In our experience of eight hundred thousand cotests, we found that the likelihood of testing hc2 positive was much less than was previously reported in smaller epidemiological studies or selected populations in the U.S. (15
). The percentage of carcinogenic HPV test positives, as measured using hc2, was 6.27%. Not surprisingly, the highest percentage of hc2 positives was found in women 30–34 (10.82%) and women 35–39 (8.03%), in the age group of KPNC female membership with highest prevalence of CIN2/3 (data not shown). These data are consistent with the prevalence of HPV in women of those ages participating in the HPV Sentinel Surveillance project (15
), in which more than half of the women enrolled in that study were between the ages of 30–39 and thus partially explaining the observed high HPV prevalence. There was the expected and pronounced decrease in HPV prevalence in the older KPNC female membershipThus, the concerns raised about introduction of HPV testing into clinical practice (19
) may be seen to have been overstated when population screening data are considered.
Although these are data from a large population, we point out that these data may not be generalizeable to all populations worldwide. The likelihood of testing HPV positive in conjunction with cotesting is population specific and depends on the age and risk behaviors in that population.
The percentage of hc2 positive results among cytologically normal women observed at Kaiser (3.99%) was similar to the percentage (3.7%) of carcinogenic HPV positives in cytologically normal women reported in a population-based study of 44,102 women using a GP5+/6+ PCR assay, which has shown to have comparable clinical performance to hc2 (20
). The percentage is also similar to the median percentage of HPV positives (4%) in all women 30 and older as reported in a survey conducted by the College of American Pathologists (21
). Interestingly, we found that the likelihood of testing carcinogenic HPV positive but cytologic negative to be only slightly more common than the likelihood of testing carcinogenic HPV negative but cytologic positive (3.99% vs. 2.90%), which is primarily (HPV-negative) ASC-US cytology (82.8%) that bears a very low risk of CIN2/3 (22
) but also requires increased surveillance and clinical follow-up according to current guidelines (11
Although Kaiser uses conventional Pap smears for detection of cytologic abnormalities while ~90% of U.S. clinics rely on liquid-based cytology, a recent meta-analysis (23
) indicates that liquid-based cervical cytology is not
more sensitive and may be less specific for detection of high-grade cervical intraepithelial neoplasia than the Pap smear. Thus, the use of LBC, widely adopted in advance without evidence of greater screening accuracy versus convention Pap smears (24
), would be expected to increase the proportion of test positives by cytology, including false positives. Regardless, the use of Pap smear at Kaiser does not alter our observations about HPV testing.
Recognition of cytologically-normal, HPV-negative women is important because extension of screening intervals from one to three years based on negative cytology alone, despite being preceded by three consecutive negative cytology results, triples the risk of invasive cervical cancer (25
). While unfamiliar with the research, many women and providers intuitively understand that fewer Paps mean more cancer risk, and the majority of women and medical care providers participating in screening in our population and that of the Southern California Kaiser Permanente Medical Care Plan were unwilling to accept recommendations made by the Kaiser clinicians in the 1980s and 1990s to abandon annual screening with cytology alone in favor of longer screening intervals (data not shown).
As the morbidities associated with the treatment of dysplasia have become more apparent (26
), and it has been recognized that half of CIN2 (which is routinely treated) regresses in 24 months (29
), the adverse consequences for the patient of annual screening come into sharper focus. Currently KPNC offers screening with Pap and HPV at 3-year intervals or screening with cytology at more frequent intervals to our female members age 30 and above. During the period from December 1, 2006 through February 26, 2007, 91.6% of KPNC members age 30 and older who participated in screening elected the cotesting option (screening every three years if Pap and HPV were both negative) instead of annual screening. Providing the reassurance required to move away from annual screening is one of the benefits of cotesting that we have observed.
We will be conducting subsequent analyses on the predictive values for ≥CIN2, ≥CIN3, and cancer of all pair-wise cotesting results. However, we already recognize that women who test positive for carcinogenic HPV and negative by cytology are at an elevated risk for cervical precancer and cancer compared to women who test negative on both (13
), and yet the positive predictive value of a single Pap-negative HPV-positive cotest for ≥CIN3 remains less than ideal. Thus, the development of a viable strategy for identifying the subset of women at highest risk of ≥CIN3 would further improve the efficiency of secondary cervical cancer prevention. Future clinical research will need to focus on identifying the best strategies for managing women who test positive for carcinogenic HPV and negative by cytology, which may include HPV genotyping for HPV16, HPV18, and possibly HPV45 (11
) or immunodetection of p16INK4a