Abbreviations: AUC, area under the ROC curve; CI, confidence interval; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesions; ROC, receiver operating characteristic. We thank Dr. Castle for his constructive and contributory commentary (1) on our meta-analysis of human papillomavirus (HPV) persistence and cervical neoplasia (2). We agree that ascertaining HPV persistence may have clinical utility and that several issues must be

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... ssed before persistence can be effectively implemented in cervical screening programs. As Dr. Castle mentioned, a single HPV test is more sensitive but less specific than a single Papanicolaou test for the detection of cervical precancer and cancer. In fact, HPV testing at a single time point has approximately 20-40 percent higher sensitivity than Papanicolaou testing and 5-10 percent lower specificity (3). Incorporating HPV persistence into routine cervical cancer screening may help to improve specificity without unduly reducing sensitivity by distinguishing women with short-term infections, and therefore lower risk of cervical precancer and cancer, from women with long-term infections, and therefore higher risk. To address this issue, we evaluated the diagnostic performance of HPV persistence as a predictor or marker for cervical intraepithelial neoplasia (CIN) 2-3 and high-grade squamous intraepithelial lesions (HSIL) or higher-level disease, including invasive cancer (termed CIN2-3/HSILþ). Although we combined the histologic (CIN2-3) and cytologic (HSIL) outcomes to maximize the number of studies available for meta-analysis (2), it is important to recognize that many of these outcomes may regress and not be linked to persistent carcinogenic HPV infection. Thus, the diagnostic performance of HPV persistence may in fact be better than presented here. Using the studies that contributed to our meta-analysis of CIN2-3/HSILþ (2), we estimated the sensitivity and specificity of each study and summary receiver operating characteristic (ROC) curves (4) for HPV persistence as a diagnostic marker for CIN2-3/HSILþ. We used the following definitions: 1) true positives: the number of women with HPV persistence and a diagnosis of CIN2-3/HSILþ; 2) false negatives: the number of women without HPV persistence but with a diagnosis of CIN2-3/HSILþ; 3) true negatives: the number of women without HPV persistence who were not diagnosed with CIN2-3/HSILþ; 4) false positives: the number of women with HPV persistence who were not diagnosed with CIN2-3/HSILþ. Sensitivity was calculated as true positives/(true positives þ false negatives) and specificity as true negatives/(true negatives þ false positives). The ROC curves were plotted in the usual way as sensitivity on the ordinate and 1 minus specificity (false-positivity rate) on the abscissa. Three ROC curves were estimated, depending on whether women with persistent infection were compared with 1) women who were consistently negative for the HPV types used to define persistence ("HPV-negative