Comparison between Prototype Hybrid Capture 3 and Hybrid Capture 2 Human Papillomavirus DNA Assays for Detection of High-Grade Cervical Intraepithelial Neoplasia and Cancer

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Abstract
We compared the performance of a prototype version of the Hybrid Capture 3 (HC3) human papillomavirus (HPV) DNA assay to the current generation Hybrid Capture 2 (HC2) assay, both of which target 13 oncogenic HPV types, for the detection of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+) with cervicovaginal lavage specimens collected at enrollment into a 10-year cohort study at Kaiser Permanente (Portland, Oreg.). HC3 results for a risk-stratified sample ( n = 4,364) were compared to HC2 results for the entire cohort ( n = 20,810) with receiver operating characteristics curves, and the optimal cut points for both tests (relative light units [RLU]/positive control [PC]) for the detection of CIN3+ were determined. Specimens were also tested for HPV16 and HPV18 with separate HC3 type-specific probes. The optimal cut point for detecting CIN3+ was 1.0 RLU/PC for HC2, as previously shown, and was 0.6 RLU/PC for HC3. At the optimal cut points, HC3 and HC2 had similar screening performance characteristics for CIN3+ diagnosed at the enrollment visit. In analyses that included cases CIN3+ at enrollment and those diagnosed during early follow-up, HC3 had nonsignificantly higher sensitivity and equal specificity for the detection of CIN3+ compared to HC2; this increase in sensitivity was primarily the result of increased detection of CIN3+ in women who were 30 years of age or older and were cytologically negative ( P = 0.006). We also compared the performance of the hybrid capture tests to MY09/11 L1 consensus primer PCR results ( n = 1,247). HC3 was less likely than HC2 to test positive for specimens that tested positive by PCR for any untargeted types ( P < 0.001). HC3 was less likely than HC2 to test positive for untargeted PCR-detected single infections with HPV53 ( P = 0.001) and HPV66 ( P = 0.01). There was good agreement between test positivity by PCR and by single type-specific HC3 probes for HPV16 (kappa = 0.76; 95% confidence interval [CI] = 0.71 to 0.82) and for HPV18 (kappa = 0.73; 95% CI = 0.68 to 0.79). In conclusion, we suggest that HC3 (≥0.6 RLU/PC) may be slightly more sensitive than and equally specific test as HC2 (≥1.0 RLU/PC) for the detection of CIN3+ over the duration of typical screening intervals.