HPV types in women with normal cervical cytology.

PCR-based hybridization methods have been used to show that some women with normal cytology are carriers of HPV DNA of the types strongly related to cervical cancer. How these women should be managed remains unclear. This chapter selectively reviews reports which have estimated type-specific HPV prevalence in relation to the presence or absence of morphological signs of HPV infection. Overall, these reports indicate that among women who were identified as carriers of HPV DNA (by PCR-based methods) and who also had a normal cytological smear, the HPV type detected in the majority of instances was a high-risk viral type for cervical cancer (HPV types 16/18 = 44.7%; HPV types 31/33/35 = 8.1%; other and unknown types = 37.9%). This suggests that screening programmes which include PCR-based HPV detection could reduce the false negative rates currently reported by screening programmes based on cytology alone.     

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.     

Deep sequencing detects human papillomavirus (HPV) in cervical cancers negative for HPV by PCR

Background Human papillomavirus (HPV) is a necessary cause of cervical cancer, although some invasive cervical cancers may test negative by HPV PCR. We previously requested all invasive cervical cancers in Sweden during 10 years and subjected them to PCR. We also optimised methods for deep sequencing of formalin-fixed paraffin-embedded samples.Methods Using Novaseq 6000, we simultaneously sequenced total DNA and cDNA from 392 HPV PCR-negative cervical cancers. Non-human reads were queried against all known HPVs. The complete database now contains PCR and/or deep sequencing data on 2850 invasive cervical cancers.Results HPV sequences were detected in 169/392 of HPV PCR-negative cervical cancers. Overall, 30 different HPV types were detected, but only 5 types were present in proportions above 3% of cancers. More than 92% of tumours were HPV-positive in PCR and/or sequencing (95% confidence interval: 91.1–93.1%). Exploring possible reasons for failure to previously detect HPV suggest that more sensitive type-specific PCRs for HPV 31, 33, 45 and 73 targeting retained regions of HPV would have detected most of these (117/392).Conclusions Unbiased deep sequencing provides comprehensive data on HPV types in cervical cancers and appears to be an important tool for quality assurance of HPV screening.Subject terms: Infectious-disease diagnostics, Viral infection, Cervical cancer     

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.     

膜式液基薄层细胞学检测联合高危型人乳头状瘤病毒分型检测在宫颈癌筛查中的应用

目的探讨膜式液基薄层细胞学检测技术(TCT)联合高危型人乳头状瘤病毒(HPV)分型检测技术在宫颈癌筛查中的应用价值。方法选取2160例有性生活史患者的宫颈脱落细胞作为筛检标本,采用TCT联合基因杂交捕获法(HC-II)对细胞学异常或临床存在高危症状的患者进行HPV分型检测,HPV阳性患者再行阴道镜下宫颈活组织病理学检查。结果 2160例受试标本中,259例(12.0%)患者TCT检查结果异常。TCT检查结果异常患者中,118例(45.6%)患者HPV分型检测阳性。宫颈活检病理结果显示,无上皮内病变或恶性病变(NILN)患者29例,宫颈上皮内瘤变(CIN)I级患者40例,CIN II级以上患者49例。宫颈癌的发生率随宫颈内病变程度的增加而升高,差异有统计学意义(P<0.05)。结论 HPV感染是诱发女性宫颈癌变的关键因素,临床应用TCT联合HPV基因分型检测技术筛查宫颈病变和早期宫颈癌更为精准、快捷、敏锐。     

Diagnostic Value of the CareTM HPV Test in Screening for Cervical Intraepithelial Neoplasia Grade 2 or Worse

Background: Cervical cancer is the fourth leading cause of cancer death in women worldwide. Persistent infection with a high risk human papillomavirus (HR-HPV) is the main etiological factor, so that early early detection of HR-HPV is very important. The aim of this study was to investigate the efficacy of CareTM HPV, a new method, as compared with Pap smear, PCR, and biopsy for screening purposes. Material and Method: In this cross-sectional study, 200 sexually active women aging from 25-50 years referred to the oncology clinic of Shahid Sodoughi Yazd Hospital in 2015 with a variety of cervix epithelial lesions or a need for colposcopy were enrolled. Results for CareTM HPV test (cervical), Pap smear, PCR, and biopsy were analyzed using SPSS 15 software and chi-square test, McNemar, and ROC curve analysis. Qualitative variables were compared using a Chi-square test. Results: CareTM HPV test sensitivity in detecting cervical intraepithelial neoplasia grade II (CIN-II) and also positive and negative predictive values were higher as compared to with other tests (p<0.05). The Pap smear test specificity was highest. There was no significant differences between CareTM HPV and PCR tests regarding detection of HPV-DNA in cases of CIN-II and worse (p>0.05). Conclusion: The CareTM HPV test has high sensitivity and predictive values for detecting HPV infection, with higher efficacy than the Pap smear test for tracking CIN-II. Therefore it may be recommended for use as a screening test in low-income areas.     

Extended duration of the detectable stage by adding HPV test in cervical cancer screening

The human papillomavirus test (HPV) test could improve the (cost-) effectiveness of cervical screening by selecting women with a very low risk for cervical cancer during a long period. An analysis of a longitudinal study suggests that women with a negative Pap smear and a negative HPV test have a strongly reduced risk of developing cervical abnormalities in the years following the test, and that HPV testing lengthens the detectable stage by 2-5 years, compared to Pap smear detection alone.     

Detection of human papillomavirus in cervical scrapes by the polymerase chain reaction in relation to cytology: possible implications for cervical cancer screening.

An HPV screening strategy based on general primer-mediated and type-specific PCR is described. A relationship was found between an increasing HPV prevalence rate and a higher degree of cervical dysplasia (up to 100% in cervical carcinoma). Based on these prevalence studies in the Netherlands and preliminary data showing that progression of cervical lesions is always associated with persistent infection of oncogenic/high-risk HPV types, a cervical cancer screening scheme incorporating PCR-based HPV detection is proposed for use in industrialized countries.     

无锡新区官颈癌试点筛查人群HPV感染现况分析

目的：调查无锡新区妇女人乳头瘤病毒（highriskhumanpapillomavirus,HPV）感染状况,分析HPV型别和年龄分布特征,HPV型别在宫颈病变患者中的分布特征,并探讨HPV检测作为宫颈癌初筛方法的可行性。方法：2012年无锡新区宫颈癌筛查项目初筛方法采用HPV基因分型检测,HPV检测结果阳性的受检者转诊进行液基细胞学检查,细胞学检查结果异常者再行阴道镜下活检,病理组织学检查作为最终诊断标准。结果：总计11322例35～64岁妇女参与了此次宫颈癌筛查,HPV结果阳性者1286例,总感染率为11．36％;癌前病变检出58例,检出率为512．28／10万;宫颈癌检出7例,检出率为61．83／10万。在总人群中,检出率前3位的型别是HPV16（2．70％）、HPV52（2．07％）和HPV58（1．93％）;在宫颈病变患者中,检出率最高的型别为HPV16（47．69％）,其次为HPV58（24．61％）和HPV18（9．23％）。55～59岁年龄组HPV感染率最高,为11．88％,各年龄组之间HPV检出率差异无统计学意义,χ^2=4．763,P=0．445;45～49岁年龄组高度癌前病变（≥CINⅡ）检出率高于其他年龄组。结论：HPV型别在总人群与宫颈病变人群中的分布存在差异,除HPV16和HPV18之外,HPV58的致癌能力可能明显高于其他高危型HPV;40～59岁是宫颈癌筛查的重点人群。与以往筛查结果相比,此次试点的筛查方法值得进一步推广。     

High-risk HPV type-specific clearance rates in cervical screening

We assessed clearance rates of 14 high-risk human papillomavirus (hrHPV) types in hrHPV-positive women with normal cytology and borderline/mild dyskaryosis (BMD) in a population-based cervical screening cohort of 44,102 women. The 6-month hrHPV type-specific clearance rates, that is, clearance of the same type as detected at baseline, in women with normal and BMD smears were 43% (95% confidence interval (CI) 39-47) and 29% (95% CI 24-34), respectively. Corresponding 18-month clearance rates were markedly higher, namely 65% (95% CI 60-69) and 41% (95% CI 36-47), respectively. The lowest clearance rates in women with normal cytology were observed for HPV16, HPV18, HPV31, and HPV33. Significantly reduced 18-month clearance rates at a significance level of 1% were observed for HPV16 (49%, 95% CI 41-59) and HPV31 (50%, 95% CI 39-63) in women with normal cytology, and for HPV16 (19%, 95% CI 12-29) in women with BMD. Among women who did not clear hrHPV, women with HPV16 persistence displayed an increased detection rate of >or=CIN3 (normal P<0.0001; BMD, P=0.005). The type-specific differences in clearance rates indicate the potential value of hrHPV genotyping in screening programs. Our data support close surveillance (i.e. referral directly, or within 6 months) of women with HPV16 and are inconclusive for surveillance of women with HPV18, HPV31, and HPV33. For the other hrHPV-positive women, it seems advisable to adopt a conservative management with a long waiting period, as hrHPV clearance is markedly higher after 18 months than after 6 months and the risk for >or=CIN3 is low.     

HPV Genotyping Linear Assay Test Comparison in Cervical Cancer Patients: Implications for HPV Prevalence and Molecular Epidemiology in a Limited-resource Area in Bandung,Indonesia

Background: Persistent infection with high risk human papillomavirus (hrHPV) is strongly associated withcervical cancer. Normal cervical cells may also harbor hrHPV, and detection of early hrHPV infection mayminimize risk of cervical cancer development. This study aimed to compare two commercial HPV genotypingassays that may affordable for early screening in a limited-resource setting in Bandung, Indonesia. Materialsand Methods: DNA from cervical biopsies with histologically confirmed as squamous cell cervical cacinoma wereHPV genotyped by Linear Assay 1 (Roche Diagnostics, Mannheim, Germany) or Linear Assay 2 (Digene HPVGenotyping RH Test, Qiagen Gaithersburg, MD). In a subset of samples of each group, HPV genotype results werethen compared. Results: Of 28 samples genotyped by linear assay 1, 22 (78.6%) demonstrated multiple infectionswith HPV-16 and other hrHPV types 18, 45 and/or 52. In another set of 38 samples genotyped by linear assay 2,28 (68.4%) were mostly single infections by hrHPV type 16 or 18. Interestingly, 4 samples that had been testedby both kits showed discordant results. Conclusions: In a limited-resource area such as in Indonesia, countrywith a high prevalence of HPV infection a reliable cervical screening test in general population for early hrHPVdetection is needed. Geographical variation in HPV genotyping result might have impacts for HPV prevalenceand molecular epidemiology as the distribution in HPV genotypes should give clear information to assess theimpact of HPV prophylactic vaccines.     

维吾尔族妇女型别特异性持续HPV感染状况及病毒学因素

目的:分析维吾尔族妇女型别特异性HPV持续感染的情况及转归。方法:以2012年9月至2013年9月在新疆自治区人民医院妇科门诊和病房自愿接受宫颈癌机会性筛查维吾尔族妇女为筛选对象，利用HC-ⅡHPV DNA检查和凯普HPV导流杂交分型技术确定HPV感染和型别，对筛查结果为HPV感染慢性宫颈 炎的妇女，通过问卷调查和36个月的随访，使用Logistic回归分析其持续感染影响因素。结果:HPV型别特异性持续感染率在12、24、36个月的复查时分别为25.5%(65/255)，15.7%(40/255)，11.0%(28/255)；在随访12个月时HPV＞1 000段相对于病毒载量1≤HPV≤100妇女型别特异性持续感染的风险增加2.40倍(95%CI:1.11~5.15)；随访24个月、36个月，发现单一型别比多重感染更容易发现型别特异性HPV持续感染(OR:3.07，95%CI:1.23~7.68；OR:4.31，95%CI:1.10~16.90)；随访12个月、24个月、36个月，发现HPV16阳性比非HPV16型发生型别特异持续感染的风险增加(OR:4.81，95%CI:2.63~8.18；OR:2.73，95%CI:1.08~6.88；OR:4.69，95%CI:1.10~19.97)。结论:HPV16阳性、极高病毒载量、单一感染是维吾尔族妇女HPV持续感染的危险因素，应加强该人群的随访检测。     

宫颈液基细胞学检查与高危型HPV检测早期筛查宫颈癌前病变的对比分析

目的:对比研究宫颈液基细胞学检查与高危型HPV检测早期筛查宫颈癌前病变。方法:选取2013年3月到2014年3月接受宫颈病理变化筛选检查的700例患者作为研究对象。采用高危型HPV检查和宫颈液基细胞检查进行早期宫颈癌前病变筛查。结果:在700例患者中,高危型HPV检查结果阳性有47例。其中HPV16型最多,占48.94%,其次是HPV18型,占21.28%。在宫颈液基细胞学检查中涂片异常病人有40例。其中LSIL占2.71%,HSIL占0.57%。高危HPV联合TCT方法,LSIL和HSIL分别是2.32%和0.54%;而TCT则是0.45%和0.19%。结论:高危型HPV检查能够提高宫颈癌前筛查的准确率,宫颈液基细胞检查联合高危HPV检查能够提高宫颈癌前病变筛查成功率。     

TCT 联合HC-II HPV 筛查宫颈病变及药物干预的方法

 目的 探讨应用液基薄层宫颈刷片细胞学检测（Thinprep cytologicaltest，TCT）及杂交捕获二代（Hybridcapture Ⅱ，HC-Ⅱ）人乳头瘤病毒（Humanpapilloma virus，HPV）分型检测筛查宫颈病变的意义和对高危病例进行药物干预的方法。方法 2004年4月～2005年8月，采用TCT和HPVDNA分型检测对17320例患者进行宫颈病变的筛查，并以病理组织学活捡为标准来验证筛查结果，同时应用氟尿嘧啶（5-Fu）可吸收缓释药膜对适宜病例进行局部干预治疗。结果 TCT结果异常者1754例，其中高危型HPV-DNA阳性450例；431例TCT提示无HPV感染病例中有172例高危型HPV-DNA阳性；TCT或TCT联合HC-ⅡHPV筛查宫颈上皮内瘤样病变（Cervical intraepithelial neoplasia，CIN）Ⅱ级及以上病变的敏感性和特异性分别为81．12％、89、65％和72．08％、97．99％；采用5Fu可吸收缓释药膜治疗25例CINI级HPV高危型感染患者后，其病毒负荷量下降幅度、转阴率和病理逆转率均明显高于对照组，差异具有统计学意义（P〈0．05）。结论 TCT和HPV分型检测联合应用于宫颈病变筛查可提高CINⅡ级及以上病变的特异性检出；5-Fu可吸收缓释药膜治疗CINI级HPV高危型感染患者可降低其病毒负荷量，甚至清除。     

基因芯片法与杂交捕获法检测人乳头瘤病毒对比分析

目的:评价杂交捕获法和基因芯片法检测宫颈人乳头瘤病毒（human papillomavirus ,HPV ）感染的方法学优势,探讨HPV 的多重感染以及HPV 病毒负荷量与不同级别宫颈病变的相关性。方法:分别采用基因芯片法和杂交捕获法对360 例宫颈癌机会性筛查的患者进行HPV-DNA的检测以及液基细胞学检测,并以基因测序为金标准评价两种检测方法的灵敏度、特异度。结果:基因芯片法和杂交捕获法的灵敏度、特异度和约登指数分别为前者98.33% 、93.40% 和0.917,后者97.56% 、98.17% 和0.957。按宫颈液基细胞学检查结果分为NSIL组、ASC 组、LSIL 组及HSIL和SCC 组,随宫颈细胞病变程度的增加,HPV 感染率、高危型HPV 感染率、多重感染率病毒逐渐增加,在宫颈上皮正常组与异常组间比较差异有统计学意义,低危型HPV 感染率无规律性改变。结论:两种HPV 检测方法相比,基因芯片法灵敏度较高,杂交捕获法特异度较高,基因芯片法可作为宫颈病变筛查方法;HPV的多重感染和病毒负荷量增加都与宫颈病变程度有一定的相关性。      

Distribution of 37 mucosotropic HPV types in women with cytologically normal cervical smears: the age-related patterns for high-risk and low-risk types

Before guidelines can be set for the use of high-risk human papillomavirus (HR HPV) testing in cervical cancer screening and vaccine preparation, age-related prevalence of HR HPV types in cytologically normal smears has to be known. Therefore, in a cross-sectional study the prevalence of 37 different HPV genotypes and putatively unidentified HPV types was determined in 3,305 cytologically normal cervical smears from the general female population (15-69 years of age) using an HPV general primer GP5+/bioGP6+ mediated PCR assay. Subsequently, HPV-positive cervical smears were typed for 19 HR and 18 low-risk (LR) HPVs with an enzyme immunoassay using HPV type-specific oligoprobes in cocktails and individually, respectively. Overall, -HR and -LR HPV prevalences appeared to be of 4.6%, 3.3%, and 1.0%, respectively. Twenty-six different HPV types were detected in the 152 HPV-positive samples, the most prevalent types being HPV 16, 31, and 18. With regard to age, a peak prevalence of 19.6% for all HPVs was found in women 25-29 years of age, which declined to a mean of 4.3% in women over 30 years. With regard cytologically normal cervical smears (n = 3, 011) of women participating in the population-based screening program in the Netherlands (30 to 60 years), all HR HPVs showed decreased occurrence with increasing age, whereas the prevalence of LR HPV types remained constant. We suggest that screening for abnormal cytology implies screening for HR HPV infections and the subsequent treatment results in a decline of HR HPV prevalence in contrast to LR HPV prevalence during the years of screening.     

Current status of cervical cancer and HPV infection in Korea

Cervical cancer is an important cause of cancer-related deaths in women in developing countries. In Korea, cervical cancer is the third leading cancer among females and is fifth highest in mortality. The persistent oncogenic human papillomavirus (HPV) infections are the greatest risk of developing cervical intraepithelial neoplasia and invasive cancer. The overall prevalence of HPV was 10.4% in Korea and strong risk factors for HPV infection included a young age at sexual debut. The National Cancer Screening Program, which includes cervical cancer screening, has the following principles: the main screening tool is the Papanicolaou test conducted by gynecologists, which targets all women age 30 and over, and which is done every 2 years. HPV DNA tests have not yet been permitted as a screening test for cervical cancer in Korea; however, these are conducted along with a Pap test for screening cervical cancer in the clinic. The use of prophylactic HPV vaccine has been accepted in Korea; The Korean Society of Gynecologic Oncology and Colposcopy''s recommendation for routine vaccination is for females aged 15-17 years with a catch-up vaccination recommended for females aged 18-26 years who have not been previously vaccinated. However, many people in Korea are not familiar with the HPV vaccine. Therefore, it is necessary to improve awareness for the disease and HPV vaccination and to establish the effective strategies to obtain funding for HPV vaccination. In the future, cervical cancer is expected to disappear throughout the world, including the Asia Pacific region, through a combination of vaccination and qualified screening programs for cervical cancer.     

Present evidence on the value of HPV testing for cervical cancer screening: a model-based exploration of the (cost-)effectiveness.

Human papillomavirus (HPV) is the main risk factor for invasive cervical cancer. High risk ratios are found in cross-sectional data on HPV prevalence. The question raised is whether this present evidence is sufficient for making firm recommendations on HPV screening. A validated cervical cancer screening model was extended by adding HPV infection as a possible precursor of cervical intraepithelial neoplasia (CIN). Two widely different model quantifications were constructed so that both were compatible with the observed HPV risk ratios. One model assumed a much longer duration of HPV infection before progressing to CIN and a higher sensitivity of the HPV test than the other. In one version of the model, the calculated mortality reduction from HPV screening was higher and the (cost-)effectiveness was much better than for Pap smear screening. In the other version, outcomes were the opposite, although the cost-effectiveness of the combined HPV + cytology test was close to that of Pap smear screening. Although small follow-up studies and studies with limited strength of design suggest that HPV testing may well improve cervical cancer screening, only large longitudinal screening studies on the association between HPV infection and the development of neoplasias can give outcomes that would enable a firm conclusion to be made on the (cost-)effectiveness of HPV screening. Prospective studies should address women aged 30-60 years.     

The potential utility of HPV genotyping in screening and clinical management

Detection of specific human papillomavirus (HPV) genotypes, or HPV genotyping, may be useful for differentiating between those women who are carcinogenic HPV-positive at lower and higher risk for cervical precancer and cancer. Considerable evidence already exists that the absolute risk for cervical precancer and cancer varies considerably among specific HPV genotypes, and that detection of HPV-16 and -18 may have clinical usefulness, especially among women who tested positive for carcinogenic HPV and have negative cytology. Detection of persistent carcinogenic HPV is strongly associated with cervical precancer and cancer and strongly predicts its development, and might be used to monitor the outcomes of HPV infections. However, several practical considerations must be addressed before HPV genotyping can be used in screening and clinical management.     

人乳头瘤病毒检测对宫颈病变的诊断价值

目的：比较分析阴道镜活检与人乳头瘤病毒（ HPV）检测对宫颈病变诊断的临床应用价值。方法选取接受宫颈病变筛查的2560例已婚妇女为研究对象,其中行阴道镜活检560例,行HPV检测2000例,对两组检查结果进行对比分析。结果560例妇女阴道镜活检HPV阳性率为44．46％,2000例妇女HPV检测HPV阳性率为42．55％,两组比较差异无统计学意义,P＞0．05。经后期确认,上述患者中宫颈囊肿患者180例,阴道镜活检检出172例,漏诊8例,漏诊率为4．44％;HPV检测检出102例,漏诊78例,漏诊率为43．33％,阴道镜活检的漏诊率明显低于HPV检测,P＜0．01,差异具有统计学意义。结论阴道镜活检与HPV检测在宫颈病变诊断中均有良好效果,根据具体情况选择合适的检测方式。