CIN2+]) were identified in 7.5% of hrHPV-positive women who had ASC-US cytology and in 0.9% of hrHPV-negative women who had ASC-US cytology. The greatest risk for CIN2+ was in single hrHPV genotype infections with HPV16 (21.1%), HPV33 (15.2%), HPV82 (10%), and HPV18 (9.9%). hrHPVGT for genotypes HPV16, HPV33, HPV82, HPV18, HPV31, HPV45, HPV58, and HPV52 identified 95% of CIN2+ cases with 90.8% sensitivity, 53.8% specificity, a positive predictive value of 10.2%, and a negative predictive value of 99%. A significantly increased viral load was associated only with women who had HPV16-related CIN2+. hrHPVGT for women who have ASC-US cytology allows for risk stratification capable of optimizing the efficiency of triage for hrHPV-positive women.

Development of a large biorepository of cervical specimens for the Improving Risk Informed HPV Screening study (IRIS).

Biomarkers of Human Papillomavirus (HPV) cervical carcinogenesis are critical to address questions of how to triage and manage women who screen positive for high-risk HPV (HrHPV) and identify those at highest cancer risk. We describe the development of a large biorepository of cervical specimens for the Improving Risk Informed HPV Screening Study (IRIS) using residual specimens collected in the regional laboratory from women aged 25 and older who had cervical cancer screening or follow-up testing with high-risk human papillomavirus (HrHPV) testing and liquid-based cytology (co-testing) at Kaiser Permanente Northern California (KPNC) from January 2016 to August 2018. Specimen selection, processing for long-term storage, follow-up tracking, consent and demographic and clinical characteristics of the women in the IRIS cohort are described. Selecting from 897,680 women who had at least one co-test during the study period, we collected 199,403 baseline and 216,390 follow-up HrHPV and cytology specimens from a stratified random sample of 81,348 women, of which 3,428 (4.2%) opted out of the study and were excluded. The majority (79.9%) of the baseline specimens were from HrHPV-positive women. The mean age was 36 years, and the cohort is racially/ethnically diverse with 56% of women being Hispanic or non-white. Over two-thirds of the cohort were members of KPNC for two or more years prior to inclusion. Of the 77,920 women included in the cohort, 57,414 (73.7%) had at least one follow-up co-test. Use of specimens from the biorepository will elucidate molecular mechanisms underlying HPV carcinogenesis and inform more effective screening and follow-up strategies.

Novel high-resolution targeted sequencing of the cervicovaginal microbiome

BackgroundThe cervicovaginal microbiome (CVM) plays a significant role in women’s cervical health and disease. Microbial alterations at the species level and characteristic community state types (CST) have been associated with acquisition and persistence of high-risk human papillomavirus (hrHPV) infections that may result in progression of cervical lesions to malignancy. Current sequencing methods, especially most commonly used multiplex 16S rRNA gene sequencing, struggle to fully clarify these changes because they generally fail to provide sufficient taxonomic resolution to adequately perform species-level associative studies. To improve CVM species designation, we designed a novel sequencing tool targeting microbes at the species taxonomic rank and examined its potential for profiling the CVM.ResultsWe introduce an accessible and practical circular probe-based RNA sequencing (CiRNAseq) technology with the potential to profile and quantify the CVM. In vitro and in silico validations demonstrate that CiRNAseq can distinctively detect species in a mock mixed microbial environment, with the output data reflecting its ability to estimate microbes’ abundance. Moreover, compared to 16S rRNA gene sequencing, CiRNAseq provides equivalent results but with improved sequencing sensitivity. Analyses of a cohort of cervical smears from hrHPV-negative women versus hrHPV-positive women with high-grade cervical intraepithelial neoplasia confirmed known differences in CST occurring in the CVM of women with hrHPV-induced lesions. The technique also revealed variations in microbial diversity and abundance in the CVM of hrHPV-positive women when compared to hrHPV-negative women.ConclusionsCiRNAseq is a promising tool for studying the interplay between the CVM and hrHPV in cervical carcinogenesis. This technology could provide a better understanding of cervicovaginal CST and microbial species during health and disease, prompting the discovery of biomarkers, additional to hrHPV, that can help detect high-grade cervical lesions.

Clinical performance of high-risk HPV testing on self-samples versus clinician samples in routine primary HPV screening in the Netherlands: An observational study.

BackgroundHigh-risk human papillomavirus (hrHPV) testing on self-collected samples has potential as a primary screening tool in cervical screening, but real-world evidence on its accuracy in hrHPV-based screening programmes is lacking.MethodsIn the Netherlands, women aged 30–60 years invited for cervical screening can choose between sampling at the clinician's office (Cervex Brush) or self-sampling at home (Evalyn Brush). HrHPV testing is performed using Roche Cobas 4800. We collected screening test results between January 2017 and March 2018 and histological follow-up until August 2019. The main outcome measures were mean cycle threshold (Ct) value, cervical intraepithelial neoplasia (CIN) grade 3 or cancer (CIN3+) and CIN grade 2 or worse (CIN2+).Findings30,808 women had a self-collected and 456,207 had a clinician-collected sample. In hrHPV-positive women with adequate cytology, Ct values were higher for self-collection than clinician-collection with a mean Ct difference of 1·25 (95% CI 0·98–1·52) in women without CIN2+, 2·73 (1·75–3·72) in CIN2 and 3·59 (3·03–4·15) in CIN3+. The relative sensitivity for detecting CIN3+ was 0·94 (0·90–0·97) for self-collection versus clinician-collection and the relative specificity was 1·02 (1·02–1·02).InterpretationThe clinical accuracy of hrHPV testing on a self-collected sample for detection of CIN3+ is high and supports its use as a primary screening test for all invited women. Because of the slightly lower sensitivity of hrHPV testing on a self-collected compared to a clinician-collected sample, an evaluation of the workflow procedure to optimise clinical performance seems warranted.FundingNational Institute for Public Health and the Environment (the Netherlands) and the European Commission.

Distribution of vaccine-related high-risk human papillomaviruses and their impact on the development of cervical dysplasia in women in Montenegro.

Cervical cancer (CC) is the third leading cause of death in women in Montenegro. Human papillomavirus (HPV) is the causative agent of CC however, HPV genotype distribution varies across regions. This study examined the distribution and impact of vaccine-related high-risk (HR)-HPVs on the development of cervical dysplasia in Montenegrin women. A total of 187 women who had a clinical indication for cervical biopsy were enrolled. Based on histopathological findings, women were classified into 2 groups, with and without dysplasia. HR-HPV was detected by real-time PCR. Twelve HR-HPV genotypes were detected in 40.6% of cervical samples. The 7 most prevalent HR-HPVs in order of decreasing frequency were HPV 16 (39.5%), 45 (23.7%), 31 (21.0%), 33 (17.1%), 18 (6.6%), 52 (6.6%), and 58 (6.6%), all of them are targeted by nonavalent vaccine. Vaccine-related HR-HPVs had a higher prevalence (92.1%) than the other HR-HPVs detected in HR-HPV-positive samples. Among HR-HPV-positive women, HPV 16 and 33 were more common in women with dysplasia than in those without dysplasia (HPV 16: 28.9 vs 7.2%; HPV 33: 11.8 vs 3.6%). HPV 16 was the most common HR-HPV genotype in cervical samples, followed by HPV 45, 31, 33, 18, 52, and 58. HPV 16 and 33 were shown to be associated with the development of cervical dysplasia. These results indicate that prophylactic nonavalent vaccine can potentially prevent approximately 90% of HR-HPV infections and 60% of cervical dysplasia cases in Montenegrin women.

Predicting Cohort-Specific Cervical Cancer Incidence From Population-Based Surveys of Human Papilloma Virus Prevalence: A Worldwide Study.

Predictions of cervical cancer burden and the impact of measures taken to control this cancer are usually data-demanding and based on complex assumptions. We propose a predictive method (called PANDORA) based on human papillomavirus (HPV) prevalence, measured 1993–2008, and cervical cancer incidence (CCI), measured 1993–2012, in the same birth cohorts from different worldwide locations, informed by data on age at detection of high-risk HPV and sexual debut. The model can predict CCI among high-risk HPV–positive women and predict CCI up to 14 years following high-risk HPV detection. We found CCI to increase during the 14 years following high-risk HPV detection in unscreened women aged <35 years but to remain mainly constant among women ≥35 years. Age at sexual debut was a significant modifier of CCI. Using our model, we accurately reproduced CCI among high-risk HPV–positive women as observed in cohort studies and in the general population of multiple countries. We also predicted the annual number of cervical cancer cases and CCI in locations with HPV prevalence data but no cancer registry. These findings could inform cervical cancer control programs in settings without cancer registries, as they can be used to predict future cervical cancer burden from population-based surveys of HPV prevalence.

The Risk Stratification for Cervical Cancer and Precursors of Domestic HPV Testing With HPV 16/18 Genotyping in Women With NILM Cytology in CentralChina: A Cohort Study.

ObjectiveTo evaluate the clinical performance and utility for risk stratification of DH3 HPV assay in women (≥30 years) with NILM cytology.MethodsA prospective cohort was established in Central China between November 8 to December 14, 2016 which consisted of 2180 women aging 30-64 years with NILM cytology. At baseline, all women were screened using DH3 HPV assay. HPV 16/18 positive women would be assigned to colposcopy and biopsied if necessary. Then, hr-HPV positive women without CIN2+ lesions would be followed up by cytology every 12 months for two years. In the 3rd year of follow up, all women that were not biopsy proven CIN2+ would be called back and screened by cytology again. In follow-up period, women with ASC-US and above were referred to colposcopy and biopsied if clinically indicated. CIN2+ was the primary endpoint in analysis. The clinical performance and utility for risk stratification of DH3 HPV assay were assessed by SPSS 22.0 and SAS 9.4.ResultsOf 2180 qualified women, the prevalence of hr-HPV was 8.5% (185/2180), 45(2.1%) were HPV 16/18 positive. The clinical performance for HPV16/18 was 91.7% for sensitivity, 98.4% for specificity, respectively against CIN2+ detection at baseline. In four years of study, the corresponding rates of HPV 16/18 were 51.5% and 98.7%, respectively. The cumulative absolute risk for the development of CIN2+ was as high as 37.8% for HPV 16/18 positive women, followed by hr-HPV positive (14.6%), other hr-HPV positive (11.0%) and HPV negative (0.3%) in three years. The relative risk was 125.6 and 3.4 for HPV 16/18 positive group when compared with HPV negative and other hr-HPV positive group, respectively.ConclusionsDH3 HPV assay demonstrated excellent clinical performance against CIN2+ detection in cervical cancer screening and utility of risk stratification by genotyping to promote scientific management of women with NILM cytology.

Clinical evaluation of a real-time optoelectronic device in cervical cancer screening

ObjectiveEarly screening and intervention are crucial for the prevention and treatment of cervical cancer. TruScreen is a real-time, intelligent, pathological diagnostic technology designed for cervical cancer screening. The aim of this study was to evaluate the clinical value of TruScreen in screening for cervical lesions. Study designA total of 458 women aged between 25 and 65 years were recruited to receive cervical cancer screening, including human papillomavirus (HPV) testing, cytological testing using the ThinPrep cytology test (TCT), and TruScreen from December 2018 to January 2020. The clinical performance of TruScreen, alone and in combination with HPV testing, was evaluated to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+ or CIN3+). ResultsFor detection of CIN2+, the sensitivity and specificity of TruScreen were 83.78% and 78.86%, respectively. The specificity of TruScreen was significantly higher than those of HPV testing (50.59%, P < 0.001) and TCT (55.58%, P < 0.001). In high-risk HPV-positive women, the specificity of HPV testing combined with TruScreen was significantly higher than that of HPV testing combined with TCT (50% vs 39.9%, P = 0.004). The sensitivity of HPV testing combined with TruScreen was comparable to that of HPV testing combined with TCT (93.94% vs 87.88%, P = 0.625). Similar patterns were also observed for CIN3+ cases. ConclusionTruScreen has the potential for screening high-grade cervical precancerous lesions and may replace cytological tests as a cervical cancer screening method in China to avoid subjectivity in the interpretation of cytological tests and requirements by pathologists.

HPV16 Load Is a Potential Biomarker to Predict Risk of High-Grade Cervical Lesions in High-Risk HPV-Infected Women: A Large Longitudinal French Hospital-Based Cohort Study.

Simple SummaryThis study aimed at assessing HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 885 women positive for hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 135 developed a high-grade lesion during the follow-up. Considering an HPV16 viral load cut-off set at 3.2 log10 GE/103 cells a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80–3.97 p ≤ 0.0001) has been identified. Moreover, a composite score based on HPV16 load, cytology and hrHPV detection allowed for CIN2+ risk stratification. To conclude, HPV16 load is a relevant biomarker to identify women at high risk for developing precancerous lesions of the cervix. High-risk HPV (hrHPV) testing has been implemented as a primary screening tool for cervical cancer in numerous countries. However, there is still a need for relevant triage strategies to manage hrHPV positive women to avoid excessive referral to colposcopy. The objective of this study was to assess, in women infected by hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 2102 women positive for hrHPV, 885 had no lesion or mild cytological abnormalities at baseline and had at least one follow-up (FU) visit. HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 15% developed a high-grade lesion during the FU. An HPV16 viral load cut-off set at 3.2 log10GE/103 cells permitted to identify a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80–3.97; p ≤ 0.0001). No specific HPV18 viral load threshold could have been defined in regard to the present study. In multivariate analysis, HPV16 load (absence/log10GE/103 cells < 3.2 vs. ≥3.2), RLU/PC 239 (1–100 pg/mL vs. >100 pg/mL) and cytology (normal vs abnormal) were independently associated with a significant increased risk of high-grade lesion development and were used to construct the prognostic score. In conclusion, HPV16 load is a relevant biomarker to identify women at high risk for developing cervical precancerous lesions.

Liquid-Based Screening Tests Results: HPV, Liquid-Based Cytology, and P16/Ki67 Dual-Staining in Private-Based Opportunistic Cervical Cancer Screening.

The baseline data from the private-based opportunistic cervical cancer screening with HRHPV14, liquid-based cytology (LBC) and p16/Ki67 testing, and its quality assessment/quality control (QA/QC) tools are lacking. The age-stratified analysis of 30,066 screening tests results in a Polish population, including the investigation of HRHPV14 status, LBC, and p16/Ki67 dual-staining reporting rates, along with immediate histopathologic correlations, was conducted. For cytopathologic QA/QC, the College of American Pathologists (CAP) benchmarks and enhanced safety protocol were used. The NILM/ASC-US/LSIL/ASC-H/HSIL/AGC reporting rates were 93.9/3.4/2.0/0.22/0.24/0.11, respectively, with correlating HRHPV14-positive rates of 8.4/48.9/77.2/84.6/90.7/26.7. The reporting rates for HSIL (CIN2+) in HRHPV-positive women with NILM/ASC-US/LSIL/ASC-H/HSIL/AGC referred for a colposcopy with biopsy were 19.1/25.8/22.5/12.4/19.1/1.1% of the total HSIL (CIN2+). In total, of the 1130 p16/Ki67 tests, 30% were positive. In NILM HRHPV14-positive women with available histology result, HSIL(CIN2+) was detected in 28.3% of cases. In the first such large-scale Polish study presenting HRHPV14, informed LBC and HSIL (CIN2+) results, the reporting rates were highly consistent with data from American and other CAP-certified laboratories, confirming the possibility of using the 2019 ASCCP risk-based guidelines as one of the screening strategies outside of the US, in conditions of proper QA/QC. The private-based screening model can be effective in cervical cancer prevention, particularly in countries with low population coverage of public funds-based systems.

Comparison of different strategies for the triage to colposcopy of women tested high-risk HPV positive on self-collected cervicovaginal samples

ObjectiveTo identify the optimal strategy for the triage of women who test high-risk (hr) HPV positive on self-collected cervicovaginal samples. MethodsThis is a diagnostic accuracy sub-analysis of the GRECOSELF study, which reported on HPV-DNA testing with self-sampling in Greece. More than 13,000 women, 25–60 years old, who resided in rural areas of Greece, provided a self-collected cervicovaginal sample. Samples were tested for HPV-DNA and HPV16/18 genotyping with the cobas® HPV test (Roche® Molecular Systems, Pleasanton, CA, USA). HrHPV positive women were referred for colposcopy. Prior to colposcopy a physician-collected sample was obtained for cytology. After colposcopy/biopsy, women were classified as having cervical disease or not, and treated accordingly. ResultsOut of 1070 hrHPV positive women, 773 were subjected to colposcopy. Seventeen triage strategies, combining HPV16/18 genotyping and cytology, were investigated. The strategy referring to colposcopy women positive for HPV16 regardless of the cytology report, and women positive for other hrHPVs, in case of a subsequent atypical squamous cells of undetermined significance or worse (ASCUS+) cytology report, presented optimal trade-off; sensitivity 96.36% [(95%CI: (91.41–100.0)], positive predictive value (PPV) 27.46% [95%CI: (21.16–33.76)], and number of colposcopies required to detect one case of Cervical Intraepithelial Neoplasia grade-2 or worse (CIN2+) 3.64. ConclusionsThe optimal strategy for the triage to colposcopy of hrHPV positive women, detected with the cobas® HPV test on self-collected cervicovaginal samples, is referring all HPV16 positive women directly to colposcopy, and women positive for HPV18 or other hrHPVs only after an ASCUS or worse cytology report.

Effectiveness of the thermal ablation in the treatment of human papillomavirus infection and cervical intraepithelial neoplasia in Chinese women

Objective: To evaluate the effectiveness of thermal ablation in the treatment of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) in Chinese women. Methods: The high-risk HPV-positive women aged 20-65 who were detected through a cervical cancer screening project implemented in three rural sites (Etuoke counties in Inner Mongolia, Xiangyuan and Yangcheng counties in Shanxi Province) and one urban site (Shenzhen) in China were included in this prospective study. Follow up evaluation was performed on HPV positive women who underwent thermal ablation (n=166) as well as received no treatment (n=2 716) in cervical cancer screening program. For women with thermal ablation treatment, HPV test and cytology were used for follow-up with the interval of 6 months or longer after treatment. For women without treatment, HPV test was used for annual follow-up. Women with positive results in either of the HPV tests or abnormal cytology were referred for a colposcopy or biopsy if necessary. The HPV clearance rate and the cure rate of CIN were compared between the two groups. Results: A total of 152 women treated with thermal ablation and 2 539 women without treatment reported for follow-up evaluation with the age M(Q1, Q3) of 42 (36, 48) and 47 (41, 54) years old, and the median time to follow-up time of 23.4 (12.4, 24.5) and 23.5 (12.4, 24.0)months, respectively. The HPV clearance rate in women undergoing thermal ablation was significantly higher than that in women with no treatment (73.0% vs 46.1%, P<0.001). The HPV16, HPV52 and HPV58 clearance rates among women receiving thermal ablation were higher than that in women without treatment with the OR (95%CI) of 2.8 (1.3-6.1), 3.2 (1.3-7.9) and 5.8 (2.1-15.6). For women with histologically confirmed CIN at baseline, cure rates were 77.4%(n=72) for thermal ablation. Cure rates of the thermal ablation were 81.0%(n=47) for CIN grade one (CIN1) and 71.4% (n=25) for CIN grade two or worse (CIN2+). Conclusions: Thermal ablation is effective to clear the HPV infection as well as to treat CIN. Particularly for the HPV genotypes with the paramount attributable proportion to cervical cancer and precancerous in China, the HPV clearance rate was significantly higher than that reported in the women without treatment.

Determining the prevalence of high-risk human papillomavirus infection using a novel cervical precancer screening approach in incarcerated women at the Nsawam Medium Security Prison, Ghana

BackgroundAcross Ghana, females comprise 1.2% of the entire prison population (n = 15,463). Cervical cancer screening services are however nonexistent and the prevalence of high-risk human papillomavirus (hr-HPV) and cervical precancer is undocumented. We aimed to screen and treat inmates for cervical precancer and determine the prevalence of hr-HPV using the novel AmpFire HPV detection system combined with colposcopy by trained nurses using a mobile colposcope (the Enhanced Visual Assessment (EVA) system).MethodsA descriptive cross-sectional study design was employed, involving all incarcerated women at the Nsawam Medium Security Prison, Ghana. After counselling and informed consent, women underwent a structured questionnaire-based interview entered into a Microsoft Excel spreadsheet. Women were co-tested for cervical pre-cancer and hr-HPV by two trained nurses using dry brush cervical samples for 15 hr-HPV types (AmpFire HPV test) after which mobile colposcopy with the EVA system was performed. EVA images were reviewed by a gynaecologist. Frequencies and percentages were used to describe categorical data, while means, standard deviations, medians and interquartile ranges (IQRs) were used to describe continuous data.Results75% of the women were convicts with a median sentence of 5 years (IQR: 2–10 years). Their mean age was 41.1 years (standard deviation: 15.5 years, range: 19–97 years). The self-reported prevalence rate of HIV was 13.1% (95% confidence interval (CI): 7.5%–21.9%), all of whom were receiving treatment. The hr-HPV prevalence rate was 47.6% (CI: 36.9%–58.3%) in the general population of imprisoned women and 63.6% (CI: 35.4%–84.8%) among HIV positive women. Six percent (6%) had lesions on the cervix, of which 3.6% were treated with thermal coagulation and 2.4% were treated with loop electrosurgical excision procedure. The average age of hr-HPV positive women was 37.8 years.ConclusionsThere is a high prevalence of hr-HPV infection among women in custody at the Nsawam Medium Security Prison. These women will benefit from structured cervical cancer prevention services, including treatment for abnormalities that are picked up during such screening.

The optimal model of diagnosis to low-grade cervical intraepithelial neoplasia by combined detecting vaginal micro-environmental factors, based on the high-risk HPV infection

Objective: To investigate the diagnostic value of different vaginal micro-environmental factors in low-grade cervical intraepithelial neoplasia (CIN Ⅰ) and determine the optimal model in high-risk human papillomavirus (HR-HPV) infection. Methods: A total of 926 women, including 623 with normal cervical (NC) condition and 303 CINⅠ patients, had undergone pathological examinations, and were enrolled in the study. All the women were from a community previously established cohort. Vaginal cleanliness, pH, H2O2, β-glucuronidase, coagulase, sialidase, and leukocyte esterase (LE) were detected by the combined detection method aerobic vaginitis/bacterial vaginosis in vaginal secretions. HPV genotyping was performed by using the flow-through hybridization technology. The data were analyzed by SAS 9.2 and SPSS 23.0. Results: The vaginal cleanliness, pH, sialidase, and LE were determined as the representative vaginal micro-environment factors by principal component analysis. Based on logistic regression theory to analyze the ROC curve, the results showed that the highest sensitivity was with pH value (76.2%), and the highest specificity was with sialidase (90.9%). The area under ROC curve were higher in combination detection modes of sialidase+LE (0.714), pH+sialidase+LE (0.719), vaginal cleanness+sialidase+LE (0.713) and pH+vaginal cleanness+sialidase+LE (0.709). According to HR-HPV infection status, the TOPSIS method was used to analyze the combined detection optimal model. Specifically, we found that the best diagnostic model was pH+sialidase +LE (Ci=0.585) in the HR-HPV positive group and vaginal cleanness+sialidase+LE (Ci=0.641) in the negative group. Conclusions: The combined detection of vaginal microenvironment factors could be used for auxiliary diagnosis for CINⅠ. It would be more effective when detecting pH, sialidase, and LE in HR-HPV positive women while vaginal cleanness, sialidase, and LE in HR-HPV negative women at the same time.

Effect of dietary water-soluble vitamins on the poor prognosis of low-grade cervical intraepithelial neoplasia-a prospective cohort study

Objective: To explore the effect of dietary water-soluble vitamins on the poor prognosis of low-grade cervical intraepithelial neoplasia (CINⅠ). Methods: A total of 564 participants with CINⅠ were selected from a community-based married women cohort established in 2014. The general baseline information was collected, and HPV genotyping was detected. A food frequency questionnaire was used to investigate dietary water-soluble vitamins' consumption and determine their exposure levels. The follow-up program was carried out for 12 months, and the regression, persistence, and progression of CINⅠ was determined according to histopathological results at 12-month. Results: The low-levels of dietary water-soluble vitamins could promote CINⅠ's persistence and progression, showing the increasing tendency of CINⅠ poor prognosis with the decrease of water-soluble vitamin levels. Especially folate, VB1, VB2, VB6, niacin, biotin, and VC (RR values were 15.22, 1.86, 1.92, 2.11, 2.98, 2.14, 2.19, respectively) played an important role. Considering the status of high-risk human papillomavirus (HR-HPV) infection, our results showed that the low levels of folate, niacin, biotin could promote the poor prognosis of CINⅠ. Conclusions: The low-level of dietary water-soluble vitamins could facilitate the poor prognosis of CINⅠ. In addition, folate, niacin, biotin were more effective on HR-HPV positive women.

Effectiveness of photodynamic therapy with 5-aminolevulinic acid on HPV clearance in women without cervical lesions

BackgroundHigh-risk HPV (hrHPV) not only increases the risk of cervical precancerous lesions and cervical cancer, but also adds psychological burden to HPV-positive women. 5-aminolevulinic acid photodynamic therapy (ALA–PDT) is a non-invasive and highly tissue-selective therapy. We aim to investigate the clinical efficacy of ALA-PDT for elimination of cervical hrHPV infection in HPV-positive women without cervical lesions. MethodsA total of 57 hrHPV-positive women without pathologically proved cervical lesions received three treatments of ALA–PDT in total. HPV DNA testing and pap cytology were performed in all patients. Patients with positive HPV16/18 or abnormal TCT results received colposcopic biopsy during the follow-up. ResultshrHPV clearance rate was 56.1 % (32/57) at 3-month follow-up and 68.1 % at 6-month follow-up. 100 % of HPV 18 and 87.5 % of HPV16 infections were cleared while the clearance rate was 48.8 % among those positive for 12 other high-risk types. Multivariate analysis showed HPV16/18 infection was associated with significantly higher clearance rate. HPV clearance rate in patients with multiple-type HPV infection was significantly lower than that in patients with single-type HPV infections. ConclusionsALA-PDT is effective on treating hrHPV infection in patients with no cervical lesions. HPV16/18 positive cases can benefit most from ALA-PDT. Multitype-infected women need more sessions of 5- ALA-PDT to eradicate hrHPV infection.

Triage of human papillomavirus infected women by methylation analysis in first-void urine

Host cell DNA methylation analysis in urine provides promising triage markers for women diagnosed with a high-risk (HR) human papillomavirus (HPV) infection. In this study, we have investigated a panel of six host cell methylation markers (GHSR, SST, ZIC1, ASCL1, LHX8, ST6GALNAC5) in cervicovaginal secretions collected within the first part of the urine void (FVU) from a referral population. Cytology, histology, and HPV DNA genotyping results on paired FVU and cervical samples were available. Urinary median methylation levels from HR-HPV (n = 93) positive women were found to increase for all markers with severity of underlying disease. Significantly elevated levels were observed for GHSR and LHX8 in relation to high-grade cervical intraepithelial neoplasia (CIN2 +; n = 33), with area under de curve values of 0.80 (95% Confidence Interval (CI) 0.59–0.92) and 0.76 (95% CI 0.58–0.89), respectively. These findings are the first to support the assertion that methylation analysis of host cell genes is feasible in FVU and holds promise as molecular, triage strategy to discern low- from high-grade cervical disease in HR-HPV positive women. Molecular testing on FVU may serve to increase cervical cancer screening attendance in hard-to-reach populations whilst reducing loss to follow-up and await further optimization and validation studies.

Analysis of colposcopic findings of high-risk HPV positive women with unsatisfactory cervical cytology

Aim: We aimed to analyze the colposcopic directed biopsy results of women with unsatisfactory cervical cytology and high-risk human papilloma virus (HPV) positivity, who were referred to the Gynecologic Oncology outpatient clinic from Cancer Early Diagnosis and Screening Centers.&#x0D; Materials and Methods: In this retrospective study, women with high-risk HPV subtypes who applied to our clinic between March 2015 and October 2017 with an inadequate cervical cytology underwent colposcopy-directed biopsy. Patients were grouped according to HPV types. The results of endocervical curettage, cervical biopsy, and cervical conization were analyzed.&#x0D; Results: Forty-six patients with unsatisfactory cervical cytology and high-risk HPV were included in this study during the 30-month period. Twenty-five (54.3%) of the patients had “non-16 non-18” HPV subtypes, while 21 (45.7%) had HPV 16 and/or HPV 18. Cervical biopsy results revealed high-grade squamous intraepithelial lesion (H-SIL) in 5 (10.9%) patients, low-grade squamous intraepithelial lesion (L-SIL) in 17 (37%), “HPV effect” in 4 (8.7%) and normal histopathology in 20 (43.5%) patients. The endocervical curettage revealed three (6.5%) women with H-SIL and seven (15.2%) with L-SIL. Seven (15.2%) patients underwent conization due to H-SIL and there were three H-SIL with negative margins and four L-SIL in the final histopathology report.&#x0D; Conclusion: Performing colposcopy seems to be crucial for women with inadequate cervical cytology and high-risk HPV regardless of HPV subtypes as there is an increased risk of H-SIL in this patient population.

DNA methylation marker for the triage of hrHPV positive women in cervical cancer screening: Real-world evidence in Taiwan

ObjectiveHuman papillomavirus (HPV) testing as the primary cervical cancer screening followed by reflex cytology if high-risk HPV is present (hrHPV+) is recently adopted in some countries. However, reflex cytology's sensitivity is variable, and a suitable triage approach for hrHPV+ remains controversial. Here, we compared the performance of three triage tools in hrHPV+ women. MethodsThree triage tools—cytology, HPV16/18 genotyping, and DNA methylation biomarker PAX1m—were analyzed for their clinical performance in hrHPV+ women. In addition, women without cervical cancer at enrollment were followed for histologically confirmed high-grade cervical intraepithelial neoplasia or worse (CIN3+) annually using Papanicolaou smear. ResultsOf 4762 women aged ≥20 years enrolled, 502 (10.5%) were hrHPV+. PAX1m and cytology demonstrated similar accuracy (>90%), sensitivity (>78%), and specificity (>92%) as triage tools in 429 hrHPV+ women aged 30–64 years. PAX1m had better accuracy and specificity (91.6% and 92.5%, respectively) than HPV16/18 (76.9% and 76.8%, respectively). The incidence of CIN3+ among hrHPV+ women was 10.7 cases/1000 person-years. The incidence was significantly greater in PAX1m-positive women than in PAX1m-negative women. ConclusionsPAX1m has comparable clinical performance to cytology and better accuracy and specificity than HPV16/18 as the triage tool for detecting CIN3+ in hrHPV+ women. The PAX1m assay is thus a promising molecular-based triage tool for early detection of CIN and predicting disease progression in hrHPV+ women. It can be especially useful in countries where adequate cytology-based infrastructure is lacking, such as some Southeast Asian countries, for cervical cancer screening and prevention.

Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse in HPV-Positive Women with Normal Cytology and Five-Year Type Concordance: A Randomized Comparison

Abstract Background: In human papillomavirus (HPV)-based cervical screening programs, management of HPV-positive women with normal cytology is debated. Longitudinal information on HPV type persistence may be employed for risk stratification. Methods: We assessed the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) after repeatedly testing positive for the same HPV type(s) in the randomized population-based screening study Amsterdam (POBASCAM). We compared 18-month CIN3+ risks in HPV-positive women (intervention, n = 1,066) to those in HPV-positive/cytology-negative women who tested HPV-positive in the next screening round (control, n = 111) five years later, stratified for HPV type concordance. Results: The 18-month CIN3+ risk was 15% in HPV-positive women in the intervention group, 40% in the control group after two-round type concordance (relative risk 2.6, 95% confidence interval 1.9–3.4), and 20% in the control group after a type switch (1.3, 0.5–3.2). The relative increase in CIN3+ risk after two-round type concordance was similar in &amp;lt;35-year-old (3.0, 2.0–4.4) and older women (2.2, 1.4–3.5), and was high in high-risk HPV-positive women who were HPV16/18/31/33/45-negative in both rounds (9.9, 4.4–21.9). Conclusions: Five-year HPV type concordance signals high CIN3+ risk and warrants referral for colposcopy without additional cytology triage. Impact: HPV screening programs become highly efficient when HPV-positive women with negative triage testing at baseline are offered repeat HPV genotyping after five years.