HPV prevalence and accuracy of HPV testing to detect high-grade cervical intraepithelial neoplasia

Concern was raised on using testing for high-risk (HR) human papillomavirus (HPV) in cervical cancer screening in populations where HPV prevalence is high. The impact of HR HPV prevalence on the efficiency of HPV test-based screening has never been directly evaluated. A meta-regression of the relationship between HR HPV prevalence and the specificity and positive predictive value (PPV) of HPV DNA testing for the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was performed. Only studies that used Hybrid Capture 2 (HC2) were included. Country income (low-medium vs. high) was used as a proxy of previous screening. Twenty-six populations from 20 studies were included. For a 10% increase in HR HPV prevalence, HC2 specificity decreased by 8.41% [95% confidence interval (CI): 8.02-8.81], whereas PPV increased by 4.74% (95% CI: 2.45-7.03). HR HPV prevalence explained 98% of the variability in HC2 specificity and 38% of the variability in PPV. Country income did not affect specificity, but low-medium income was associated with higher PPV (3.81%; 95% CI: 1.53-6.10) after adjustment for HR HPV prevalence. When HR HPV prevalence is high, the specificity of HPV testing for CIN2+ decreases, but PPV does not decrease and it is high in inadequately screened populations. The number of HPV-positive women needing further assessment or treatment per CIN2+ case detected will therefore decrease and screening efficiency will improve. This is explained by the fact that HR HPV causes CIN2+: an increase in HR HPV prevalence is inevitably accompanied by an increase in CIN2+.     

Thin-layer liquid-based cervical cytology and PCR for detecting and typing human papillomavirus DNA in Flemish women

The objective of this study was to document the occurrence and to correlate the prevalence of different human papillomavirus (HPV) types with the cytological results on simultaneously performed thin-layer preparations in a large population of Flemish women. During 1 year, 69 290 thin-layer preparations were interpreted using the Bethesda classification system. Using an algorithm for HPV testing based on consensus primers and type-specific PCRs in combination with liquid-based cytology, we determined the occurrence and distribution of 14 different oncogenic HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68). Reflex HPV testing was performed on cytologically abnormal samples and on an age matched randomly selected control group with normal cervical cytology (n=1351). Correlation between cytology, age and prevalence for the 14 different high-risk HPV types is given. There is a significant increase in predominance of high-risk HPV types, with increasing abnormal cytology. Coinfection with multiple HPV types also increased with cytological abnormalities, and was highest in HSIL (16.7%). In Flanders, HSIL was most often associated with HPV types 16, 33, 35, 31, 18 and 51. Using thin-layer liquid-based cytology and PCR to detect HPV, it is feasible to screen large numbers of women.     

HPV immunisation and increased uptake of cervical screening in Scottish women; observational study of routinely collected national data

Background:

To measure the uptake of first invitation to cervical screening by vaccine status in a population-based cohort offered HPV immunisation in a national catch-up campaign.

Methods:

A retrospective observational study of routinely collected data from the Scottish Cervical Screening Programme. Data were extracted and linked from the Scottish Cervical Call Recall System, the Scottish Population Register and the Scottish Index of Multiple Deprivation. Records from 201 023 women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. Attendance for screening was within 12 months of the first invitation at age 20 years.

Results:

There was a significant decline in overall attendance from the 1988 cohort to the 1993 cohort with the adjusted attendance ratio of the 1988 cohort being 1.49 times (95% CI 1.46–1.52) that of the 1993 cohort. Immunisation compensated for this decrease in uptake with unvaccinated individuals having a reduced ratio of attendance compared with those fully vaccinated (RR=0.65, 95% CI 0.64–0.65). Not taking up the opportunity for HPV immunisation was associated with an attendance for screening below the trend line for all women before the availability of HPV immunisation.

Conclusions:

HPV immunisation is not associated with the reduced attendance for screening that had been feared. Immunised women in the catch-up cohorts appear to be more motivated to attend than unimmunised women, but this may be a result of a greater awareness of health issues. These results, while reassuring, may not be reproduced in routinely immunised women. Continued monitoring of attendance for the first smear and subsequent routine smears is needed.     

Hormonal contraceptive use, pregnancy and parity, and the risk of cervical intraepithelial neoplasia 3 among oncogenic HPV DNA-positive women with equivocal or mildly abnormal cytology

Oral contraceptive (OC) use, hormonal contraceptive use and multiparity are potential risk factors for cervical precancer, cervical intraepithelial neoplasia 3 (CIN3), but a limited number of studies have adequately accounted for possible confounding effect of oncogenic human papillomavirus (HPV) infection. To examine the relationships of these factors with CIN3, we conducted an analysis of women (n = 5,060) with minimally abnormal Pap smears who were enrolled in the ASCUS and LSIL Triage Study (ALTS), a clinical trial to evaluate management strategies. Cervical specimens collected at enrollment were tested for HPV DNA using 2 methods. Multivariate logistics regression models were used to assess associations (odds ratio [OR] with 95% confidence intervals [CI]) of the potential risk factors (e.g., OC use and parity) with testing oncogenic HPV positive among controls (相似文献   

Prevalence of types 16 and 33 is increased in high-risk human papillomavirus positive women with cervical intraepithelial neoplasia grade 2 or worse

High-risk human papillomavirus (hrHPV) types are causally related to cervical cancer and its high-grade precursor lesions. The risk posed by the different hrHPV types for the development of cervical intraepithelial neoplasia grade 2 or worse (> or =CIN2) needs to be established. Here, we present the hrHPV type-distribution in relation to cytology and histology for women participating in a cervical screening program. From 44,102 women who participated in a population-based cervical screening program in the Netherlands, 2,154 hrHPV GP5+/6+ PCR positive women were recruited to determine the distribution of 14 hrHPV types by reverse line blotting of GP5+/6+ PCR products. For each HPV type, associations with cytology and histologically confirmed > or =CIN2 were measured by odds ratios. HPV types 16 and 33 were more prevalent in women, amongst those containing a single hrHPV type, with moderate dyskaryosis or worse (>BMD) than in women with normal cytology, but only in case of underlying > or =CIN2 (OR 4.10, 95%CI 2.98-5.64 and OR 2.68, 95%CI 1.39-5.15, respectively). Similar results were obtained for women with double infections (OR 3.29, 95% CI 1.61-6.75 and OR 4.37, 95% CI 1.17-16.34). Coexisting types did not influence the prevalence of > or =CIN2 in HPV 16 or 33 positive women. The increased prevalence of type 16 and 33 in hrHPV positive women with > or =CIN2, compared to women with normal cytology, suggests that infection with these types confers an increased risk for development of > or =CIN2. Distinguishing these types may therefore have implications for future cervical screening strategies.     

Patterns of persistent HPV infection after treatment for cervical intraepithelial neoplasia (CIN): A systematic review

A systematic review of the literature was conducted to determine the estimates of and definitions for human papillomavirus (HPV) persistence in women following treatment of cervical intra‐epithelial neoplasia (CIN). A total of 45 studies presented data on post‐treatment HPV persistence among 6,106 women. Most studies assessed HPV persistence after loop excision (42%), followed by conization (7%), cryotherapy (11%), laser treatment (4%), interferon‐alpha, therapeutic vaccination, and photodynamic therapy (2% each) and mixed treatment (38%). Baseline HPV testing was conducted before or at treatment for most studies (96%). Follow‐up HPV testing ranged from 1.5 to 80 months after baseline. Median HPV persistence tended to decrease with increasing follow‐up time, declining from 27% at 3 months after treatment to 21% at 6 months, 15% at 12 months, and 10% at 24 months. Post‐treatment HPV persistence estimates varied widely and were influenced by patient age, HPV‐type, detection method, treatment method, and minimum HPV post‐treatment testing interval. Loop excision and conization appeared to outperform cryotherapy procedures in terms of their ability to clear HPV infection. This systematic review provides evidence for the substantial heterogeneity in post‐treatment HPV DNA testing practices and persistence estimates.     

Cumulative risk of cervical intraepithelial neoplasia for women with normal cytology but positive for human papillomavirus: Systematic review and meta-analysis

Most women positive for human papillomavirus (HPV) are cytology normal. The optimal screen-management of these women is unclear given their risk of developing precancer. We performed a systematic review and meta-analysis of progression rates to precancer and cancer for HPV-positive, cytology normal women. We searched MEDLINE, EMBASE and Scopus for prospective studies measuring the cumulative incidence of precancer and cervical cancer in HPV-positive, cytology/histology normal women. Record screening was performed independently by two reviewers. We modeled the cumulative incidence over time using a multilevel random-effects meta-regression model. We used the model to predict HPV type-specific risks of precancer and cancer over follow-up. Data from 162 unique records were used in our analysis. The average incidence rate of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in high-risk HPV positive but cytology/histology normal women was 1.0 per 100 women-years (95% CI: 1.0-1.1). This corresponds to an average cumulative risk at 1, 3 and 5 years of 2.1% (95% prediction interval 0.0-9.5), 4.3% (95% prediction interval 0.0-11.5) and 6.4% (95% prediction interval 0.0-13.5). HPV type was a strong predictor of the risk of oncogenic progression. There was substantial heterogeneity in the background precancer risk across studies (P-value < .0001). Our HPV type-specific progression risk estimates can help inform risk-based cervical cancer screening guidelines for HPV-positive women. However, precancer and cervical cancer risks are highly variable and may not be generalizable between populations.     

HPV prevalence and cervical intraepithelial neoplasia among HIV-infected women in Yunnan Province, China: a pilot study

Objectives: To determine the prevalence of HPV and cervical neoplasia among HIV-infected women insouthwestern China. Methods: Cervical cytology, HPV detection by Hybrid Capture-2™ assay, and diagnosticcolposcopy were followed by cervical biopsy if indicated. Logistic regression analysis was used to analyzeassociations between HPV co-infection and cervical intraepithelial neoplasia (CIN), and HIV-related clinicaland laboratory parameters. Results: Colposcopic-histopathologically proven CIN2+ lesions were present in7/83 (8.4%) HIV-infected women. Nearly half (41/83, 43%) were co-infected with carcinogenic HPV genotypes.HPV co-infection was higher in women with colposcopic-histopathologically proven CIN2+ lesions than womenwith 相似文献   

HPV genotypes in CIN 2-3 lesions and cervical cancer: a population-based study

The distribution of human papillomavirus (HPV) varies between countries and continents leading to different effectiveness of upcoming prophylactic HPV vaccines. This study analyses the HPV distribution in CIN 2-3, recurrent CIN 2-3 and cervical cancer in Iceland. About 80% of incident cases with CIN 2-3 lesions in 1990 and 1999, 99% of cancer cases in 1990-1994 and 1999-2003, and cases with recurrent CIN 2-3 after conization in 1990 were tested with PCR analysis for the presence of 12 oncogenic HPV types. About 95% of the CIN 2-3 and 92% of the cancer cases tested positive for the included HPV types. HPV 16 was the most frequent type followed by HPV 33, 31, 52, 35, 18, 58, 56, 39, 45, 59 in CIN 2-3 and by HPV 18, 33 45, 31, 39, 52, 35, 51, 56 in cancer. HPV 16 and 18 were associated with a significantly increased cancer risk and HPV 52 and 31 with decreased cancer risk compared to the risk of CIN 3. The HPV distribution differed between histological cancer types, stages and age groups. The number of HPV types was not a significant predictor of cancer. Oncogenic HPV types were found in all persistent or recurrent CIN 2-3 disease after conization. Vaccination against HPV 16/18 is estimated to achieve a minimum 40% reduced rate of CIN 2-3 and a minimum 60% reduced cancer rate. This rate could, however, be increased to 95% and 92% respectively by including all the 12 HPV types tested for in this study.     

Risk of high-grade cervical intra-epithelial neoplasia based on cytology and high-risk HPV testing at baseline and at 6-months

Adding a test for high-risk human papillomavirus (hrHPV) to cytological screening enhances the detection of high-grade cervical intraepithelial neoplasia (>or=CIN2), but data are required that enable long-term evaluation of screening. We investigated the >or=CIN2 risk for women participating in population-based screening as a function of hrHPV and cytology testing results at baseline and at 6 months. We included 2,193 women aged 30-60 years participating in a population-based screening trial who received colposcopy or a repeat testing advice at baseline. The main endpoint was histologically confirmed >or=CIN2 diagnosed within 36 months. hrHPV testing was more sensitive than cytology for >or=CIN2 (relative sensitivity 1.4, 95%CI: 1.3-1.5; absolute sensitivity 94.1 and 68.0%, respectively). The 18-month >or=CIN2 risks in women with a hrHPV-positive smear and in women with abnormal cytology were similar (relative risk 0.9, 95%CI: 0.8-1.1). Women with HPV16 and/or HPV18 had a higher >or=CIN2 risk than other hrHPV-positive women irrespective of the cytological grade. Repeat testing showed that both cytological regression and viral clearance were strongly associated with a decrease in >or=CIN2 risk. Notably, women who had a double negative repeat test at 6 months had a >or=CIN2 risk of only 0.2% (95%CI: 0.0-1.1) and hrHPV-negative women with baseline borderline or mild dyskaryosis and normal cytology at 6 months had a >or=CIN2 risk of 0% (95%CI: 0.0-0.8). Using hrHPV and/or cytology testing, risk of >or=CIN2 can be assessed more accurately by repeat testing than single visit testing. Hence, when hrHPV testing is implemented, patient management with repeat testing is a promising strategy to control the number of referrals for colposcopy.     

Differences in human papillomavirus type distribution in high‐grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe

Knowledge of differences in human papillomavirus (HPV)‐type prevalence between high‐grade cervical intraepithelial neoplasia (HG‐CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV‐infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG‐CIN or ICC from 17 European countries were enrolled in two parallel cross‐sectional studies (108288/108290). Centralised histopathology review and standardised HPV‐DNA typing were applied to formalin‐fixed paraffin‐embedded cervical specimens dated 2001–2008. The pooled prevalence of individual HPV types was estimated using meta‐analytic methods. A total of 3,103 women were diagnosed with HG‐CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV‐positive, respectively. The most common HPV types in women with HG‐CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG‐CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/‘other’ (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/‘other’ (15/23/20/17 years). In Europe, HPV16 predominates in both HG‐CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG‐CIN and associated with a high median age of HG‐CIN, with a narrow age interval between HG‐CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45‐related cervical lesions.     

HPV for cervical cancer screening (HPV FOCAL): Complete Round 1 results of a randomized trial comparing HPV‐based primary screening to liquid‐based cytology for cervical cancer

Complete Round 1 data (baseline and 12‐month follow‐up) for HPV FOCAL, a randomized trial establishing the efficacy of HPV DNA testing with cytology triage as a primary screen for cervical cancer are presented. Women were randomized to one of three arms: Control arm – Baseline liquid‐based cytology (LBC) with ASCUS results triaged with HPV testing; Intervention and Safety arms – Baseline HPV with LBC triage for HPV positives. Results are presented for 15,744 women allocated to the HPV (intervention and safety combined) and 9,408 to the control arms. For all age cohorts, the CIN3+ detection rate was higher in the HPV (7.5/1,000; 95%CI: 6.2, 8.9) compared to the control arm (4.6/1,000; 95%CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1,000; 95%CI: 14.6, 18.6) vs. the control arm (10.1/1,000; 95%CI: 8.3, 12.4). In women ≥35 years, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1,000 vs. 5.2/1,000; CIN3+: 4.2/1,000 vs. 2.2/1,000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25–29 compared to LBC (63.7/1,000; 95%CI: 51.9, 78.0 vs. 32.4/1,000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1,000; 95%CI: 55.4, 62.7 vs. control: 30.9/1,000; 95%CI: 27.6, 34.6). At completion of Round 1 HPV‐based cervical cancer screening in a population‐based program resulted in greater CIN2+ detection of across all age cohorts compared to LBC screening.     

Impact of HPV vaccination on outcome of cervical cytology screening in Denmark—A register‐based cohort study

4vHPV vaccination has been tested in randomized controlled trials under almost ideal conditions, and studies of real‐life use have compared outcome between vaccinated and unvaccinated women from the same birth cohort and mostly before screening age. Here we present the first—to our knowledge—evaluation of the impact of the 4vHPV vaccination in real life without selection bias in the reported data. The study has been carried out by comparing the results after first cervical screening between an HPV‐vaccinated and an unvaccinated birth cohort, consisting of women born in Denmark in 1993 and 1983, respectively. Cytology data covering an 8‐year period, from the age of 15 (age of HPV‐vaccination) to age 23 (age of invitation to first cervical screening), were retrieved from the Danish National Pathology Register. Abnormal cytology, defined as atypical squamous cell of undetermined significance and worse (ASCUS+) was detected in 9.4% of women born in 1993 as compared with 9.0% of women born in 1983; RR = 1.04 (95% CI 0.96–1.12), p = .29. Detection of high‐grade squamous intraepithelial lesion (HSIL) was statistically significantly lower in the 1993 than in the 1983 cohort, RR = 0.6 (95% CI 0.5–0.7), p < .0001, while the opposite pattern was seen for ASCUS RR = 1.4 (95% CI 1.2–1.6), p < .0001. The decrease in HSIL means that more women can be spared referral for colposcopy and biopsy. The increase of ASCUS could be explained by transition from conventional to liquid‐based cytology, but this observation requires further monitoring.     

国产HPV杂交捕获技术在农村宫颈癌筛查中的应用

目的 人乳头瘤病毒(human papillomavirus,HPV)检测是国内外公认的宫颈癌筛查有效方式.近年来,我国研发了低成本、快速、简单的HPV检测方法,为HPV检测应用到人群筛查提供了希望.本研究分析国产HPV杂交捕获技术(hybrid capture 2,HC2)初筛不分流及DH2初筛HPV16/18分型检测分流检出宫颈癌前病变与宫颈癌的情况,评价此种检测技术应用于农村地区宫颈癌筛查的可行性.方法 按整群抽样的方法,对新密市7个乡镇35～64岁的农村妇女使用DH2检测进行宫颈癌筛查,阳性者召回做阴道镜,对镜下发现的可疑病变取活组织检查,病理诊断作为金标准,宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)≥2级(CIN2+)患者需手术治疗.对DH2阳性者同时进行HPV16/18分型检测,探索DH2初筛和HPV16/18分型检测分流策略对宫颈疾病的检出情况 .结果 DH2筛查阳性率为12.23％(1 512/12 358),其中≥50岁组HPV感染率和＜50岁组HPV感染率分别为13.40％(749/5 588)和11.27％(763/6 770),比值比(odds ratio,OR)=1.22(1.09～1.36),差异有统计学意义,x2=12.98,P＜0.001.共检出CIN2+ 87例(0.72％),CIN3+ 50例(0.41％),达到新密市近年最高水平.采用HPV16/18分型检测分流策略的阳性率为2.66％(319/11 981),检出CIN2+ 62例(0.52％),CIN3+ 37例(0.31％).HPV16/18分流检出CIN2+占总病例的73.81％(62/84),检出CIN3+占总病例的77.08％(37/48).结论 DH2检测对宫颈癌前病变及宫颈癌的检出率较高,可作为宫颈癌筛查方法使用.HPV16/18分流策略虽然可以降低阴道镜转诊率,但是会漏诊部分CIN2+患者,漏诊患者的基因型别有待进一步分析.     

高危型HPV阳性细胞学阴性维吾尔族妇女的分流管理

目的 统计≥30岁维吾尔族妇女不同型别人乳头瘤病毒(human papillomavivus,HPV)感染和宫颈细胞学检查结果,分析不同型别HPV感染发生高度宫颈病变(≥CIN2)的风险,为规范化管理未发生宫颈病变和HPV阳性的妇女提供理论依据.方法 收集2012-01-01-2014-02-28新疆维吾尔自治区人民医院妇产科不同型别HPV感染且宫颈细胞学检查未见异常的维吾尔族妇女199例,根据不同HPV型别进行分组,常规全部行阴道镜检查,行宫颈多点活检组织病理学检查,根据病检结果分析各个型别宫颈高度病变的患病率,运用Logistic回归分析不同型别HPV妇女发生高度宫颈病变的风险.结果 199例宫颈细胞学检查未见异常,但HPV分型检测15种高危型HPV阳性的维吾尔族妇女中感染位居前5位的为HPV16、58、52、53和31型.其中高度宫颈病变的患病率为18.59％(37/199),HPV阳性的各个型别中诊断≥CIN2级病变有HPV 16、58、52、31和18型,HPV16型阳性患者发生≥CIN2级病变的患病率为38.48％(20/58),HPV58型阳性的患病率为30.23％(13/43),HPV52型的患病率为5.90％(2/34),HPV31型阳性的患病率为3.70％(1/27),HPV18型阳性的患病率为11.11％(1/9).HPV16型感染发生≥CIN2级的危险是无HPV16型感染者的3.839倍,95％CI为1.829～8.060,P＜0.001;HPV58型感染发生≥CIN2级的危险是无HPV58型感染者的2.365倍,95％CI为1.476～7.669,P=0.004.结论 对于≥30岁维吾尔族妇女宫颈细胞学检查未见异常但高危型HPV阳性者尤其是HPV16和58型阳性者,发生宫颈高度病变的风险较高,应行阴道镜检查,必要时做活检.