Fanghui Zhao

Impact of government-organized screening programs on the economic burden of cervical cancer across five disease courses: a multistage regression and mediation analysis

Objective: To evaluate the impact of government-organized screening on the economic burden among patients with cervical cancer and precancerous lesions, and explore mediating pathways across diagnosis, initial treatment, radiotherapy/chemotherapy, follow-up, and recurrence/progression/metastasis. Methods: A multicentre, nationwide survey across 5 disease courses was conducted from 26 hospitals in China. Multivariable regression and structural equation modeling were used to assess the effects of government-organized screening on economic burden by comparing government-organized screening with workplace check-up, self-paid check-up, and symptom-based detection. Results: Workplace check-up, self-paid check-up, and symptom-based detection were associated with progressively higher costs across diagnosis [β: 1.10, 95% confidence interval (CI): 0.54–1.67; β: 1.46, 95% CI: 1.00–1.92; and β: 1.68, 95% CI: 1.25–2.11, respectively], initial treatment (β: 0.36, 95% CI: 0.18–0.55; β: 0.51, 95% CI: 0.35–0.66; and β: 0.56, 95% CI: 0.42–0.70, respectively), and follow-up (β: 0.63, 95% CI: 0.38–0.88; β: 0.83, 95% CI: 0.61–1.04; and β: 0.85, 95% CI: 0.65–1.06, respectively) compared to government-organized screening (all P < 0.05). Earlier clinical staging and greater use of lower-level hospitals mediated 44.74%–54.97% of cost differences in diagnosis, 73.27%–85.04% in initial treatment, and 30.38%–54.73% in follow-up. Fifteen percent of the cost differences during initial treatment were related to lower overtreatment for precancerous lesions. Conclusions: Government-led cervical cancer screening was associated with lower economic burden with pathways involving earlier-stage diagnosis, reduced overtreatment, and decreased reliance on higher-level hospitals, suggesting potential clinical benefits, efficient resource use, and improved equity in cancer care.

Age-specific clinical performance of HPV-based vs. cytology-based cervical cancer screening in China

Cervical cancer remains a significant health burden, and effective screening is essential, yet the age-specific performance of HPV primary screening is rarely studied. This multicenter study evaluates age-specific performance of primary human papillomavirus (HPV) testing as cross-sectional and longitudinal screening for cervical cancer among 28,501 Chinese women. At baseline, HPV screening with cytology triage demonstrates higher sensitivity (96.9% vs. 79.7%) but slightly lower specificity (88.8% vs. 92.7%) than cytology with HPV triage for cervical intraepithelial neoplasia grade 2 or worse (CIN2+). HPV sensitivities remain high across age groups (≤35: 100.0%; 36-45: 96.4%; >45: 96.8%), consistently exceeding the corresponding cytology sensitivities (66.7%, 75.7%, and 84.9%). Over a three-year follow-up, HPV screening maintains superior sensitivity (93.1% vs. 58.1%) and slightly lower specificity (89.6% vs. 92.4%) compared with cytology. Age-stratified analyses in the longitudinal setting reveal trends similar to those observed in the cross-sectional analyses. Women positive for HPV16/18 have a 43.0% three-year risk of CIN2+, compared with 0.2% for HPV-negative women. These findings support the durable protection of HPV-based screening and the feasibility of extending screening intervals.

Deep learning enabled liquid-based cytology model for cervical precancer and cancer detection

Deep learning (DL) enabled liquid-based cytology has potential for cervical cancer screening or triage. Here, we develop a DL model using whole cytology slides from 17,397 women and test it on 10,826 additional cases through a three-stage process. The DL model achieves robust performance across nine hospitals. In a multi-reader, multi-case study, it outperforms cytopathologists' sensitivity by 9%. Reading time significantly decreases with DL assistance (218s vs 30s; p  0.999), yet it has reduced specificity (0.831 vs 0.901; p < 0.0001). Notably, hospital-based opportunistic screening shows that junior cytopathologists with DL assistance significantly improve both their sensitivity and specificity (0.857 vs 0.657, 0.840 vs 0.737; both p < 0.0001). When triaging human papillomavirus-positive cases, DL assistance exhibits better performance than junior cytopathologists alone. These findings support using the DL model as an assistance tool in cervical screening and case triage.

The variations in the natural history of high‐risk human papillomavirus infections in Chinese healthy women aged 27–45 years compared with 18–26 years: A prospective cohort study

AbstractData investigating the natural history of high‐risk human papillomavirus (HR‐HPV) infection in mid‐adult women compared with young adult women from regions exhibiting a bimodal distribution pattern are scarce. From November 2012 to September 2019, 3681 healthy women aged 18–45 years from the control group of a bivalent HPV vaccine Phase 3 trial in China were followed over 5.5 years. At scheduled visits (Day 0, months 7, 12, 18, 24, 30, 42, 54, and 66), cervical samples were collected for ThinPrep Pap tests and HPV DNA testing, women with abnormal cytology were referred for colposcopy. Data was analyzed using Cox regression model and a competing risk model. Sensitivity analyses were performed among participants attending all scheduled visits. The incidences of HR‐HPV persistent infections (over 6 months [6mPIs]) were 35.5 and 29.0 per 1000 person‐years (PYs) (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.00, 1.46), and HR‐HPV associated CIN grade 2 or greater (CIN2+) were 4.3 and 1.9 per 1000 PYs (HR = 2.31, 95% CI: 1.25, 4.26) in women aged 18–26 and 27–45 years. Competing risk models showed that the cumulative incidence of HR‐HPV infections that progressed to CIN2+ was significantly higher in women aged 18–26 than in women aged 27–45 (5.3% vs. 2.9%, Gray's test p = .0291). The cumulative clearance rates of HR‐HPV infections in women aged 18–26 and 27–45 were similar (94.7% vs. 95.8%, Gray's test p = .3309) during the study period. In conclusion, although mid‐adult women exhibit lower incidences of HR‐HPV infection and associated cervical lesions compared to young women, this population continues to face a substantial risk of acquiring causal HPV infections, which may progress to cervical lesion.

Criteria for second generation comparator tests in validation of novel HPV DNA tests for use in cervical cancer screening

Abstract While HC2 and GP5+/6+ PCR‐EIA were pivotal in test validation of new HPV assays, they represent the first generation of comparator tests based upon technologies that are not in widespread use anymore. In the current guideline, criteria for second‐generation comparator tests are presented that include more detailed resolution of HPV genotypes. Second‐generation comparator tests should preferentially target only the 12 genotypes classified as carcinogenic (IARC‐group I), and show consistent non‐inferior sensitivity for CIN2+ and CIN3+ and specificity for ≤CIN1 compared to one of the first‐generations comparators, in at least three validation studies using benchmarks of 0.95 for relative sensitivity and 0.98 for relative specificity. Validation should take into account used storage media and other sample handling procedures. Meta‐analyses were conducted to identify the assays that fulfill these stringent criteria. Four tests fulfilled the new criteria: (1) RealTime High‐Risk HPV Test (Abbott), (2) Cobas‐4800 HPV test (Roche Molecular System), (3) Onclarity HPV Assay (BD Diagnostics), and (4) Anyplex II HPV HR Detection (Seegene), each evaluated in three to six studies. Whereas the four assays target 14 carcinogenic genotypes, the first two identify separately HPV16 and 18, the third assay identifies five types separately and the fourth identifies all the types separately.

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

AbstractObjectiveTo 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.MethodsA 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.ResultsA 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.ConclusionsOur 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.

Efficacy and immunogenicity of AS04‐HPV‐16/18 vaccine in females with existing cervical HR‐HPV infection at first vaccination: A pooled analysis of four large clinical trials worldwide

AbstractFemales with existing high‐risk HPV (HR‐HPV) infections remain at risk of subsequent multiple or recurrent infections, on which benefit from HPV vaccines was under‐reported. We pooled individual‐level data from four large‐scale, RCTs of AS04‐HPV‐16/18 vaccine to evaluate efficacy and immunogenicity in females DNA‐positive to any HR‐HPV types at first vaccination. Females receiving the AS04‐HPV‐16/18 vaccine in the original RCTs constituted the vaccine group in the present study, while those unvaccinated served as the control group. Vaccine efficacy (VE) against new infections and associated cervical intraepithelial neoplasia (CIN) 2+ in females DNA‐negative to the considered HR‐HPV type but positive to any other HR‐HPV types, VE against reinfections in females DNA‐positive to the considered HR‐HPV type but cleared naturally during later follow‐up, and levels of anti‐HPV‐16/18 IgG were assessed. Our final analyses included 5137 females (vaccine group = 2532, control group = 2605). The median follow‐up time was 47.88 months (IQR: 45.72‐50.04). For the prevention of precancerous lesions related to the non‐infected HR‐HPV types at baseline, VE against HPV‐16/18 related CIN 2+ was 82.70% (95% CI: 63.70‐93.00%). For the prevention of reinfections related to the infected HR‐HPV types following natural clearance, VE against HPV‐16/18 12MPI was non‐significant (p &gt; .05), albeit robust immunity persisted for at least 48 months. Females with existing HR‐HPV infections at first vaccination still benefit from vaccination in preventing precancers related to the non‐infected types at baseline. VE against reinfections related to the infected types following natural clearance remains to be further investigated.

Efficacy of point‐of‐care thermal ablation among high‐risk human papillomavirus positive women in China

AbstractThermal ablation is a point‐of‐care ablative treatment technique for cervical intraepithelial neoplasia (CIN). However, limited information is available about its efficacy in low‐ and middle‐income countries. We evaluated the efficacy of thermal ablation in treatment of CIN detected through high‐risk human papillomavirus (HPV) screening in China. Women positive on high‐risk HPV and having colposcopically suspected lesions eligible for ablation underwent colposcopy, biopsy and thermal ablation in one visit. Women ineligible were recalled for large loop excision of transformation zone (LLETZ) when histopathology results were high‐grade CIN. Posttreatment follow‐up at 6 months or more was with HPV test and cytology followed by colposcopy and biopsy for HPV and/or cytology‐positive women. Cure was defined as either negative cytology and HPV test or absence of histopathology proved CIN in any positive women. Of total 218 HPV‐positive women treated with thermal ablation (n = 170) or LLETZ (n = 48), 196 reported for follow‐up evaluation. For women with histologically confirmed CIN at baseline (thermal ablation‐104; LLETZ‐38), cure rates were 84.6% for thermal ablation and 86.8% for LLETZ. Cure rates after thermal ablation were 90.3% for CIN grade one (CIN1) and 76.2% for CIN grade two or worse (CIN2+). HPV clearance rate was 80.4% in women undergoing thermal ablation, which was lower for HPV16/18 compared to other oncogenic types (67.6% vs 85.7%). HPV test had a negative predictive value (NPV) of 98.7% to detect CIN2+ at follow‐up and the positive predictive value (PPV) was 40.4%. Thermal ablation is effective to treat CIN as well as to clear the high‐risk HPV infection. HPV test has high PPV and NPV in following up patients posttreatment.

Development and validation of an artificial intelligence system for grading colposcopic impressions and guiding biopsies

AbstractBackgroundColposcopy diagnosis and directed biopsy are the key components in cervical cancer screening programs. However, their performance is limited by the requirement for experienced colposcopists. This study aimed to develop and validate a Colposcopic Artificial Intelligence Auxiliary Diagnostic System (CAIADS) for grading colposcopic impressions and guiding biopsies.MethodsAnonymized digital records of 19,435 patients were obtained from six hospitals across China. These records included colposcopic images, clinical information, and pathological results (gold standard). The data were randomly assigned (7:1:2) to a training and a tuning set for developing CAIADS and to a validation set for evaluating performance.ResultsThe agreement between CAIADS-graded colposcopic impressions and pathology findings was higher than that of colposcopies interpreted by colposcopists (82.2% versus 65.9%, kappa 0.750 versus 0.516,p &lt; 0.001). For detecting pathological high-grade squamous intraepithelial lesion or worse (HSIL+), CAIADS showed higher sensitivity than the use of colposcopies interpreted by colposcopists at either biopsy threshold (low-grade or worse 90.5%, 95% CI 88.9–91.4% versus 83.5%, 81.5–85.3%; high-grade or worse 71.9%, 69.5–74.2% versus 60.4%, 57.9–62.9%; allp &lt; 0.001), whereas the specificities were similar (low-grade or worse 51.8%, 49.8–53.8% versus 52.0%, 50.0–54.1%; high-grade or worse 93.9%, 92.9–94.9% versus 94.9%, 93.9–95.7%; allp &gt; 0.05). The CAIADS also demonstrated a superior ability in predicting biopsy sites, with a median mean-intersection-over-union (mIoU) of 0.758.ConclusionsThe CAIADS has potential in assisting beginners and for improving the diagnostic quality of colposcopy and biopsy in the detection of cervical precancer/cancer.

A nationwide post-marketing survey of knowledge, attitude and practice toward human papillomavirus vaccine in general population: Implications for vaccine roll-out in mainland China

Human papillomavirus (HPV) vaccine has been increasingly discussed in mainland China since its first approval in 2016. To date, nearly all studies assessing HPV vaccine perceptions and attitudes were implemented during pre-licensure period. Therefore, the nationwide post-marketing survey was conducted to update knowledge, attitudes and practice on HPV vaccine among general population in mainland China. Participants aged 18-45 years living in mainland China were recruited in April 2019 by multi-stage non-randomized sampling. Sociodemographic factors, HPV and HPV vaccine related awareness, knowledge, attitudes, vaccine uptake and potential obstacles were assessed in questionnaires. Bivariate analysis and multivariate regression were used to identify disparity among subgroups with different sociodemographic characteristics. 4,000 women (32.1 ± 7.81y) and 1,000 men (31.8 ± 7.96y) were included in final analysis. Less than one third of participants had heard of HPV (female: 31%; male: 22%) and HPV vaccine (female: 34%; male: 23%). Knowledge score was also unfavorable on HPV (female: 3 out of 13; male: 1.8 out of 13) and HPV vaccine (female: 3 out of 6; male: 2 out of 5). Only 3% females had been vaccinated three years after HPV licensure in China, although willingness to get vaccinated among those unvaccinated were high (mean willingness score ± SD: female: 3.3 ± 0.97; male: 3.0 ± 0.98). Industry of employment and household income were the major factors related to awareness and knowledge of vaccine, whereas HPV and HPV vaccine awareness were key influential factors for willingness. The main obstacles of vaccination were safety concerns, lack of knowledge, and high price of HPV vaccines. Findings highlight a lack of vaccine awareness, knowledge, and poor uptake in mainland China and underscore the necessity of health education campaigns. The identified priority groups, contents to be delivered and practical obstacles could furthermore provide insight into health education to reduce disparities and accelerate HPV vaccine roll-out in China.

Triage options to manage high‐risk human papillomavirus‐positive women: A population‐based cross‐sectional study from rural China

AbstractImprovement in managing HPV‐positive women is urgently needed. Based on a population‐based study which included 2112 women aged 49 to 69 from Shanxi, China, we aimed to evaluate the clinical performance of multiple triage strategies based on liquid‐based cytology (LBC), p16INK4a, viral load and partial genotyping, as a single or combined strategy for detecting cervical intraepithelial neoplasia grade 2/3 or higher (CIN2+/CIN3+) in women who tested positive by Hybrid Capture 2 (HC2). Among 452 HC2‐positive women, the test positivity of LBC (ASC‐US+), p16INK4a, HPV16/18 and HPV16/18/31/33/45 were 39.6%, 38.5%, 18.0% and 40.0%, respectively. Compared to LBC (ASC‐US+) triage, a single triage strategies using p16INK4a or extended genotyping (SureX HPV16/18/31/33/45) achieved comparable sensitivity (relative sensitivity: 1.08, 95% confidence interval [CI]: 0.93‐1.26 and 0.96, 95% CI: 0.76‐1.22) and specificity (relative specificity: 1.05, 95% CI: 0.96‐1.14 and 1.02, 95% CI: 0.92‐1.14) for CIN3+. Viral load triage using a ≥50 RLU/CO cut‐point also yielded similar results with LBC (ASC‐US+). Among combined triage strategies, HPV16/18 genotyping with reflex p16INK4a showed higher sensitivity and slightly lower specificity than LBC (ASC‐US+) for CIN3+ detection, however, the differences were not statistically significant. Of note, after a negative result by p16INK4a or LBC among HPV16/18 negative women, the posttest probability of CIN3+ was lower than 1%. Our study suggested that p16INK4a, extended genotyping and increased viral load cut‐point could be promising alternatives to cytology triage. Combined triage algorithms of HPV16/18 with reflex p16INK4a or cytology, if negative, are associated with the substantial low posttest risk sufficient to release women to next screening round.

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

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

Outcomes in women with biopsy-confirmed cervical intraepithelial neoplasia grade 1 or normal cervix and related cofactors: A 15-year population-based cohort study from China

To estimate long-term outcomes of biopsy-confirmed cervical intraepithelial neoplasia grade 1 (CIN1) or normal cervix and identify the cofactors during disease progression. In 1999, a cervical cancer screening cohort in Shanxi, China, enrolled 1997 women aged 35-45. They were followed up at year 6, 11, and 15 after enrollment with high-risk human papillomavirus (hrHPV) DNA testing, liquid-based cytology, and visual inspection with acetic acid. Progression, persistence, and regression rates were calculated, stratified by baseline hrHPV and cytological status. Risk factors associated with hrHPV acquisition, persistence, and progression were examined. The cumulative rates of progression to CIN2+ among CIN1 over 6, 11, and 15 years were 7.5%, 21.4%, and 24.0%, respectively; the regression rates to normal cervix were 85.0%, 76.7%, and 72.9%, respectively. Over 6, 11, and 15 years, 0.7%, 2.9%, and 5.2% of normal cervix developed CIN2+, respectively, but over 90% remained normal after 15 years. CIN1 or normal cervix positive for hrHPV had significantly higher progression rates to CIN2+ than those without hrHPV. Similarly, the severity of cytological status was found to be associated with an increased risk of developing CIN2+. Women who had an earlier sexual debut were at a higher risk of acquiring new HPV infection and repeated HPV infections. Clinical follow-up strategies for women with CIN1 or normal cervix could be adjusted accordingly based on hrHPV/cytology status.

Comparison of the performance of paired urine and cervical samples for cervical cancer screening in screening population

AbstractThe main objective of this work is to determine the performance of urine for human papillomavirus (HPV) detection in cervical cancer screening in screening population. Paired urine and cervical samples were collected from 2038 women (careHPV group: 1002, cobas4800 group: 1036) in 2015. Urine was tested by a new urine‐based HPV test and cervical samples by careHPV or cobas4800 HPV test. Women were triaged based on cervical results and then referred to colposcopy with biopsy as clinically indicated. In 2017, women were followed up and screened with cotesting strategy, women with any positive would be referred and biopsied if necessary. In careHPV group, the HPV prevalence of urine was 14.1%, and 16.4% for cervical samples. In cobas4800 group, it was 19.1% and 20.4%, correspondingly. The concordance of urine samples compared with cervical samples was moderate (careHPV group: 86.6%; κ = 0.48; cobas4800 group: 83%; κ = 0.46). The baseline sensitivity and specificity for urine against CIN2+  detection were 85.7%, 86.8% in careHPV group, and 69.2%, 82.3% in cobas4800 group, respectively. Cervical samples were 100% sensitive for both tests (careHPV and cobas4800) and 85.2% specific in careHPV group and 81.9% specific in cobas4800 group, respectively. The corresponding cumulative sensitivity and specificity were 68.8% and 87.1%, 58.8% and 81.9%, 87.5% and 85.5%, and 94.1% and 81.4%. Urine demonstrated certain potential in cervical cancer screening and could be an alternative if no better screening strategies available.

Clinical evaluation of p16INK4a immunocytology in cervical cancer screening: A population‐based cross‐sectional study from rural China

BackgroundCervical cancer screening with cytology suffers from low sensitivity, whereas the efficiency of human papillomavirus (HPV)‐based screening is limited by low specificity. The authors evaluated a novel p16INK4a immunocytology approach in cervical cancer screening compared with HPV‐based and cytology‐based screening.MethodsIn total, 2112 women aged 49 to 69 years from Shanxi, China were screened from March to July 2019. HPV testing, liquid‐based cytology (LBC), and p16INK4a immunocytology were performed on samples from all women. Any positive result triggered a referral to colposcopy with biopsy, if indicated. Screening performance for detecting cervical intraepithelial neoplasia grade 2 and 3 or worse (CIN2+/CIN3+) was evaluated using multiple algorithms.Resultsp16INK4a had a lower positive rate (10.0%) than LBC abnormality (vs 12.1%; P = .004) and a high‐risk HPV positivity (21.4%; P &lt; .001). For the detection of CIN3+, the relative sensitivity of p16INK4a compared with HPV and LBC was 0.93 (95% CI, 0.82‐1.07) and 1.12 (95% CI, 0.95‐1.32), respectively. The specificity of p16INK4a was significantly higher than that for HPV and LBC, with a relative specificity of 1.13 (95% CI, 1.11‐1.16) and 1.02 (95% CI, 1.01‐1.04), respectively. In addition, p16INK4a alone yielded a clinical performance very similar to that of the current mainstream strategy of using HPV16/18 with reflex cytology (ASC‐US+, atypical squamous cells of undetermined significance or worse). The immediate risk of CIN3+ was 14.6% if p16INK4a results were positive and 0.2% if p16INK4a results were negative.ConclusionsWith minimal colposcopy referrals, p16INK4a screening demonstrated promising utility for risk stratification and yielded a better balance between sensitivity and specificity compared with HPV and LBC primary screening. Moreover, with accuracy and efficiency similar to what is achieved using mainstream cotest algorithms, p16 may simplify the screening practice. More evidence will be required before clinical recommendation.

Implementation of visual inspection with acetic acid and Lugol's iodine for cervical cancer screening in rural China

AbstractObjectiveTo address the value of visual inspection where HPV‐based screening is not yet available, we evaluated the real‐world effectiveness of visual inspection with acetic acid (VIA) and with Lugol's iodine (VILI) as a primary screening method for cervical cancer in rural China.MethodsA total of 206 133 women aged 30–59 years received two rounds of VIA/VILI screening for cervical cancer in 2006–2010. Women with positive screening results underwent colposcopy and direct biopsy, and were treated if cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was diagnosed. Clinical effectiveness of VIA/VILI was evaluated by process and outcome measures.ResultsThe VIA/VILI positivity rate, biopsy rate and detection rate of CIN2+ in the second round were significantly lower than in the first round. The 2‐year cumulative detection rate of CIN2+ varied from 0.53% to 0.90% among the four cohorts initiated in 2006, 2007, 2008, and 2009. The first round of screening detected 60%–83% of CIN2, 70%–86% of CIN3, and 88%–100% of cervical cancer. Over 92% of CIN2+ were found at the early stage.ConclusionMultiple rounds of visual inspection with continuous training and quality assurance could act as a temporary substitutional screening method for cervical cancer in resource‐restricted settings.

Triage performance and predictive value of the human gene methylation panel among women positive on self‐collected HPV test: Results from a prospective cohort study

AbstractTriaging of women positive for high‐risk human papillomavirus (hrHPV) on self‐collected samples requires a molecular reflex test to avoid recall for cytology or visual tests. We assessed triage performance and predictive value of human gene methylation panel (ZNF671/ASTN1/ITGA4/RXFP3/SOX17/DLX1) alone and with combination of HPV16/18 genotyping in a longitudinal screening study. Out of 9526 women at baseline, 1758 women positive for hrHPV on self‐collected samples followed up yearly were included in the current analysis. Satisfactory risk stratification to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was demonstrated by the methylation panel with an odds ratio (OR) of 11.3 among methylation‐positive women compared to methylation‐negative counterparts. Triaging with methylation panel reduced colposcopy referral rate by 67.2% with sensitivity and specificity of 83.0% and 69.9% to detect CIN2+. The corresponding values for the combining methylation and HPV 16/18 were 96.6% and 58.3%. The cumulative 3‐year incident CIN2+ risk was 6.8% (95% CI: 4.9%‐8.6%) for hrHPV positive women, which was reduced to 4.5% (95% CI: 2.7%‐6.3%) and 2.9% (95% CI: 1.2%‐4.5%) for women negative on methylation triaging alone and negative on the combined strategy. The corresponding risk for women positive for both methylation and HPV 16/18 reached 33.7% (95% CI: 19.0%‐45.8%). Our study demonstrated the satisfactory triage performance and predictive value of the methylation panel, especially in combination with HPV 16/18 genotyping. The substantially lower risk of CIN2+ among the triage negative women over the next 3 years suggests that the interval for repeat HPV test can be safely extended to at least 2 years.

Temporal Trends and Projection of Cancer Attributable to Human Papillomavirus Infection in China, 2007–2030

Abstract Background: Information on temporal trends of cancer attributable to human papillomavirus (HPV) in China is limited. Methods: Cancer incidence and mortality during 2007 to 2015 were extracted from the Chinese Cancer Registry Annual Report and the national population from the National Bureau of Statistics. HPV-attributable cancer burden and the average annual percentage change during 2007 to 2015 were estimated and cancer burden during 2016 to 2030 was projected. Results: HPV-attributable cancer cases have increased by 3.8% [95% confidence interval (CI), 2.9%–4.8%] annually from 85,125 to 113,558 and age-standardized incidence rate (ASIR) rose by 3.0% (95% CI, 2.5%–3.5%) from 4.67 to 5.83 per 100,000 persons during 2007 to 2015. Cervical, female anal, and vulva cancer cases have increased by 3.8% (95% CI, 2.8%–4.7%), 6.5% (95% CI, 1.2%–12.2%), and 3.7% (95% CI, 1.6%–5.8%) per year. Male anal and oropharyngeal cancer cases have elevated by 7.5% (95% CI, 2.8%–12.5%) and 4.4% (95% CI, 2.4%–6.3%) annually. The increases of cervical and anal cancer were most rapid among those aged 50 and older. HPV-attributable cancer deaths and mortality rate have risen by 4.7% (95% CI, 2.9%–6.7%) and 3.3% (95% CI, 0.9%–5.8%) respectively. HPV-attributable cancer cases and ASIR are projected to reach 214,077 and 9.35 of 100,000 persons by 2030 respectively, with 87.7% being cervical cancer, and anal cancer cases are expected to triple. Conclusions: HPV-attributable cancer burden has largely increased in the past and will keep rising for the next decade. Cervical cancer control should be the priority and anal cancer prevention should be addressed. Impact: This study supplies fundamental evidence for policy-making on HPV-attributable cancer control.

Tackling barriers to scale up human papillomavirus vaccination in China: progress and the way forward

AbstractThe human papillomavirus (HPV) vaccine is the first vaccine developed specifically targeting the prevention of cervical cancer. For more than 15 years, China has expedited a series of efforts on research and development of the domestically manufactured HPV vaccines, producing local population-based evidence, promoting free HPV vaccination from pilots, and launching action plans to tackle barriers in the scale-up of HPV vaccination. To further roll out the HPV vaccination program in China, several challenges should be addressed to support the steps forward. The availability of more locally manufactured HPV vaccines, pricing negotiation and local evidence supporting the efficacy of one-dose schedule would greatly alleviate the continued supply and financial constraints in China. Meanwhile, more attention should be paid to girls living in low-resource areas and males to ensure equal access to the HPV vaccination. Furthermore, linkage to secondary prevention and further real-world monitoring and evaluation are warranted to inform effective cervical cancer prevention strategies in the post-vaccine era. Graphical Abstract

Temporal trends in cervical cancer incidence and mortality in economically emerging countries, 1992–2021: an age-period-cohort analysis

Introduction The economically emerging countries contributed to over half of the global cervical cancer (CC) burden and are good examples showing how rapid economic growth and health policy change affect the trends of CC burden. This study aimed to analyse the time trends of CC burden across Brazil, Russia, India, China and South Africa (BRICS) and associations with age, period and birth cohort from 1992 to 2021. Methods Data on CC incident cases, deaths, age-standardised incidence rates (ASIRs) and age-standardised mortality rates (ASMRs) were sourced from the Global Burden of Disease Study 2021 to demonstrate the temporal trends of CC burden for BRICS countries from 1992 to 2021. An age-period-cohort model was used to determine the net drift, local drift, longitudinal age curves, as well as period and cohort relative risks regarding CC incidence and mortality. Results Between 1992 and 2021, the ASIR of CC decreased from 16.5 to 15.6 per 100 000 women (−5.5%) and the ASMR declined from 10.1 to 6.7 per 100 000 women (−33.7%) in BRICS. Brazil reported continuous decreases in both CC incidence (net drift: −1.1%, 95% CI −1.1% to −1.0%) and mortality (net drift: −1.7%, 95% CI −1.80% to −1.6%). India also had reduced CC incidence and mortality but experienced worsening period effects from 2012 onwards. Russia and China experienced decreasing trends in mortality yet increasing trends in incidence, and there were apparent unfavourable trends among young and middle-aged women in Russia. South Africa maintained the highest CC incidence (40.0 per 100 000 women, 95% CI 35.0 to 45.6) and mortality (21.3 per 100 000 women, 95% CI 18.8 to 24.1) across the BRICS and had the steepest growth of CC incidence and mortality rates with increasing age. Conclusion Despite an overall decreasing trend of CC burden in BRICS, substantial heterogeneity exists across nations. Identifying country-specific priority groups and tailoring interventions is essential, and the patterns observed have implications for public health strategies applicable not just to BRICS nations but also to many other emerging economies facing substantial CC burden.

Cervical Cancer Incidence and Mortality Trends in China: The Role of Screening

In China, cervical cancer incidence and mortality have continued to increase despite more than 15 years of nationwide organized screening, raising questions about the population-level impact of screening. Using national cancer registry data from 2004 to 2018, we analyzed temporal trends in age-standardized incidence rates (ASIRs) and mortality rates (ASMRs), as well as age-specific rates, using Joinpoint regression, and assessed their correlations with age-specific screening coverage. From 2004 to 2018, ASIR increased from 6.06 to 11.81 per 100,000, but the annual growth rate slowed markedly after 2007, declining from 12.5 % (95 % CI: 9.7 ∼ 15.5 %) to 3.1 % (95 % CI: 2.7 ∼ 3.4 %). Among women aged 35-44 years, incidence trends shifted from a sharp rise to a sustained decline. By contrast, ASMR rose steadily from 2.07 to 3.44 per 100,000, with an average annual increase of 4.1 % (95 % CI: 3.4 ∼ 4.8 %). Notably, mortality stabilized after a rapid early rise among women aged 40-44 years, the group with the highest screening coverage. Correlation analysis revealed strong positive associations between higher screening coverage and the deceleration of incidence (ρ = 0.85, p < 0.001) and mortality trends (ρ = 0.69, p = 0.014). These findings suggest that increased screening coverage may already be moderating incidence and mortality trends in specific age groups, particularly women aged 35-44 years. However, nationwide declines have yet to emerge, especially in rural populations where screening coverage remains low and disease burden is high. Expanding access and improving screening quality are critical to accelerate progress toward cervical cancer control in China.

Type‐ and age‐specific natural history of high‐risk human papillomavirus infections in healthy women: A prospective cohort study in China

Abstract As cervical cancer screening shifts from cytology to HPV testing, clarifying the type‐ and age‐specific natural history of HR‐HPV is crucial, especially in regions with bimodal prevalence patterns where longitudinal data remain limited. We analyzed baseline HR‐HPV‐positive participants from the control arm of a bivalent HPV‐16/18 vaccine trial in China, with follow‐up over 5.5 years. Cox regression and competing risk models were applied to evaluate the progression, clearance, and persistence of these HR‐HPV infections. Among 534 HR‐HPV‐positive women at baseline, 98 CIN2+ lesions were identified (52 at baseline, 46 during follow‐up). HPV‐16 and HPV‐31 exhibited the highest immediate CIN2+ risk (21.1%), followed by HPV‐33 (17.1%) and HPV‐58 (12.7%). When stratified by baseline cytology, the LSIL+ group showed the highest immediate risk of CIN2+ (29.5% among the HR‐HPV‐positive participants), followed by the ASC‐US (10.5%). In the longitudinal analysis, competing risk models revealed significant type‐specific differences in progression (Gray's test P  = 0.0158) and clearance (Gray's test P  &lt;0.0001). HPV‐16, ‐31, ‐18, and ‐58 showed relatively high progression (27.1%, 19.2%, 16.1%, and 11.2%) and low clearance (72.9%, 69.2%, 83.9%, and 88.8%). CIN2+ risk was strongly genotype‐dependent; beyond HPV‐16/18, types ‐31, ‐33, and ‐58 also warrant particular attention in screening and clinical management. Additionally, although a slightly higher CIN2+ progression risk was observed in younger women compared to older women, the difference was not statistically significant (Gray's test P =  0.4389), indicating the need for confirmation in larger studies. These findings enhance the understanding of the natural history of type‐specific HR‐HPV and age‐specific progression in initially screen‐positive populations.

Primary Cervical Cancer Screening by Self-sampling HPV Test

Cervical cancer seriously threatens women's health and HPV infection is the main cause of cervical cancer. Traditionally, Cervical cancer screening is based on cervical exfoliated cell samples collected by health care provider, which is labor consuming and the coverage and compliance are both relatively low in some areas. Non-invasive hrHPV self-sampling test appears to be more acceptable and may improve the HPV screening coverage. This study aims to evaluate the clinical performance of a newly developed urine/vaginal self-sampling hrHPV test in Cervical cancer screening.