hrHPV-positive Women Research Articles

Cervical cancer screening: efficacy of PAX1 and JAM3 methylation assay in the triage of atypical squamous cell of undetermined significance (ASC-US)

BackgroundAtypical squamous cells of undetermined significance (ASC-US) often present diagnostic challenges with cytology-based results, leading to potential underdiagnosis or overdiagnosis. An effective triage method is essential for managing these cases to reduce unnecessary referrals and treatment.MethodsA total of 322 women diagnosed with ASC-US were tested for HPV-DNA and the PAX1 and JAM3 methylation (PAX1m/JAM3m) test in the study.ResultsMethylation levels of PAX1 and JAM3 were significantly elevated in cervical lesions classified as CIN2 or more severe lesions (CIN2+). The methylation assay demonstrated a sensitivity of 83.8% and a specificity of 95.8%, outperforming HPV-DNA testing in differentiating high-grade cervical lesions among women with ASC-US. Moreover, PAX1m/JAM3m testing significantly reduced the colposcopy referral rate for further diagnostic procedures in high-risk HPV-positive women by 79.5%.ConclusionsPAX1m/JAM3m testing shows promise as a reliable supplemental method to HPV-DNA testing for the triage of women with cytologic ASC-US. In addition, the molecular triage based on the CISCER assay or single PAX1 or JAM3 methylation, had better effects in the women with non-HPV16/18 group. This approach could potentially minimize overtreatment and unnecessary referrals in clinical practice, enhancing patient management and resource utilization.

Prediction of high-grade cervical precancerous abnormalities: The role of personal factors, vaginal microflora, sexually transmitted infections, and high-risk human papillomavirus.

High-risk human papillomavirus infection (HR-HPV) is necessary but not the only factor needed to develop cervical cancer. It is essential to estimate cervical cancer development risk in the population of high-risk HPV-positive women and to avoid unnecessary examinations and treatment in low-risk individuals. The study aimed to identify associations between different personal factors, vaginal microflora, sexually transmitted, high-risk HPV infection, and various degrees of cervical precancerous lesions. A study was performed in 2016-2020. The study group consisted of 112 patients with abnormal cervical cytology results referred for colposcopic examination. 120 women who came for a routine gynecological check-up were included in the control group. Material from the cervix and upper vaginal fornix was taken for pH measurement, wet mount microscopy, testing the six most common high-risk HPV DNA types (16/18, 31, 33, 45, 58), HPV E6/E7 mRNA, and 7 genital infections-C. trachomatis, N. gonorrhea, T. vaginalis, M. hominis, M. genitalium, U. urealyticum, U. parvum. Results showed that women with all grades of cervical intraepithelial neoplasia (CIN) more often were smokers, had increased vaginal pH levels, and had positive HR-HPV DNA and HR HPV E6/E7 mRNA expression. Abnormal vaginal microflora, especially types associated with aerobic vaginitis, and M. hominis were significantly more often found in women with CIN2+. The presence of C.trachomatis, U. parvum, and U.urealyticum did not differ between the groups. The most important factors independently associated with CIN2+ were positive high-risk HPV E6/E7 mRNA expression (OR 59.4, 95% CI 14.84-237.51), and positive high-risk HPV DNA (OR 3.9, 95% CI 1.16-13.23). Higher education level was associated with reduced risk of CIN2+ (OR 0.2, 95% CI 0.07-0.71). In conclusion, this study reports HR-HPV DNA of the most common six types and E6/E7 mRNA positivity as the most significant factors associated with CIN2+ lesions and higher education related to lower risk of high-grade cervical lesions.

Coexistence of aerobic vaginitis caused by Enterococcus faecalis and human papilloma virus (HPV) infection as a risk factor for the development of cervical intraepithelial lesions

<p><strong>Aim</strong> To determine the prevalence of aerobic vaginitis (AV) caused by <em>Enterococcus faecalis (E. faecalis)</em> in human papilloma virus (HPV)-positive women with pathological Pap test and to determine the most prevalent HPV type associated with <em>E. faecalis</em> infection.<br /><strong>Methods</strong> This prospective study was conducted at the Gynaecology Centre "Dr. Mahira Jahić" Tuzla and Primary Health Care Centre Tešanj (Bosnia and Herzegovina) in the period between February 2023 and March 2024. The research included 200 women aged 25 to 50 years. The examined group consisted of 100 women with a pathological (examined group) and 100 with a normal (control group) Pap test result.<br /><strong>Results</strong> Pathological Pap smears were found in 60 (out of 100; 60 %) women in the examined group: cervical intraepithelial neoplasia (CIN) 1 and CIN 2  in two women, respectively, CIN 3 in seven, atypical squamous cells of undetermined significance (ASCUS) in 29 and atypical squamous cells-high-grade cannot be excluded (ASC-H) in two women. Overall (both groups) prevalence of <em>E. faecalis</em> was 25.5% (51women); in 45 (22.5%) women <em>E. faecalis</em> was the only bacterial isolate, of which 42 (21%) in the examined group and three (1.5%) in the control group. High-risk HPV types were found in 62 (out of  100; 62%) women with the pathological Pap smear test. The association of <em>E. faecalis</em> and high-risk HPV positive women was found in 35 (35%) cases (moderately positive correlation; r=0.198).<br /><strong>Conclusion</strong> E. faecalis is very common in HPV 16 and 18 positive women and may represent a risk factor in the development of cervical intraepithelial lesions.</p>

Genital infections in high-risk human papillomavirus positive Paraguayan women aged 30-64 with and without cervical lesions.

To determine the prevalence of genital infections (GIs), including sexual transmitted STIs: Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, and opportunistic pathogens that generally do not cause STIs, non-classic STI: Ureaplasma urealyticum, Ureaplasma parvum and Mycoplasma hominis, in women with high-risk oncogenic human papillomavirus (hr-HPV) infection and their association with cervical lesions. A cross-sectional study was carried out including 231 hr-HPV positive women. Of these, 46 has histologically confirmed cervical intraepithelial neoplasia 3 (CIN3) or more (including CIN3 and cervical cancer lesions-CIN3+). GIs were detected by multiplex real time PCR. Odds ratios (OR) were estimated to explore possible associations between GIs and the presence or absence of CIN3+ lesions. Additionally, we examined associations between sociodemographic, sexual, and clinical characteristics and the presence of GIs. In total, there were 174/231 cases of GIs corresponding to an overall prevalence of 75.3% (95%CI: 69.4-80.4), being non-classic STIs the most common (72.3%) compared to STIs (12.6%). The most prevalent non-classic STI and STI were U. parvum (49.8%) and C. trachomatis (7.4%), respectively. The odds of presenting GIs were 3 times higher in women under 46 years compared to older counterparts (OR: 3.32, 95%CI: 1.74-6.16), and in women with a normal Pap smear with inflammation compared to those without inflammation (OR: 3.31, 95%CI: 1.15-9.77). GIs were equally present in women with and without CIN3+ lesions. We observed an association of GIs with inflammation in the Pap smear, but no association with CIN3+, as some of them are very common and likely part of the normal vaginal flora, suggesting that such infections do not appear to be cofactors in cervical carcinogenesis, although larger prospective studies are needed.

The role of co-infections on cervical intraepithelial neoplasia prevalence in western Kenya.

Screening for co-infections with HIV, HSV-2 and Chlamydia trachomatis (CT) among high-risk human papilloma virus (hr-HPV) positive women remains essential in alleviating high morbidity of cervical cancer (CC). The aim of this study was to determine the prevalence of cervical intraepithelial neoplasia (CIN) among women referred for CC screening at a referral hospital in Kisumu County, Kenya; and to establish the role of co-infection on CIN. In a cross-sectional study, we collected HPV, HIV, HSV-2 and CT data, cervical cytology results, and demographic information from 517 referrals. Blood samples were obtained for HIV and HSV-2 tests; urine for CT test and cervical swabs for hr-HPV test. The overall prevalence of CIN was 18.4% (95/517) with CIN1 observed in 56(29.6%), CIN2 in 27(`14.3%), CIN3 + in 12(6.3%) and normal biopsy in 94(49.7%) of the patients out of which high grade CIN2 and above (CIN2+) was 7.54% (39/517) equivalent to 32.5 per 100,000 women per year. HPV/HIV co-infection (infected vs. uninfected: OR 2.79; 95% CI 1.56-5.10, p < 0.001); HPV/HSV-2 co-infection (infected vs. uninfected: OR 2.41, 95% CI: 1.12-5.46, p < 0.024); HPV/CT co-infection (infected vs. uninfected: OR 3.83; 95% CI 1.84-8.51, p < 0.001) were found to be significantly associated with CIN. Overall prevalence of CIN was high in the region although high-grade CIN2 + remained relatively lower as reported earlier. Age factor, widowhood and co-infections with HIV, HSV-2 or Chlamydia trachomatis were associated with increased risk of testing positive for CIN.

Relationship between p16/ki67 immunoscores and PAX1/ZNF582 methylation status in precancerous and cancerous cervical lesions in high-risk HPV-positive women

BackgroundThe risk of cervical cancer progression in high-risk human papillomavirus (HR-HPV)-positive women is associated with cervical lesion severity and molecular heterogeneity. Classification systems based on p16 and Ki67 expression cumulative scores (0–3 each)—p16/Ki67 collectively known as an immunoscore [IS]—are an accurate and reproducible method for grading cervical intraepithelial neoplasia (CIN) lesions. Meanwhile, DNA methylation is an early event in the development of cervical cancer. Hence, this study evaluated the relationship among CIN, p16/Ki-67 IS, and PAX1/ZNF582 methylation.MethodsIn this study, 414 HPV-positive paraffin-embedded specimens were collected, and PAX1/ZNF582 methylation and the p16/ki67 IS were determined. A total of 43 invalid samples were excluded and 371 were included in the statistical analyses. There were 103 cervicitis, 95 CIN1, 71 CIN2, 89 CIN3, and 13 squamous cell carcinoma (SCC) cases. The association between PAX1/ZNF582 methylation and p16/Ki6 immunohistochemical staining scores was analyzed.ResultsThe ΔCp of PAX1m (PAX1 methylation) and ZNF582m (ZNF582 methylation) decreased with cervical lesion severity (Cuzick trend test, all P < 0.001). The severity of the cervical lesions and p16, Ki67, and p16/Ki67 IS showed an increasing trend (Multinomial Cochran-Armitage trend test, all P < 0.001). The prevalence of PAX1m/ZNF582m increased with an increase in the IS of p16, Ki67, and p16/Ki67 (Cochran-Armitage trend test, all P < 0.001). In cervical SCC, the IS was 5–6, and the PAX1m/ZNF582m was positive. Meanwhile, heterogeneity was observed in CIN lesions: 10 cases had an IS of 3–4 and were PAX1m/ZNF582m-positive in ≤ CIN1; 1 case had an IS of 0–2 and was PAX1m/ZNF582m-positive in CIN2/3.ConclusionsSignificant heterogeneity was observed in CIN lesions for p16 and Ki67 immunohistochemical staining scores and PAX1/ZNF582 methylation. This may help clinicians personalize the management of CIN based on the predicted short-term risk of cancer progression, minimizing the rate of missed CIN1 diagnoses and incorrect treatment of CIN2/3.

Nationwide registry-based trial of risk-stratified cervical screening.

In well-screened populations, most cervical cancers arise from small groups of women with inadequate screening. The present study aims to assess whether registry-based cancer risk assessment could be used to increase screening intensity among high-risk women. The National Cervical Screening Registry identified the 28,689 women residents in Sweden who had either no previous cervical screening or a screening history indicating high risk. We invited these women by SMS and/or physical letter to order a free human papillomavirus (HPV) self-sampling kit. The Swedish national HPV reference laboratory performed extended HPV genotyping and referred high-risk HPV-positive women to their regional gynecologist. A total of 3691/28,689 (12.9%) women ordered a self-sampling kit and 10.0% (2853/28,689) returned a sample for testing. Participation among women who had never attended screening was low, albeit improved. Up to 22.5% of women in other high-risk groups attended. High-risk HPV types were detected in 8.3% of samples. High-risk HPV-positive women (238/2853) were referred without further triaging and severe cervical precancer or cancer (HSIL+) in histopathology were detected in 36/158 (23%) of biopsied women. Repeat invitations gave modest additional participation. Nationwide contacting of women with high risk for cervical cancer with personal invitations to order HPV self-sampling kits resulted in high yield of detected CIN2+. Further efforts to improve risk-stratified screening strategies should be directed to improving (i) the precision of the risk-stratification algorithm, (ii) the convenience for the women to participate and, (iii) ensuring that screen-positive women are followed-up.

Evaluating PAX1 methylation for cervical cancer screening triage in non-16/18 hrHPV-positive women

BackgroundIn China, the national cervical cancer screening protocol involves initial testing for high-risk human papillomavirus (hrHPV), followed by cytology for hrHPV-positive cases. This study evaluates the effectiveness of PAX1 methylation (PAX1m) analysis in identifying precancerous or cancerous lesions in cervical samples from Chinese women positive for non-16/18 hrHPV strains.MethodsBetween February 2022 and March 2023, 281 cervical samples from non-16/18 hrHPV-positive women underwent cytological examination and PAX1m analysis. The study assessed the statistical relationship between PAX1m levels and the presence of cervical lesions, comparing the diagnostic performance of PAX1m to conventional cytology.ResultsA significant association was found between PAX1 methylation levels and the risk of CIN2 + and CIN3 + lesions, with 47 instances of CIN2 + detected. Odds ratios (ORs) for moderate and high PAX1m levels were 8.86 (95% CI: 2.24–42.17) and 166.32 (95% CI: 47.09-784.97), respectively. The area under the ROC curve for PAX1m in identifying CIN2 + lesions was 0.948 (95% CI: 0.895–0.99). PAX1m demonstrated similar sensitivity and negative predictive value (NPV) to cytology but reduced the colposcopy referral rate from 47.7% with cytology alone to 25.6% with PAX1m, showing superior specificity and positive predictive value across age groups.ConclusionsPAX1 methylation is a strong indicator of CIN2 + and CIN3 + risk, offering diagnostic performance comparable to cytology with the added benefit of reduced unnecessary colposcopy referrals. These findings support the use of PAX1m analysis as a reliable tool for triaging non-16/18 hrHPV-positive women in outpatient settings.

Performance of CADM1, MAL and miR124-2 methylation as triage markers for early detection of cervical cancer in self-collected and clinician-collected samples: an exploratory observational study in Papua New Guinea

ObjectiveWHO recommends human papillomavirus (HPV) testing for cervical screening, with triage of high-risk HPV (hrHPV) positive women. However, there are limitations to effective triage for low-resource, high-burden settings, such as...

Zipime-Weka-Schista study protocol: a longitudinal cohort study and economic evaluation of an integrated home-based approach for genital multipathogen screening in women, including female genital schistosomiasis, human papillomavirus, Trichomonas and HIV in Zambia

IntroductionMultiplathogen home-based self-sampling offers an opportunity to increase access to screening and treatment in endemic settings with high coinfection prevalence of sexually transmitted (HIV, Trichomonas vaginalis (Tv), human papillomavirus (HPV))...

Clinical evaluation of primary human papillomavirus (HPV) testing with extended HPV genotyping triage for cervical cancer screening: A pooled analysis of individual patient data from nine population-based cervical cancer screening studies from China.

To assess the clinical values of extended human papillomavirus (HPV) genotyping in triage of high-risk HPV-positive women, focusing on the trade-off between cervical precancer detections and colposcopy referrals. A bivariate random-effects model was used to estimate the diagnostic accuracy of primary HPV screening with following triage strategies to detect cervical precancers: (i) partial genotyping for HPV16/18 combined with cytological testing at atypical squamous cells of undetermined significance threshold (used as the comparator), (ii) genotyping for HPV16/18/58/52, (iii) genotyping for HPV16/18/58/52/33, (iv) genotyping for HPV16/18/58/33/31, (v) genotyping for HPV16/18/58/52/33/31, and (vi) genotyping for HPV16/18/58/52/33/31/39/51. Internal risk benchmarks for clinical management were used to evaluate the risk stratification of each triage strategy. A total of 16,982 women (mean age 46.1 years, range 17-69) were included in this analysis. For CIN3+ detection, triage with HPV16/18/58/33/31 genotyping achieved lower positivity (6.85% vs. 7.35%, p = 0.001), while maintaining similar sensitivity (91.35% vs. 96.42%, p = 0.32) and specificity (94.09% vs. 93.67%, p = 0.56) compared with the comparator strategy. Similar patterns were observed for CIN2+ detection. Women with a positive HPV16/18/58/33/31 genotyping test had high enough risk for CIN3+ for colposcopy referral, while the risk for women with a negative test was below the 1-year return decision threshold according to internal benchmarks. Our findings suggested extended HPV genotyping is of potential to be used as a triage technique integrated into HPV-based cervical cancer screening, leading to reduced need for colposcopy referral while maintaining similar disease detection and efficient risk stratification.

Human Papillomavirus Genotype Distribution in a Hospital-based Single-Center Study

Background: Cervical cancer is reported as one of the most prevalent malignancies worldwide in women. There is a substantial connection between cervical diseases and infection with Human Papillomavirus (HPV), especially Types 16 and 18 of HPV. Objective: This study aimed to assess the HPV genotype distribution to determine its most common type at a referral hospital in Iran. Methods: This cross-sectional study was conducted on 400 women with positive HPV result tests who visited the gynecologic oncology clinic of Baqiyatallah Hospital from 2017-2021. Results: The average age of subjects was 37.46±9.75 years (range=19-74). About 167 (41.8%) of the patients were between 25 to 35 years. The analysis showed that 137 (34.2%) patients had only low-risk (LR) typing, 129 (32.2%) patients had only high-risk (HR) typing, and 134 (33.5%) patients had both HR and LR typing. The most frequent LR HPV types were HPV 6 (18.5%) and 11 (17%), and the most frequent HR HPV types were HPV-16 (14.7%), 52 (8.2%), 18, and 31 (6.5%). Conclusion: This study showed that the most frequent age category in both low- and HR HPVpositive women is the age 25 to 35 years. The second most common HR-HPV subtypes included HPV-52, not HPV-18, which indicates variations in HR-HPV subtypes in different populations and races and warrants further research.

The performance of single and combination test strategies using visual inspection, cytology, high-risk HPV DNA and HPV16/18 to screen South African women with and without HIV-infection

BackgroundCervical cancer screening strategies should ideally be informed by population-specific data. Strategies recommended for secondary prevention, are often inadequately studied in populations with high cervical disease burdens. This report describes the test performance measured against CIN2 + /CIN3 + histology in HIV-positive women (HPW) and HIV-negative women (HNW) with the aim to determine the most effective strategies to identify South African women at risk.MethodsPrimary screening using visual inspection, cytology and HPV DNA (cobas®) was performed in two South African provinces on 456 HPW and 639 HNW participating in the multicentric DiaVACCS trial. Histology was obtained for 91.7% screen-positive and 42.7% screen-negative participants, and unavailable histology was determined by multiple imputation to adjust for verification bias. Cross-sectional test performance was calculated for single and combination test strategies with and without intermediate risk categories using different cut-offs. Minimum acceptability for sensitivity and specificity, treatment and follow-up numbers were considered to evaluate strategies.ResultsThe only single test to reach acceptability in HPW was cytology (LSIL) [sensitivity 71.2%; specificity 90.5%; treatment 33.4%]; in HNW only HPV (hr) qualified [sensitivity 68.2%; specificity 85.2%; treatment 23.5%]. The universally best performing strategy which also resulted in smaller treatment numbers without intermediate risk group was primary HPV(hr), with treatment of both HPV(16/18) and cytology (ASCUS +) [HPW: sensitivity 73.6%; specificity 89.7%; treatment 34.7%. HNW: sensitivity 59.1%; specificity 93.6%; treatment 13.9%].DNA testing for hrHPV (any) and hrHPV (16/18) was the best universally acceptable strategy with an intermediate risk category (early follow-up) in HPW [sensitivity 82.1%; specificity 96.4%; treatment 17.1%; follow-up 31.4%] and HNW [sensitivity 68.2%; specificity 96.7%; treatment 7.6%; follow-up 15.9%]. In comparison, using both HPV (16/18) and cytology (ASCUS +) as secondary tests in hrHPV positive women, decreased follow-up [HPW 13.8%, HNW 9.6%], but increased treatment [HPW 34.7%, HNW 13.9%].ConclusionUsing hrHPV (any) as primary and both HPV16/18 and cytology as secondary tests, was universally acceptable without an intermediate risk group. Strategies with follow-up groups improved screening performance with smaller treatment numbers, but with effective management of the intermediate risk group as prerequisite.

Human Papillomavirus Genotype Detection and Cytology Using a New Self-Sampling Method.

High-risk human papillomavirus (hrHPV) testing using dry-type self-sampled vaginal specimens is becoming more widespread worldwide due to increased screening uptake. However, for the triage of hrHPV-positive women, a visit to a general practitioner is required for reflex cytology. This study aimed to evaluate the hrHPV detection capability of CellSoft®, a wet-type self-sampling method that also allows for cytology. Thirty-eight women aged 20 years and older were included in the study. The women self-sampled using CellSoft® after using an Evalyn® Brush. PCR-based HPV genotyping was performed on both specimens and hrHPV detection results of both devices were compared. Additionally, cytological exam was performed on CellSoft® samples. Overall agreement between self-sampling devices for the detection of hrHPV in CellSoft® and Evalyn Brush was observed in 97.4% (37/38) of participants. More hrHPV genotypes were detected with Evalyn Brush than with CellSoft®. Among the 22 CellSoft® hrHPV-positive cases, 11 (47.6%) were atypical squamous cells of undetermined significance or worse. CellSoft® hrHPV genotype detection results were in good agreement with those of Evalyn Brush. CellSoft® provided a sufficient cell volume for HPV testing and cytological evaluation.

Preliminary outcomes of the Cervical Cancer Screening Program of Northern Portugal: A snapshot

BackgroundCervical cancer screening remains an essential preventive tool worldwide. First line high-risk Human Papillomavirus (HrHPV) genotyping became gold standard for cervical cancer screening, and has been adopted by several countries, including Portugal. Herein, we aimed to assess the early outcomes of the regional Cervical Cancer Screening Program of Northern Portugal. MethodsThe analysis of a representative set of cases evaluated during a one-month period (January 2020), with adequate follow-up was performed. Descriptive analysis was performed. ResultsOverall, 7278 samples were received, of which 15.2% were HrHPV positive, most of these disclosing a negative result in subsequent liquid-based cytology. Nearly half of the HrHPV-positive women were referred to colposcopy. Within this group, HPV16/18+ cases depicted the higher frequency of high-grade squamous intraepithelial lesion (HSIL) or worse, compared with abnormal cytology or persistent HrHPV infection. Among women with non-HPV16/18 HrHPV infection and negative cytology, which are eligible for repeat sampling in one year, 65% were re-tested. Importantly, nearly half of these cleared HrHPV infection. Furthermore, referral to colposcopy due to HPV16/18 infection and/or abnormal cytology results were associated with > 40% risk for HSIL or worse lesion. ConclusionsOur study confirmed the reliability and effectiveness of first line HrHPV genotyping in the Cervical Cancer Screening Program of Northern Portugal. Nonetheless, it also raised concerns about excessive referral to colposcopy, with the inherent human and financial costs. Thus, further improvement and optimization are key to ensure the sustainability of the program.

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

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

The risk of vaginal, vulvar and anal precancer and cancer according to high-risk HPV status in cervical cytology samples.

High-risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five-year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV-positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV-negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV-positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non-cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow-up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high-risk groups and acceptable risk thresholds.

Performance of urine samples compared to cervical samples for detection of precancer lesions among HPV-positive women attending colposcopy clinic in Mexico City.

High-risk human papillomavirus (hrHPV) detection in self-collected urine samples (SeCUS) may be a promising alternative for cervical cancer screening because of its greater acceptability, as long as it can offer comparable sensitivity to clinician-collected cervical samples (CCoS) for detecting precancer lesions. To evaluate the performance of the SeCUS compared to that of the CCoS for cervical intraepithelial neoplasia grade 3 (CIN3) detection among hrHPV-positive women receiving colposcopy in Mexico City using different specific extended HPV typing procedures: HPV16/18, HPV16/18/35/39/68 or HPV16/18/35/39/68/31. From March 2017 to August 2018, 4,158 female users of the cervical cancer screening program at Tlalpan Sanitary Jurisdiction in Mexico City were invited to participate in the FRIDA-Tlalpan study. All participants provided ≥ 30mL of SeCUS, and then a CCoS was obtained with Cervex-Brush®, which was used for hrHPV typing. Participants who tested positive for hrHPV in CCoS were referred for colposcopy for diagnostic confirmation, and all SeCUS of these women were also tested for hrHPV typing. In total, 561 hrHPV-positive women were identified by CCoS via colposcopy, and 82.2% of the SeCUS of these women were also hrHPV positive. From both CCoS and SeCUS, 7 cases of CIN3 were detected. Considering HPV16/18 typing, CCoS and SeCUS detected 4 cases of CIN3, but after HPV16/18/35/39/68/31 extension typing, both CCoS and SeCUS detected all 7 of the CIN3 cases among the hrHPV-positive women. Using extended hrHPV typing based on HPV16/18/35/39/68/31, our results suggest that the performance of SeCUS may be equivalent to that of CCoS for detecting CIN3 lesions. Although our results are inconclusive, they support the hypothesis that SeCUS may be an attractive alternative worthy of further research.

PCDHGB7 hypermethylation-based Cervical cancer Methylation (CerMe) detection for the triage of high-risk human papillomavirus-positive women: a prospective cohort study

BackgroundImplementation of high-risk human papillomavirus (hrHPV) screening has greatly reduced the incidence and mortality of cervical cancer. However, a triage strategy that is effective, noninvasive, and independent from the subjective interpretation of pathologists is urgently required to decrease unnecessary colposcopy referrals in hrHPV-positive women.MethodsA total of 3251 hrHPV-positive women aged 30–82 years (median = 41 years) from International Peace Maternity and Child Health Hospital were included in the training set (n = 2116) and the validation set (n = 1135) to establish Cervical cancer Methylation (CerMe) detection. The performance of CerMe as a triage for hrHPV-positive women was evaluated.ResultsCerMe detection efficiently distinguished cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) from cervical intraepithelial neoplasia grade 1 or normal (CIN1 −) women with excellent sensitivity of 82.4% (95% CI = 72.6 ~ 89.8%) and specificity of 91.1% (95% CI = 89.2 ~ 92.7%). Importantly, CerMe showed improved specificity (92.1% vs. 74.9%) in other 12 hrHPV type-positive women as well as superior sensitivity (80.8% vs. 61.5%) and specificity (88.9% vs. 75.3%) in HPV16/18 type-positive women compared with cytology testing. CerMe performed well in the triage of hrHPV-positive women with ASC-US (sensitivity = 74.4%, specificity = 87.5%) or LSIL cytology (sensitivity = 84.4%, specificity = 83.9%).ConclusionsPCDHGB7 hypermethylation-based CerMe detection can be used as a triage strategy for hrHPV-positive women to reduce unnecessary over-referrals.Trial registrationChiCTR2100048972. Registered on 19 July 2021.

HPV DNA Testing and Mobile Colposcopy for Cervical Precancer Screening in HIV Positive Women: A Comparison Between Two Settings in Ghana and Recommendation for Screening.

Women living with HIV (WLHIV) have higher prevalence and persistence rates of high-risk human papillomavirus (hr-HPV) infection with a six-fold increased risk of cervical cancer. Thus, more frequent screening is recommended for WLHIV. This retrospective descriptive cross-sectional study was conducted to investigate and compare the prevalence of hr-HPV infection and abnormal findings on mobile colposcopy in two cohorts of WLHIV following cervical screening in rural and urban settings in Ghana. Through the mPharma 10 000 Women Initiative, WLHIV were screened via concurrent hr-HPV DNA testing (MA-6000; Sansure Biotech Inc., Hunan, China) and visual inspection (Enhanced Visual Assessment [EVA] mobile colposcope; MobileODT, Tel Aviv, Israel) by trained nurses. The women were screened while undergoing routine outpatient reviews at HIV clinics held at the Catholic Hospital, Battor (rural setting) and Tema General Hospital (urban setting), both in Ghana. Two-hundred and fifty-eight WLHIV were included in the analysis (rural, n = 132; urban, n = 126). The two groups were comparable in terms of age, time since HIV diagnosis, and duration of treatment for HIV. The hr-HPV prevalence rates were 53.7% (95% CI, 45.3-62.3) and 48.4% (95% CI, 39.7-57.1) among WLHIV screened in the rural vs urban settings (p-value = .388). Abnormal colposcopy findings were found in 8.5% (95% CI, 5.1-11.9) of the WLHIV, with no significant difference in detection rates between the two settings (p-value = .221). Three (13.6%) of 22 women who showed abnormal colposcopic findings underwent loop electrosurgical excision procedure (LEEP), leaving 19/22 women from both rural and urban areas with pending treatment/follow-up results, which demonstrates the difficulty faced in reaching early diagnosis and treatment, regardless of their area of residence. Histopathology following LEEP revealed CIN III in 2 WLHIV (urban setting, both hr-HPV negative) and CIN I in 1 woman in the rural setting (hr-HPV positive). There is a high prevalence of hr-HPV among WLHIV in both rural and urban settings in this study in Ghana. Concurrent HPV DNA testing with a visual inspection method (colposcopy/VIA) reduces loss to follow-up compared to performing HPV DNA testing as a standalone test and recalling hr-HPV positive women for follow up with a visual inspection method. Concurrent HPV DNA testing and a visual inspection method may also pick up precancerous cervical lesions that are hr-HPV negative and may be missed if HPV DNA testing is performed alone.