Diagnostic value of human papillomavirus (HPV) 16 and HPV18 viral loads for the detection of high-grade cervical intraepithelial neoplasia (CIN2+) in a cohort of African women living with HIV.

African women living with HIV (WLHIV) are at high risk of cervical cancer but rarely adequately screened. Better strategies enabling identification of WLHIV with high-grade cervical intraepithelial lesions (CIN2+) are required. To investigate the diagnostic value of HPV16 and HPV18 viral loads in a cohort of African WLHIV. HPV16 and HPV18 viral loads were determined by quantitation of the E6 gene DNA by real-time PCR in cervical specimens collected at baseline and endline (16 months) from 245 African WLHIV positive for HPV16 or/and HPV18. Cervical biopsies were graded using the histopathological CIN classification. Women with CIN2+ had higher viral load for HPV16 (p < 0.0001) or HPV18 (p = 0.03) than those without CIN2+. HPV16 viral load ≥3.59 log copies/1000 cells detected CIN2+ with sensitivity and specificity of 93.5% (95%CI: 81.7-98.3%) and 74.1% (95%CI: 66.3-80.6%), respectively, whereas HPV18 viral load ≥1.63 log copies/1000 cells detected CIN2+ with sensitivity and specificity of 59.1% (95%CI: 38.7-76.7%) and 66.9% (95%CI: 58.8-74.1%), respectively. A high baseline HPV16 viral load was significantly associated with persistence of, or progression to CIN2+ at endline; these findings were not observed for HPV18. HPV16 viral load is a powerful marker of CIN2+ in African WLHIV. HPV18 viral load is of lower diagnostic value in this population.

Segondy M ，Ngou J ，Kelly H ，Omar T ，Goumbri-Lompo O ，Doutre S ，Mayaud P ，Didelot MN ... -  《-》

Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study.

The ATHENA study was designed to assess the performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping compared with liquid-based cytology for cervical cancer screening in a large US population aged 21 years and older. We did a subanalysis of this population to compare the screening performance of the cobas HPV test versus liquid-based cytology in women aged 25 years and older, and assess management strategies for HPV-positive women. Women aged 25 years or older who were attending routine cervical screening were enrolled from 61 clinical centres in 23 US states. Cervical specimens were obtained for liquid-based cytology and HPV DNA testing with two first-generation assays (Amplicor HPV test and Linear Array HPV genotyping test) and the second-generation cobas HPV test (with individual HPV16 and HPV18 detection). Colposcopy and diagnostic biopsies were done on women with atypical squamous cells of undetermined significance (ASC-US) or worse cytology, those who tested positive with either first-generation HPV test, and a random sample of women who tested negative for HPV and cytology. All women not selected for colposcopy received their results and exited the study. Participants and colposcopists were masked to cytology and HPV test results until the colposcopy visit was completed. The primary endpoint for this substudy was histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3) or worse. This study is registered with ClinicalTrials.gov, number NCT00709891; the study is in the follow-up phase, which is due to be completed in December, 2012. From May 27, 2008, to Aug 27, 2009, 47,208 women were enrolled, of whom 41,955 met our eligibility criteria. Valid cobas HPV and liquid-based cytology test results were available for 40,901 women (97%), who were included in this analysis. Of these, 4275 women (10%) tested cobas HPV positive and 2617 (6%) had abnormal cytology. 431 women were diagnosed with CIN2 or worse and 274 with CIN3 or worse. In women who had colposcopy, the cobas HPV test was more sensitive than liquid-based cytology for detection of CIN3 or worse (252/274 [92·0%, 95% CI 88·1-94·6] vs 146/274 [53·3%, 95% CI 47·4-59·1]; difference 38·7%, 95% CI 31·9-45·5; p<0·0001). Addition of liquid-based cytology to HPV testing increased sensitivity for CIN3 or worse to 96·7% (265/274, 95% CI 93·9-98·3), but increased the number of screen positives by 35·2% (5783/40,901 vs 4275/40,901) compared with HPV testing alone. As a triage test to identify CIN3 or worse in HPV-positive women, detection of HPV16, HPV18, or both alone was equivalent to detection of ASC-US or worse alone in terms of sensitivity (150/252 [59·5%] vs 133/252 [52·8%]; p=0·11) and positive predictive value (PPV) (150/966 [15·5%] vs 133/940 [14·1%]; p=0·20). Among HPV-positive women, detection of HPV16, HPV18, or both or low-grade squamous intraepithelial lesion or worse cytology had better sensitivity (182/252 [72·2%]; p<0·0001) and similar PPV (182/1314 [13·9%]; p=0·70) for detection of CIN3 or worse than ASC-US or worse cytology alone. Furthermore, detection of HPV16, HPV18, or both or high-grade squamous intraepithelial lesion or worse cytology had higher sensitivity (165/252 [65·5%]; p=0·0011) and PPV (165/1013 [16·3%]; p=0·031) for detection of CIN3 or worse than ASC-US or worse cytology alone. HPV testing with separate HPV16 and HPV18 detection could provide an alternative, more sensitive, and efficient strategy for cervical cancer screening than do methods based solely on cytology. Roche Molecular Systems.

Castle PE ，Stoler MH ，Wright TC Jr ，Sharma A ，Wright TL ，Behrens CM ... -  《-》

HPV16 and HPV18 genotyping triage in young women with borderline cytology or mild dyskaryosis: effect of age on genotype-specific risk of high-grade CIN.

Human papillomavirus (HPV) triage of borderline cytology or mild dyskaryosis is limited by the higher prevalence of HPV in women with these findings relative to those with high-grade cervical intraepithelial neoplasia (≥CIN2). This is particularly relevant in young women in whom HPV prevalence is discernible. In a previous analysis of HPV triage and colposcopy outcomes in Northern Ireland, we revealed a substantial amount of prevalent high-grade disease in women below 30 years of age. We explored the role of genotyping for HPV16/HPV18 in this population by assessing the risk of high-grade lesions associated with these genotypes and the effect of age on type-specific risk. Of the 866 women eligible for HPV triage, those who tested positive for HPV were referred to colposcopy. The relative risk of ≥CIN2 for HPV16, HPV18 and non-HPV16/18 high-risk genotype positivity was determined for cobas(®) HPV Test-positive results. The relative risk of high-grade CIN was significantly greater in women infected with HPV16 and/or HPV18 compared with non-HPV16/18 infections, regardless of age (2.23 and 0.45, respectively). In women under 30 years of age, HPV16-associated risk of ≥CIN2 was significantly greater than that of HPV18 and the non-HPV16/18 genotypes (1.74 versus 1.03 and 0.58, respectively). In women aged ≥30 years, HPV18 infection presented the greatest risk of ≥CIN2 (3.03). The relative risk of ≥CIN2 associated with non-HPV16/18 genotypes was lower (range, 0.32-0.58) for both age groups. This analysis demonstrates the value of genotyping for HPV16/HPV18 and age stratification to improve the specificity of HPV triage and to tailor management relative to the risk of high-grade CIN and cancer.

McKenna M ，McMenamin M ，McDowell A 《-》

The association between human papillomavirus 16, 18 DNA load and E6 protein expression in cervical intraepithelial neoplasia and cancer.

It has been reported that high HPV DNA load and elevated E6 protein expression correlate with cervical cancer, but no epidemiological study has been performed. To assess the association between type-specific HPV DNA load and presence of E6 protein in cervical intraepithelial neoplasia and cancer. This study was a cross-sectional multicenter study performed between 2013 and 2017. A total of 1717 women (normal histopathology: n = 916; CIN1: n = 94; CIN2: n = 63; CIN3: n = 130; SCC: n = 474; adenocarcinoma: n = 40) were included. HPV DNA load and presence of E6 protein were detected. DNA load was measured as log copies/10,000 cells. The HPV16/18-E6 positivity rates increased from negative for DNA to the highest load grade. Compared to the HPV16 DNA negatives, women with low (RR = 31.5, 95%CI = 18.9-52.5), medium-low (RR = 133.5, 95%CI = 77.3-230.7), medium-high (RR = 247.9, 95%CI = 134.9-455.6) and high DNA loads (RR = 677.9, 95%CI = 301.6-1523.7) had increasingly higher relative ratios of HPV16-E6 expression. The association of HPV18-E6 with its DNA load was also significant for low (RR = 27.9, 95%CI = 10.4-74.9), medium-low (RR = 89.0, 95%CI = 32.8-241.3), medium-high (RR = 276.8, 95%CI = 76.7-998.9) and high grade (RR = 441.2, 95%CI = 97.7-1992.4). The positivity rates of both HPV16 DNA and E6 protein increased consistently with the severity of diseases from normal histopathology to SCC. Unlike HPV16, the trends of HPV18 DNA and E6 protein fluctuated consistently among women from normal histopathology to cancer. DNA load in E6-positive women was significantly higher than E6-negative for both types. There is a type-dependent association between HPV16/18 DNA load and E6 protein; our study furthers the understanding of the natural history of cervical cancer.

Wu Z ，Yu L ，Lei X ，Qin Y ，Zhang X ，Chen W ，Qiao Y ... -  《-》

Three-year longitudinal data on the clinical performance of the Abbott RealTime High Risk HPV test in a cervical cancer screening setting.

Testing cervical smears for the presence of high-risk human papillomaviruses (hrHPV) increases the sensitivity for detecting women with underlying high-grade cervical intraepithelial neoplasia (CIN) and provides better and longer protection against invasive cervical cancer compared to cytology testing alone. The Abbott RealTime High Risk HPV test (RealTime) is a hrHPV DNA test with concurrent partial genotyping for HPV16 and HPV18 and aggregate detection of 12 other hrHPV types that have been extensively analytically and clinically evaluated over the last 6 years. To provide the first 3-year longitudinal data regarding the clinical performance of RealTime, the risk of CIN2+ according to various negative baseline characteristics, and baseline and future risk for CIN2+ at 3 years for women with baseline infection with various hrHPV types were assessed in a cohort of 3,920 Slovenian women that had hrHPV DNA and/or cytology in 36- to 48-month follow-up results after a baseline screening round in 2009/2010. A total of 36 CIN2+ cases were identified in the second screening round. Of these, 17 CIN2+ cases were identified passively through questionnaires/data registries and 19 cases actively as the result of actions triggered by second-round cytology and/or HPV test results. Accumulation of CIN2+ cases during follow-up occurred predominantly in woman with normal cytology at baseline. Among women >30 years old, significantly better protection against CIN2+ at 3 years was associated with a negative hrHPV DNA result at baseline (risk for CIN2+ 0.04% [95 CI, 0.00-0.22%]) than by normal cytology at baseline (risk for CIN2+ 0.68% [95 CI, 0.40-1.08%]). Women with baseline HPV16 infection had a significantly higher risk of CIN2+ at baseline (21.9% [95 CI, 15.2-30.4%]) and baseline plus future risk at 3 years for CIN2+ (33.3% [95 CI, 24.7-44.0%]) in comparison to women with baseline non-HPV16/18 hrHPV infection (7.0% [95 CI, 4.6-10.2%]) or those that were hrHPV-positive (11.7% [95 CI, 9.1-14.9%]). 3-year longitudinal data reinforce evidence from previous studies that RealTime can be safely used in primary HPV-based cervical cancer screening. Concurrent partial genotyping for HPV16/18 should be strongly considered as a triage method for HPV screen-positive women.

Poljak M ，Oštrbenk A ，Seme K ，Šterbenc A ，Jančar N ，Vrtačnik Bokal E ... -  《-》