Invited commentary: is monitoring of human papillomavirus infection for viral persistence ready for use in cervical cancer screening?

Abstract

Persistent cervical infections by approximately 15 carcinogenic genotypes of human papillomavirus (HPV) cause virtually all cases of cervical cancer and its immediate precancerous precursor, cervical intraepithelial neoplasia grade 3 or carcinoma in situ. As is shown in a meta-analysis by Koshiol et al. (Am J Epidemiol 2008;168:123-137), detection of carcinogenic HPV viral persistence could be used to identify women at the greatest risk of cervical precancer. Specifically, women who have carcinogenic HPV infection that persists for at least 1 year versus those whose infections clear are at significantly elevated risk of having or developing cervical precancer. However, before detection of HPV persistence can be used in cervical cancer screening, several considerations need to be addressed: 1) validation and Food and Drug Administration approval of a reliable HPV genotyping test, 2) rational clinical algorithms based on risk of precancer and cancer for the clinical management of HPV persistence, 3) clinician and patient acceptability of monitoring of HPV infections (including not responding excessively to the first positive HPV test and waiting 1-2 years for infections to either persist or resolve), and 4) patient compliance with recommended follow-up. Investigators will need to address these and other key issues in order to realize the potential utility of HPV viral monitoring for improving the accuracy of cervical cancer screening.

FIGURE 1.

A proposed clinical algorithm for using carcinogenic human papillomavirus (HPV) testing as the primary screening test and HPV genotyping to triage carcinogenic HPV-positive results and monitor viral persistence as a risk factor for cervical precancer and cancer. If the molecular HPV test used for screening (e.g., Hybrid Capture 2 (Digene Corporation, Gaithersburg, Maryland)) does not provide information on the individual HPV genotype(s) present, only on whether a woman is or is not positive for carcinogenic HPV, a second test would be necessary to determine which HPV genotype(s) are present. Cytologic analysis may be a useful adjunct for women whose screening history is unknown, with women having cytologically detected high-grade squamous intraepithelial lesions (HSIL) being referred to colposcopy immediately. Depending on the exact format of the HPV testing (full or partial HPV genotyping), the most robust use of HPV genotyping, and the associated risks of cervical intraepithelial neoplasia grade 3 or cervical cancer (≥CIN3), women who repeatedly test positive for the other carcinogenic HPV genotypes (individually or in aggregate) may need increased surveillance or colposcopy (31). Following a carcinogenic HPV-negative test, women may be rescreened at an extended interval of 3 or more years, depending on the acceptable risk of ≥CIN3 (and, more specifically, the reassurance against cancer), which may depend on the previous test results.

FIGURE 2.

Cumulative (absolute) risk of histologic cervical intraepithelial neoplasia grade 3 or cervical cancer (≥CIN3) over 11 years of follow-up following the results of two carcinogenic human papillomavirus tests conducted at a 2-year interval in women aged 20–29 years at baseline (adapted from Kjaer et al. (11)). The results are stratified according to the paired results. The bracket indicates the period of typical screening intervals.