Abstract
Background:
Monitoring human papillomavirus (HPV) types detected in cervical precancers has been one approach to evaluate HPV vaccination impact in the United States. During 2008–2014, the proportion of cervical precancers positive for HPV16/18 decreased overall and among some demographic and histologic subgroups. This updated analysis describes trends through 2019.
Methods:
We analyzed cervical precancers among women aged 20–39 years from a 5-site, population-based surveillance program for cervical intraepithelial neoplasia grades 2 or higher and adenocarcinoma in situ (AIS; collectively CIN2+). Available archived diagnostic tissue was tested for HPV 16, 18, and other HPV types. We evaluated the average annual percent change (AAPC) in the proportion of cervical precancers with HPV 16 or 18 detected overall and by vaccination status, age group, diagnosis, race/ethnicity, and surveillance site.
Results:
During 2008–2019, 17,323 CIN2+ cases had valid typing results. The proportion of cases positive for HPV16/18 significantly decreased 3.6% per year. The largest decrease occurred among cases in vaccinated women (AAPC = –8.9), with smaller but still significant decreases among unvaccinated women (AAPC = −2.3). Significant decreases were observed among all subgroups evaluated except women aged 35–39 years, AIS, and Asian women.
Conclusions:
During 2008–2019, decreases in the proportion of CIN2+ that were HPV16/18-positive among vaccinated and unvaccinated women, and in most subgroups evaluated, suggest direct and indirect HPV vaccination impact.
Impact:
HPV vaccination impact on precancers is prognostic of future decreases in cervical cancer. Continued monitoring can enable evaluation of vaccination impact in population subgroups.
Introduction
Human papillomavirus (HPV) is the most common sexually transmitted infection. 1 Persistent infection with high-risk (HR) HPV types can lead to cervical precancers, which, if untreated, can progress to invasive cervical cancers. HPV 16 and 18 cause the majority of cervical cancer cases. 2 The quadrivalent HPV vaccine, which protects against HPV types 6, 11, 16, and 18, was first licensed and recommended in 2006 in the United States for females, with routine vaccination for males recommended in 2011. 3,4 In 2014, the 9-valent HPV vaccine was licensed, offering protection against 5 additional types (31, 33, 45, 52, and 58). Since late 2016, the 9-valent vaccine has been the only HPV vaccine available in the United States. 5,6 Routine HPV vaccination is recommended for all adolescents at age 11–12 years with catch-up through 26 years; the vaccination series can be started at age 9 years. 7 Since introduction of HPV vaccination, coverage among adolescents has increased, and in 2023 coverage with ≥1 dose among female adolescents aged 13–17 years was 78.5%. 8 Among women aged 18–26 years, based on self-report, vaccination coverage with ≥1 dose was 53.6% in 2018. Only 21.9% of those vaccinated received vaccine at the routine age. 9
Vaccine impact on cervical cancer may take many years to observe; therefore, vaccine impact monitoring has focused on outcomes that can be observed sooner after HPV exposure, including HPV infection and cervical precancer. The National Health and Nutrition Examination Survey (NHANES) monitors prevalence of HPV infection through self-collected cervicovaginal specimens. Data from the 2015–2018 NHANES showed quadrivalent-vaccine HPV type prevalence decreased 81% compared to the prevaccine era among women aged 20–24 years. 10 Studies in the United States have demonstrated decreases in cervical precancer incidence during the HPV vaccination era among young adult women, using screened women as the denominator to account for changes in screening frequency recommendations during this time. 11–17
Evaluation of the proportion of cervical precancers caused by specific HPV types is a complementary approach to evaluating vaccination impact that may be less subject to confounding by changes in screening practices and can provide information on impact in population subgroups. A previous analysis from the Human Papillomavirus Vaccine Impact Monitoring Project (HPV-IMPACT) evaluated the proportion of cervical intraepithelial neoplasia grades 2–3 and adenocarcinoma in situ (collectively CIN2+) cases in which HPV types 16 or 18 were detected (i.e., HPV16/18-positive) during 2008–2014, overall and stratified by vaccination status, age group, race/ethnicity, and diagnosis. 18 That analysis described trends qualitatively and demonstrated significant decreases in the proportion of precancers that were HPV16/18-positive overall and in most subgroups, particularly among younger women. This analysis updates and extends the previous analysis by describing quantitative trends in proportion of precancers that were HPV16/18-positive through 2019.
Materials and Methods
Study design/population
The Human Papillomavirus Vaccine Impact Monitoring Project (HPV-IMPACT) is a population-based laboratory surveillance network established by the Centers for Disease Control and Prevention (CDC) in 2008 to monitor high-grade cervical lesions. Sites are part of the Emerging Infections Program (EIP) and, in total, conduct surveillance of >1.5 million women aged ≥18 years in Alameda County, California; New Haven County, Connecticut; Monroe County, New York; 28 zip codes in metropolitan Portland, Oregon; and Davidson County, Tennessee. CDC and most sites determined HPV-IMPACT to be public health surveillance and exempt from institutional review board (IRB) review. IRB approvals were obtained from one site (California). This activity is not human subjects research, therefore patient consent was not required. Details about the project have been previously described. 19,20
Histopathology laboratories within the catchment areas report all cases of CIN2+ to the HPV-IMPACT sites. Because different classification systems and nomenclature have been used for cervical histopathology diagnoses, cases are identified using all major terminology systems (e.g., CIN, dysplasia, lower anogenital squamous terminology), and site staff standardize classification and reporting of CIN grades. Site staff obtained demographic and clinical information (e.g., vaccination history, screening history, histologic diagnosis) from medical chart reviews and immunization registries. Some sites supplemented this information with patient interviews and administrative data.
Residual diagnostic tissue from lesions in women aged <40 years was sent to CDC for HPV typing. Typing was restricted to this age group because vaccination impact was expected to be seen first in younger people. Details of laboratory methods have been previously described. 21 For specimens tested at the CDC during 2008–2019 (regardless of specimen collection date), Linear Array HPV Genotyping Assay was used (Supplementary Figure 1). Specimens with inadequate or HPV-negative results were retested using a Line Probe Assay (LiPA).22 After Linear Array was discontinued in 2019, the Novaplex II HPV28 Detection Assay (Novaplex) was the primary assay used. A validation study was conducted that compared Novaplex to Linear Array with reflex to the Line Probe Assay and demonstrated high agreement between the assays. 23 TypeSeq was used on 130 specimens collected in 2015–2019 (1.8% of cases typed during this period) due to possible sample degradation because they were stored for prolonged times during the COVID-19 pandemic. 24 All assays detect and identify HPV 16 and 18, other 9-valent HPV vaccine types, and all other HR-HPV types, but vary in which other HPV types are identified.
Study variables
This analysis was restricted to HPV-IMPACT CIN2+ cases in women aged 20–39 years that had valid typing results and included data on cases diagnosed during 2008–2019. If either HPV 16 or 18 was detected in the lesion, the case was considered HPV16/18-positive. Age was categorized into four groups: 20–24, 25–29, 30–34, and 35–39 years, and diagnosis year was analyzed as three 4-year periods. HPV vaccination status was categorized as vaccinated before abnormal screen (≥1 HPV vaccine dose received at any time before the screening test that triggered evaluation of the lesion), not vaccinated before abnormal screen (documentation of no vaccination or vaccinated on the same day or after date of screening test), vaccinated with unknown timing, and vaccination status unknown. Lesions were classified based on the diagnostic pathology report as CIN2, CIN2/3, CIN3, or AIS (individuals diagnosed with both AIS and CIN2–3 were included in the AIS category). Race/ethnicity was categorized as non-Hispanic White, non-Hispanic Black or African American, Hispanic, Asian, other (including multiple races), and unknown.
Statistical analysis
We described characteristics (i.e., demographic, clinical, site, time period of diagnosis) in cases with typing results available by patient age. We also described eligibility for vaccination by age and CIN2+ diagnosis year according to national vaccination recommendations. We calculated the annual proportion of CIN2+ lesions that were HPV16/18-positive from 2008–2019 overall and stratified by vaccination status, age group, race/ethnicity (excluding other and unknown race), diagnosis, and surveillance site. These analyses were conducted in SAS version 9.4 (SAS Institute, RRID: SCR_008567).
Using the proportions calculated above, trends in the proportion of CIN2+ cases that were HPV16/18-positive were estimated using log-linear joinpoint models (Joinpoint Regression Program, v5.3.0.0, RRID:SCR_018129). We used the weighted Bayesian information criterion for model selection and the empirical quantile method to calculate confidence intervals. Trends were estimated overall and stratified by subgroup. Results were reported as average annual percent change (AAPC), and 95% confidence intervals (CIs) were interpreted as statistically significant if they did not include zero. For models with joinpoints, the annual percent change (APC) for each segment was reported. Based on the number of years included in this analysis, the maximum number of joinpoints considered for models was 2, and segments required at least 4 data points.
Data availability
Access to the HPV-IMPACT data will be through CDC. https://www.cdc.gov/hpv-impact/data/index.html
Results
From 2008 through 2019, 26,351 CIN2+ cases diagnosed among women aged 20–39 years were reported to HPV-IMPACT. Of the CIN2+ cases, 17,323 (66%) had valid typing results. Of these, 13% were in women who were vaccinated before an abnormal screen and 50% were CIN2. About a third of cases were diagnosed during each four-year time period (32%–34%) (Table 1, Supplementary Table 1).
Table 1:
Characteristics of 20–39-year-olds with CIN2+ with typing data by age group, HPV-IMPACT, 2008–2019 (N = 17,323).
| Characteristics among typed cases | Total N=17,323 | Age group (years) | |||
|---|---|---|---|---|---|
| 20–24 N= 3387 | 25–29 N=6253 | 30–34 N=4970 | 35–39 N=2713 | ||
| n (col %) | n (col %) | n (col %) | n (col %) | n (col%) | |
| HPV vaccination status | |||||
| Vaccinated before abnormal screen | 2294 (13.2) | 838 (24.7) | 1151 (18.4) | 271 (5.5) | 34 (1.3) |
| Vaccinated with unknown timing | 399 (2.3) | 148 (4.4) | 176 (2.8) | 69 (1.4) | 6 (0.2) |
| Not vaccinated before abnormal screen1 | 5063 (29.2) | 1170 (34.5) | 1626 (26.0) | 1352 (27.2) | 915 (33.7) |
| Unknown vaccination status | 9567 (55.2) | 1231 (36.3) | 3300 (52.8) | 3278 (66.0) | 1758 (64.8) |
| Histologic grade of lesion | |||||
| CIN2 | 8668 (50.0) | 2061 (60.9) | 3171 (50.7) | 2228 (44.8) | 1208 (44.5) |
| CIN2/3 | 3002 (17.3) | 511 (15.1) | 1059 (16.9) | 931 (18.7) | 501 (18.5) |
| CIN3 | 5349 (30.9) | 792 (23.4) | 1938 (31.0) | 1701 (34.2) | 918 (33.8) |
| AIS | 304 (1.8) | 23 (0.7) | 85 (1.4) | 110 (2.2) | 86 (3.2) |
| Race/ethnicity | |||||
| Asian | 1070 (6.2) | 88 (2.6) | 334 (5.3) | 392 (7.9) | 256 (9.4) |
| Black or African American, non-Hispanic | 2473 (14.3) | 642 (19.0) | 869 (13.9) | 640 (12.9) | 322 (11.9) |
| White, non-Hispanic | 9889 (57.1) | 1956 (57.8) | 3642 (58.2) | 2819 (56.7) | 1472 (54.3) |
| Hispanic | 2637 (15.2) | 463 (13.7) | 931 (14.9) | 760 (15.3) | 483 (17.8) |
| Other (including multiple races) | 275 (1.6) | 43 (1.3) | 107 (1.7) | 95 (1.9) | 30 (1.1) |
| Unknown | 979 (5.7) | 195 (5.8) | 370 (5.9) | 264 (5.3) | 150 (5.5) |
| Time period of diagnosis | |||||
| 2008–2011 | 5950 (34.3) | 1841 (54.4) | 2005 (32.1) | 1327 (26.7) | 777 (28.6) |
| 2012–2015 | 5548 (32.0) | 1032 (30.5) | 2082 (33.3) | 1601 (32.2) | 833 (30.7) |
| 2016–2019 | 5825 (33.6) | 514 (15.2) | 2166 (34.6) | 2042 (41.1) | 1103 (40.7) |
| Site | |||||
| California | 3736 (21.6) | 419 (12.4) | 1368 (21.9) | 1246 (25.1) | 703 (25.9) |
| Connecticut | 3779 (21.8) | 935 (27.6) | 1329 (21.3) | 976 (19.6) | 539 (19.9) |
| New York | 3279 (18.9) | 906 (26.7) | 1097 (17.5) | 822 (16.5) | 454 (16.7) |
| Oregon | 3435 (19.8) | 492 (14.5) | 1281 (20.5) | 1081 (21.8) | 581 (21.4) |
| Tennessee | 3094 (17.9) | 635 (18.7) | 1178 (18.8) | 845 (17.0) | 436 (16.1) |
HPV: Human papillomavirus; CIN: cervical intraepithelial neoplasia; AIS: adenocarcinoma in situ with or without CIN
Documentation of no vaccination or vaccinated on the same day or after date of screening test.
Age at diagnosis of women with CIN2+ varied by HPV vaccination status, histologic grade, race/ethnicity, and time period. A higher proportion of women aged 20–24 years were vaccinated before an abnormal screen (25%) compared to women aged 35–39 years (1%). A slightly higher proportion of women aged 35–39 years were diagnosed with AIS (3%) compared to women in the other age groups (1%–2%). Lastly, a plurality of women aged 35–39 years were diagnosed during 2016–2019 (41%) whereas the majority of women aged 20–24 years were diagnosed in 2008–2011 (54%).
Women had different opportunities for vaccination based on age and diagnosis year (Figure 1). Women diagnosed with CIN2+ at younger ages in 2014–2019 (3%) would have been eligible for vaccination at the routine age, i.e., they were aged ≤12 years when HPV vaccination was first recommended in 2006. Most women in this analysis were older than the routine age for vaccination when the vaccine was first recommended and would only have been eligible for catch-up vaccination (aged 13–26 years, 79%) or not age eligible for either routine or catch-up vaccination (18%). Of the 2,294 cases among women vaccinated before an abnormal screen, 1,666 (73%) were in women aged ≥18 years at time of vaccination and only 32 (1%) were vaccinated at 11 or 12 years of age.
Figure 1:
Vaccine eligibility by age and year of diagnosis among 20- to 39-year-old women, HPV-IMPACT, 2008–2019. The proportion is the proportion of all typed cases in each vaccination category. Since 2006, CDC has recommended routine vaccination for females aged 11–12 years and catch-up vaccination for females aged 13–26 years. Shared clinical decision-making for consideration of vaccination of adults aged 27–45 years was not recommended until 2019.
The proportion of typed CIN2+ cases that were positive for HPV16/18 significantly decreased from 53.1% in 2008 to 36.4% in 2019 (AAPC = −3.6%) (Table 2, Figure 2A, Supplementary Table 2). From 2008 to 2019, a significant decrease of 8.9% per year, on average, was seen among cases in women vaccinated before an abnormal screen; a smaller, significant decrease of 2.3% per year was seen among those not vaccinated before an abnormal screen (Figure 2A). Significant decreases were seen among the younger age groups, i.e. <35 years (Figure 2B). Decreases were greatest in women aged 20–24 years (AAPC = −8.3), followed by women aged 25–29 years (AAPC = −5.7), and then by women aged 30–34 years (AAPC = −2.0). A joinpoint was present in 2012 for the 25–29-year-old age group with a steeper decrease from 2012 to 2019 years (APC = −7.8) that was similar to the decrease seen in 20–24-year-olds. No decrease was observed in women aged 35–39 years. Within specific histologic diagnoses, significant decreases were seen among CIN2 (AAPC = −4.2%), CIN2/3 (AAPC = −3.7%), and CIN3 (AAPC = −2.7%), but not AIS (AAPC = −0.7%) (Figure 2C). Both CIN2 and CIN3 trends had joinpoints. For CIN2, a large decrease during 2008–2016 was followed by a plateau or small non-significant increase during 2016–2019 (APC = 1.0%); for CIN3, a slight, non-significant decrease during 2008–2014 was followed by a steeper, significant decrease during 2014–2019 (APC = −4.7%). By race/ethnicity, significant decreases in proportion of CIN2+ cases positive for HPV16/18 were seen among non-Hispanic White, non-Hispanic Black or African American, and Hispanic women (Figure 2D). The decreases among non-Hispanic White (AAPC = −4.0%) and non-Hispanic Black or African American women were similar (AAPC = −4.7%). Smaller decreases were observed among Hispanic (AAPC = −1.9%) women. The decrease among Asian women was not significant (AAPC = −2.5%). Lastly, significant decreasing trends were seen in all surveillance sites, with AAPCs ranging from −1.9% in Tennessee to −4.2% in New York (Figure 2E).
Table 2:
Average annual percent change (AAPC) and segment-specific annual percent change (APC) in proportion of CIN2+ among 20- to 39-year-old women that were HPV16/18-positive overall and stratified by vaccination status, age group, diagnosis, race/ethnicity, and site, HPV-IMPACT, 2008–2019.
| Subgroup | AAPC (95% CI) | APC (95% CI) |
|---|---|---|
| Overall | −3.6* (−4.2, −3.1) | |
| HPV vaccination status 1 | ||
| Vaccinated before abnormal screen | −8.9* (−12.9, −5.4) | |
| Not vaccinated before abnormal screen2 | −2.3* (−3.4, −1.5) | |
| Unknown vaccination status | −2.8* (−3.5, −2.1) | |
| Age (years) 3 | ||
| 20–24 | −8.3* (−11.7, −6.6) | |
| 25–29 | −5.7* (−7.7, −4.6) | 2008–2012: −2.0 (−4.9, 3.6) |
| 2012–2019: −7.8* (−14.6, −6.3) | ||
| 30–34 | −2.0* (−2.7, −1.1) | |
| 35–39 | −0.2 (−1.2, 1.0) | |
| Diagnosis | ||
| CIN2 | −4.2* (−5.7, −3.3) | 2008–2016: −6.1* (−9.7, −4.7) |
| 2016–2019: 1.0 (−5.0, 5.4) | ||
| CIN2/3 | −3.7* (−4.6, −3.0) | |
| CIN3 | −2.7* (−3.6, −2.1) | 2008–2014: −1.1 (−2.2, 1.3) |
| 2014–2019: −4.7* (−8.2, −3.1) | ||
| AIS | −0.7 (−2.0, 0.2) | |
| Race/Ethnicity 4 | ||
| White, non-Hispanic | −4.0* (−5.0, −3.2) | |
| Black or African American, non-Hispanic | −4.7* (−8.2, −2.0) | |
| Hispanic | −1.9* (−3.7, −0.1) | |
| Asian | −2.5 (−6.4, 1.8) | |
| Site | ||
| California | −3.8* (−6.2, −2.2) | 2008–2011: 2.5 (−3.3, 10.2) |
| 2011–2019: −6.1* (−14.0, −4.7) | ||
| Connecticut | −4.0* (−5.9, −2.5) | |
| New York | −4.2* (−6.7, −2.6) | |
| Oregon | −4.0* (−5.4, −2.8) | |
| Tennessee | −1.9* (−3.5, −0.2) | |
HPV: Human papillomavirus; CIN: cervical intraepithelial neoplasia; AIS: adenocarcinoma in situ with or without CIN; AAPC: Average Annual Percent Change; APC: Annual Percent Change
399 cases were vaccinated but timing of vaccination in relation to screening was unknown. The AAPC among these 399 cases was −8.1% (95% CI = −13.2% to −2.7%).
Documentation of no vaccination or vaccinated on the same day or after date of screening test.
The previous HPV-IMPACT analysis included 18–20- and 21–24-year-olds, but due to changes in screening recommendations, very few cases have been diagnosed in 18–19-year-olds in recent years. HPV-IMPACT now reports data in standard 5-year age groups starting at age 20 years.
Other (including multiple races) and unknown excluded from analysis (n=1254).
Indicates p <.05.
Figure 2:
Proportion and trends of CIN2+ cases among 20- to 39-year-old women that were HPV16/18-positive by vaccination status (Panel A), age group (Panel B), diagnosis (Panel C), race/ethnicity (Panel D), and site (Panel E) by year, HPV-IMPACT, 2008–2019. Gray bars indicate proportion of cases positive for HPV16/18 for each year and lines are estimated from joinpoint models. Different shades of gray indicate years; 2008 is darkest gray and 2019 is lightest gray. CIN: cervical intraepithelial neoplasia; AIS: adenocarcinoma in situ with or without CIN; AAPC: Average Annual Percent Change; APC: Annual Percent Change; NH: non-Hispanic; * Indicates p <.05.
Discussion:
This analysis of data from a multi-site, population-based surveillance project revealed a significant average decrease of 3.6% per year in the proportion of CIN2+ cases that were HPV16/18-positive from 2008 to 2019. Significant decreases were observed among both those vaccinated and not vaccinated before an abnormal screen, with the greatest decrease, 8.9% per year, observed among women with documented vaccination before an abnormal screen. In 2008, more than half of all cervical precancers in women aged 20–39 years were HPV16/18-positive. In 2019, 13 years after vaccine introduction, this proportion had decreased to 36.4% overall and was 21.9% among those vaccinated before an abnormal screen. Importantly, significant decreases were observed in histologic and demographic subgroups where decreases were not previously observed in our analyses (i.e., CIN3 diagnoses and Hispanic women).18
In this analysis, the magnitude of decreases in the proportion of precancers that were HPV16/18-positive varied by age. The largest decrease was among 20–24-year-olds and smaller decreases were observed in older age groups consistent with the higher proportion of women vaccinated in younger age groups; older women in this analysis did not have the same eligibility for vaccination as younger women because of the timing of the HPV vaccine recommendation in the United States. In addition, among women aged 25–29 years, a more rapid decrease was seen after 2012. This more rapid decline is likely due to increasing percentage of women in this age group having been vaccinated. Based on NHANES data, vaccination coverage with ≥1 HPV vaccine dose in women aged 25–29 years increased from 5.1% in 2007–2008 to 19.9% in 2011–2012 and continued to increase to 37.1% in 2015–2016.25 Continued declines in the proportion of precancers HPV16/18-positive were evident among women aged 30–34 years: HPV16/18 detection was 50.0% in 2008, 45.5% in 2014, and 43.1% in 2019. Consistent with the earlier analysis, no decrease in HPV16/18 detection was seen among women aged 35–39 years. This finding is not unexpected because no women in this age group were eligible for routine vaccination and most were not eligible for catch-up vaccination. Over time, vaccine impact in older age groups has been observed in analyses of CIN2+ incidence and HPV prevalence. 10,16 Analyses have demonstrated decreased risk of CIN2+ associated with earlier age of vaccination. 17 Vaccination is most effective when initiated prior to any sexual experience. Therefore, future trends of HPV16/18 detection among CIN2+ are likely to demonstrate greater and more rapid decreases when more women vaccinated prior to HPV exposure enter screening age groups.
Significant decreases in HPV16/18 detection were seen for all grades of CIN, notably CIN3. CIN3 has a higher likelihood of progressing to cervical cancer than lower grade precancer and is the most proximal outcome to squamous cell carcinoma. Decreases in the proportion of CIN3 diagnoses with HPV16/18 detected are most indicative of future decreases in cervical cancers. In the previous analysis, there was no significant decrease in the proportion of CIN3 lesions that were HPV16/18-positive from 2008 to 2014 18 whereas a significant decrease from 2014 to 2019 was observed in this analysis. This is likely due in part to increases in women vaccinated at younger ages. Decreases in the proportion of CIN3/AIS lesions that were HPV16/18-positive among women aged 18–25 years during the vaccine era have also been seen in a study from Australia, where there is a strong vaccination program leading to higher HPV vaccination coverage compared to the United States. 26
Continuing trends seen in our previous analysis, 18 we observed decreases in the proportion of CIN2 and CIN2/3 cases that were HPV16/18-positive. The proportion of CIN2 cases that were HPV16/18-positive decreased 4.2% per year from 41.1% in 2008 to 25.0% in 2019, although the decrease plateaued after 2016. The proportion of CIN2/3 that were HPV16/18-positive decreased steadily by 3.7% per year from 2008 to 2019.
We found no significant decrease in HPV16/18 detection among AIS diagnoses, though a decrease in AIS incidence was observed among screened 21–24 year-olds during 2008–2015, suggesting that HPV vaccination has had an impact on this outcome. 27 There are several possible reasons why no significant decrease in proportion with HPV16/18 detection occurred. Since over 90% of AIS cases were attributable to HPV16 or HPV18 in 2008 and few other HPV types have been associated with AIS, 27 it may be difficult to detect a proportional decrease, even though absolute numbers of AIS cases have decreased. Another reason is that a higher proportion of women aged 35–39 years were diagnosed with AIS compared to other age groups, meaning most did not have the opportunity to be vaccinated based on age eligibility, and if they were vaccinated, they did not receive vaccination at the recommended routine age. In addition, this analysis included a small number of AIS cases, limiting statistical power to evaluate significant changes in trends.
AAPCs indicated decreases during 2008–2019 at all surveillance sites and among most racial/ethnic groups evaluated. Overall, these data suggest that decreases in HPV16/18-attributable cervical precancer are not limited to specific population subgroups. However, differences in the magnitude of decreases were observed by racial/ethnic group, with the largest decreases among non-Hispanic White and non-Hispanic Black or African American women. Racial/ethnic differences might be explained by varying characteristics (i.e., age, diagnosis, vaccination status) by racial/ethnic group in this surveillance project, reported previously. 18 In the previous analysis, compared to non-Hispanic White and non-Hispanic Black or African American women, lower proportions of Asian and Hispanic women were vaccinated and Asian and Hispanic women had higher proportions of CIN3 diagnoses. Also, Asian women were older on average. There was no significant decline in proportion of CIN2+ that were 16/18-positive among Asian women, the smallest racial/ethnic population subgroup in our analysis, and a smaller but statistically significant decline among Hispanic women. However, a higher proportion of women with a CIN2+ diagnosis aged 35–39 years were Asian or Hispanic compared to younger age groups. No one in this age group diagnosed before 2015 was eligible for vaccination, and none in this age group had the opportunity to receive vaccination at the routine age, when vaccination is most effective. Based on national adolescent HPV vaccination coverage among different racial/ethnic groups, which shows equitable vaccination coverage, 28 we do not expect this differential trend in HPV16/18 detection in cervical precancer cases by race/ethnicity to continue.
The 12 percentage-point decrease among those not vaccinated before an abnormal screen suggests indirect vaccination impact through herd protection, also noted previously in HPV-IMPACT data through 2014, when the decrease was 8 percentage points. 18 Herd protection for HPV infection has been observed in NHANES, the survey that monitors US HPV prevalence, and in monitoring systems in other countries. 29,30 Other than our HPV-IMPACT analyses, we are unaware of studies showing herd protection for cervical precancer.
Cervical precancer cases are monitored to evaluate vaccine impact, as they are a proximal outcome to cervical cancer and develop more rapidly than cervical cancer. Not all precancers will progress to cancer. HPV types have varying oncogenic potential, with HPV types 16 and 18 being the most oncogenic. With the high vaccination impact in the United States, it is likely that the less oncogenic HPV types will account for increasing proportions of precancer cases detected by screening. With decreased risk of progression to cancer of screen-detected precancer, current cervical cancer screening practices may result in an increase in the number needed to screen to detect one cancer. Cervical cancer screening recommendations that account for the decreasing HPV16/18 prevalence and vaccination history may need to be considered in the future. 17,31,32
This analysis had limitations. Vaccination status was not known on >50% of cases; ascertainment of adolescent vaccination records among adults remains challenging in the absence of comprehensive vaccination registries. Timing of vaccination in relation to first HPV exposure was unknown. Histological diagnosis classification is based on pathology reports, which incorporate terminology that has changed over time; 33 however, HPV-IMPACT uses multiple terms to ensure complete case ascertainment, and we do not think any potential case misclassification is likely to impact HPV 16/18 detection trends. Tissue for HPV typing was not available for all cases. However, the proportions typed are likely large enough to be generalizable, and it is unlikely that selection bias in typed cases had a notable impact on results. Different assays were used during the surveillance period for HPV detection. Concordance between Linear Array with reflex to LiPA and Novaplex is high, and, specifically, concordance for HPV16/18 is 90.5%. 23 Therefore, it is unlikely that the assay transition affected trends in HPV16/18 detection. Interpretation of any racial and ethnic group finding should be done cautiously given the inherent limitations of racial and ethnic group classifications (i.e., lack of standardization and poor surrogate marker for biological or sociologic constructs). 34 In addition, cases among Asian women came predominantly from the California site, limiting generalizability. Finally, some subgroups had small numbers which likely impacted our power to detect significant trends.
In conclusion, we found significant decreases in the proportions of precancer cases that were HPV16/18-positive in age groups most likely to have been vaccinated and in a variety of population subgroups. Findings in this report add to previous analyses from HPV-IMPACT and other US monitoring systems from earlier time periods; decreases in proportion of CIN2+ that were HPV16/18-positive and rates of HPV16/18-positive CIN2+ had been observed as well as other vaccine-type specific decreases. 10,15,17,18 Together, these data provide robust demonstration of HPV vaccination impact in the United States among young adult women and forecast future decreases in cancer. Continued HPV type-specific monitoring of cervical precancers, including the 5 additional types protected by the 9-valent HPV vaccine, will increase our understanding of vaccination impact among different population subgroups.
Supplementary Material
Acknowledgments
This work was supported by a cooperative agreement through the CDC's Emerging Infections Program [grant nos. U50CK000643 (California), U50CK000644 (Connecticut), U50CK000650 (New York), U50CK000651 (Oregon), and U50CK000652 (Tennessee)].
Ellen J. Giampoli, MD, University of Rochester School of Medicine and Dentistry; Developmental Histology/Tissue Microarray Facility, Yale Pathology Tissue Services; Angelique W. Levy, MD, Yale School of Medicine; We thank current and former laboratory members of the CDC Division of High-Consequence Pathogens and Pathology, including Juanita M. Onyekwuluje, Sonya Patel, Krystle Love, Farha Choudhury, Rodolfo Santini, Elyse Ostroske, Cameron Grimes, Comfort Kai, Patrick McKibben, Danielle Miller, and Martin Steinau for their contributions to HPV testing.
Footnotes
Conflict of interest: L.M. Niccolai reports personal fees from Merck outside the submitted work. E.R. Unger reports a financial gift from Serum Institute of India to the CDC HPV serology laboratory for providing advice and transferring HPV serologic technology (all funds not related to this analysis and provided to the institution). No disclosures were reported by the other authors.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Prior Presentations: Preliminary versions of this work were presented at the 2024 Epidemic Intelligence Service (EIS) Conference and ASCCP 2024.
Contributor Information
the HPV-IMPACT Working Group:
Deborah Adeyemi, Sarah E. Clarke, Emily L. Delikat, Kyle Higgins, James Meek, and Michael J. Silverberg
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Access to the HPV-IMPACT data will be through CDC. https://www.cdc.gov/hpv-impact/data/index.html