Reduction in HPV 16/18-associated high grade cervical lesions following HPV vaccine introduction in the United States – 2008–2012☆
Introduction
The discovery that persistent infection with certain human papillomavirus (HPV) types is causally associated with cervical cancer, and the subsequent development of vaccines to prevent HPV-attributable cancers are among the most important milestones in science and medicine [1], [2]. Two HPV vaccines directed against HPV 16 and 18, types that cause 70% of invasive and 50% of pre-invasive cervical lesions worldwide, are currently available [3], [4]. In clinical trials, both HPV vaccines were highly efficacious against vaccine type-associated cervical intraepithelial neoplasia grades 2 and 3 and adenocarcinoma in situ (CIN2+), pre-invasive lesions that may progress to cervical cancer if left untreated [5], [6].
The real-world benefits of vaccination against associated cancers may not be evident for decades given the slow progression from infection to invasive disease, but population impact against earlier outcomes has already been demonstrated in numerous settings worldwide [7], [8], [9], [10], [11], [12]. In the United States, routine HPV vaccination has been recommended since June 2006 for females aged 11 or 12 years, through age 26 years in those not previously vaccinated [13]. However, coverage remains suboptimal. In 2013, fewer than 57% of girls aged 13–17 years had received at least one dose of quadrivalent HPV vaccine, which accounts for about 99% of all HPV vaccines distributed in the United States [14], and only 38% had completed the 3-dose series [15]; coverage in the older age group has been even lower [16]. Despite low coverage, significant reductions in vaccine-type HPV prevalence have been shown in young females [17].
Measuring vaccine impact on screening-detected cervical lesions in the United States is more challenging given incomplete reporting of adolescent vaccination to state-based immunization registries, lack of national screening registries, and changing screening recommendations. Over the past decade, the recommended age for initiating cervical cancer screening has been raised to 21 years and screening intervals have been increased, particularly if HPV-based co-testing is used [18]. Monitoring vaccine-types associated with lesions can help distinguish the impact of vaccination from the effects resulting from changing screening practices.
We previously reported preliminary results in the first few years post-vaccine introduction on HPV vaccine effectiveness against HPV 16/18-type CIN2+, pre-invasive lesions that include a continuum of histologic lesions with increasing severity [19]. In this paper, we extend the analysis to a longer time period in the vaccine era and larger number of cases to produce estimates of vaccine effectiveness on HPV 16/18-attributable CIN2+ as well as on a subset of highest grade lesions (CIN3/AIS), which are most likely to progress to cervical cancer. Additionally, we examined temporal trends in the prevalence of HPV 16/18-related CIN2+ after vaccine introduction in the United States.
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Materials and methods
Data were obtained from the HPV-IMPACT Project, a population-based surveillance system for monitoring HPV vaccine impact on type-specific CIN2+ among females aged ≥18 years residing in catchment areas in California, Connecticut, New York, Oregon, and Tennessee [20]. The total population of females aged 18 years and older ranges from 230,000 to 330,000 in each participating site according to the 2010 U.S. Census data. This project was reviewed by the US Centers for Disease Control, Oregon Health
Results
From 2008 to 2012, 7346 women who were age-eligible for vaccination (aged ≤26 years in 2006, when HPV vaccine was first recommended in the United States) were reported to HPV-IMPACT. Specimens were tested for 4693 women, and valid HPV DNA results were obtained for 4678 (99.7%). HPV DNA was detected in 4575 (97.8%); 23.3% had >1 type detected. Among women with typing results, HPV vaccination status was determined for 2463 (52.7%); 1189 (25.4%) had received ≥1 dose and of those, 667 (56.1%) had
Discussion
Within 6 years of HPV vaccine introduction in the United States, and despite persistently low vaccination coverage, evidence of vaccine impact on early outcomes is emerging, with reported reductions in vaccine-type HPV prevalence [17] and genital warts among adolescent females [22]. A few countries with high vaccine coverage have reported significant decreases in high grade cervical lesions post vaccine introduction [7]. In addition, studies from Australia, Denmark, and Scotland have
Financial support
This work was supported by the U.S. Centers for Disease Control and Prevention cooperative agreement CIU01000307.
Conflict of interest
L. Niccolai was a consultant/advisory board member for Merck. All other authors declare no conflict of interest.
Acknowledgements
We gratefully acknowledge James Hadler, Jill Sharma, and Danielle Miller for their expert contribution in the planning and design and/or laboratory testing of the project.
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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.
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The HPV-IMPACT Working Group: Heidi Bauer, MD, MS, MPH, Ashley Williamson, MPH (California Department of Public Health, STD Control Branch and California Emerging Infections Program); James Meek, MPH, Kyle Higgins (Yale School of Public Health, Connecticut Emerging Infections Program); Deven Patel, MPH (University of Rochester, New York Emerging Infections Program); Robert Laing, MPH (Oregon Public Health Division); Manideepthi Pemmaraju, MPH (Vanderbilt University); Lynn Sosa (Connecticut Department of Public Health).