Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study

Abstract

Objective: To evaluate the cumulative incidence of cervical intraepithelial neoplasia II or worse (grade II+) or cervical intraepithelial neoplasia grade III+ after short term persistence of prevalently detected carcinogenic human papillomavirus (HPV).

Design: Population based cohort study.

Setting: Guanacaste, Costa Rica.

Participants: 2282 sexually active women actively followed after enrolment.

Main outcome measures: Primary end points: three year and five year cumulative incidence of histologically confirmed cervical intraepithelial neoplasia grade II+ (n=70). Cervical specimens collected at each visit tested for more than 40 HPV genotypes. HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82 were considered the primary carcinogenic genotypes.

Results: Women who tested positive for a carcinogenic HPV at enrolment and after about one year (9-21 months) (positive/positive) had a three year cumulative incidence of cervical intraepithelial neoplasia grade II+ of 17.0% (95% confidence interval 12.1% to 22.0%). Those who tested negative/positive (3.4%, 0.1% to 6.8%), positive/negative (1.2%, -0.2% to 2.5%), and negative/negative (0.5%, 0.1% to 0.9%) were at a significantly lower risk. There was little difference in the cumulative incidence of cervical intraepithelial neoplasia grade II+ between testing positive twice for any carcinogenic HPV genotype (same genotype or different genotypes) v testing positive twice for the same carcinogenic genotype (17.0% v 21.3%, respectively). Short term persistence of HPV 16 strongly predicted cervical intraepithelial neoplasia grade II+, with a three year cumulative incidence of 40.8% (26.4% to 55.1%). Similar patterns were observed for the five year cumulative incidence of grade II+ and for three year and five year cumulative incidence of grade III+.

Conclusions: Short term persistence of a prevalently detected carcinogenic HPV infection, especially HPV 16, strongly predicts a subsequent diagnosis of cervical intraepithelial neoplasia II+ over the next few years.

Fig 1 Flow of women through trial. High risk refers to women with positive results on screening or with risk factors (such as five or more lifetime sexual partners) for HPV or cervical neoplasia. Low risk refers to women with negative results and no risk factors. CIN= cervical intraepithelial neoplasia; PCR=polymerase chain reaction

Fig 2 Cumulative incidence of cervical intraepithelial neoplasia (CIN) grade II or worse (II+) and grade III+ after repeat measurements of carcinogenic human papillomavirus (HPV) at about one year interval (9-21 months) in women who tested positive for carcinogenic HPV twice (Pos/Pos), positive for carcinogenic HPV at enrolment but negative at follow-up (“cleared”), negative for carcinogenic HPV at enrolment but positive at follow-up (“acquired”), or negative at both time points (Neg/Neg). In right panels the Pos/Pos category is further stratified into those with at least one persistent carcinogenic HPV genotype (persistence) v positive for different carcinogenic HPV genotypes (Pos/Pos (no persistence)), with unstratified Pos/Pos curves shown for reference. Time 0* indicates start time of analysis, 9-21 months after enrolment

Fig 3 Cumulative incidence of cervical intraepithelial neoplasia (CIN) grade II or more severe (grade II+) or grade III+ after repeat measurements of human papillomavirus (HPV) at about one year interval (9-21 months) in women who had persistent HPV 16, had persistent HPV 18, tested positive for carcinogenic HPV twice (Pos/Pos), tested positive for carcinogenic HPV at enrolment but negative at follow-up (“cleared”), tested carcinogenic HPV negative at enrolment but positive at follow-up (“acquired”), and tested negative at both time points (Neg/Neg). In right panels same groups are stratified by age. Time 0* indicates start time of analysis, 9-21 months after enrolment