Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection

Abstract

Background: The natural history of human papillomavirus (HPV) infections in older women is critical for preventive strategies, including vaccination and screening intervals, but is poorly understood. In a 7-year population-based cohort study in Guanacaste, Costa Rica, we examined whether women's age and the duration of carcinogenic HPV infections influenced subsequent persistence of infection and risk of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse disease.

Methods: At enrollment, of the 9466 participants eligible for pelvic examination, 9175 were screened for cervical neoplasia using multiple methods; those with CIN 2 or worse disease were censored and treated. Participants at low risk of CIN 2 or worse (n = 6029) were rescreened at 5-7 years (passively followed), whereas higher-risk participants (n = 2115) and subsets of low-risk women (n = 540) and initially sexually inactive women (n = 410) were rescreened annually or semiannually (actively followed) for up to 7 years. HPV testing was done using a polymerase chain reaction-based method. We determined, by four age groups (18-25, 26-33, 34-41, and > or =42 years), the proportion of prevalent infections (found at baseline) and newly detected infections (first found during follow-up) that persisted at successive 1-year time points and calculated absolute risks of CIN 2 and CIN grade 3 (CIN 3) or worse during follow-up. P values are two-sided.

Results: Regardless of the woman's age, newly detected infections were associated with very low absolute risks of persistence, CIN 2, or worse disease. For newly detected infections, the rate of progression to CIN 2+ (or CIN 3+), after 3 years of follow-up, was not higher for women aged 34 years and older than for younger women. Moreover, rates of newly detected infections declined sharply with age (in the actively followed group, at ages 18-25, 26-33, 34-41, and > or =42 years, rates were 35.9%, 30.6%, 18.1%, and 13.5%, respectively; P < .001). Among prevalent infections, persistent infections among older women (> or =42 years) was higher than that among younger age groups or new infections at any age (P < .01 for comparison of eight groups). Most (66 of 85) CIN 2 or worse detected during follow-up was associated with prevalent infections. Only a small subset (25 of 1128) of prevalent infections persisted throughout follow-up without apparent CIN 2 or worse.

Conclusions: The rate of new infections declines with age, and new infections typically do not progress to CIN 2 or worse disease in older women; thus, overall potential benefit of prophylactic vaccination or frequent HPV screening to prevent or detect new carcinogenic HPV infections at older ages is low.

Figure 1

Persistence of baseline-detected and newly detected carcinogenic genotypes of human papillomavirus (HPV) infection by age group. The proportion of carcinogenic type-specific infections still persisting among those tested at each time point was calculated for prevalent and newly detected infections by age groups. They were color coded as follows: red, prevalent infections among women 18–25 years old; gray, prevalent infections among women 26–33 years old; yellow–green, prevalent infections among women 34–41 years old; black with stars, prevalent infections among women aged 42 years or older; dark blue, new infections among women 18–25 years old; magenta, new infections among women 26–33 years old; dark green, new infections among women 34–41 years old; light blue, new infections among women aged 42 years or older. The percentages of carcinogenic HPV infections that persisted 6 years after enrollment among passively followed prevalent infections were 5.1% among women 18–25 years old, 14.4% among women 26–33 years old, 12.2% among women 34–41 years old, and 18.2% among women aged 42 years or older.