title: High-risk human papillomavirus DNA load in a population-based cervical screening cohort in relation to the detection of high-grade cervical intraepithelial neoplasia and cervical cancer.
abstract: In a population-based cervical screening cohort, we determined the value of type-specific viral load assessment for the detection of high-grade cervical intraepithelial neoplasia and cervical cancer (>or=CIN2). Viral load was determined by type-specific real-time PCR in women with single HPV16,-18,-31 and -33 infections, as determined by GP5+/6+-PCR. Study endpoints were the detection of cumulative >or=CIN2 or>or=CIN3 within 18 months of follow-up. High viral loads of HPV16,-31, and -33 were predictive for >or=CIN2 (relative risk of 1.6 (95% CI: 1.3-1.9), 1.7 (95% CI: 1.1-2.7) and 1.9 (95% CI: 1.1-3.1) per 10-fold change in viral load, respectively). For HPV18, the relative risk was of similar magnitude (1.5, 95% CI: 0.7-3.1), though not significant (p=0.3). Subsequently, we determined the sensitivities of viral load for >or=CIN2 and >or=CIN3 in HPV DNA-positive women using viral load thresholds previously defined in a cross-sectional study. These thresholds were based on the 25th, 33rd and 50th percentiles of type-specific HPV16,-18,-31 or -33 viral load values found in women with normal cytology. For all types, combined sensitivities for >or=CIN2 were 93.5%, 88.8% and 77.7% for the 25th, 33rd and 50th percentile thresholds, respectively. Response-operator-characteristics (ROC) curve analysis showed that viral load testing on HPV DNA-positive women in addition to or instead of cytology may result in an increased sensitivity for >or=CIN2, but at the cost of a marked decrease in specificity in relation to cytology. Similar results were obtained when using >or=CIN3 as endpoint. In conclusion, in a cervical screening setting viral load assessment of HPV16, 18, 31 and 33 has no additive value to stratify high-risk HPV GP5+/6+-PCR-positive women for risk of >or=CIN2 or>or=CIN3.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Albertus T
authors.initials: AT
authors.lastname: Hesselink
authors.forename: Johannes
authors.initials: J
authors.lastname: Berkhof
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Nicole W J
authors.initials: NW
authors.lastname: Bulkmans
authors.forename: Jurjen E H
authors.initials: JE
authors.lastname: van Tellingen
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
mesh_terms: D014408:Biomarkers, Tumor; D015331:Cohort Studies; D004279:DNA, Viral; D018450:Disease Progression; D055088:Early Detection of Cancer; D005260:Female; D005814:Genes, Viral; D006801:Humans; D008403:Mass Screening; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism*; D011237:Predictive Value of Tests; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000821:virology*
chemical_list: D014408:Biomarkers, Tumor; D004279:DNA, Viral