Persistence of type-specific human papillomavirus infection and increased long-term risk of cervical cancer

Abstract

Background: Human papillomavirus (HPV) persistence is the pivotal event in cervical carcinogenesis. We followed a large-scale community-based cohort for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer including invasive and in situ carcinoma.

Methods: At the baseline examination in 1991-1992, 11,923 participants (aged 30-65 years) consented to HPV testing and cytology; 6923 participants were reexamined in 1993-1995. For HPV testing, we used a polymerase chain reaction-based assay that detected 39 HPV types. Women who developed cervical cancer were identified from cancer and death registries. Cumulative risks for developing cervical cancer among infected and persistently infected women were calculated by the Kaplan-Meier method.

Results: Of 10,123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV16, HPV58 (without HPV16), or other carcinogenic HPV types (without HPV16 or HPV58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV-negative at both visits (hazard ratio = 75.4, 95% confidence interval = 31.8 to 178.9). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age: The risks were 5.5%, 14.4%, and 18.1% for women aged 30-44 years, 45-54 years, and 55 years and older, respectively. However, newly acquired infections were associated with a low risk of cervical cancer regardless of age.

Conclusions: HPV negativity was associated with a very low long-term risk of cervical cancer. Persistent detection of HPV among cytologically normal women greatly increased risk. Thus, it is useful to perform repeated HPV testing following an initial positive test.

Figure 1

CONSORT diagram of study participants in long-term follow-up study on cervical neoplasia, including carcinoma in situ (CIS) and invasive cervical cancer (ICC). At the baseline examination in 1991–1992, 11 923 participants (aged 30–65 years) consented to human papillomavirus (HPV) testing and cytology (Pap); following the exclusions noted, 6923 participants were reexamined in 1993–1995. Women who developed cervical cancer were identified from cancer and death registries, permitting calculation of cumulative risk related to baseline status and also related to the combination of results from baseline and second examinations. Only women who were initially normal were included for the analyses for baseline HPV infection (n = 10123) and repeated HPV testing (n = 6666).

Figure 2

Kaplan–Meier estimates of cumulative risk (%) of histologically confirmed cervical carcinoma in situ (CIS) and invasive cancer (ICC) during 16-year follow-up by type-specific human papillomavirus (HPV) infection. The cumulative risk by various HPV infection status and age at study entry were derived by using Kaplan–Meier method. A) Cumulative risk by type-specific HPV infection at baseline examination: 13.5% (95% confidence interval [CI] = 6.5% to 28.0%) for HPV16 infection, 10.3% (95% CI = 4.9% to 21.7%) for HPV58 infection, 4.0% (95% CI = 2.6% to 6.2%) for carcinogenic types (without HPV16 and HPV58) infection, 2.1% (95% CI = 0.7% to 6.6%) for probably and/or possibly carcinogenic types (without carcinogenic types) infection, 1.1% (95% CI = 0.4% to 2.8%) for other types infection, and 0.26% (95% CI = 0.17% to 0.41%) for HPV-negative women. B) Cumulative by HPV infection of carcinogenic types at baseline and second examinations: 12.4% (95% CI = 8.0% to 19.2%) for persistent of carcinogenic types, 0.77% (95% CI = 0.19% to 3.1%) for clearance of carcinogenic types, 0.0% for purely acquisition of carcinogenic types, and 0.14% (95% CI = 0.07% to 0.3%) for persistent negative. Asterisk indicates there were no cases of CIS or cancer among women with pure acquisition of carcinogenic HPV types in the absence of persistence or clearance of other types. C) Cumulative risk by age at study entry for persistent carcinogenic type (on a type-specific basis): 5.5% (95% CI = 1.7% to 17.7%) for women aged 30–44 years, 14.4% (95% CI = 6.9% to 30.4%) for women aged 45–54 years, 18.1% (95% CI = 9.8% to 33.3%) for women aged 55–65 years.