Effectiveness of high-risk human papillomavirus genotyping for cervical cancer screening. A multicentre screening cohort study in rural China.

BACKGROUND: This study aimed to assess the effectiveness of high-risk human papillomavirus (HR-HPV) primary testing for cervical cancer screening in China's rural areas. METHODS: Women aged 21-64 years were recruited. Cervical cytology was diagnosed following the Bethesda 2001 classification system, HPV infection (HR-HPV, HPV-16, HPV-18, and other 12 genotypes) identified by Cobas-4800, and colposcopy and biopsy performed when required. Primary outcomes were defined as the cumulative incidence of cervical intraepithelial neoplasia grade 2/3/higher (CIN2/3+) and its relative risk at baseline and at the 36-month follow-up. RESULTS: The study included 9,218 women; mean age was 45.15 years (SD: 8.74); 81% completed the follow-up. The most frequent type of cytological lesions (12.4% ) were ASCUS (8.4%) and LSIL (2.2%). HR-HPV infection (16.3%) was more prevalent in HPV-16 than in HPV-18 (3 vs 1.5%); a positive relationship with the severity of the lesions, from 29.8% in ASCUS to 89.6% in HSIL was found. At baseline, 3.5% of the patients underwent colposcopy; 20% had a positive diagnosis. At the 36-month follow-up, the cumulative incidences of CIN2+ and CIN3+ were higher in women with HR-HPV infection (16.9 vs 0.5% and 8.2 vs 0.2%). The relative risk of CIN2/3+ was lower in HR-HPV-negative women compared to those with a negative cytology at baseline (0.4; 95%CI: 0.3-0.4). CONCLUSIONS: High-risk HPV-based screening may significantly reduce the risk of CIN2/3+ compared with cytology testing. This may be a new resource for public health demands in China's rural areas.

Comparison of primary cytology, primary HPV testing and co-testing as cervical cancer screening for Chinese women: a population-based screening cohort.

OBJECTIVES: We compared clinical performance of three strategies of primary human papillomavirus (HPV) testing, primary cytology and co-testing for cervical cancer screening. DESIGN: A population-based prospective cohort study of clinical performance of screening strategy. SETTING: Patients recruited from community in Changzhi County, Shanxi Province, China. PATIENT: 3209 women aged 30-64 years without gynaecological issues. PRIMARY AND SECONDARY OUTCOME MEASURES: The performance of different screening strategies for detecting cervical intraepithelial neoplasia grade 2 or more severe (CIN2+). RESULTS: A total of 53 CIN2+ and 31 CIN3+ cases are detected. For CIN2+, sensitivity of primary HPV (95.9%) and co-testing (98.0%) are not statistically different, but significantly higher than primary cytology (48.0%). Specificity (86.8%), colposcopy referral rate (7.8%) and number of colposcopies required to detect one case (9.8) for primary HPV are better than co-testing (79.8%, 11.9%, 14.3%, respectively). For CIN3+, primary HPV, co-testing have 100% of sensitivity and specificity, which is significantly higher than primary cytology (56.7% and 90.2%). Number of colposcopies required to detect one case for primary HPV (15.9) is better than co-testing (23.8). CONCLUSIONS: Compared with co-testing, HPV primary screening had comparable sensitivity and higher specificity for CIN2+ detection, and both of them showed better performance than cytology primary screening in cervical cancer screening.

Efficacy, safety, and immunogenicity of an Escherichia coli-produced Human Papillomavirus (16 and 18) L1 virus-like-particle vaccine: end-of-study analysis of a phase 3, double-blind, randomised, controlled trial.

BACKGROUND: This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. METHODS: This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18-45 years, with intact cervix and 1-4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18-26 and 27-45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. FINDINGS: Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2-100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9-99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. INTERPRETATION: The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Cervical cytology screening facilitated by an artificial intelligence microscope: A preliminary study.

BACKGROUND: Cervical cytology screening is usually laborious with a heavy workload and poor diagnostic consistency. The authors have developed an artificial intelligence (AI) microscope that can provide onsite diagnostic assistance for cervical cytology screening in real time. METHODS: A total of 2167 cervical cytology slides were selected from a cohort of 10,601 cases from Shenzhen Maternity and Child Healthcare Hospital, and the training data set consisted of 42,073 abnormal cervical epithelial cells. The recognition results of an AI technique were presented in a microscope eyepiece by an augmented reality technique. Potentially abnormal cells were highlighted with binary classification results in a 10× field of view (FOV) and with multiclassification results according to the Bethesda system in 20× and 40× FOVs. In addition, 486 slides were selected for the reader study to evaluate the performance of the AI microscope. RESULTS: In the reader study, which compared manual reading with AI assistance, the sensitivities for the detection of low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions were significantly improved from 0.837 to 0.923 (P < .001) and from 0.830 to 0.917 (P < .01), respectively; the κ score for atypical squamous cells of undetermined significance (ASCUS) was improved from 0.581 to 0.637; the averaged pairwise κ of consistency for multiclassification was improved from 0.649 to 0.706; the averaged pairwise κ of consistency for binary classification was improved from 0.720 to 0.798; and the averaged pairwise κ of ASCUS was improved from 0.557 to 0.639. CONCLUSIONS: The results of this study show that an AI microscope can provide real-time assistance for cervical cytology screening and improve the efficiency and accuracy of cervical cytology diagnosis.

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

Thermal 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.

Association Between Common Vaginal Infections and Cervical Non-Human Papillomavirus (HPV) 16/18 Infection in HPV-Vaccinated Women.

BACKGROUND: How vaginal infections such as bacterial vaginosis, Candida spp, and Trichomonas vaginalis affect persistence of human papillomavirus (HPV) infection is not well established. Our study aimed to evaluate the association between common vaginal infections and cervical non-HPV16/18 infection, as risk factors associated with persistence of nonvaccine HPV types will become increasingly relevant in the setting of HPV vaccination. METHODS: We performed an analysis in 2039 AS04-HPV16/18-vaccinated women enrolled in a phase II/III trial in China, who were HPV DNA negative at month 0 and 6 and had at least 1 subsequent follow-up visit. Vaginal infections were detected in liquid-based cytology according to the diagnostic criteria of the Bethesda System. Associations between vaginal infections and incident and 6-month persistent non-HPV16/18 infections in the cervix were evaluated using generalized estimating equations, adjusting for the age at initial vaccination, as well as HPV types in the persistence analysis. RESULTS: Study visits with any vaginal infection had a statistically significant increased risk of incident non-HPV16/18 infection compared to those without vaginal infections (odds ratio [OR], 1.44 [95% confidence interval {CI}, 1.09-1.92]). However, vaginal infections were not associated with 6-month persistent non-HPV16/18 infection (OR, 1.02 [95% CI, .62-1.69]). CONCLUSIONS: Our study suggests that common vaginal infections are not associated with persistence of non-HPV16/18 infection among HPV16/18-vaccinated women.

Effect of Sequential Rounds of Cervical Cancer Screening on Management of HPV-positive Women: A 15-year Population-based Cohort Study from China.

Women are anticipated to go through more than two rounds of cervical screening in their lifetime. Human papillomavirus (HPV) testing is increasingly used as the primary cervical cancer screening test. However, triage strategies for HPV-positive women were usually evaluated at baseline screening. We assessed the effect of sequential rounds of cervical screening on several algorithms for HPV triage. A total of 1,997 women ages 35-45 years were enrolled in 1999 in Shanxi, P.R. China and followed up three times at approximately 5-year intervals. Cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) prevalence by prior HPV results and performance of 12 triage algorithms with cytology, genotyping, and prior HPV were examined among 229 HPV-positive women at the fourth round. CIN2+ prevalence varied from 56.5% (95% confidence interval, 36.8%-74.4%) following 15 years HPV persistence to 3.5% (1.2%-9.9%) with an incident HPV within 15 years. Triage with cytology (with threshold of atypical squamous cells of undetermined significance) yielded positive predictive value (PPV) of 21.4% (13.8%-29.0%), entailing immediate colposcopic referral, and negative predictive value (NPV) of 97.4% (94.6%-100%), permitting retesting at short intervals. Triage with genotyping (16/18/31/33/45/52/58) or prior HPV results showed comparable performance with cytology. Among 11 triage algorithms with similar NPV to cytology, triage with prior HPV results and reflex genotyping (16/18) achieved highest PPV of 28.9% (18.8%-39.1%) and lowest colposcopy referral of 33.2% (27.4%-39.5%). HPV persistence across rounds is an effective risk stratifier in HPV-positive women. Mainstream cytology and genotyping, with or without consideration of prior HPV results, remain effective for HPV triage at fourth round. PREVENTION RELEVANCE: The study highlights the sustained effectiveness of mainstream HPV triage methods, such as cytology and genotyping, after sequential rounds of cervical screening. It also suggests that use of HPV persistence across rounds can improve management of HPV-positive women in cervical cancer screening.

Risk stratification of HPV 16 DNA methylation combined with E6 oncoprotein in cervical cancer screening: a 10-year prospective cohort study.

BACKGROUND: How to best triage human papillomavirus (HPV) positive women remains controversial in an era of HPV primary screening of cervical cancer. Here, we assessed the long-term risk stratification for triaging HPV 16 positive women by standalone HPV 16 methylation and combined with E6 oncoprotein. METHODS: A total of 1742 women underwent screening with HPV DNA testing, cytology, and visual inspection with acetic acid (VIA) in 2005 and were followed for 10 years. Seventy-seven women with HPV 16 positivity determined by HPV genotyping test were examined via E6 oncoprotein detection and bisulfite pyrosequencing for quantitative methylation of L1 and LCR genes of HPV 16. RESULTS: The 10-year cumulative incidence rate (CIR) of cervical intraepithelial neoplasia grade 3 or severe (CIN3+) for HPV 16 positive women was 25.3% (95% CI 14.7-37.3%), which significantly increased in women with high methylation at six sites (CpG 5602, 6650, 7034, 7461, 31, and 37) and in women with positive E6 oncoprotein. A methylation panel based on the above six sites showed a competitive risk stratification compared to cytology (HR 11.5 vs. 8.1), with a higher 10-year CIR of CIN3+ in panel positives (57.2% vs 36.8%) and comparable low risk in panel negatives (5.7% vs 4.8%).The sensitivity and specificity for accumulative CIN3+ was 85.7% (95%CI 60.1-96.0%) and 78.4% (95%CI 62.8-88.6%) for a methylation panel and 57.1% (95%CI 32.6-78.6%) and 86.5% (95%CI 72.0-94.1%) for E6 oncoprotein. The AUC values of methylation standalone and the co-testing of methylation panel and E6 oncoprotein were around 0.80, comparable to 0.68 for cytology, 0.65 for viral load, and superior to 0.52 for VIA (p < 0.05). CONCLUSIONS: Our findings indicated the promising use of HPV 16 methylation alone or combined with E6 oncoprotein for triaging HPV 16 positive women based on the long-term risk stratification ability.

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.

OBJECTIVE: To estimate long-term outcomes of biopsy-confirmed cervical intraepithelial neoplasia grade 1 (CIN1) or normal cervix and identify the cofactors during disease progression. METHODS: 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. RESULTS: 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. CONCLUSIONS: Clinical follow-up strategies for women with CIN1 or normal cervix could be adjusted accordingly based on hrHPV/cytology status.

Efficacy, Safety, and Immunogenicity of an Escherichia coli-Produced Bivalent Human Papillomavirus Vaccine: An Interim Analysis of a Randomized Clinical Trial.

BACKGROUND: The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. METHODS: A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18-45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission. RESULTS: In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. CONCLUSIONS: The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18-associated high-grade genital lesions and persistent infection in women.

Efficacy, immunogenicity and safety of the AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years: End-of-study results from a phase II/III, randomised, controlled trial.

BACKGROUND: Cervical cancer is a major public health concern in China. We report the end-of-study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04-human papillomavirus (HPV)-16/18 vaccine in Chinese women aged 18-25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported. METHODS: Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of AS04-HPV-16/18 vaccine or Al(OH)3 (control) at Months 0-1-6. Vaccine efficacy against HPV-16/18 infection and cervical intraepithelial neoplasia (CIN), cross-protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according-to-protocol efficacy (ATP-E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC-E; vaccine N = 2987; control N = 2985) and TVC-naïve (vaccine N = 1660; control N = 1587). RESULTS: In initially HPV-16/18 seronegative/DNA-negative women, vaccine efficacy against HPV-16/18-associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP-E, 88.7% (95% CI: 18.5, 99.7) in the TVC-E, and 100% (95% CI: 17.9, 100) in the TVC-naïve. Cross-protective efficacy against incident infection with HPV-31, HPV-33 and HPV-45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP-E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and anti-HPV-18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group. CONCLUSIONS: This is the first large-scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV-16/18-associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China. TRIAL REGISTRATION: NCT00779766.

Eight-type human papillomavirus E6/E7 oncoprotein detection as a novel and promising triage strategy for managing HPV-positive women.

The management of HPV-positive women becomes particularly crucial in cervical cancer screening. Here we assessed whether detection of E6 or E7 oncoproteins targeting eight most prevalent HPV types could serve as a promising triage option. Women (N = 1,416) aged 50-60 from Shanxi, China underwent screening with HPV testing and liquid-based cytology (LBC), with any positive results referring to colposcopy and biopsy if necessary. Women with HPV-positive results received further tests using DNA-based genotyping, E6 or E7 oncoprotein detection targeting HPV16/18 (for short: E6 (16/18) Test) or HPV16/18/31/33/35/45/52/58 (for short: E6/E7 (8 types) Test), respectively. Among HPV-positive women, E6/E7 (8 types) oncoproteins had lower positivity (17.37%) compared to DNA-based genotyping for same eight types (58.30%) and LBC with ASC-US threshold (50.97%); HPV16 was the genotype showing the highest frequency (8.49%) for oncoprotein detection followed by HPV52 (3.47%), 58 (2.32%), 33 (1.54%), 18 (1.16%), 45 (0.77%), 35 (0.39%) and 31 (0%). For detection of cervical intraepithelial neoplasia Grade 3 or higher (CIN3+), E6/E7 (8 types) Test had similar sensitivity (100.00%) and superior specificity (85.94%) as well as positive predictive value (PPV, 22.22%) compared to both LBC and DNA-based genotyping (8 types); For detection of CIN2+, E6/E7 (8 types) Test was less sensitive (67.74%) but still more specific (89.47%) and risk predictive with PPV of 46.67%. Notably, E6/E7 (8 types) Test remarkably decreased the number of colposcopies needed to detect one CIN2+ and CIN3+ (2.14 and 4.50). E6/E7 oncoprotein detection showed a good "trade-off" between sensitivity and specificity with more efficient colposcopy referrals, which is of great importance to maximize the benefits of HPV-based screening program, especially applicable for the areas with high HPV prevalence and low-resources.

Durability of clinical performance afforded by self-collected HPV testing: A 15-year cohort study in China.

OBJECTIVE: Self-collected HPV testing could substantially reduce disparities in cervical cancer screening, with slightly lower sensitivity compared to physician-collected specimens cross-sectionally. We aimed to evaluate the comprehensive long-term performance of self-collected HPV testing prospectively. METHODS: In 1999, 1997 women were screened by HPV testing on self-collected and physician-collected samples, cytology and visual inspection with acetic acid (VIA) and followed up in 2005, 2010 and 2014, respectively. HPV testing was performed with Hybrid Capture II. Prospective performance, baseline clinical efficiency, and 15-year cumulative risk of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) were analyzed. RESULTS: Self-collected HPV testing prospectively detected 83.3% (95% CI:74.9%,89.3%), 70.3% (95% CI:62.5%,77.2%) and 63.3% (95% CI:55.7%, 70.2%) of cumulative CIN2+ at 6-year, 11-year and 15-year follow-up, respectively. Relative cumulative sensitivity of physician-collected HPV testing versus self-collected HPV testing was stable over 15 years at about 1.16. Cumulative sensitivity of self-collected HPV testing was comparable to cytology and significantly higher than VIA. Among women positive by self-collected HPV testing at baseline, 26.2% (95% CI:21.5%, 30.9%) developed CIN2+ during 6-year follow-up and no difference was observed with physician-collected HPV testing even 15 years after baseline. Negative self-collected HPV results provided greater protection against CIN2+ than VIA and ascertained CIN2+ cumulative incident rates as low as 1.1% at the 6-year follow-up. CONCLUSIONS: Self-collected HPV testing demonstrates lower sensitivity than physician-collected HPV testing but performs comparably to cytology prospectively and provides satisfactory assurance against CIN2+, indicating an alternative role in cervical cancer primary screening with five-year interval as an option especially in low-resource settings.

Risk of high-risk human papillomavirus infection and cervical precancerous lesions with past or current trichomonas infection: a pooled analysis of 25,054 women in rural China.

BACKGROUND: Trichomonas vaginitis (TV) infection has obviously been implicated in gynecological morbidity but still unclear in cervical lesions. OBJECTIVE: To evaluate the risk of hr-HPV infection and cervical intraepithelial neoplasia grade 2 or worse (CIN2 + ) by TV infection. STUDY DESIGN: The pooled study was conducted among 12 population-based, cervical cancer screening studies throughout China (N = 24,054). HPV was detected by Hybrid Capture®2 (HC2) test. Past TV infection was measured by self-reporting, current TV infection was diagnosed by liquid-based cytology (LBC), cervical lesions was diagnosed by histopathology. RESULTS: Respective prevalence of hr-HPV and CIN2+ were 17.4% and 3.3%. Out of 24,054 women, 14.6% reported past TV infection, and out of 11,853 women, 9.9% had current TV infection. Current TV-positive women had an increased risk for hr-HPV (OR 1.31, 95%CI: 1.11-1.56). The risk of CIN2+ decreased for hr-HPV positive women with current TV infection (adjusted OR 0.50, 95% CI: 0.30-0.84) and past TV infection (adjusted OR 0.68, 95% CI: 0.54-0.86). Among hr-HPV negative women, no significant associations were observed between past or current TV infection and risk of CIN2+. CONCLUSIONS: Women infected with HPV are more likely to be infected by other types of sexually transmitted diseases. Current TV-positive women had an increased risk for hr-HPV infection compared to currently TV-negative women. Both past and current TV-positive women had a decreased risk for CIN2+, especially among high-risk HPV positive women. More direct investigation into the interaction between TV, HPV, inflammatory signals, and risk of carcinogenesis are further needed.

Pooled analysis on the necessity of random 4-quadrant cervical biopsies and endocervical curettage in women with positive screening but negative colposcopy.

Controversy remains over whether random cervical biopsies and endocervical curettage (ECC) should be used in women with positive screening but negative colposcopy. Our paper aims to determine the indications for random biopsies and ECC among these screened positive women.Three thousand two hundred thirteen women with any positive screening test result but negative colposcopy, who received random 4-quadrant biopsies, were pooled from 17 population-based cervical cancer screening studies done in China from 1999 to 2008. The detection rates of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN grade 3 or worse (CIN3+) stratified by cytology and high-risk human papillomavirus (HR-HPV) status were assessed, as well as the false negative rates for CIN2+ and CIN3+ by random biopsies without ECC.Compared with women with negative cytology and positive HR-HPV, those with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL) and negative HR-HPV had the equivalent lower risks of CIN2+ and CIN3+, but ascending risks were observed in the groups of ASC-US/LSIL and positive HR-HPV, and atypical glandular cells/atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion or worse (AGC/ASC-H/HSIL+). If random biopsies were only taken without ECC, 9.3% of CIN2+ and 18.5% of CIN3+ would have been missed.For women with any positive screening but negative colposcopy, in areas with good cytological infrastructure, it was necessary to perform random biopsies plus ECC on those with cytological ASC-US/LSIL and positive HR-HPV, AGC, ASC-H, or HSIL+. In contrast, those with other results should be followed up.

Efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine in Chinese women aged 18-25 years: event-triggered analysis of a randomized controlled trial.

We previously reported the results of a phase II/III, double-blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7-99.9) HPV-16/18 AS04-adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6-month (M) persistent infection (PI) with a mean follow-up of <2 years, and immunogenicity until 7 months post-dose 1. Here, we report efficacy and safety results from an event-triggered analysis with ~3 years longer follow-up, and immunogenicity until M24. Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of HPV-16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV-16/18-associated CIN2+, and cross-protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according-to-protocol efficacy cohort, in initially seronegative/DNA-negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV-16/18-associated CIN2+ was 87.3% (5.3-99.7); VE against incident infection or against 6-month persistent infection associated with HPV-31/33/45 was 50.1% (34.3-62.3) or 52.6% (24.5-70.9), respectively. At least, 99.6% of HPV-16/18-vaccines remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and -18 geometric mean titers were 1271.1 EU/mL (1135.8-1422.6) and 710.0 EU/ml (628.6-801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination-related (blinded data). VE against HPV-16/18-associated CIN2+ was demonstrated and evidence of cross-protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile.

Evaluation of multiple primary and combination screening strategies in postmenopausal women for detection of cervical cancer in China.

As China's population ages, the importance of determining prevalence of cervical disease and accurate cervical cancer screening strategies for postmenopausal women is increasing. Seventeen population-based studies were analyzed to determine prevalence of cervical neoplasia in postmenopausal women. All women underwent HPV DNA testing, visual inspection with acetic acid (VIA) and cytology testing. Diagnostic values for primary and combinations screening methods included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate and area under curve (AUC) were calculated using directed biopsy or four quadrants biopsy as reference standard. Premenopausal and postmenopausal women had equal HPV infection and cervical neoplasia rates (p > 0.05). HPV DNA testing CIN3+ sensitivity, specificity, PPV, NPV, referral rate and AUC were 97.9% (95% CI: 90.2-99.9%), 84.2% (95% CI: 82.8-85.5%), 9.9% (95% CI: 7.4-12.8%), 100% (95% CI: 99.8-100%), 17.2% (95% CI: 15.9-18.7%), 0.911, respectively. VIA values were 41.7% (95% CI: 28.4-55.9%), 94.5% (95% CI: 93.6-95.3%), 11.8% (95% CI: 7.5-17.3%), 98.9% (95% CI: 98.5-99.3%), 6.2% (95% CI: 5.3-7.1%) and 0.681, respectively. Values for VIA with HPV triage were 39.6% (95% CI: 26.6-53.8%), 99.2% (95% CI: 98.8-99.5%), 45.2% (95% CI: 30.8-60.4%), 98.9% (95% CI: 98.5-99.3%), 1.5% (95% CI: 1.1-2.0%) and 0.694, respectively. VIA and HPV DNA co-test values were 100% (95% CI: 94.0-100%), 79.5% (95% CI: 78.0-81.0%), 8.0% (95% CI: 6.0-10.3%), 100% (95% CI: 99.9-100%), 21.9% (95% CI: 20.4-23.4%) and 0.898, respectively. VIA sensitivity decreases significantly in postmenopausal women compared to premenopausal performance. HPV DNA testing maintains performance between pre- and postmenopausal women and is the most accurate primary modality for screening postmenopausal populations in low resource areas of China.

Evaluation of p16/Ki-67 dual staining in detection of cervical precancer and cancers: a multicenter study in China.

PURPOSE: To analyze the clinical performance of p16/Ki-67 dual-stained cytology identifying high-grade cervical intraepithelial neoplasia (CIN2+) in Chinese women. METHODS: 1079 women attending ongoing cervical cancer screening and 211 "enriched" women aged ≥30yrs with biopsy-confirmed CIN2+ from five Chinese hospitals were enrolled during year 2014-2015. Cervical specimens were collected for high-risk human papillomavirus (HR-HPV) DNA analysis, Liquid-based cytology (LBC) and p16/Ki-67 dual staining. Colposcopy and biopsy were performed on women with any abnormal result. RESULTS: p16/Ki-67 positivity increased with histologic severity. It was 18.4%(183/996) in normal histology, 54.0%(34/63) in CIN1, 81.0%(34/42) in CIN2, 93.3%(111/119) in CIN3, 71.4% (5/7) in adenocarcinoma and 95.2%(60/63) in squamous cell carcinoma. Compared with the HR-HPV negatives, p16/Ki-67 expression was significantly higher in the HPV16/18 positive (OR: 35.45(95%CI: 23.35-53.84)) and other 12 HR-HPV types positive group (OR: 8.01(95%CI: 5.81-11.05). The sensitivity and specificity of p16/Ki-67 to detect CIN2+ in the entire population were 90.9% and 79.5%, respectively. In women with ASC-US and LSIL, sensitivity and specificity for detection of CIN2+ were 87.5% and 66.4%, respectively, with a referral rate of 43.8%. In women who tested positive for HR-HPV, sensitivity and specificity of dual-staining for detection of CIN2+ were 92.7% and 52.7%, respectively, and the referral rate was 68.7%. CONCLUSIONS: p16/Ki-67 dual-stained cytology provided a high sensitivity and moderate specificity to detect underlying cervical precancer and cancers in various settings, and might be considered as an efficient screening tool in China.

Risk assessment to guide cervical screening strategies in a large Chinese population.

Three different cervical screening methods [cytology, human papillomavirus(HPV) testing and visual inspection with acetic acid(VIA)] are being considered in China for the national cervical screening program. Comparing risks of CIN3 and cervical cancer (CIN3+) for different results can inform test choice and management guidelines. We evaluated the immediate risk of CIN3+ for different screening results generated from individual and combined tests. We compared tests using a novel statistic designed for this purpose called Mean Risk Stratification (MRS), in a pooled analysis of 17 cross sectional population-based studies of 30,371 Chinese women screened with all 3 methods and diagnosed by colposcopically-directed biopsies. The 3 tests combined powerfully distinguished CIN3+ risk; triple-negative screening conferred a risk of 0.01%, while HPV-positive HSIL+ that was VIA-positive yielded a risk of 57.8%. Among the three screening tests, HPV status most strongly stratified CIN3+ risk. Among HPV-positive women, cytology was the more useful second test. In HPV-negative women, the immediate risks of CIN3+ ranged from 0.01% (negative cytology), 0.00% (ASC-US), 1.1% (LSIL), to 6.6 (HSIL+). In HPV-positive women, the CIN3+ risks were 0.9% (negative cytology), 3.6% (ASC-US), 6.3% (LSIL) and 38.5% (HSIL+). VIA results did not meaningful stratify CIN3+ risk among HPV-negative women with negative or ASC-US cytology; however, positive VIA substantially elevated CIN3+ risk for all other, more positive combinations of HPV and cytology compared with a negative VIA. Because all 3 screening tests had independent value in defining risk of CIN3+, different combinations can be optimized as pragmatic strategies in different resource settings.

Human Papillomavirus Genotyping to Predict the Risk of Cervical Precancerous Lesions or Cancer in Women with Minor Abnormal Cytology in China.

OBJECTIVE: To evaluate the role of human papillomavirus (HPV) genotyping in predicting the risk of cervical precancerous lesions or cancer in women with minor abnormal cytology. METHODS AND MATERIALS: This study was conducted on 329 women with atypical squamous cells of undetermined significance (ASC-US) and 77 women with low-grade squamous intraepithelial lesions (LSIL) out of a total of 4,215 participants in a multicenter, cross-sectional study. Liquid-based cytology and the Hybrid Capture 2 test (HC2) were used to screen eligible women, and a Linear Array HPV genotyping test was performed on women with positive HC2 results. RESULTS: The sensitivity and specificity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) based on HPV 16/18 were 82% [95% confidence interval (CI): 52-95%] and 91% (95% CI: 87-94%) in women with ASC-US and 67% (95% CI: 35-88%) and 84% (95% CI: 73-91%) in women with LSIL. The women infected with HPV 16/18 had a significantly higher risk of developing CIN2+ than those infected with other high-risk HPV types in both the ASC-US (OR 9.93, 95% CI: 2.02-48.88) and LSIL (OR 7.45, 95% CI: 1.60-34.68) arms. CONCLUSIONS: Genotyping for HPV 16/18 greatly improves specificity, but at the expense of potential sensitivity in the triage of minor cytology abnormalities. The role of genotyping for HPV 16/18 in order to triage women with minor abnormal cytology should be further evaluated in future studies.