A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study

Abstract

Background: Human papillomavirus (HPV) DNA testing is more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 3 and cancer (≥CIN3). Adding HPV testing to cytology is recommended for women ≥30 but long-term prospective studies of HPV testing are rare.

Methods: Beginning in 1989-1990, ~20,000 women in a prepaid health maintenance organization (median age = 34) were followed passively by recommended annual cytology. We tested archived cervicovaginal lavage specimens collected at enrollment, primarily by MY09-MY11 PCR-based methods, for carcinogenic HPV types. We calculated positive and negative predictive values for the entire study period, and Kaplan-Meier estimates of cumulative probability for ≥CIN3, up to 18 years of follow-up.

Results: We observed 47 cases of invasive cervical cancer during the study period, and 156 cases of CIN3. Predictive values and Kaplan-Meier analyses yielded the same conclusions. In women 30 and older, the reassurance against ≥CIN3 following a single negative HPV test was long-lasting (cumulative probability = 0.7% during follow-up). In this age group, a single HPV test (positive vs. negative, hazard ratio of 8.5, 95% CI = 4.8-15.1) provided greater long-term risk stratification than a single cytologic result (abnormal vs. normal, HR = 2.9, 95% CI = 1.2-6.6). The risk for ≥CIN3 was higher for HPV16 than for the average of the other carcinogenic types (hazard ratio = 2.7).

Conclusion and impact: The data from this cohort study show the long-term predictive value of HPV testing, particularly in women ≥30, and a possible role for distinguishing particularly carcinogenic types like HPV16.

Figure 1

Consort Diagram for Portland Cohort Study.

Figure 2

Type-specific HPV results at enrollment, and positive predictive value of worst disease observed in follow-up. Figure 2a. Women <30. Figure 2b. Women 30+.

Figure 3

Cumulative Probability of ≥CIN3 Stratified by HPV Test Results. The curves exclude enrollment cases of cytologic HSIL or histologic ≥CIN2, to permit calculation of hazard ratios using proportional hazards methods. The percentages of excluded enrollment cases are plotted separately as plus signs in the first year time bin. The numbers of women still at risk for each HPV test stratum are listed below the graph. The cumulative risk (cumulative probability) is plotted using Kaplan-Meier methods that take into account censoring due to cytologic HSIL or histologic ≥CIN2 or losses to follow-up. The PPV includes all cases observed combining enrollment and follow-up, but does not take into account censoring. Figure 3a. Women <30: HPV16 infection, cumulative probability = 14.6 (95% CI = 10.0-20.9) and PPV = 11.1 (8.1-14.0); other carcinogenic types, cumulative probability = 7.0 (4.2-11.4), PPV= 3.2 (2.0-4.3); no carcinogenic types, cumulative probability = 1.8 (1.2-2.5) and PPV = 0.7 (0.4-0.9). Figure 3b. Women 30+: HPV16 infection, cumulative probability = 8.5 (95% CI = 4.1-17.2) and PPV = 13.8 (8.2-19.4); other carcinogenic types, cumulative probability = 3.1 (1.6-6.1) and PPV= 3.7 (2.0-5.4); no carcinogenic types, cumulative probability = 0.7 (0.5-0.9) and PPV = 0.4 (0.3-0.5).

Figure 4

Cumulative Probability of CIN2 Stratified by HPV Test Results. The curves exclude enrollment cases of cytologic HSIL or histologic ≥CIN2, to permit calculation of hazard ratios using proportional hazards methods. The percentages of excluded enrollment cases are plotted separately as plus signs in the first year time bin. The numbers of women still at risk for each HPV test stratum are listed below the graph. The cumulative risk (cumulative probability) is plotted using Kaplan-Meier methods that take into account censoring due to cytologic HSIL or histologic ≥CIN2 or losses to follow-up. The PPV includes all cases observed combining enrollment and follow-up, but does not take into account censoring. Figure 4a. Women <30: HPV16 infection, cumulative probability = 19.5 (95% CI = 14.2-26.3) and PPV = 14.7 (11.4-18.0); other carcinogenic types, cumulative probability = 14.1 (9.9-19.8), PPV= 7.8 (6.0-9.6); no carcinogenic types, cumulative probability = 4.1 (3.4-5.0) and PPV = 1.8 (1.5-2.2). Figure 4b. Women 30+: HPV16 infection, cumulative probability = 9.7 (95% CI = 2.7-31.4) and PPV = 15.9 (9.9-21.8); other carcinogenic types, cumulative probability = 10.1 (7.0-14.4), PPV= 10.4 (7.6-13.2); no carcinogenic types, cumulative probability = 1.3 (1.0-1.8) and PPV = 0.8 (0.6-0.9).

Figure 5

Cumulative Probability of ≥CIN2 Stratified by HPV Test and Cytology Results. The curves exclude enrollment cases of ≥CIN2, to permit calculation of hazard ratios using proportional hazards methods. The percentages of excluded enrollment cases are plotted separately as plus signs in the first year time bin. The numbers of women still at risk for each HPV test stratum are listed below the graph. The cumulative probability is plotted using Kaplan-Meier methods that take into account censoring due to cytologic HSIL or histologic ≥CIN2 or losses to follow-up. The PPV includes all cases observed combining enrollment and follow-up, but do not take into account censoring. Figure 5a. Women <30: HPV+ ASC/LSIL, cumulative probability = 8.9 (95% CI = 5.2-15.0) and PPV = 14.9 (11.1-18.6); HPV- ASC/LSIL, cumulative probability = 6.4 (2.2-17.7), AR= 5.8 (2.1-9.5); HPV+ NILM, cumulative probability = 15.2 (11.7-19.6) and PPV = 7.2 (5.5-8.8), HPV- NILM, cumulative probability = 3.9 (3.1-4.9) and AR = 1.6 (1.3-1.9). Figure 5b. Women 30+: HPV+ ASC/LSIL, cumulative probability = 7.4 (95% CI = 3.4-15.8) and PPV = 24.2 (16.5-31.8); HPV- ASC/LSIL, cumulative probability = 1.4 (0.5-3.7), PPV= 2.3 (0.8-3.8); HPV+ NILM, cumulative probability = 8.9 (5.9-13.5) and PPV = 6.1 (3.9-8.3), HPV- NILM, cumulative probability = 1.1 (0.9-1.4) and PPV = 0.7 (0.5-0.8).