Can a longer HPV screening interval adequately protect patients?
A basic concern that clinicians have with the 3-year screening interval is that some women may not come in for screening until 4 or 5, or even more, years. Their concern is justified; numerous studies have confirmed that extending the screening interval beyond 3 years for women screened by cytology significantly decreases protection.
How protected would women be if they were screened with an HPV test? Dillner and colleagues demonstrated in their study that women who have a negative HPV test could have their interval safely extended for at least 6 years. Their work suggests that women who are screened infrequently would be significantly protected well beyond the 3-year interval now recommended in the United States with co-testing. However, it is important to point out that no screening test is perfect, and the reduction of cancer risk to zero is unlikely.
WHAT THIS MEANS FOR PRACTICE
Although the recommended screening interval is 3 years after a negative co-test, women screened by HPV testing have a margin of safety for at least 6 years. Irregularly screened women are therefore likely to be better protected even if the next screen surpasses 3 years.
2 “Better management of screen positives”—we wait for new testing technology
Ginocchio CC, Barth D, Zhang F. Comparison of the Third Wave Invader human papillomavirus (HPV) assay and the Digene HPV hybrid capture 2 assay for detection of high-risk HPV DNA. J Clin Microbiol. 2008;46:1641–1646.
Wong AK, Chan RC, Nichols WS, Bose S. Invader human papillomavirus (HPV) type 16 and 18 assays as adjuncts to HPV screening of cervical Papanicolaou smears with atypical squamous cells of undetermined significance. Cancer. 2009;115:823–832.
Castle PE, Dockter J, Giachetti C, et al. A cross-sectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer. Clin Cancer Res. 2007;13:2599–2605.
Type-specific HPV testing identifies highest risk
By 2006, it had become clear that testing for HPV types 16 and 18 would identify those HPV-positive women who are at highest risk of CIN 2,3+. Investigators introduced a potential management algorithm that would likely alter the care of Pap-/HPV+ women once such testing became available.
Three years later, however, type-specific HPV testing still isn’t available. Why not?
One reason may be that type-specific HPV testing is much more complicated than the molecular tests that we use to identify a single virus or bacterium (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae) because the test has to identify several or more HPV types in a single assay. Proof of clinical utility requires more complex clinical studies than required for other sexually transmitted infections that have a quick therapeutic solution.
As we end the first quarter of 2009, no new HPV test or marker has yet been approved by the Food and Drug Administration (FDA) for clinical use. However, one of the three most promising candidates, HPV DNA testing for HPV 16, 18 (Invader HPV DNA [Hologic]) may be close to approval, and another, based on detection of messenger RNA (mRNA) has begun clinical trials (Aptiva mRNA [GenProbe]).
The Invader HPV (Inv2) test detects 14 high-risk HPV subtypes that are grouped in three probe sets on the basis of their interrelatedness. Results are reported as positive or negative for the entire probe set, not for individual viral types. The probe sets are:
- A5/A6 (HPV types 51, 56, and 66)
- A7 (types 18, 39, 45, 59, and 68)
- A9 (types 16, 31, 33, 35, 52, and 58).
The types in the A7 probe set are found more often in glandular lesions, such as adenocarcinoma in situ. Types in the A9 group are more often responsible for the squamous lesions of CIN 3 and squamous cell cervical cancer (although types in both groups can cause either type of lesion).
HPV E6/E7 mRNA testing for high-risk types may correlate better with the severity of lesions than HPV DNA testing—because up-regulation of mRNA from the oncogene region of the HPV genome (E6 and E7) is likely to be more predictive of which HPV-infected women are most likely to persist and progress to a high-grade lesion and cancer.
Castle and co-workers reported in their study that subjects in their study tested positive for HPV E6/E7 mRNA in 94% of cases of CIN 3 (46 of 49 women) and in all five cases of cancer. Overall, fewer specimens that were not characterized by a high-grade lesion tested positive for HPV E6/E7 mRNA than for HPV DNA.
WHAT THIS MEANS FOR PRACTICE
A move to a more efficient and, potentially, more cost-effective cervical disease screening paradigm awaits FDA approval of 1) a type-specific HPV test or 2) a marker test that is more predictive of which HPV-infected women are likely to persist and progress to a high-grade lesion and cancer.