Age‐stratified 5‐year risks of cervical precancer among women with enrollment and newly detected HPV infection

It is unclear whether a woman's age influences her risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) upon detection of HPV. A large change in risk as women age would influence vaccination and screening policies. Among 972,029 women age 30–64 undergoing screening with Pap and HPV testing (Hybrid Capture 2, Qiagen, Germantown, MD) at Kaiser Permanente Northern California (KPNC), we calculated age‐specific 5‐year CIN3+ risks among women with HPV infections detected at enrollment, and among women with “newly detected” HPV infections at their second screening visit. Women (57,899, 6.0%) had an enrollment HPV infection. Among the women testing HPV negative at enrollment with a second screening visit, 16,724 (3.3%) had a newly detected HPV infection at their second visit. Both enrollment and newly detected HPV rates declined with age (p < 0.001). Women with enrollment versus newly detected HPV infection had higher 5‐year CIN3+ risks: 8.5% versus 3.9%, (p < 0.0001). Risks did not increase with age but declined slightly from 30–34 years to 60–64 years: 9.4% versus 7.4% (p = 0.017) for enrollment HPV and 5.1% versus 3.5% (p = 0.014) for newly detected HPV. Among women age 30–64 in an established screening program, women with newly detected HPV infections were at lower risk than women with enrollment infections, suggesting reduced benefit vaccinating women at older ages. Although the rates of HPV infection declined dramatically with age, the subsequent CIN3+ risks associated with HPV infection declined only slightly. The CIN3+ risks among older women are sufficiently elevated to warrant continued screening through age 65.     

Lower cost strategies for triage of human papillomavirus DNA‐positive women

Using human papillomavirus (HPV) testing for cervical cancer screening in lower‐resource settings (LRS) will result in a significant number of screen‐positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV‐positive women in LRS. This was a population‐based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self‐collected and two clinician‐collected specimens. The self‐collected and one clinician‐collected specimen were tested by two HPV DNA tests—careHPV? and Hybrid Capture 2; the other clinician‐collected specimen was tested for HPV16/18/45 E6 protein. CareHPV?‐positive specimens were tested for HPV16/18/45 DNA. HPV DNA‐positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA‐positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA‐positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.     

Test positivity cutoff level of a high risk human papillomavirus test could be increased in routine cervical cancer screening

We present data on test positivity, relative sensitivity, rates of detection and relative specificity for primary human papillomavirus (HPV) testing with different cutoff levels for test positivity, in comparison to conventional cytology. In 2003-2004, 18,438 women were screened primarily with Hybrid Capture 2 (HC 2) assay, a test for oncogenic HPV DNA, and 21,446 with conventional cytology within the organised screening programme in Finland. A cytological triage test was performed for the HPV positives. Women with cytology equal to low grade squamous intraepithelial lesion (LSIL) or worse were referred for colposcopy. The relative sensitivity measured as relative risk (RR) of any cervical intraepithelial neoplasia (CIN) or cancer was 1.58 for the HPV test at the relative light units (rlu) ratio cutoff 1.00, in comparison to cytology. With the cutoff 3.00, all CIN 2+ lesions were detected. With cutoff 10.00, 2 of the 22 CIN 3+ lesions were missed. Relative specificity for HPV screening for any CIN was 92.6% at cutoff 1.00, 94.6% at cutoff 3.00 and 96.3% at cutoff 10.00. For CIN 3+ specificity estimates for these cutoffs were 92.1%, 94.1% and 95.8%, respectively. Used for routine screening as the sole test, the HPV test cutoff can be increased from the level recommended for clinical use. With HC 2, the detection rate at rlu ratio cutoff 10.00 is still at the level of high-quality conventional screening. At that level, the false positive rate is reduced by about half and the specificity of the HPV test becomes equal to the average specificity of conventional cytology.     

A cohort study of cervical screening using partial HPV typing and cytology triage

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk‐stratification (“triage”) of HPV‐positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3‐year or 18‐month CIN3+ risks. We typed ～9,000 archived specimens, taken at enrollment (2007–2011) into the NCI‐Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+‐woman KPNC screening population. Based on 3‐year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups (“high‐grade,” ASC‐US/LSIL, NILM). For the resultant 15 HPV group‐cytology combinations, 3‐year CIN3+ risks ranged 1,000‐fold from 60.6% to 0.06%. To guide management, we compared the risks to established “benchmark” risk/management thresholds in this same population (e.g., LSIL predicted 3‐year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3‐year risk thresholds (supplemented by 18‐month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow‐up to permit HPV “clearance”; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV‐positive women using partial HPV typing and cytology.     

Impact of HPV testing in opportunistic cervical screening: Support for primary HPV screening in the United States

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real-world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population-based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real-world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main outcomes. Of cytology-negative screens, 165 595 (67.1%) were cotests and 4.8% of these led to biopsy within 2 years vs 3.2% in the cytology-only group. Among cytology-negative, HPV tested women, 347 of 398 (87.2%) CIN2+ cases were diagnosed in HPV-positive women, as were 147 of 164 (89.6%) CIN3+ cases. Only 29/921 (3.2%) CIN3+ and 67/1964 (3.4%) CIN2+ cases were diagnosed in HPV-negative, cytology-positive women with biopsies. Under U.S. opportunistic screening, across a diversity of health care delivery practices, and in a population suffering multiple disparities, we show adding HPV testing to cytology substantially increased the yield of CIN2+ and CIN3+. CIN3+ was rarely diagnosed in HPV-negative women with abnormal cytology, supporting U.S. primary HPV-only screening.     

Cumulative 5-year diagnoses of CIN2, CIN3 or cervical cancer after concurrent high-risk HPV and cytology testing in a primary screening setting

The aim of our study was to assess the cumulative 5-year diagnoses of CIN2, CIN3 or invasive cervical cancer (CIN2+) after concurrent screening by high-risk HPV test and Pap smear in a primary screening setting. Four thousand thirty-four women from Eastern Thuringia/Germany were recruited from 1996 to 1998 for baseline screening that included routine cytology, high-risk HPV testing by consensus primer PCR GP5+/6+ and routine colposcopy. After a median of 59 months 3,153 women participated in final screening using identical methods. Women with abnormal cytology or colposcopy or a positive high-risk HPV test at any time during the study period were recalled for expert colposcopy and histologic verification. CIN2+ was detected in 160 women resulting in a cumulative 5-year proportion of 4.4% (95% CI: 3.7-5.0%). Of 3,702 women who were high-risk HPV negative at baseline, 34 (1.1-95% CI: 0.7-1.4%) had either prevalent CIN2+ or developed CIN2+ within the observation period. HPV/cytology double negatives at baseline were at lowest risk for CIN2+ (1.0-95% CI: 0.7-1.4%) compared to screening positives (16.8-100% depending on combined test results). The 5-year negative predictive value in HPV-/Cyto- women was 99.0% (95% CI: 98.6-99.3%). This suggests that a prolongation of the screening intervals in this group is feasible. However, it should be noted that 1 woman developed a microinvasive carcinoma within the observation period. Moreover, 2 women with prevalent cancer were missed by both tests. The prognostic relevance of concurrent high-risk HPV/cytology screening needs to be verified further by randomized trials.     

Overview of the European and North American studies on HPV testing in primary cervical cancer screening

Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35-49 and 50+. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy.     

The age-specific prevalence of human papillomavirus and risk of cytologic abnormalities in rural Nigeria: implications for screen-and-treat strategies

Cervical screening for carcinogenic human papillomavirus (HPV) infection is being considered for low-income countries. Effectiveness requires targeted screening in older women in whom prevalent infections are more likely to be persistent and predictive of precancer. Some studies in West Africa have found unusually high HPV prevalences across all adult ages, which may reduce the positive predictive value (PPV) of HPV-based screening, if positivity in older women does not sufficiently predict elevated risk. We conducted a population-based study in rural Nigeria to identify HPV prevalence and associated cervical abnormalities. Using stratified random sampling, we enrolled women age 15+. Nonvirgins had a cervical exam including liquid-based cytology and PCR HPV DNA testing from residual cytology specimens. Two-thirds of invited women participated, and 14.7% had detectable carcinogenic HPV, a proportion that did not decline with age (p-trend = 0.36) and showed slight peaks in the 15-29 and 60-69 age groups. Among women of the age typically considered for screen-and-treat programs (30-49 years), 12.8% were HPV positive, and the PPV for high-grade or worse cytology was 16.4%. Comparatively, women age < 30 were more likely to be HPV positive (18.9%, p = 0.03) with a lower PPV (4.2% p = 0.05). Among women age 50+ (typically excluded from screening in resource-poor settings because inexpensive treatment is not available), HPV positivity was 14.2% with a PPV of 13.9%. In Irun and similar settings where HPV does not decline with age, HPV-based screen-and-treat programs might be feasible for mid-adult women because prevalence is sufficiently low and positivity predicts elevated risk of more easily treated precancer.     

Long‐term follow‐up of the risk for cervical intraepithelial neoplasia grade 2 or worse in HPV‐negative women after conization

Little research has been conducted on the long‐term value of human papillomavirus (HPV) testing after conization. We investigated whether cytology adds to the value of a negative HPV test for long‐term prediction of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In addition, we compared risk of CIN2+ following a negative HPV test in women after conization with that in women from the general population. During 2002–2005, 667 women treated for CIN2+ were tested for HPV and cytology 46 months after conization. Only HPV‐negative women were included. Women participating in routine screening were age‐matched with post‐conization HPV‐negative women, leaving 13,230 and 477 women, respectively, for analysis. By linkage to the Pathology Data Bank, we identified all cases of CIN2+ by December 2013. The 3‐, 5‐, 8‐ and 10‐year risks for CIN2+ were 0.7, 0.9, 2.8 and 5.7% after a negative HPV test and 0.5, 0.8, 2.9 and 6.1% in HPV and cytology‐negative women. HPV‐negative women in the general population had similar 3‐year and 5‐year risks of 0.4 and 1.0%; thereafter, they had lower risks of 1.9% at 8 years and 2.7% at 10 years. Our results indicate that HPV testing may be used as a test of cure after conization. In the first 5 years after testing, the risk for CIN2+ of women who were HPV‐negative at 34 months after conization was similar to that of HPV‐negative women in the general population. After 67 years, however, women who have undergone conization may be at higher risk for CIN2+.     

Risk stratification and long‐term risk prediction of E6 oncoprotein in a prospective screening cohort in China

E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five‐year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA) and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five‐ and ten‐year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and 10‐year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year 10, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (OR_adjusted = 40.0 and 21.2, respectively). E6 oncoprotein could serve as a low‐cost, highly specific, strongly indicative point‐of‐care method in the triage and treatment of HPV positive women.     

A rapid HPV typing assay to support global cervical cancer screening and risk-based management: A cross-sectional study

The World Health Organization recommends human papillomavirus (HPV) testing for cervical screening. Extended genotyping can identify the highest-risk HPV-positive women. An inexpensive, rapid, mobile isothermal amplification assay (ScreenFire HPV RS test) was recently redesigned to yield four channels ordered by cancer risk (ie, hierarchical approach): HPV16, HPV18/45, HPV31/33/35/52/58 and HPV39/51/56/59/68. Stored specimens from 2076 women (mean age 30.9) enrolled in a colposcopy clinic, with high HPV prevalence, were tested with ScreenFire. We calculated hierarchical channel positivity and non-hierarchical channel and type positivity, according to histologic diagnosis (256 cancer, 350 cervical intraepithelial neoplasia [CIN]3, 409 CIN2, 1020 < CIN2) and known virologic reference results (Linear Array and TypeSeq). Additionally, we analyzed ScreenFire time-to-positive up to 60 min by channel and histology. Overall clinical sensitivity for CIN3+ was 94.7% (95% confidence interval 92.6-96.4), similar to Linear Array (92.3, 89.7-94.3) and TypeSeq (96.0, 93.9-97.6). Sensitivity was high for all types and channels. The hierarchical approach was well in line with HPV typing and histologic diagnosis, prioritizing higher risk women having HPV16 and precancer. For HPV16, time-to-positive was shorter in women with precancer. ScreenFire showed excellent agreement with research reference typing tests and detection of CIN2+. Risk-based type results could help guide clinical management of HPV-positive women. Time-to-positive combined with genotyping might be useful. ScreenFire is rapid, mobile, relatively inexpensive and designed for implementation of HPV-based screening and management, including in lower-resource settings. Further validation in screening by self-sampling and practical effectiveness merit evaluation.     

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 30,371Chinese 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.     

Combined use of cytology,p16 immunostaining and genotyping for triage of women positive for high-risk human papillomavirus at primary screening

Human papillomavirus (HPV) testing is very sensitive for primary cervical screening but has low specificity. Triage tests that improve specificity but maintain high sensitivity are needed. Women enrolled in the experimental arm of Phase 2 of the New Technologies for Cervical Cancer randomized controlled cervical screening trial were tested for high-risk HPV (hrHPV) and referred to colposcopy if positive. hrHPV-positive women also had HPV genotyping (by polymerase chain reaction with GP5+/GP6+ primers and reverse line blotting), immunostaining for p16 overexpression and cytology. We computed sensitivity, specificity and positive predictive value (PPV) for different combinations of tests and determined potential hierarchical ordering of triage tests. A number of 1,091 HPV-positive women had valid tests for cytology, p16 and genotyping. Ninety-two of them had cervical intraepithelial neoplasia grade 2+ (CIN2+) histology and 40 of them had CIN grade 3+ (CIN3+) histology. The PPV for CIN2+ was >10% in hrHPV-positive women with positive high-grade squamous intraepithelial lesion (61.3%), positive low-grade squamous intraepithelial lesion (LSIL+) (18.3%) and positive atypical squamous cells of undetermined significance (14.8%) cytology, p16 positive (16.7%) and, hierarchically, for infections by HPV33, 16, 35, 59, 31 and 52 (in decreasing order). Referral of women positive for either p16 or LSIL+ cytology had 97.8% sensitivity for CIN2+ and women negative for both of these had a 3-year CIN3+ risk of 0.2%. Similar results were seen for women being either p16 or HPV16/33 positive. hrHPV-positive women who were negative for p16 and cytology (LSIL threshold) had a very low CIN3+ rate in the following 3 years. Recalling them after that interval and referring those positive for either test to immediate colposcopy seem to be an efficient triage strategy. The same applies to p16 and HPV16.     

Age-dependent prevalence of 14 high-risk HPV types in the Netherlands: implications for prophylactic vaccination and screening

We determined the prevalence of type-specific hrHPV infections in the Netherlands on cervical scrapes of 45 362 women aged 18-65 years. The overall hrHPV prevalence peaked at the age of 22 with peak prevalence of 24%. Each of the 14 hrHPV types decreased significantly with age (P-values between 0.0009 and 0.03). The proportion of HPV16 in hrHPV-positive infections also decreased with age (OR=0.76 (10-year scale), 95% CI=0.67-0.85), and a similar trend was observed for HPV16 when selecting hrHPV-positive women with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) (OR=0.76, 95% CI=0.56-1.01). In women eligible for routine screening (age 29-61 years) with confirmed CIN2+, 65% was infected with HPV16 and/or HPV18. When HPV16/18-positive infections in women eligible for routine screening were discarded, the positive predictive value of cytology for the detection of CIN2+ decreased from 27 to 15%, the positive predictive value of hrHPV testing decreased from 26 to 15%, and the predictive value of a double-positive test (positive HPV test and a positive cytology) decreased from 54 to 41%. In women vaccinated against HPV16/18, screening remains important to detect cervical lesions caused by non-HPV16/18 types. To maintain a high-positive predictive value, screening algorithms must be carefully re-evaluated with regard to the screening modalities and length of the screening interval.     

高危型 HPV 载量与分型检测对宫颈高级别病变预测价值的前瞻性队列研究*

目的:评价高危型人乳头瘤病毒（highriskhumanpapillomavirus,hrHPV ）载量和分型检测在中国农村地区妇女人群中预测宫颈鳞状上皮高级别病变发生的价值。方法:2012年5 月至2015年5 月以农村妇女人群为基础选取江西省兴国县、靖安县和玉山县2 257 例,年龄35～64岁纳入本前瞻性队列研究。同时采用HC- 2（hybridcapture-2）和导流杂交技术（HybriMax ）两种方法分别检测hrHPV 载量和亚型,两种方法中任一亚型阳性者行阴道镜及活检检查,并将HC- 2 检测阳性结果中病毒载量< 10.0 RLU/CO认定为低病毒载量,病毒载量≥ 10.0 RLU/CO为高病毒载量。对hrHPV 结果阴性或病理诊断为CIN 1 的2 211 例妇女行24个月无干预随访。根据随访分别评价hrHPV 载量和HybriMax 分型两种检测方法预测宫颈鳞状上皮高级别病变（CINgrade2 orworse,CIN 2 +）的效果。结果:纳入基线、随访数据完整的女性共1 636 例。2 年内采用HC- 2 检测的132 例基线高病毒载量妇女中CIN 2 +的发生率为3.03%（4/ 132）,其相对危险度（RR）值为42.24（95%CI 为4.76～375.2）;采用HybriMax 分型检测的159 例基线分型HPV 16或18型阳性妇女中CIN 2 + 的发生率为2.51%（4/ 159）,RR值为33.06（95%CI 为3.72～293.9）。 对2 年内HC- 2 检测中高病毒载量例数和HybriMax 分型检测中HPV 16/ 18型别阳性例数进行比较,CIN 2 + 的发病率差异无统计学意义（P > 0.05）。 结论:HPV高载量和HPV 16/ 18型别阳性妇女人群进展为CIN 2 + 的风险均较高。在不具有持续监测hrHPV 条件的农村地区,HC- 2 检测的病毒载量≥ 10.0 RLU/CO阈值设定,与HybriMax 分型检测HPV 16/ 18型别均对hrHPV 初筛有分流作用,并对CIN 2+ 发生有预测作用。      

Long-term follow-up of cervical abnormalities among women screened by HPV testing and cytology-Results from the Hammersmith study

Several studies have shown that HPV testing is substantially more sensitive than cytology for primary cervical screening. However, less data exist concerning the duration of protection afforded by a negative HPV test compared to a normal cytological outcome. Here we report the long-term findings from the Hammersmith study in women aged 35 or more. HPV testing by Hybrid Capture II was performed on all available samples from the baseline screening visit. Passive surveillance of subsequent cytology screening results for the 2,982 women in the study was undertaken using a national registry. Histological outcomes were sought for all women with abnormal smears. The primary outcome was duration of protection against histologically confirmed CIN2+ afforded by a negative HPV test compared to normal cytology. 2,516 women had at least one further smear at least 1 year after entry and 20 new cases of CIN2+ were identified during a median follow-up of 6.4 years. Including disease identified at baseline, the risk of developing CIN2+ at 1, 5 and 9 years after a normal cytology was 0.33%, 0.83% and 2.20% respectively whereas it was 0.19%, 0.42% and 1.88% after a negative HPV test. HPV testing offered excellent protection from CIN2+ for at least 6 years after a negative test, whereas the protection from cytology began to wane after about 3 years. Substantially more CIN2+ lesions were found in the follow-up period in those initially HPV positive compared to those HPV negative (HR = 6.52, p = 0.001), whereas there was little difference according to initial cytology (HR = 1.64, p = 0.51).     

Stratifying HPV‐positive women for CIN3+ risk after one and two rounds of HPV‐based screening

A main challenge of human papilloma (HPV)‐based screening for cervical cancer is to adequately identify HPV‐positive women at highest risk of cervical intraepithelial neoplasia grade 3 or worse, CIN3+. The prognostic value of currently used adjunct markers (HPV16/18 genotyping and reflex cytology) may change after multiple rounds of HPV‐based screening because of a change in the proportion of HPV‐positive women with incident infections. To this end, we re‐analyzed results from the POBASCAM trial (Population Based Screening Study Amsterdam). Women were randomized to HPV/cytology cotesting (intervention group) or to cytology‐only (HPV blinded; control group) at enrolment. Our analytical population consisted of women with an HPV‐positive result at the second round, 5 years after enrolment (n = 381 intervention, n = 392 control). Nine‐year CIN3+ risks were estimated by Kaplan–Meier. HPV‐positive women were stratified by risk markers: HPV16/18 genotyping, reflex cytology and preceding HPV results. When comparing one to two rounds of HPV‐based screening, the prognostic value of an abnormal cytology result did not change (40.0% vs. 42.3%, p = 0.5617), but diminished for an HPV16/18 positive result (25.4% vs. 38.0%, p = 0.0132). HPV16/18 genotyping was nondiscriminative in women with incident HPV infections (HPV16/18 positive 10.0% vs. negative 12.1%, p = 0.3193). Women from the intervention group were more likely to have incident infections compared to women from the control group (incident screen‐positive results 75.6% vs. 64.6%, p = 0.001) Our results indicate that at a second round of HPV‐based screening, risk differentiation by cytology remained strong, but was diminished for HPV 16/18 genotyping because of a larger proportion of incident infections.     

The influence of type‐specific human papillomavirus infections on the detection of cervical precancer and cancer: A population‐based study of opportunistic cervical screening in the United States

There are limited data on the prospective risks of detecting cervical precancer and cancer in United States (US) populations specifically where the delivery of opportunistic cervical screening takes place outside managed care and in the absence of organized national programs. Such data will inform the management of women with positive screening results before and after widespread human papillomavirus (HPV) vaccination and establishes a baseline preceding recent changes in US cervical cancer screening guidelines. Using data reported to the statewide passive surveillance systems of the New Mexico HPV Pap Registry, we measured the 3‐year HPV type‐specific cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and grade 3 or more severe (CIN3+) detected during real‐world health care delivery across a diversity of organizations, payers, clinical settings, providers and patients. A stratified sample of 47,541 cervical cytology specimens from a screening population of 379,000 women underwent HPV genotyping. Three‐year risks for different combinations of cytologic interpretation and HPV risk group ranged from <1% (for several combinations) to approximately 70% for CIN2+ and 55% for CIN3+ in women with high‐grade (HSIL) cytology and HPV16 infection. A substantial proportion of CIN2+ (35.7%) and CIN3+ (30.9%) were diagnosed following negative cytology, of which 62.3 and 78.2%, respectively, were high‐risk HPV positive. HPV16 had the greatest 3‐year risks (10.9% for CIN2+,8.0% for CIN3+) followed by HPV33, HPV31, and HPV18. Positive results for high‐risk HPV, especially HPV16, the severity of cytologic interpretation, and age contribute independently to the risks of CIN2+ and CIN3+.     

2012年美国宫颈癌筛查新指南解读

本文就2012年ACOG、ACS/ASCCP/ASCP指南中宫颈癌筛查的新建议及相关证据进行解读,并对宫颈癌筛查的新标志物、HPV检测新技术和未来可能的宫颈癌筛查新策略进行综述。2012年宫颈癌筛查新指南建议,宫颈癌筛查应从21岁开始,无论性生活开始的年龄或是否有其他行为相关的危险因素,对21岁以前的人群不应进行筛查。新指南还延长了细胞学检查的时间间隔：21~29岁的妇女细胞学检查间隔时间由过去的2年延长至3年,在30~65岁无高危因素的妇女中若HPV联合细胞学两项检查均为阴性可将筛查间隔时间延长至5年,并将终止筛查的年龄提前至65岁,因良性病变（无宫颈CIN2+或宫颈癌病史）而行子宫切除术的妇女不需要再进行筛查。但已接种疫苗妇女仍需继续同未接种疫苗的妇女一样按照指南进行宫颈癌筛查。最新的指南中将HPV联合细胞学检查作为30岁以上妇女的最佳筛查策略,并建议将HPV16、18分型检测作为分流HPV检测阳性而细胞学阴性患者的标准。HPVE6/E7mRNA、p16和Ki-67等新标志物的检测可能成为HPV检测阳性而细胞学检查阴性的患者进行分流管理的新生物学指标,并使筛查策略得到优化。