Application Value Of HPV Detection With 16/18 Genotyping In Cervical Cancer Screening

Cervical cytological examination has greatly reduced the incidence of cervical cancer in developed countries.However,due to the low sensitivity and large dependence on cytologists,applications of cytological examination in developing countries are limited.HPV infection is an essential factor in the development of cervical cancer,which determines the value of HPV testing in cervical cancer screening.In 2001,ASCCP recommended HPV testing for ASC-US shunting.In 2006,ASCCP recommended cotesting with HPV and cytology testing.In 2008,EUROGIN proposed HPV-based cervical cancer screening program.The greatest advantage of HPV testing compared to cytology is the high sensitivity and negative predictive value.In 2011-2015,the United States released baseline data and three-year follow-up data of the Addressing the Need for Advanced HPV Diagnostics study(ATHENA).It is confirmed that Cobas HPV testing is safer and more effective as a primary screening than TCT primary screening.Accordingly,the US Food and Drug Administration(FDA)approved Cobas HPV alone to screen for cervical cancer in women over the age of 25.In 2015,ASCCP issued an interim guide using FDA-approved HPV testing for primary screening of cervical cancer in women over 25 years old.Cytological examination can be replaced by HPV-based primary screeningAs the largest developing country,cervical cancer incidence and mortality in China are still rising.In 2015,new cases of cervical cancer is estimated to be 98,900 and deaths to be 30,500.Due to the severe lack of cytologists,cytology-based screening and cotesting are limited.As the latest FDA-approved HPV DNA detection technology,Cobas HPV can simultaneously detect 14 high-risk HP Vs and can detect HPV16 and HPV18 separately.Due to its HPV 16/18 genotyping function,it can further reduce its reliance on cytologists,especially applicable for China and other developing countries.But so far,we have not yet obtained relevant data of Cobas HPV testing for the Chinese population.To this end,we evaluated the Cobas HPV testing and the Cobas HPV-based protocol in cervical cancer screening by conducting a large-scale cross-sectional study based on the general population,using cytological examination as a control,and colposcopy and biopsy as the gold standard.This would provide evidence for HPV-based screening strategy for cervecal cancer in China.PART I Comparison of the efficacy between Cobas HPV and cytology in cervical cancer screeningObjectivesTo evaluate the efficacy of Cobas HPV testing in cervical cancer screening through conducting a population-based large-scale cross-sectional study,using cytological examination as a control,and colposcopy and cervical biopsy as the gold standard.Methods332 administrative villages and communities that had not conducted cervical cancer screening for the past 3 years were randomly selected in Longyou County,Zhejiang Province,China.A total of 11,356 women aged 21-65 years with a history of sexual life who were willingly to participate in this trial were recruited in April and May,2015.Inclusion criteria:complete cervix;non-pregnancy or puerperium;no previous cervical and vulvovaginal intraepithelial neoplasia,or cervical cancer,or other history of malignant tumor;no serious autoimmune disease or uremia;not vaccinated with HPV,no plan for HPV vaccination in near future.Cervical exfoliated cells were collected,Cobas HPV testing and liquid-based cytology(TCT)were performed,and histopathological diagnosis was used as the gold standard.CIN2+ and CIN3+ were used as the end points seperately.The sensitivity,specificity,positive predictive value(PPV),negative predictive value(NPV),positive likelihood ratio(PLR)and negative likelihood ratio(NLR)were calculated and compared to evalute the efficacy of Cobas HPV method and TCT method.Results1.There were 11,064 effective cases,427 CIN1,53 CIN2,75 CIN3(including 2 cases of adenocarcinoma in situ)and 12 cases of cervical squamous cell carcinoma.The rates of HPV positivity and cytology abnormality were 9.8%and 6.1%,respectively.The HPV positivity rate had two age peaks,21-24(15.4%)and 60-65(14.4%)years.2.With CIN2+ as the end point,the sensitivity and NPV of Cobas HPV testing x were significantly higher than cytological examination(90.0%vs.66.7%,99.9%vs.99.5%,respectively,all P=0.000).Cobas HPV testing also had an acceptable specificity(91.3%)and PPV(12.5%).Similar results were obtained with CIN3+ as the end point.3.With CIN2+ as the end point,the sensitivity of HPV testing in the 50-to 65-year group was higher than that in the 25-to 49-year group(97.6%vs.87.2%),but the effect was not significant,and the NPV was similar(99.97%vs.99.8%).However,the specificity in the 50-to 65-year group was significantly lower than that in the 25-to 49-year group(89.3%vs.92.4%),and the PPV in the 50-to 65-year group was significantly lower than that in the 25-to 49-year group(9.0%vs.15.1%).The differences in effectiveness between the 25-to 49-and 50-to 65-year groups were similar when CIN3+ was the end point.Conclusions1.The age-specific prevalence of high-risk HPV infection in Zhejiang Province is"U-shaped",and the second age peak is over 60 years old.2.Cobas HPV is superior to cytology in the detection of CIN2+,suggesting that HPV testing can be used for cervical cancer screening,especially in areas where cytologists are scarce.3.The specificity of HPV testing in predicting high-grade lesions in the 50-to 65-year group is lower than that in the 25-to 49-year group,suggesting that peri-menopausal and postmenopausal women in areas with high HPV infection should be shunted when they are HPV positive.PART Ⅱ Comparison of the efficacy among four internationally recommended screening strategies in cervical cancer screeningObjectivesTo evaluate the effectiveness of screening strategy of primary HPV testing with type 16/18 genotyping in detecting high-grade cervical intraepithelial lesions in Chinese women aged 25-65 years through a population-based cross-sectional study,and to provide evidence of the suitability of an HPV-based screening strategy in China.MethodsCobas HPV and TCT were performed on 11,356 women aged 21-65 who had a history of sexual life and were willing to participate in cervical cancer screening in April and May,2015.Of these,10,929 women aged 25-65 were eligible.Four strategies that were currently used for cervical cancer screening were evaluated.They were Co-testing,Primary cytology with triage by HPV testing,Primary HPV testing with triage by cytology and Primary HPV testing with type 16/18 genotyping.With CIN2+and CIN3+ as the end point,and the histopathological diagnosis as gold Standard,the sensitivity,specificity,positive Predictive value(PPV),negative predictive value(NPV)and the number of screening test and colposcopy for detecting a high-grade CIN were calculated and compared.Results1.The strategy of Co-testing demonstrated an optimal effectiveness,with a sensitivity of 72.7%and specificity of 96.9%for identifying CIN2+,but it consumed maximum tests(220.2)and colposcopies(4.4)to detect one case of CIN2+.2.The strategy of Primary cytology with triage by HPV testing had the same sensitivity(72.7%),specificity(96.9%)and number of performed colposcopies((4.4))to detect one case of CIN2+,but it required nearly half of the tests to detect one case of CIN2+(112.7)compared to cotesting.3.The strategy of Primary HPV testing with triage by cytology had the highest specificity(98.0%)and PPV(29.2%)with the lowest number of performed colposcopies(3.4)to detect one case of CIN2+.But it had the lowest sensitivity(63.6%)and NPV(99.5%)of the four strategies and required more performed tests(134.2)than the strategy of Primary HPV testing with triage by cytology to detect one case of CIN2+.4.The strategy of Primary HPV testing with type 16/18 genotyping demonstrated the highest sensitivity(78.6%)and NPV(99.7%),and the least tests(106.3)to detect one case of CIN2+ of the four strategies,and it had a similar specificity(96.8%),PPV(23.9%)and number of performed colposcopies(4.2)as Co-testing and Primary cytology with triage by HPV testing.ConclusionsAmong the four commonly used cervical cancer screening strategies,the strategy of Primary HPV testing with type 16/18 genotyping has the highest sensitivity,the similar specificity,and the lowest cost-effectiveness.It is suitable for cervical cancer screening in areas where cytologists are deficient.