Comparison of human papillomavirus genotyping and cytology triage,COMPACT Study: Design,methods and baseline results in 14 642 women

Although cytology‐based screening programs have significantly reduced mortality and morbidity from cervical cancer, the global consensus is that primary human papillomavirus (HPV) testing for cervical screening increases detection of high‐grade cervical intraepithelial neoplasia (CIN) and invasive cancer. However, the optimal triage strategy for HPV‐positive women to avoid over‐referral to colposcopy may be setting specific. As Japan requires data that have been generated domestically to modify screening guidelines, we conducted a 3‐year prospective study, COMparison of HPV genotyping And Cytology Triage (COMPACT), to evaluate the potential role of HPV16/18 partial genotyping and cytology for primary HPV screening. In total, 14 642 women aged 20 to 69 years undergoing routine screening at 3 centers in Hokkaido were enrolled. Conventional cytology and HPV testing were carried out. Women with abnormal cytology or HPV16/18 positivity underwent colposcopy. Those with 12 other high‐risk (hr) HPV types underwent repeat cytology after 6 months. Primary study endpoints were detection of high‐grade cervical disease defined as CIN2/CIN3 or greater as determined by consensus pathology. Prevalence of cytological abnormalities was 2.4%. hrHPV, HPV 16, and HPV 18 were detected in 4.6%, 0.9%, and 0.3% of women, respectively. HPV16/18 were detected in all (8/8) invasive cervical cancers and in all (2/2) adenocarcinomas in situ. Both cytological abnormalities and hrHPV positivity declined with increasing age. This is the first Japanese study to investigate the role of partial genotyping and cytology in an HPV‐based screening program. Results should help policy‐makers develop guidelines for future cervical screening programs and management of cervical abnormalities based on HPV genotype.     

Management of HPV-positive women in cervical screening using results from two consecutive screening rounds

We studied whether triage of human papillomavirus (HPV)-positive women participating in an HPV-based screening programme can be improved by including the HPV result at the previous screen in the triage algorithm. We analyzed data of a subgroup of 366 women from the POBASCAM trial, screened by cytology and HPV cotesting. Women were included if they tested HPV-positive in the second HPV-based screening round. We evaluated the clinical performance of 16 strategies, consisting of cytology, HPV genotyping, and/or previous screen HPV result. The clinical endpoint was cervical precancer or cancer (CIN3+). The current Dutch triage testing policy for HPV-positive women is to refer women for colposcopy if they have abnormal cytology at baseline or after 6–18 months. In the second HPV-based screening round, this strategy yielded a negative predictive value (NPV) of 95.8% (95% confidence interval: 91.9–98.2) and colposcopy referral rate of 37.6% (32.3–43.2%). Replacing repeat cytology by the previous screen HPV result yielded a similar NPV (96.9%, 93.3–98.9) and colposcopy referral rate (38.8%, 33.4–44.4). A higher NPV (99.2%, 96.3–100%) at the cost of a higher colposcopy referral rate (49.2%, 43.6–54.8) was achieved when cytology was combined with HPV16/18 genotyping. The other 13 triage strategies yielded a lower NPV, a higher colposcopy referral rate or performed similarly but required additional testing. HPV-positive women in the second HPV-based screening round can be suitably managed by cytology, HPV16/18 genotyping and the HPV result at the previous screen, obviating the need for repeat testing of HPV-positive, cytology negative women.     

Reducing overtreatment associated with overdiagnosis in cervical cancer screening—A model-based benefit–harm analysis for Austria

A general concern exists that cervical cancer screening using human papillomavirus (HPV) testing may lead to considerable overtreatment. We evaluated the trade-off between benefits and overtreatment among different screening strategies differing by primary tests (cytology, p16/Ki-67, HPV alone or in combinations), interval, age and diagnostic follow-up algorithms. A Markov state-transition model calibrated to the Austrian epidemiological context was used to predict cervical cancer cases, deaths, overtreatments and incremental harm–benefit ratios (IHBR) for each strategy. When considering the same screening interval, HPV-based screening strategies were more effective compared to cytology or p16/Ki-67 testing (e.g., relative reduction in cervical cancer with biennial screening: 67.7% for HPV + Pap cotesting, 57.3% for cytology and 65.5% for p16/Ki-67), but were associated with increased overtreatment (e.g., 19.8% more conizations with biennial HPV + Papcotesting vs. biennial cytology). The IHBRs measured in unnecessary conizations per additional prevented cancer-related death were 31 (quinquennial Pap + p16/Ki-67-triage), 49 (triennial Pap + p16/Ki-67-triage), 58 (triennial HPV + Pap cotesting), 66 (biennial HPV + Pap cotesting), 189 (annual Pap + p16/Ki-67-triage) and 401 (annual p16/Ki-67 testing alone). The IHBRs increased significantly with increasing screening adherence rates and slightly with lower age at screening initiation, with a reduction in HPV incidence or with lower Pap-test sensitivity. Depending on the accepted IHBR threshold, biennial or triennial HPV-based screening in women as of age 30 and biennial cytology in younger women may be considered in opportunistic screening settings with low or moderate adherence such as in Austria. In organized settings with high screening adherence and in postvaccination settings with lower HPV prevalence, the interval may be prolonged.     

Evaluation of cervical screening strategies with adjunct high-risk human papillomavirus testing for women with borderline or mild dyskaryosis

The management of women with a smear read as borderline/mild dyskaryosis (BMD) found by cervical cancer screening is still under discussion as only few of these cases are associated with high-grade lesions. To determine the optimal screening strategy for these women, a simulation model of cervical cancer development was used that is based on high-risk human papillomavirus (hrHPV) infection. The current strategy of repeat cytological testing at 6 and 18 months after BMD was compared to strategies with adjunct hrHPV testing. Calculations were done for both conventional and liquid-based cytology as the primary screening tool. In comparison to current screening, adjunct hrHPV testing was more effective in preventing cancer and more woman-friendly (reduction in colposcopy referrals with outcome < cervical intraepithelial neoplasia (CIN2) of up to 56% and in repeat smears of 30-100%). In combination with conventional cytology, cost-effective strategies were the ones in which a sample for high-risk human papillomavirus (hrHPV) testing is collected at a return visit within 1 month or in which hrHPV testing is restricted to repeat smears taken at 6 and 18 months. For these strategies, co-collection of samples for hrHPV testing at baseline is not necessary which has organizational and cost advantages. In combination with liquid-based cytology, it was cost-effective to perform a reflex hrHPV test at baseline from the liquid-based specimen. Liquid-based screening was more effective than conventional screening, but annual diagnosis costs were euro5 million higher (population size 16 million). In conclusion, our calculations indicate that implementation of hrHPV testing for the management of women with borderline or mild dyskaryosis (BMD) is feasible both in settings where conventional and liquid-based cytology is current practice.     

Can papilloma virus testing be used to improve cervical cancer screening?

This report investigates different options for using human papillomavirus (HPV) testing in cervical cancer prevention. These options are evaluated by a stochastic model of the progression of pre-malignancy and its relationship to HPV infection. Three screening policies are compared: 2 based on cytological screening, with or without HPV testing, and I in which HPV testing is the primary screening method. A policy of HPV testing for women with mildly abnormal smears would have little effect on the overall incidence of invasive cancer when compared with a policy of repeat cytology, provided follow-up is efficient. Moreover, the potential value of HPV testing as a primary screening method is strongly dependent on the proportion of neoplasias that are HPV-negative. Important factors in assessing the future role of HPV testing would be cost-effectiveness and benefits from improved compliance. © 1996 Wiley-Liss, Inc.     

Prediction of high-grade cervical intraepithelial neoplasia in cytologically normal women by human papillomavirus testing

Human papillomavirus (HPV) testing has been suggested for primary screening of cervical cancer. Prediction of future high-grade cervical lesions is crucial for effectiveness and cost. We performed a case control study in a retrospective cohort of women with at least two cervical smears, all but the last one being negative, from the organized cervical screening programme in Florence, Italy. We searched for high-risk HPV in all previous, archival, smears from cases (new histologically confirmed cervical intraepithelial neoplasia (CIN) grade II or worse) and in one previous smear from each control (last smear cytologically normal, matched by age and interval (latency) from last smear). We applied polymerase chain reaction (PCR), and the b-globin gene was used as a DNA preservation marker. High-risk HPV was identified in 71/92 (77.17%) previous smears from 79 cases and 17/332 controls (5.12%). The odds ratio (OR) was 63.76 (95% CI 30.57-132.96). Among cases the proportion of HPV-positive smears declined slightly with increasing latency. Among cases, HPV was found in 81.24% (95% CI 69.93-88.96%) of smears with latency < 4 years and in 67.80% (95% CI 47.72-82.93%) of those taken at longer intervals, up to 6 years. These findings suggest that testing for high-risk HPV allows predicting 80% of CINII/III 3 years before the cytological diagnosis and two thirds 6 years before. They also suggest that testing women negative for high-risk HPV at longer interval and strictly following-up women who are HPV positive could be an effective strategy for cervical cancer screening.     

Screening for cervical cancer: is there a place for incorporating tests for the human papillomavirus?

Well organized screening programmes for cervical cancer, based on exfoliative cervical cytology, are known to be effective at reducing the incidence of invasive cervical cancer and mortality from the disease. HPV testing should not replace cervical cytology as the first-line approach in screening for cervical cancer, as HPV testing is not sufficiently reliable and some cancers are not associated with HPV infection. Even though there are many unanswered questions about the validity of HPV tests, it is timely to consider whether HPV testing might improve the management of the substantial number of women whose smears are neither clearly normal nor abnormal, but are described as atypical, suspicious or mildly dyskaryotic. The efficacy and costs of incorporating HPV testing into a cervical cancer screening programme need to be evaluated in controlled trials.     

HPV testing in primary screening of older women.

Certain types of the human papilloma virus (HPV) are well established as the primary cause of cervical cancer. Several studies have shown that HPV testing can improve the detection rate of high-grade cervical intraepithelial neoplasia (CIN), but these have been carried out primarily in younger women. In this study we evaluated the role of HPV testing as an adjunct to cytology in women aged 35 or over. An additional aim was to evaluate commercially available kits for HPV testing. A total of 2988 eligible women aged 34 or more attending for a routine smear in 40 general practitioner practices received HPV testing in addition to routine cytology, after having given written informed consent. Samples were assayed by polymerase chain reaction (PCR) and two versions of the Hybrid Capture test for HPV, and women were invited for colposcopy if there was any cytological abnormality (including borderline smears) or the PCR test was positive. Any apparent abnormality was biopsied and loop-excision was performed as necessary. CIN was judged by histology; 42 women had high-grade CIN, of which six were cytology negative (86% sensitivity for borderline or worse) and three had a borderline smear (79% sensitivity for mild dyskaryosis or worse). The positive predictive value of a borderline smear was only 3.1%. Eleven high-grade lesions were negative by the PCR HPV test (sensitivity 74%). The first generation Hybrid Capture II test had a similar sensitivity but an unacceptably high false positive rate (18.3%), while the newer Hybrid Capture II microtitre kit had a 95% sensitivity and a 2.3% positivity rate in normal women when used at a 2 pg ml(-1) cut-off (positive predictive value 27%). Cytology performed very well in this older cohort of women. The newer Hybrid Capture II microtitre test may be a useful adjunct, especially if the results reported here are reproducible in other studies. A combined screening test offers the possibility of greater protection and/or longer screening intervals, which could reduce the overall cost of the screening programme.     

Human papillomavirus type-specific 18-month risk of high-grade cervical intraepithelial neoplasia in women with a normal or borderline/mildly dyskaryotic smear.

INTRODUCTION: High-risk human papillomavirus (hrHPV) DNA testing is an increasingly used instrument in cervical cancer prevention along cervical cytology. The inclusion of hrHPV testing in cervical screening requires efficient management as many hrHPV infections are transient. We investigated the potential value of hrHPV genotyping in normal and borderline/mildly dyskaryotic (BMD) smears. MATERIALS AND METHODS: From a screening population of 44,102 women in the Netherlands, we included hrHPV-positive women with a normal or BMD smear. We assessed the type-specific 18-month risk of high-grade cervical intraepithelial neoplasia (CIN). RESULTS: In hrHPV-positive women, 18-month risk of CIN grade 3 or invasive cancer (> or =CIN3) was 6% [95% confidence interval (95% CI), 4-9] after normal cytology and 20% (95% CI, 16-25) after BMD. If positive for HPV16, > or =CIN3 risks were 14% (95% CI, 9-21) and 37% (95% CI, 28-48), respectively. In the subset of hrHPV-positive women without HPV16, HPV18 was associated with an increased risk of high-grade CIN after normal cytology and HPV31 and HPV33 were associated with an increased risk, particularly after BMD. HPV16 and HPV18 were also associated with an increased risk of high-grade CIN in women with an hrHPV-positive normal baseline smear and a repeat normal smear at 6 months. DISCUSSION: HrHPV-positive women without type 16, 18, 31, or 33 had a relatively low risk of high-grade CIN. Among women with baseline normal cytology and among women with a baseline and repeat normal smear, HPV16/18-positive women showed an increased risk of high-grade CIN. This warrants more aggressive management of HPV16/18-positive women compared with other hrHPV-positive women.     

宫颈癌多种筛查方案的研究

目的 探索适宜我国不同地区的宫颈癌筛查方案,以提高我国妇女宫颈癌的防治水平.方法 利用1999年在山西省襄垣县开展的一项以人群为基础的宫颈癌筛查横断面研究的资料,所有筛查对象均进行了薄层液基细胞学(LBC)、荧光镜检、醋酸染色法(VIA)、阴道镜检查、自我取样人乳头瘤病毒(HPv)检测和医生取样HPV检测等6种宫颈癌筛查方法 ,而且每位筛查对象均有病理诊断结果 .采用筛查试验的串、并联法组合各种筛查技术,比较所得方案识别宫颈高度以上病变[≥宫颈上皮内瘤变(CIN)2]的灵敏度、特异度和阴道镜转诊率等指标,以受试者工作特征曲线(ROC)下面积综合分析各筛查方案.结果 LBC检测以未明确意义的不典型鳞状细胞(ASC-US)为阳性,HPV检测以HPV DNA≥1.0 ps/mi为阳性.在LBC和HPV检测组合方案中,并联初筛方法 (即两者任一项阳性即判断为筛查阳性)的灵敏度为100.O%,特异度为68.6%,阴道镜转诊率为34.4%;LBC初筛HPV分流方法 (即ASC-US者进行HPV检测)的灵敏度为93.0%,特异度为89.9%,阴道镜转诊率为13.7%;HPV初筛LBC分流方法 (即 HPV阳性者进行LBC检测)的灵敏度为91.7%,特异度为93.0%,阴道镜转诊率为10.6%.经ROC分析,LBC初筛HPV分流方法 和HPV初筛LBC分流方法 明显优于单纯并联初筛方法 (P=0.0003;P=0.0002).单独以LBC或HPV检测作为筛查方案时,以ASC-US或低度病变(LSIL)为筛查阳性的LBC方法 灵敏度、特异度和阴道镜转诊率分别为94.2%、77.3%、25.7%和87.2%、93.5%、10.O%;医生取样HPV检测方法 和自我取样HPV检测方法 的灵敏度、特异度和阴道镜转诊率分别为97.6%、84.8%、18.8%和83.5%、85.9%、17.1%.经ROC分析,医生取样HPV检测方法 优于以ASC-US为筛查阳性的LBC方法 或自我取样HPV检测方法 (P=0.005,P=0.002).在VIA及其与HPV检测的组合方案中,单独采用VIA筛查方法 的灵敏度为70.9%,特异度为74.3%,阴道镜转诊率为27.6%;HPV初筛VIA分流方法 (即自我取样HPV检测阳性者进行VIA检查)的灵敏度、特异度和阴道镜转诊率分别为65.9%、95.2%和7.4%.经ROC分析,HPV初筛VIA分流方法 明显优于单独使用VIA方法 (P=0.004).结论 根据地区资源条件和个人意愿,我国经济发达地区可选用HPV初筛LBC分流方法 或LBC初筛HPV分流方法 作筛查手段;中等经济发展水平的中小城市可选用单独以LBC或HPV检测方法 作为筛查手段;VLA是欠发达地区可行的筛查方法 ,在廉价HPV检测试剂盒上市后,可选择HPV初筛VIA分流方法 ,以进一步提高宫颈癌的筛查效力.     

Screening with a primary human papillomavirus test does not increase detection of cervical cancer and intraepithelial neoplasia 3

Aim:To determine cross-sectional validity of primary human papillomavirus (HPV) screening in comparison to cytological screening.Methods:During 2003–2004, 61,149 women were individually randomised to screening with a test for oncogenic HPV DNA or to conventional cytological screening within the Finnish cervical screening programme.Results:For HPV screening, cross-sectional relative sensitivity for cervical intraepithelial neoplasia (CIN) or cancer was 1.58 (95 % confidence interval 1.19–2.09) in comparison to cytology. At the level of CIN 3 or cancer no increase in relative sensitivity was observed. Cross-sectional specificity estimates for the screening arms were comparable, but the specificity of screening with sole HPV DNA test was clearly inferior.Conclusions:Primary HPV screening with cytology triage finds more CIN lesions compared to conventional screening but mild lesions are overrepresented. This is likely to result in overdiagnosis since most mild lesions are regressive.     

Human papillomavirus in cervical cancer screening: important role as biomarker.

Cervical cytology screening has reduced cervical cancer morbidity and mortality but shows important shortcomings in terms of sensitivity and specificity. Infection with distinct types of human papillomavirus (HPV) is the primary etiologic factor in cervical carcinogenesis. This causal relationship has been exploited for the development of molecular technologies for viral detection to overcome limitations linked to cytologic cervical screening. HPV testing has been suggested for primary screening, triage of equivocal Pap smears or low-grade lesions and follow-up after treatment for cervical intraepithelial neoplasia. Determination of HPV genotype, viral load, integration status and RNA expression could further improve the effectiveness of HPV-based screening and triage strategies. The prospect of prophylactic HPV vaccination stresses the importance of modification of the current cytology-based screening approach.     

New technologies in cervical cancer precursor detection

The current literature reflects three routes toward improving cervical cancer screening. The first is to improve the test qualities of cytology-based screening. The use of liquid-based cytology and computerized analysis of Papanicolaou tests are examples of attempts at this approach. Secondly, through various combinations of parallel or sequential tests, either the sensitivity or the specificity of a given test could be improved depending on the tests chosen and the order in which they were performed (eg, Papanicolaou test followed by human papillomavirus [HPV] or vice versa). Several excellent studies have been published this year on the use of HPV DNA testing as a primary screening modality and as an adjunct to the triage of mildly abnormal cytologic findings. The recent literature also reflects increasing interest in visual inspection of the cervix and self-collected samples for HPV testing as an equally effective and viable alternative to cytology in low-resource settings. A third possibility is to make use of advances in digital and spectroscopic techniques. In these cost-conscious times, a significant number of articles address the cost-effectiveness of these technologies and the real value of cervical cancer screening. This article reviews the current literature concerning both the advent of new cervical cancer screening technologies and the rediscovery of old ones.     

Triage using HPV-testing in persistent borderline and mildly dyskaryotic smears: proposal for new guidelines

In the Netherlands 2% of cervical smears in the cervical cancer screening program are read as borderline or mildly dyskaryotic cytology (BMD smear). Only in about 10% of these women a high-grade CIN lesion (CIN II-III) is present; therefore referral is for the majority unnecessary. In our study triage with high-risk HPV (hrHPV) testing was used to identify women at risk for development of high-grade CIN lesions after a repeat BMD smear. A "wait-and-see" period was incorporated allowing clearance of HPV and regression of the lesion. Women with a low-grade lesion, irrespective of their HPV status, were monitored at 12 months; women with a high-grade lesion were monitored at 6 and 12 months. Fifty-one of the 105 women (49%) were hrHPV negative at baseline; none of them showed progression of the lesion within the first year of follow-up (NPV 100%). High-grade CIN was present in 1 patient who was HPV negative at baseline (2%); she demonstrated regression after 12 months. Nineteen of the hrHPV positive women (35%) demonstrated a high-grade CIN lesion at baseline and 3 cleared hrHPV after 6 months, with a subsequent regression of CIN. Ten women remained hrHPV positive with persistence of high-grade CIN and were eventually treated. At baseline, 35 hrHPV positive women demonstrated a low-grade lesion, 19 remained hrHPV positive after 12 months and 5 developed high-grade CIN. Sixteen out of the 35 cleared the hrHPV infection without progression of the lesion. In conclusion, triage, using hrHPV testing for women with persistent BMD cytology, can select women who are not at risk for development of high-grade CIN. We recommend return to the screening program without referral for colposcopic examination if hrHPV is absent. For hrHPV positive women, a repeat hrHPV test after another 6 months is suggested. Referral is only required if persistence of hrHPV is established.     

Cost-Effectiveness Analysis of Different Management Strategies for Detection CIN2+ of Women with Atypical Squamous Cells of Undetermined Significance (ASC-US) Pap Smear in Thailand

Background: To identify the optimal cost effective strategy for the management of women having ASC-USwho attended at King Chulalongkorn Memorial Hospital (KMCH). Design: An Economical Analysis based ona retrospective study. Subject: The women who were referred to the gynecological department due to screeningresult of ASC-US at King Chulalongkorn Memorial Hospital, a general and tertiary referral center in BangkokThailand, from Jan 2008 - Dec 2012. Materials and Methods: A decision tree-based was constructed to evaluatethe cost effectiveness of three follow up strategies in the management of ASC-US results: repeat cytology, triagewith HPV testing and immediate colposcopy. Each ASC-US woman made the decision of each strategy afterreceiving all details about this algorithm, advantages and disadvantages of each strategy from a doctor. The modelcompared the incremental costs per case of high-grade cervical intraepithelial neoplasia (CIN2+) detected asmeasured by incremental cost-effectiveness ratio (ICER). Results: From the provider’s perspective, immediatecolposcopy is the least costly strategy and also the most effective option among the three follow up strategies.Compared with HPV triage, repeat cytology triage is less costly than HPV triage, whereas the latter providesa more effective option at an incremental cost-effectiveness ratio (ICER) of 56,048 Baht per additional case ofCIN 2+ detected. From the patient’s perspective, the least costly and least effective is repeat cytology triage.Repeat colposcopy has an incremental cost-effectiveness (ICER) of 2,500 Baht per additional case of CIN2+detected when compared to colposcopy. From the sensitivity analysis, immediate colposcopy triage is no longercost effective when the cost exceeds 2,250 Baht or the cost of cytology is less than 50 Baht (1USD = 31.58 THB).Conclusions: In women with ASC-US cytology, colposcopy is more cost-effective than repeat cytology or triagewith HPV testing for both provider and patient perspectives.     

Cost‐effectiveness analysis of cervical cancer prevention based on a rapid human papillomavirus screening test in a high‐risk region of China

This study assessed the cost‐effectiveness of a new, rapid human papillomavirus (HPV)‐DNA screening test for cervical cancer prevention in the high‐risk region of Shanxi, China. Using micro‐costing methods, we estimated the resources needed to implement preventive strategies using cervical cytology or HPV‐DNA testing, including the Hybrid Capture 2 (hc2) test (QIAGEN Corp., Gaithersburg, MD) and the rapid HPV‐DNA careHPV? test (QIAGEN). Data were used in a previously published model and empirically calibrated to country‐specific epidemiological data. Strategies differed by initial test, targeted age, frequency of screening, number of clinic visits required (1, 2 or 3) and service delivery setting (national, county and township levels). Outcomes included lifetime risk of cancer, years of life saved (YLS), lifetime costs and incremental cost‐effectiveness ratios (cost per YLS). For all screening frequencies, the most efficient strategy used 2‐visit rapid HPV‐DNA testing at the county level, including screening and diagnostics in the first visit, and treatment in the second visit. Screening at ages 35, 40 and 45 reduced cancer risk by 50% among women compliant with all 3 screening rounds, and was US$ 150 per YLS, compared with this same strategy applied twice per lifetime. This would be considered very cost‐effective evaluated against China's per‐capita gross domestic product (US$ 1,702). By enhancing the linkage between screening and treatment through a reduced number of visits, rapid HPV‐DNA testing 3 times per lifetime is more effective than traditional cytology, and is likely to be cost‐effective in high‐risk regions of China.     

An evaluation of liquid-based cytology and human papillomavirus testing within the UK cervical cancer screening programme

The aim of this study is to evaluate different options for introducing liquid-based cytology (LBC) and human papillomavirus (HPV) testing into the UK cervical cancer screening programme. These include options that incorporate HPV testing either as a triage for mild and borderline smear abnormalities or as a primary screening test. Outcomes include the predicted impact on resource use, total cost, life years and cost-effectiveness. Extensive sensitivity analysis has been carried out to explore the importance of the uncertainty associated with disease natural history and the impact of screening. Under baseline assumptions, the cost-effectiveness of different options for introducing LBC appears favourable, and these results are consistent under a range of assumptions for its impact on the diagnostic effectiveness of cytology. However, if we assume a higher marginal cost of LBC in comparison to conventional methods, primary smear testing options are predicted to be more cost-effective without LBC. Combined LBC primary smear and HPV testing with a 5-year interval is similar in both cost and effectiveness to the other 3-yearly options of primary smear testing or primary HPV testing alone. However, both primary HPV testing and combined options would give rise to a far greater risk of inappropriate colposcopy throughout a woman's lifetime.British Journal of Cancer (2004) 91, 84-91. doi:10.1038/sj.bjc.6601884 www.bjcancer.com Published online 25 May 2004     

HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial

To evaluate the effectiveness of human papillomavirus (HPV) testing in primary cervical screening. This was a cross-sectional study from the recruitment phase of a prospective randomised trial. Women were screened for HPV in addition to routine cervical cytology testing. Greater Manchester, attendees at routine NHS Cervical Screening Programme. In all, 24 510 women aged 20-64 screened with liquid-based cytology (LBC) and HPV testing at entry. HPV testing in primary cervical screening. Type-specific HPV prevalence rates are presented in relation to age as well as cytological and histological findings at entry. In all, 24 510 women had adequate cytology and HPV results. Cytology results at entry were: 87% normal, 11% borderline or mild, 1.1% moderate and 0.6% severe dyskaryosis or worse. Prevalence of HPV decreased sharply with age, from 40% at age 20-24 to 12% at 35-39 and 7% or less above age 50. It increased with cytological grade, from 10% of normal cytology and 31% of borderline to 70% mild, 86% moderate, and 96% of severe dyskaryosis or worse. HPV 16 or HPV 18 accounted for 64% of infections in women with severe or worse cytology, and one or both were found in 61% of women with severe dyskaryosis but in only 2.2% of those with normal cytology. The majority of young women in Greater Manchester have been infected with a high-risk HPV by the age of 30. HPV testing is practicable as a primary routine screening test, but in women aged under 30 years, this would lead to a substantial increase in retesting and referral rates. HPV 16 and HPV 18 are more predictive of underlying disease, but other HPV types account for 30% of high-grade disease.     

The clinical value of HPV genotyping in triage of women with high‐risk‐HPV‐positive self‐samples

Cytology alone, or combined with HPV16/18 genotyping, might be an acceptable method for triage in hrHPV‐cervical cancer screening. Previously studied HPV‐genotype based triage algorithms are based on cytology performed without knowledge of hrHPV status. The aim of this study was to explore the value of hrHPV genotyping combined with cytology as triage tool for hrHPV‐positive women. 520 hrHPV‐positive women were included from a randomised controlled self‐sampling trial on screening non‐attendees (PROHTECT‐3B). Eighteen baseline triage strategies were evaluated for cytology and hrHPV genotyping (Roche Cobas 4800) on physician‐sampled triage material. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate, and number of referrals needed to diagnose (NRND) were calculated for CIN2+ and CIN3+. A triage strategy was considered acceptable if the NPV for CIN3+ was ≥98%, combined with maintenance or improvement of sensitivity and an increase in specificity in reference to the comparator, being cytology with a threshold of atypical cells of undetermined significance (ASC‐US). Three triage strategies met the criteria: HPV16+ and/or ≥LSIL; HPV16+ and/or ≥HSIL; (HPV16+ and/or HPV18+) and/or ≥HSIL. Combining HPV16+ and/or ≥HSIL yielded the highest specificity (74.9%, 95% CI 70.5–78.9), with a sensitivity (94.4%, 95% CI 89.0–97.7) similar to the comparator (93.5%, 95% CI 87.7–97.1), and a decrease in referral rate from 52.2% to 39.5%. In case of prior knowledge of hrHPV presence, triage by cytology testing can be improved by adjusting its threshold, and combining it with HPV16/18 genotyping. These strategies improve the referral rate and specificity for detecting CIN3+ lesions, while maintaining adequate sensitivity.