Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence

Abstract

Background: Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type-specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types.

Methods: A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time.

Results: For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%).

Conclusion: HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA-negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary.

Figure 1

Absolute risks of cervical intraepithelial neoplasia grade 3 (CIN3) or worse after infection with different high-risk human papillomavirus (HPV) types in women with normal cytological findings at baseline. Error bars correspond to 95% confidence intervals. HR HC2 positive = positive to high-risk HPV types as measured by the Hybrid Capture 2 test. HC2 neg = HC2 negative.

Figure 2

High-risk human papillomavirus (HPV) type–specific prevalence of infection, percentage of women with a persistent infection, and percentage of women with persistent infection who developed cervical intraepithelial neoplasia grade 3 or worse during follow-up. CIN3+ = cervical intraepithelial neoplasia grade 3 or worse.

Figure 3

Absolute risks of developing cervical intraepithelial neoplasia grade 3 (CIN3) or worse in women with normal cytological findings at baseline in relation to various measures of human papillomavirus (HPV) status. HPV16 persistence = positive to HPV16 at the first and at the second study examination. HR HC2 persistence = positive for high-risk HPV types as measured by the Hybrid Capture 2 at the first and the second study examination; incident HPV16 = negative to HPV16 at the first study examination and positive to HPV16 at the second study examination; incident HR HC2 = negative for high-risk HPV by the HC2 assay at the first and positive at the second study examination; HR HC2 negative/negative = negative for high-risk HPV by the HC2 assay at the first and the second study examination, Error bars correspond to 95% confidence intervals.