We found superior accuracy of the HCII test to detect CIN 2/3 or worse in the screening group. No significant difference was observed between the areas under the ROC curves for the screening and diagnosis groups, but a higher LR+ was observed in the screening group when compared to the diagnosis group (10.24 vs. 4.06, respectively).
This finding points toward the use of the HCII test as an alternative to the Papanicolaou smear for the screening of cervical cancer in similar populations. Other researchers have reported results similar to ours. A recent randomized clinical trial conducted by Mayrand et al. (4
) compared the HCII test to the Papanicolaou smear and reported the performance of both tests in a screening population. Considering their definition of disease and use of strategies to correct verification bias, their results may be comparable to our screening group results. Mayrand et al. (4
) defined two categories of disease: liberal and conservative. The former was defined using any histologic result available from the colposcopically-directed biopsies or loop electrosurgical excision procedure (LEEP) specimens, and the latter was defined using only LEEP specimens. In this way, their liberal definition of disease is more like the definition used in our study, which allows us to compare the two sets of results. Similar to our study, the researchers implemented strategies to reduce verification bias by confirming the histology diagnosis in a random sample of participants with negative tests reporting the crude and corrected operating characteristics of the HCII. Using the liberal definition of disease, Mayrand et al. (4
) reported a sensitivity of 82.8% and a specificity of 61.1% as the crude operating characteristics of the HCII test, and a sensitivity of 45.9% and a specificity of 94.2% as the corrected operating characteristics of the HCII test.
The sensitivity in our screening group was higher than the adjusted sensitivity reported by Mayrand et al. (4
) (68.8% vs. 45.9%, respectively). The differences in our results may be explained by the study sampling and the natural history of HPV infection. While women in our study were allocated into a screening or diagnosis group based on their history of Papanicolaou smear results, participants in the Mayrand et al. (4
) study were recruited from a screening program. Indeed, Mayrand et al. (4
) reported that approximately 28% of the participants had a history of abnormal Papanicolaou smears, and 2% had never been tested. Thus, participants in the Mayrand et al. (4
) study may have been infected with HPV at the time of the first abnormal test and had an increased length of exposure to the HPV virus compared to our group of women with a history of normal smears.
Differences in the performance of the HCII test have also been explained by local differences in the processing and handling of samples, as suggested by Sankaranarayanan et al. while conducting a multicenter study of the HCII test in India (8
). The three other studies that avoided verification bias (9
) showed operating characteristics that were quite similar to the ones found in our study. Small variations exist, which may indicate that the test as used in our study was operating at a different point on the hypothetically same ROC curve.
Our evaluation of HCII test performance may not reflect actual clinical practice because not all patients in a screening group are referred to colposcopy, and biopsies are not usually obtained from tissue of normal colposcopic appearance. Moreover, endocervical curettages are not performed in screening populations. While our study methods helped to establish the disease or non-disease status of each woman, they may have increased the detection of small lesions that are not usually discovered when performing a routine colposcopic examination.
Current U.S. guidelines for cervical cancer screening suggest that the tests can be used simultaneously in women over 30 years old with the option of extending the screening intervals up to every three years if both tests are negative. Our data, in fact, support the use of the HCII test in conjunction with the Papanicolaou smear rather than as a follow-up test for an abnormal cytological test. We observed the best sensitivity and specificity with the concurrent use of either the Papanicolaou smear or the HCII test with near perfect predictive value negative. Even the use of the HCII test alone in either the screening group or the diagnosis group generated superior sensitivity and specificity when compared to previous reports for Papanicolaou testing alone. Additional issues, such as economic and epidemiological considerations, would need to be considered before making evidence-based guidelines for public policy. These questions are particularly relevant for determining policy in limited resource settings.
The HCII test is limited to detecting the 13 most common HPV high-risk viral strains associated with cervical cancer, and cannot determine specific viral strains. Moreover, a false negative result may be caused by the presence of small numbers of viral copies in the study sample. From the perspective of epidemiological studies, the test may provide a general overview of the prevalence of infection with high-risk viral strains, but the distribution of each high-risk strain in a study population needs to be addressed using other tests that are not clinically approved.
Using the HCII test, we have demonstrated the potential of HPV testing in two subgroups of women. There is greater potential for clinical applicability using the HCII test for women in a screening population than in a diagnosis population. The operating characteristics of the HCII test seem superior when compared to those of the conventional Papanicolaou smear, and are perhaps competitive with liquid-based technologies. For a screening population, we would like to minimize the number of false positives that would require additional testing or intervention. Since cervical cancer is fairly slow in developing, a lower sensitivity can be accommodated by repeated screening. However, we want to minimize false negatives for a diagnosis population which has likely experienced previous cytological abnormalities and is likely to be at an increased risk for future abnormalities. This allows for minimal numbers of missed diagnoses. In addition, the use of the HCII test alone in this population may cause some pathologies to be missed; this could be avoided by adding cytological screening to HPV DNA testing. Our results support the use of the HCII test in screening for cervical dysplasia. However, further study may be required to determine whether the use of HPV testing as a primary screening tool for cervical pre-cancer should become standard practice.