Vaccine 32 (2014) 1939–1945
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HPV vaccination: Are we initiating too late? Annika M. Hofstetter a,b,∗ , Melissa S. Stockwell a,b,c , Noor Al-Husayni a , Danielle Ompad d,e,f , Karthik Natarajan b,g , Susan L. Rosenthal a,b , Karen Soren a,b,c a
Department of Pediatrics, Columbia University, New York, NY, USA NewYork-Presbyterian Hospital, New York, NY, USA Department of Population and Family Health, Mailman School of Public Health, Columbia University, New York, NY, USA d Department of Nutrition, Food Studies, and Public Health, Steinhardt School of Culture, Education and Human Development, New York University, New York, NY, USA e Center for Health, Identity, Behavior, and Prevention Studies, Steinhardt School of Culture, Education and Human Development, New York University, New York, NY, USA f Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA g Department of Biomedical Informatics, Columbia University, New York, NY, USA b c
a r t i c l e
i n f o
Article history: Received 23 September 2013 Received in revised form 27 January 2014 Accepted 30 January 2014 Available online 14 February 2014 Keywords: Human papillomavirus Vaccination Initiation Papanicolaou Chlamydia
a b s t r a c t Background: Human papillomavirus (HPV) vaccination is recommended in early adolescence. While limited data suggest that patients frequently delay initiation of the three-dose series, age-based variability in initiation of HPV vaccination and its clinical relevance are not well described. Thus, this study aims to characterize HPV vaccination delay among adolescent and young adult females. Methods: This retrospective cohort study examined age at HPV vaccination initiation and missed opportunities for receipt of the first vaccine dose (HPV1) among 11–26 year-old females (n = 22,900) receiving care at 16 urban academically-affiliated ambulatory care clinics between 2007 and 2011. Predictors of timely vaccination and post-licensure trends in age at HPV1 receipt were assessed using multivariable logistic regression and a generalized linear mixed model, respectively. Chlamydia trachomatis and Papanicolaou screening before HPV vaccination initiation, as markers of prior sexual experience and associated morbidity, were examined in a subcohort of subjects (n = 15,049). Results: The proportion of 11–12 year-olds who initiated HPV vaccination increased over time (44.4% [2007] vs. 74.5% [2011], p < 0.01). Initiation rates also improved among 13–26 year-olds. Thus, the mean age at HPV1 receipt remained unchanged between 2007 and 2011 (16.0 ± 2.7 vs. 15.9 ± 4.0 years, p = 0.45). Spanish language was a positive predictor (AOR 1.62, 95% CI 1.05–2.48) of HPV vaccination initiation among 11–12 year-olds in 2011. The majority (70.8–76.4%) of unvaccinated subjects experienced missed vaccination opportunities. Of the subcohort, 36.9% underwent Chlamydia screening before HPV1 receipt (19.1% with ≥1 positive result). Of those with prior Papanicolaou screening (16.6%), 32.1% had ≥1 abnormal result. Conclusions: These low-income, minority females frequently delayed initiation of HPV vaccination. Many had evidence of prior sexual experience and associated morbidity, placing them at risk of HPV-related complications. Promoting timely HPV vaccination and reducing missed vaccination opportunities are crucial. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Abbreviations: ACIP, Advisory Committee on Immunization Practices; EzVac, NewYork-Presbyterian Hospital immunization registry; HPV, human papillomavirus; HPV1, first dose of human papillomavirus vaccine; NIS-Teen, National Immunization Survey-Teen; Pap, Papanicolaou. ∗ Corresponding author at: Division of Child and Adolescent Health, Department of Pediatrics, Columbia University College of Physicians & Surgeons 622 W. 168th Street, VC 417, New York, NY 10032, USA. Tel.: +1 212 305 0896; fax: +1 212 305 8819. E-mail addresses: [email protected] (A.M. Hofstetter), [email protected] (M.S. Stockwell), [email protected] (N. Al-Husayni), [email protected] (D. Ompad), [email protected] (K. Natarajan), [email protected] (S.L. Rosenthal), [email protected] (K. Soren). 0264-410X/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2014.01.084
Since 2007, the Advisory Committee on Immunization Practices (ACIP) has recommended human papillomavirus (HPV) vaccination of 11–12 year-old females with catch-up vaccination through 26 years [1]. These recommendations are based upon epidemiologic patterns of HPV infection and higher antibody responses to the HPV vaccine in younger vs. older individuals [1–5]. Targeting younger adolescents is also advantageous given their increased health care utilization for preventive services compared to older adolescents [6].
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A.M. Hofstetter et al. / Vaccine 32 (2014) 1939–1945
Despite ACIP recommendation, studies suggest that initiation of HPV vaccination may be delayed. Survey studies have shown that many parents decline/defer HPV vaccination in part due to agerelated concerns and perceptions of low infection risk [7,8]. These findings are consistent with recent National Immunization SurveyTeen (NIS-Teen) data demonstrating that 13 year-old females were less likely to have received ≥1 dose(s) compared to 14–17 year-old females [9]. Further delineation of the precise age when patients are initiating HPV vaccination and examination of age-based trends since vaccine licensure have not been described, but may help us to better understand the problem of HPV vaccine delay. Moreover, identifying predictors of HPV vaccination at the recommended 11–12 years could be useful when designing interventions aimed at improving timely vaccination. Similarly, recent NIS-Teen data revealed that many unvaccinated girls aged 11–17 years experienced missed opportunities for HPV vaccination at visits when other vaccines were administered [10]. Survey studies have found that fewer providers “strongly” or “always”/“usually” recommend HPV vaccination to 11–12 year-olds vs. older patients [11–13], suggesting that missed opportunities may be particularly common in early adolescence. Few studies have assessed age-based differences in missed opportunities using a comprehensive medical record database [14]. Delayed initiation of HPV vaccination may leave individuals vulnerable to HPV infection. One study found that 25% of 258 females (mean age: 14.0 ± 2.3 years) had medical record documentation of sexual experience before initiating HPV vaccination [15]. A more recent study of 259 females aged 13–21 years revealed evidence of HPV infection at the time of HPV vaccination initiation among 70% of sexually experienced and 12% of sexually inexperienced females [16]. Since parents commonly underestimate their adolescent’s sexual experience [17,18] and providers may have inaccurate perceptions of which adolescents are sexually experienced [19], vaccination decisions based upon such assumptions could be problematic, particularly since HPV acquisition often occurs shortly after sexual debut [2]. Further examination of sexual experience and associated morbidity before HPV vaccination initiation in a much larger patient population is warranted. This study’s primary purpose was to characterize age at HPV vaccination initiation, including determinants of timely HPV vaccination and preceding sexual experience, among adolescent and young adult females. Secondary aims were to assess time trends in and missed opportunities for HPV vaccination initiation. We hypothesized that, despite improvements over time, many patients would fail to initiate HPV vaccination at the recommended 11–12 years, missed opportunities for first vaccine dose (HPV1) receipt
would be common, and many would have prior sexual experience placing them at risk of HPV infection and associated sequelae.
2. Methods 2.1. Study design This retrospective cohort study examined age at and missed opportunities for HPV vaccination initiation among adolescent and young adult females in an urban low-income community between 2007 and 2011 (Fig. 1). Chlamydia trachomatis screening, as a marker of sexual experience, and Papanicolaou (Pap) screening results, as an indication of potential morbidity, before HPV vaccination initiation were also assessed in a subcohort of subjects.
2.2. Study setting This study was conducted in four paediatric, six school-based health (SBHC), one family medicine, one family planning, and four obstetric/gynecology clinics within an ambulatory care network of a large academic medical center in New York City. Community residents are primarily Latino, Spanish-speaking, foreign-born, and receive federal income assistance [20]. This study was approved by the Columbia University Medical Center Institutional Review Board.
2.3. Study population Age at HPV vaccination initiation and missed opportunities for HPV1 receipt were examined in five annual cohorts (2007–2011). Females were included if they were 11–26 years-old and had ≥1 visit to a study site during the year of interest. All had active vaccine records in the hospital immunization registry. Sexual health screening before HPV vaccination initiation was examined in a subcohort of females aged 11–19 years-old as of January 1, 2007 (i.e., approximate date when HPV vaccine became routinely available to female patients at these practices) who had ≥1 visit to a study site after that time. This age range was selected a priori given the focus on early adolescence, yet recognizing that some patients may not receive HPV1 until older adolescence or beyond. In a random sample of this subcohort (n = 414), medical chart abstractions for age of sexual debut were performed using a standardized form.
Fig. 1. Schematic of study population and study design.
A.M. Hofstetter et al. / Vaccine 32 (2014) 1939–1945
2.4. Data sources Demographic (i.e., language, insurance, race/ethnicity) and clinic visit data were obtained from the network registration system. Categorization of race/ethnicity occurred at point of service by clinic staff. Some visits, primarily at SBHCs and family planning clinics, were paid for by service grants; additional insurance data were unavailable for these subjects. Chlamydia and Pap screening data were collected from the medical center’s clinical data warehouse. HPV vaccine data were obtained from the hospital immunization registry, EzVac, which collects immunization data for patients seen at the hospital and/or affiliated clinics. It is estimated that EzVac captures >95% of vaccines administered at these sites. It also reports to and receives data from the New York Citywide Immunization Registry, a provider-mandated registry that is estimated to include >93% of all Vaccines For Children immunizations given in New York City [21]. 2.5. Measures Initiation of HPV vaccination was defined as receipt of ≥1 dose between vaccine licensure and April 13, 2012 (data abstraction date). A missed opportunity was defined as any visit (i.e., acute or preventive care) to a study site during which a patient was eligible for HPV1, yet failed to receive it. Chlamydia screening was conducted using nucleic acid amplification or hybridization tests. Tests performed before 11 years of age were excluded (n = 11; all negative results). Pap screening was conducted using the ThinPrep liquid cytology system; cytology was classified as normal or abnormal according to the Bethesda System 2001 [22].
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year of interest were determined among those eligible to receive HPV1 as of January 1 that year (i.e., previously unvaccinated). Findings were stratified by age: 11–12 years (i.e., ACIP-recommended age range), 13–17 years (i.e., age range for available coverage data) [9,10], and 18–26 years (i.e., otherwise eligible for HPV vaccination). A generalized linear mixed model assessed trends in HPV vaccination initiation between 2007 and 2011, accounting for repeated measurements among subjects. Multivariable logistic regression examined the impact of language, insurance, and clinic site on HPV vaccination initiation among 11–12 year-olds in the most recent cohort (2011). Since many patients were categorized as “other” race and a high proportion had missing ethnicity data, race/ethnicity was not included in the primary analysis, but adjusted for in a secondary analysis. In the subcohort, the proportions with Chlamydia or Pap screening and/or abnormal results before HPV vaccination initiation were determined. To assess whether Chlamydia screening was a reasonable proxy for sexual experience, we examined its concordance with documented age of sexual debut in a subcohort sample. Analyses were performed using SAS Version 9.3 (Cary, NC). 3. Results 3.1. Annual cohort characteristics A total of 22,900 individuals were included in the 2007–2011 cohorts (mean per cohort: n = 10,489; 63% included in >1 cohort) (Table 1). They were predominantly non-white, Latina, Spanishspeaking, publicly insured, and distributed widely across clinics. 3.2. Age at HPV vaccination initiation
2.6. Analysis For each annual cohort, the proportion of subjects who had initiated HPV vaccination and mean age at HPV1 receipt were calculated; all doses received before December 31 of the given year were included. Missed opportunities for HPV1 receipt during the
The proportion of subjects aged 11–12 years, 13–17 years, 18–26 years, and 11–26 years (total) who initiated HPV vaccination increased between 2007 and 2011 (Fig. 2). Given the simultaneous rise in initiation rates across age groups, the mean age at HPV vaccination initiation remained unchanged over time (16.0 ± 2.7 years in
Table 1 Characteristics of study populationa .
Age (yr), mean (SD)b Race, % (n)c White Black Other Ethnicity, % (n)c Latina Non-Latina Primary language, % (n)c Spanish English Other Insurance, % (n)c Public Grantd Uninsured Private Clinic, % (n) Family planning Obstetrics/gynecology Paediatric School-based health Family medicine
2007 (n = 9209)
2008 (n = 9888)
2009 (n = 10,885)
2010 (n = 11,206)
2011 (n = 11,259)
Subcohort (n = 15,049)
17.4 (3.8)
17.7 (3.8)
18.3 (4.0)
18.5 (4.0)
18.6 (4.1)
15.6 (2.5)
29.2 (2672) 8.8 (809) 62.0 (5668)
27.6 (2714) 9.1 (889) 63.3 (6219)
25.5 (2753) 8.1 (873) 66.4 (7186)
19.8 (2201) 7.3 (815) 72.9 (8120)
14.4 (1603) 6.3 (699) 79.3 (8849)
28.7 (4282) 9.7 (1438) 61.6 (9188)
79.0 (3400) 21.0 (905)
77.8 (3489) 22.2 (997)
78.9 (3621) 21.1 (971)
78.5 (3142) 21.5 (860)
79.0 (2907) 21.0 (771)
77.2 (5531) 22.8 (1630)
59.5 (5037) 39.9 (3379) 0.6 (46)
58.5 (5349) 40.9 (3735) 0.7 (59)
58.3 (6171) 41.1 (4355) 0.6 (63)
59.1 (6353) 40.2 (4325) 0.7 (71)
59.9 (6214) 40.4 (4264) 0.7 (79)
56.7 (7713) 42.7 (5800) 0.6 (84)
73.6 (6777) 17.4 (1603) 4.7 (431) 4.3 (397)
73.7 (7289) 17.8 (1763) 4.5 (440) 4.0 (395)
74.7 (8133) 17.5 (1901) 4.6 (498) 3.2 (352)
75.5 (8456) 17.7 (1989) 4.0 (453) 2.8 (308)
74.8 (8422) 19.3 (2170) 3.3 (371) 2.6 (294)
71.9 (10815) 20.6 (3102) 4.4 (668) 3.1 (462)
28.5 (2623) 24.0 (2208) 23.0 (2219) 16.6 (1531) 7.9 (728)
27.4 (2708) 23.4 (2311) 23.4 (2316) 18.2 (1804) 7.6 (749)
25.7 (2793) 26.6 (2899) 22.5 (2451) 18.1 (1967) 7.1 (775)
25.3 (2830) 27.3 (3060) 23.2 (2597) 17.9 (2006) 6.3 (712)
25.5 (2864) 25.1 (2829) 23.0 (2591) 20.0 (2250) 6.4 (721)
31.3 (4708) 23.7 (3562) 20.0 (3008) 19.5 (2939) 5.5 (829)
a The five annual cohorts (2007–2011) were comprised of 22,900 unique individuals (63% were included in >1 cohort). In a subcohort of these individuals, sexual health screening prior to initiation of HPV vaccination was examined. b Age as of January 1 of given year (2007–2011). For the subcohort, age as of January 1, 2007. c There were some missing data in select seasons. d Funding from service grants was used primarily in school-based health and family planning clinics.
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A.M. Hofstetter et al. / Vaccine 32 (2014) 1939–1945 Table 3 Factors associated with initiation of HPV vaccination among 11–12 year-old females in 2011. Variable Parental language (REF: English/other) Spanish Insurance (REF: public/grant/uninsured)c Private Clinic (REF: paediatric) Family medicine School-based health Race (REF: white) Black Other
AORa (95% CI)
AORb (95% CI)
1.77 (1.17, 2.70)
1.75 (1.12, 2.75)
0.59 (0.23, 1.54)
0.59 (0.22, 1.53)
0.41 (0.14, 1.19) 0.56 (0.36, 0.85)
0.42 (0.14, 1.22) 0.65 (0.34, 1.25)
– –
0.96 (0.43, 2.16) 1.23 (0.63, 2.40)
a
Model includes language, insurance, and clinic site. Model includes language, insurance, clinic site, and race. c Funding from service grants was used for some visits to school-based health clinics. Values in bold signify p < 0.05. b
Fig. 2. Initiation of HPV vaccination among 11–26 year-old females attending ambulatory care clinics, 2007–2011.
2007 vs. 15.9 ± 4.0 years in 2011, p = 0.45). In 2011, 74.5% of 11–12 year-olds initiated HPV vaccination. Spanish speakers were more likely to have initiated HPV vaccination at 11–12 years, whereas those attending SBHCs were less likely to have timely initiation, although not after adjusting for race (Table 2). 3.3. Missed opportunities The majority (70.8–76.4%) of subjects with a clinic visit who were eligible to initiate HPV vaccination failed to do so within a given year, particularly those who were older (Table 3). By definition, all of these unvaccinated subjects had ≥1 missed opportunity for HPV1 receipt; the median number of missed opportunities was 2 in 2007–2010 and 3 in 2011. Among eligible subjects who did initiate HPV vaccination within the year, 49.2–57.1% had ≥1 missed opportunity that year before HPV1 receipt. 3.4. Subcohort characteristics There were 15,049 adolescents included in the subcohort examining sexual health screening (Table 1). Over one-third (37.9%) Table 2 Missed opportunities for HPV vaccination initiation among 11–26 year-old females attending ambulatory care clinics, 2007–2011a . Year
Age (yr)
n Value
No HPV1 receipt, % (n)b
2007
11–12 13–17 18–26 Total 11–12 13–17 18–26 Total 11–12 13–17 18–26 Total 11–12 13–17 18–26 Total 11–12 13–17 18–26 Total
588 3926 4653 9167 398 2397 4337 7132 316 1454 4612 6382 330 1055 4096 5481 279 876 3463 4618
56.1 (330) 58.2 (2284) 83.3 (3874) 70.8 (6488) 53.5 (213) 55.9 (1339) 85.1 (3689) 73.5 (5241) 51.9 (164) 64.4 (936) 80.3 (3702) 75.2 (4802) 46.4 (153) 66.5 (702) 81.3 (3330) 76.4 (4185) 49.8 (139) 65.8 (576) 78.8 (2730) 74.6 (3445)
2008
2009
2010
2011
a Among only those eligible for the first HPV vaccine dose (HPV1) as of January 1 of given year. b By December 31 of given year.
had undergone Pap screening in their lifetime. Of these, 31.4% had ≥1 abnormality. The majority (79.2%) had undergone Chlamydia screening in their lifetime; the cumulative proportion increased by age (11 year-olds: 0.1%; 12 year-olds: 0.6%; 13 year-olds: 2.6%; 14 year-olds: 8.0%; 15 year-olds: 18.4%; 16 year-olds: 31.4%; 17 yearolds: 44.9%; 18 year-olds: 55.8%; 19 year-olds: 64.2%). In total, 24.3% had ≥1 Chlamydia infection. In the subcohort sample examining concordance between Chlamydia screening and sexual experience, 51.2% (n = 212) had a documented age of sexual debut (mean: 15.7 years; range: 10–22 years). Only 9.4% (n = 20) underwent their first Chlamydia screening before this age of debut; half of these were within the preceding 6 months.
3.5. Sexual health screening before HPV vaccination initiation In the subcohort, two-thirds (66.7%, n = 10,038) had initiated HPV vaccination at a mean age of 16.7 years (SD 2.8). Of initiators, 36.9% and 16.6% had undergone Chlamydia or Pap screening, respectively, at some point before HPV1 receipt (Fig. 3). Of those with prior Chlamydia screening, 19.1% had ≥1 infection before HPV1 receipt. Of those with prior Pap screening, 32.1% had ≥1 abnormality before HPV1 receipt.
Fig. 3. Chlamydia and Papanicolaou (Pap) screening before HPV vaccination initiation among adolescent and young adult females.
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4. Discussion This study examined initiation of HPV vaccination among 22,900 urban, low-income, minority adolescent and young adult females. It reveals that, even in a setting with high initiation rates, HPV vaccination is frequently delayed beyond the recommended 11–12 years, and missed opportunities for HPV1 receipt are common in all age groups. It also illustrates the potential consequences of this delay. Over one-third already had undergone Chlamydia screening, suggesting prior sexual experience, and nearly one-third of those with Pap screening already had an abnormality, indicating prior HPV exposure. These findings, in addition to our understanding of health care utilization in this population [6], support a universal approach to timely initiation of HPV vaccination, per ACIP recommendations. Optimization of HPV vaccine delivery could potentially enhance the encouraging recent finding that HPV vaccine introduction has substantially reduced HPV prevalence at a population-level [23]. In this study, initiation rates of HPV vaccination improved significantly over time. By 2011, over two-thirds of subjects had initiated HPV vaccination. Comparatively, 2011 NIS-Teen data demonstrated that only half of 13–17 year-old females in New York State (46.6%) and nationally (53.0%) had received ≥1 dose [9]. Despite promising trends in initiation rates in the study population overall, there was some recent plateauing among 11–12 and 13–17 year-olds, the latter also shown nationally [9,10]. Moreover, HPV vaccination remained delayed, as evidenced by the unchanged mean age at HPV1 receipt of 16 years. This is concerning since earlier age at vaccination is associated with a more robust anti-HPV response [3–5], and HPV vaccine is most effective as a prevention strategy when received before sexual debut [1]. Delayed HPV vaccination in the present study could be explained by multiple factors. Spanish language was associated with early HPV vaccination initiation, consistent with its positive impact on influenza vaccination in this population [24,25]. Conversely, SBHC attendance was negatively associated with timely HPV vaccination, which may reflect parental preference for adolescent vaccination in a doctor’s office compared to school or public health clinic and lower willingness to consent to schoollocated administration of HPV vs. other vaccines [26]. The effect of SBHC attendance disappeared after adjusting for race, possibly due to the greater proportion of black adolescents in this setting (data not shown); black adolescents were recently shown to be less likely than white adolescents to initiate HPV vaccination [27]. General parental reluctance to vaccinate against HPV also could have played a role. Prior investigations have shown that parents often decline/defer HPV vaccination for a variety of reasons, including beliefs about the need for vaccination and perceptions of risk (i.e., not sexually active) [7,28–31]. Data, however, indicate that parents often underestimate their adolescent’s sexual experience [17,18]. Moreover, some parents worry that HPV vaccination could result in behavioral disinhibition and risky sexual behaviors [32], despite substantial evidence to the contrary [33–36]. Providers have the opportunity to clarify misconceptions and strongly recommend HPV vaccine, thereby positively influencing vaccine uptake [37–40]. In the present study, however, providers likely contributed to the frequent missed opportunities for timely HPV vaccination since even eligible patients who initiated HPV vaccination within the year (i.e., did not continuously decline/defer vaccination) had 2–3 missed opportunities before HPV1 receipt. Moreover, approximately half of eligible 11–12 year-olds had ≥1 missed opportunity to receive HPV1 at the recommended time, which is consistent with survey data indicating that providers less often/strongly recommend HPV vaccine to them [11–13]. These findings could be explained by a lack of provider
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awareness of adolescent sexual behaviors, including age of sexual debut [19] and HPV infection risk [11,13]. Moreover, perceived obligation to discuss sexuality before recommending HPV vaccine has been associated with not strongly recommending HPV vaccine to 11–12 year-olds [11]. These data illustrate the need for educational interventions tailored specifically to the informational needs of adolescents, parents, and providers. Electronic health record alerts that contain vaccine-related information and prompt discussions about HPV vaccine are one potential strategy that has been proposed [41]. They may be particularly beneficial during acute care visits since many adolescents do not present for timely preventive care [6] and for older patients who also commonly experienced missed vaccination opportunities. The potential consequences of delayed initiation of HPV vaccination in our study population are concerning since over one-third had undergone Chlamydia screening and nearly one-third of those with Pap screening had an abnormality at some point before initiating HPV vaccination. This indicates that many had engaged in sexual behaviors placing them at risk of HPV acquisition before HPV vaccination, consistent with a smaller recent study [16]. While our subjects may be at higher risk than observed nationally given their lower mean age of sexual debut and higher rate of abnormal screening [42–44], their risk may be similar to other urban, lowincome, minority adolescents and young adults [45]. Regardless, our findings as well as previous data illustrating the difficulties of predicting age of sexual debut [17–19] support the ACIP recommendation for HPV vaccination of all young adolescents. This study has some limitations. First, by focusing on individuals with clinic utilization during the study period, it may have overestimated HPV vaccination initiation rates and underestimated age at HPV1 receipt within the larger clinic population, community, and/or general population. Conversely, underreporting of vaccine administration may have occurred, although unlikely given routine vaccine data extractions and reporting mandates. Additionally, Chlamydia screening likely underestimated sexual experience since screening is typically performed based upon patient disclosure of sexual activity and at provider discretion. Nonetheless, we found strong concordance between first Chlamydia screening and documented age of sexual debut, consistent with another study showing longitudinal consistency in self-reported age at first sex [46]. Further, the use of Pap screening as an indication of associated morbidity likely had the greatest utility prior to the 2009 American College of Obstetrics and Gynecology recommendation that Pap screening begin at 21 years of age [47]. Lastly, these data did not permit further characterization of missed opportunities (i.e., type of visit, reason why vaccine was not given) or examination of other factors shown to impact HPV vaccination (i.e., parental beliefs, provider recommendation) [7,28–31,37–40].
5. Conclusion This large retrospective cohort study of low-income minority adolescent and young adult females found that, even in a setting conducive to HPV vaccination, initiation of the three-dose series was often delayed. Moreover, many who ultimately initiated HPV vaccination already had evidence of sexual experience and associated morbidity before HPV1 receipt. HPV vaccination in early adolescence is important for optimizing protection prior to exposure and necessary given the challenges of predicting which adolescents will engage in early sexual behaviors. Vaccination of young adolescents also aligns well with health care utilization patterns. Given the frequent missed opportunities for timely HPV vaccination, enhanced education of adolescents, parents, and providers is needed.
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Conflicts of interest statement This study was funded in part through an Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this manuscript are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. As of July 2013, Drs. Hofstetter and Rosenthal receive support from the Pfizer Medical Education Group for an investigator-initiated study. The other authors have no conflicts of interest to disclose. Acknowledgments We would like to thank NewYork-Presbyterian Hospital for its support of the EzVac immunization registry as well as the NewYork-Presbyterian Hospital Ambulatory Care Network. We ˜ and Balendu DasGupta would especially like to thank Oscar Pena for their work on EzVac and Alla Babina for her assistance with the sexual health screening data collection. References [1] Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent human Papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-2):1–24. [2] Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157(3):218–26. [3] Giuliano AR, Lazcano-Ponce E, Villa L, Nolan T, Marchant C, Radley D, Golm G, McCarroll K, Yu J, Esser MT, et al. Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine. J Infect Dis 2007;196(8):1153–62. [4] Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD, Castellsague X, Rusche SA, Lukac S, Bryan JT, et al. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 2006;118(5):2135–45. [5] Dobson SR, McNeil S, Dionne M, Dawar M, Ogilvie G, Krajden M, Sauvageau C, Scheifele DW, Kollmann TR, Halperin SA, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA 2013;309(17):1793–802. [6] Rand CM, Shone LP, Albertin C, Auinger P, Klein JD, Szilagyi PG. National health care visit patterns of adolescents: implications for delivery of new adolescent vaccines. Arch Pediatr Adolesc Med 2007;161(3):252–9. [7] Bair RM, Mays RM, Sturm LA, Zimet GD. Acceptability of the human papillomavirus vaccine among Latina mothers. J Pediatr Adolesc Gynecol 2008;21(6):329–34. [8] Dempsey AF, Abraham LM, Dalton V, Ruffin M. Understanding the reasons why mothers do or do not have their adolescent daughters vaccinated against human papillomavirus. Ann Epidemiol 2009;19(8):531–8. [9] Centers for Disease Control and Prevention. National and state vaccination coverage among adolescents aged 13–17 years—United States, 2011. MMWR Morb Mortal Wkly Rep 2012;61(34):671–7. [10] Centers for Disease Control and Prevention. Human papillomavirus vaccination coverage among adolescent girls, 2007–2012, and postlicensure vaccine safety monitoring, 2006–2013—United States. MMWR Morb Mortal Wkly Rep 2013;62(29):591–5. [11] Daley MF, Crane LA, Markowitz LE, Black SR, Beaty BL, Barrow J, Babbel C, Gottlieb SL, Liddon N, Stokley S, et al. Human papillomavirus vaccination practices: a survey of US physicians 18 months after licensure. Pediatrics 2010;126(3):425–33. [12] Vadaparampil ST, Kahn JA, Salmon D, Lee JH, Quinn GP, Roetzheim R, Bruder K, Malo TL, Proveaux T, Zhao X, et al. Missed clinical opportunities: provider recommendations for HPV vaccination for 11–12 year old girls are limited. Vaccine 2011;29(47):8634–41. [13] Kahn JA, Cooper HP, Vadaparampil ST, Pence BC, Weinberg AD, LoCoco SJ, Rosenthal SL. Human papillomavirus vaccine recommendations and agreement with mandated human papillomavirus vaccination for 11-to-12-year-old girls: a statewide survey of Texas physicians. Cancer Epidemiol Biomarkers Prev 2009;18(8):2325–32. [14] Wong CA, Taylor JA, Wright JA, Opel DJ, Katzenellenbogen RA. Missed opportunities for adolescent vaccination, 2006–2011. J Adolesc Health 2013;53(4):492–7. [15] Neubrand TP, Breitkopf CR, Rupp R, Breitkopf D, Rosenthal SL. Factors associated with completion of the human papillomavirus vaccine series. Clin Pediatr (Phila) 2009;48(9):966–9. [16] Widdice LE, Brown DR, Bernstein DI, Ding L, Patel D, Shew M, Fortenberry JD, Kahn JA: Prevalence of human papillomavirus infection in young women receiving the first quadrivalent vaccine dose. Arch Pediatr Adolesc Med, 166(8):774-776.
[17] Jaccard J, Dittus PJ, Gordon VV. Parent-adolescent congruency in reports of adolescent sexual behavior and in communications about sexual behavior. Child Dev 1998;69(1):247–61. [18] Mollborn S, Everett B. Correlates and consequences of parent-teen incongruence in reports of teens’ sexual experience. J Sex Res 2010;47(4):314–29. [19] Hughes CC, Jones AL, Feemster KA, Fiks AG. HPV vaccine decision making in pediatric primary care: a semi-structured interview study. BMC Pediatr 2011;11:74. [20] New York City Department of City Planning. Manhattan Community District 12. Inwood, Washington Heights: New York City Department of City Planning; 2013 [cited March 8, 2013] Available from: http://www.nyc.gov/html/dcp/html/neigh info/mn12 info.shtml. [21] Metroka AE, Hansen MA, Papadouka V, Zucker JR. Using an immunization information system to improve accountability for vaccines distributed through the Vaccines for Children program in New York City, 2005–2008. J Public Health Manage Pract 2009;15(5):E13–21. [22] Solomon D, Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright Jr T, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287(16):2114–9. [23] Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, Unger ER. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010. J Infect Dis 2013;208(3): 385–93. [24] Hofstetter AM, Natarajan K, Martinez RA, Rabinowitz D, Vawdrey DK, Stockwell MS. Influenza vaccination coverage and timeliness among children requiring two doses, 2004–2009. Prev Med 2013;56(3–4):165–70. [25] Stockwell MS, Martinez RA, Hofstetter A, Natarajan K, Vawdrey DK. Timeliness of 2009 H1N1 vaccine coverage in a low-income pediatric and adolescent population. Vaccine 2013;31(16):2103–7. [26] Kelminson K, Saville A, Seewald L, Stokley S, Dickinson LM, Daley MF, Suh C, Kempe A. Parental views of school-located delivery of adolescent vaccines. J Adolesc Health 2012;51(2):190–6. [27] Prislin R, Suarez L, Simpson DM, Dyer JA. When acculturation hurts: the case of immunization. Soc Sci Med 1998;47(12):1947–50. [28] Brewer NT, Gottlieb SL, Reiter PL, McRee AL, Liddon N, Markowitz L, Smith JS. Longitudinal predictors of human papillomavirus vaccine initiation among adolescent girls in a high-risk geographic area. Sex Transm Dis 2010;38(3):197–204. [29] Freed GL, Clark SJ, Butchart AT, Singer DC, Davis MM. Parental vaccine safety concerns in 2009. Pediatrics 2010;125(4):654–9. [30] Darden PM, Thompson DM, Roberts JR, Hale JJ, Pope C, Naifeh M, Jacobson RM. Reasons for not vaccinating adolescents: National Immunization Survey of Teens, 2008–2010. Pediatrics 2013;131(4):645–51. [31] Dorell C, Yankey D, Strasser S. Parent-reported reasons for nonreceipt of recommended adolescent vaccinations, National Immunization Survey-Teen, 2009. Clin Pediatr (Phila) 2011;50(12):1116–24. [32] Marlow LA, Forster AS, Wardle J, Waller J. Mothers’ and adolescents’ beliefs about risk compensation following HPV vaccination. J Adolesc Health 2009;44(5):446–51. [33] Bednarczyk RA, Davis R, Ault K, Orenstein W, Omer SB. Sexual activity-related outcomes after human papillomavirus vaccination of 11- to 12-year-olds. Pediatrics 2012;130(5):798–805. [34] Cummings T, Zimet GD, Brown D, Tu W, Yang Z, Fortenberry JD, Shew ML. Reduction of HPV infections through vaccination among at-risk urban adolescents. Vaccine 2012;30(37):5496–500. [35] Forster A, Wardle J, Stephenson J, Waller J. Passport to promiscuity or lifesaver: press coverage of HPV vaccination and risky sexual behavior. J Health Commun 2010;15(2):205–17. [36] Mullins TL, Zimet GD, Rosenthal SL, Morrow C, Ding L, Shew M, Fortenberry JD, Bernstein DI, Kahn JA. 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HPV vaccination: Are we initiating too late? Annika M. Hofstetter a,b,∗ , Melissa S. Stockwell a,b,c , Noor Al-Husayni a , Danielle Ompad d,e,f , Karthik Natarajan b,g , Susan L. Rosenthal a,b , Karen Soren a,b,c a
Department of Pediatrics, Columbia University, New York, NY, USA NewYork-Presbyterian Hospital, New York, NY, USA Department of Population and Family Health, Mailman School of Public Health, Columbia University, New York, NY, USA d Department of Nutrition, Food Studies, and Public Health, Steinhardt School of Culture, Education and Human Development, New York University, New York, NY, USA e Center for Health, Identity, Behavior, and Prevention Studies, Steinhardt School of Culture, Education and Human Development, New York University, New York, NY, USA f Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA g Department of Biomedical Informatics, Columbia University, New York, NY, USA b c
a r t i c l e
i n f o
Article history: Received 23 September 2013 Received in revised form 27 January 2014 Accepted 30 January 2014 Available online 14 February 2014 Keywords: Human papillomavirus Vaccination Initiation Papanicolaou Chlamydia
a b s t r a c t Background: Human papillomavirus (HPV) vaccination is recommended in early adolescence. While limited data suggest that patients frequently delay initiation of the three-dose series, age-based variability in initiation of HPV vaccination and its clinical relevance are not well described. Thus, this study aims to characterize HPV vaccination delay among adolescent and young adult females. Methods: This retrospective cohort study examined age at HPV vaccination initiation and missed opportunities for receipt of the first vaccine dose (HPV1) among 11–26 year-old females (n = 22,900) receiving care at 16 urban academically-affiliated ambulatory care clinics between 2007 and 2011. Predictors of timely vaccination and post-licensure trends in age at HPV1 receipt were assessed using multivariable logistic regression and a generalized linear mixed model, respectively. Chlamydia trachomatis and Papanicolaou screening before HPV vaccination initiation, as markers of prior sexual experience and associated morbidity, were examined in a subcohort of subjects (n = 15,049). Results: The proportion of 11–12 year-olds who initiated HPV vaccination increased over time (44.4% [2007] vs. 74.5% [2011], p < 0.01). Initiation rates also improved among 13–26 year-olds. Thus, the mean age at HPV1 receipt remained unchanged between 2007 and 2011 (16.0 ± 2.7 vs. 15.9 ± 4.0 years, p = 0.45). Spanish language was a positive predictor (AOR 1.62, 95% CI 1.05–2.48) of HPV vaccination initiation among 11–12 year-olds in 2011. The majority (70.8–76.4%) of unvaccinated subjects experienced missed vaccination opportunities. Of the subcohort, 36.9% underwent Chlamydia screening before HPV1 receipt (19.1% with ≥1 positive result). Of those with prior Papanicolaou screening (16.6%), 32.1% had ≥1 abnormal result. Conclusions: These low-income, minority females frequently delayed initiation of HPV vaccination. Many had evidence of prior sexual experience and associated morbidity, placing them at risk of HPV-related complications. Promoting timely HPV vaccination and reducing missed vaccination opportunities are crucial. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Abbreviations: ACIP, Advisory Committee on Immunization Practices; EzVac, NewYork-Presbyterian Hospital immunization registry; HPV, human papillomavirus; HPV1, first dose of human papillomavirus vaccine; NIS-Teen, National Immunization Survey-Teen; Pap, Papanicolaou. ∗ Corresponding author at: Division of Child and Adolescent Health, Department of Pediatrics, Columbia University College of Physicians & Surgeons 622 W. 168th Street, VC 417, New York, NY 10032, USA. Tel.: +1 212 305 0896; fax: +1 212 305 8819. E-mail addresses: [email protected] (A.M. Hofstetter), [email protected] (M.S. Stockwell), [email protected] (N. Al-Husayni), [email protected] (D. Ompad), [email protected] (K. Natarajan), [email protected] (S.L. Rosenthal), [email protected] (K. Soren). 0264-410X/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2014.01.084
Since 2007, the Advisory Committee on Immunization Practices (ACIP) has recommended human papillomavirus (HPV) vaccination of 11–12 year-old females with catch-up vaccination through 26 years [1]. These recommendations are based upon epidemiologic patterns of HPV infection and higher antibody responses to the HPV vaccine in younger vs. older individuals [1–5]. Targeting younger adolescents is also advantageous given their increased health care utilization for preventive services compared to older adolescents [6].
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A.M. Hofstetter et al. / Vaccine 32 (2014) 1939–1945
Despite ACIP recommendation, studies suggest that initiation of HPV vaccination may be delayed. Survey studies have shown that many parents decline/defer HPV vaccination in part due to agerelated concerns and perceptions of low infection risk [7,8]. These findings are consistent with recent National Immunization SurveyTeen (NIS-Teen) data demonstrating that 13 year-old females were less likely to have received ≥1 dose(s) compared to 14–17 year-old females [9]. Further delineation of the precise age when patients are initiating HPV vaccination and examination of age-based trends since vaccine licensure have not been described, but may help us to better understand the problem of HPV vaccine delay. Moreover, identifying predictors of HPV vaccination at the recommended 11–12 years could be useful when designing interventions aimed at improving timely vaccination. Similarly, recent NIS-Teen data revealed that many unvaccinated girls aged 11–17 years experienced missed opportunities for HPV vaccination at visits when other vaccines were administered [10]. Survey studies have found that fewer providers “strongly” or “always”/“usually” recommend HPV vaccination to 11–12 year-olds vs. older patients [11–13], suggesting that missed opportunities may be particularly common in early adolescence. Few studies have assessed age-based differences in missed opportunities using a comprehensive medical record database [14]. Delayed initiation of HPV vaccination may leave individuals vulnerable to HPV infection. One study found that 25% of 258 females (mean age: 14.0 ± 2.3 years) had medical record documentation of sexual experience before initiating HPV vaccination [15]. A more recent study of 259 females aged 13–21 years revealed evidence of HPV infection at the time of HPV vaccination initiation among 70% of sexually experienced and 12% of sexually inexperienced females [16]. Since parents commonly underestimate their adolescent’s sexual experience [17,18] and providers may have inaccurate perceptions of which adolescents are sexually experienced [19], vaccination decisions based upon such assumptions could be problematic, particularly since HPV acquisition often occurs shortly after sexual debut [2]. Further examination of sexual experience and associated morbidity before HPV vaccination initiation in a much larger patient population is warranted. This study’s primary purpose was to characterize age at HPV vaccination initiation, including determinants of timely HPV vaccination and preceding sexual experience, among adolescent and young adult females. Secondary aims were to assess time trends in and missed opportunities for HPV vaccination initiation. We hypothesized that, despite improvements over time, many patients would fail to initiate HPV vaccination at the recommended 11–12 years, missed opportunities for first vaccine dose (HPV1) receipt
would be common, and many would have prior sexual experience placing them at risk of HPV infection and associated sequelae.
2. Methods 2.1. Study design This retrospective cohort study examined age at and missed opportunities for HPV vaccination initiation among adolescent and young adult females in an urban low-income community between 2007 and 2011 (Fig. 1). Chlamydia trachomatis screening, as a marker of sexual experience, and Papanicolaou (Pap) screening results, as an indication of potential morbidity, before HPV vaccination initiation were also assessed in a subcohort of subjects.
2.2. Study setting This study was conducted in four paediatric, six school-based health (SBHC), one family medicine, one family planning, and four obstetric/gynecology clinics within an ambulatory care network of a large academic medical center in New York City. Community residents are primarily Latino, Spanish-speaking, foreign-born, and receive federal income assistance [20]. This study was approved by the Columbia University Medical Center Institutional Review Board.
2.3. Study population Age at HPV vaccination initiation and missed opportunities for HPV1 receipt were examined in five annual cohorts (2007–2011). Females were included if they were 11–26 years-old and had ≥1 visit to a study site during the year of interest. All had active vaccine records in the hospital immunization registry. Sexual health screening before HPV vaccination initiation was examined in a subcohort of females aged 11–19 years-old as of January 1, 2007 (i.e., approximate date when HPV vaccine became routinely available to female patients at these practices) who had ≥1 visit to a study site after that time. This age range was selected a priori given the focus on early adolescence, yet recognizing that some patients may not receive HPV1 until older adolescence or beyond. In a random sample of this subcohort (n = 414), medical chart abstractions for age of sexual debut were performed using a standardized form.
Fig. 1. Schematic of study population and study design.
A.M. Hofstetter et al. / Vaccine 32 (2014) 1939–1945
2.4. Data sources Demographic (i.e., language, insurance, race/ethnicity) and clinic visit data were obtained from the network registration system. Categorization of race/ethnicity occurred at point of service by clinic staff. Some visits, primarily at SBHCs and family planning clinics, were paid for by service grants; additional insurance data were unavailable for these subjects. Chlamydia and Pap screening data were collected from the medical center’s clinical data warehouse. HPV vaccine data were obtained from the hospital immunization registry, EzVac, which collects immunization data for patients seen at the hospital and/or affiliated clinics. It is estimated that EzVac captures >95% of vaccines administered at these sites. It also reports to and receives data from the New York Citywide Immunization Registry, a provider-mandated registry that is estimated to include >93% of all Vaccines For Children immunizations given in New York City [21]. 2.5. Measures Initiation of HPV vaccination was defined as receipt of ≥1 dose between vaccine licensure and April 13, 2012 (data abstraction date). A missed opportunity was defined as any visit (i.e., acute or preventive care) to a study site during which a patient was eligible for HPV1, yet failed to receive it. Chlamydia screening was conducted using nucleic acid amplification or hybridization tests. Tests performed before 11 years of age were excluded (n = 11; all negative results). Pap screening was conducted using the ThinPrep liquid cytology system; cytology was classified as normal or abnormal according to the Bethesda System 2001 [22].
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year of interest were determined among those eligible to receive HPV1 as of January 1 that year (i.e., previously unvaccinated). Findings were stratified by age: 11–12 years (i.e., ACIP-recommended age range), 13–17 years (i.e., age range for available coverage data) [9,10], and 18–26 years (i.e., otherwise eligible for HPV vaccination). A generalized linear mixed model assessed trends in HPV vaccination initiation between 2007 and 2011, accounting for repeated measurements among subjects. Multivariable logistic regression examined the impact of language, insurance, and clinic site on HPV vaccination initiation among 11–12 year-olds in the most recent cohort (2011). Since many patients were categorized as “other” race and a high proportion had missing ethnicity data, race/ethnicity was not included in the primary analysis, but adjusted for in a secondary analysis. In the subcohort, the proportions with Chlamydia or Pap screening and/or abnormal results before HPV vaccination initiation were determined. To assess whether Chlamydia screening was a reasonable proxy for sexual experience, we examined its concordance with documented age of sexual debut in a subcohort sample. Analyses were performed using SAS Version 9.3 (Cary, NC). 3. Results 3.1. Annual cohort characteristics A total of 22,900 individuals were included in the 2007–2011 cohorts (mean per cohort: n = 10,489; 63% included in >1 cohort) (Table 1). They were predominantly non-white, Latina, Spanishspeaking, publicly insured, and distributed widely across clinics. 3.2. Age at HPV vaccination initiation
2.6. Analysis For each annual cohort, the proportion of subjects who had initiated HPV vaccination and mean age at HPV1 receipt were calculated; all doses received before December 31 of the given year were included. Missed opportunities for HPV1 receipt during the
The proportion of subjects aged 11–12 years, 13–17 years, 18–26 years, and 11–26 years (total) who initiated HPV vaccination increased between 2007 and 2011 (Fig. 2). Given the simultaneous rise in initiation rates across age groups, the mean age at HPV vaccination initiation remained unchanged over time (16.0 ± 2.7 years in
Table 1 Characteristics of study populationa .
Age (yr), mean (SD)b Race, % (n)c White Black Other Ethnicity, % (n)c Latina Non-Latina Primary language, % (n)c Spanish English Other Insurance, % (n)c Public Grantd Uninsured Private Clinic, % (n) Family planning Obstetrics/gynecology Paediatric School-based health Family medicine
2007 (n = 9209)
2008 (n = 9888)
2009 (n = 10,885)
2010 (n = 11,206)
2011 (n = 11,259)
Subcohort (n = 15,049)
17.4 (3.8)
17.7 (3.8)
18.3 (4.0)
18.5 (4.0)
18.6 (4.1)
15.6 (2.5)
29.2 (2672) 8.8 (809) 62.0 (5668)
27.6 (2714) 9.1 (889) 63.3 (6219)
25.5 (2753) 8.1 (873) 66.4 (7186)
19.8 (2201) 7.3 (815) 72.9 (8120)
14.4 (1603) 6.3 (699) 79.3 (8849)
28.7 (4282) 9.7 (1438) 61.6 (9188)
79.0 (3400) 21.0 (905)
77.8 (3489) 22.2 (997)
78.9 (3621) 21.1 (971)
78.5 (3142) 21.5 (860)
79.0 (2907) 21.0 (771)
77.2 (5531) 22.8 (1630)
59.5 (5037) 39.9 (3379) 0.6 (46)
58.5 (5349) 40.9 (3735) 0.7 (59)
58.3 (6171) 41.1 (4355) 0.6 (63)
59.1 (6353) 40.2 (4325) 0.7 (71)
59.9 (6214) 40.4 (4264) 0.7 (79)
56.7 (7713) 42.7 (5800) 0.6 (84)
73.6 (6777) 17.4 (1603) 4.7 (431) 4.3 (397)
73.7 (7289) 17.8 (1763) 4.5 (440) 4.0 (395)
74.7 (8133) 17.5 (1901) 4.6 (498) 3.2 (352)
75.5 (8456) 17.7 (1989) 4.0 (453) 2.8 (308)
74.8 (8422) 19.3 (2170) 3.3 (371) 2.6 (294)
71.9 (10815) 20.6 (3102) 4.4 (668) 3.1 (462)
28.5 (2623) 24.0 (2208) 23.0 (2219) 16.6 (1531) 7.9 (728)
27.4 (2708) 23.4 (2311) 23.4 (2316) 18.2 (1804) 7.6 (749)
25.7 (2793) 26.6 (2899) 22.5 (2451) 18.1 (1967) 7.1 (775)
25.3 (2830) 27.3 (3060) 23.2 (2597) 17.9 (2006) 6.3 (712)
25.5 (2864) 25.1 (2829) 23.0 (2591) 20.0 (2250) 6.4 (721)
31.3 (4708) 23.7 (3562) 20.0 (3008) 19.5 (2939) 5.5 (829)
a The five annual cohorts (2007–2011) were comprised of 22,900 unique individuals (63% were included in >1 cohort). In a subcohort of these individuals, sexual health screening prior to initiation of HPV vaccination was examined. b Age as of January 1 of given year (2007–2011). For the subcohort, age as of January 1, 2007. c There were some missing data in select seasons. d Funding from service grants was used primarily in school-based health and family planning clinics.
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A.M. Hofstetter et al. / Vaccine 32 (2014) 1939–1945 Table 3 Factors associated with initiation of HPV vaccination among 11–12 year-old females in 2011. Variable Parental language (REF: English/other) Spanish Insurance (REF: public/grant/uninsured)c Private Clinic (REF: paediatric) Family medicine School-based health Race (REF: white) Black Other
AORa (95% CI)
AORb (95% CI)
1.77 (1.17, 2.70)
1.75 (1.12, 2.75)
0.59 (0.23, 1.54)
0.59 (0.22, 1.53)
0.41 (0.14, 1.19) 0.56 (0.36, 0.85)
0.42 (0.14, 1.22) 0.65 (0.34, 1.25)
– –
0.96 (0.43, 2.16) 1.23 (0.63, 2.40)
a
Model includes language, insurance, and clinic site. Model includes language, insurance, clinic site, and race. c Funding from service grants was used for some visits to school-based health clinics. Values in bold signify p < 0.05. b
Fig. 2. Initiation of HPV vaccination among 11–26 year-old females attending ambulatory care clinics, 2007–2011.
2007 vs. 15.9 ± 4.0 years in 2011, p = 0.45). In 2011, 74.5% of 11–12 year-olds initiated HPV vaccination. Spanish speakers were more likely to have initiated HPV vaccination at 11–12 years, whereas those attending SBHCs were less likely to have timely initiation, although not after adjusting for race (Table 2). 3.3. Missed opportunities The majority (70.8–76.4%) of subjects with a clinic visit who were eligible to initiate HPV vaccination failed to do so within a given year, particularly those who were older (Table 3). By definition, all of these unvaccinated subjects had ≥1 missed opportunity for HPV1 receipt; the median number of missed opportunities was 2 in 2007–2010 and 3 in 2011. Among eligible subjects who did initiate HPV vaccination within the year, 49.2–57.1% had ≥1 missed opportunity that year before HPV1 receipt. 3.4. Subcohort characteristics There were 15,049 adolescents included in the subcohort examining sexual health screening (Table 1). Over one-third (37.9%) Table 2 Missed opportunities for HPV vaccination initiation among 11–26 year-old females attending ambulatory care clinics, 2007–2011a . Year
Age (yr)
n Value
No HPV1 receipt, % (n)b
2007
11–12 13–17 18–26 Total 11–12 13–17 18–26 Total 11–12 13–17 18–26 Total 11–12 13–17 18–26 Total 11–12 13–17 18–26 Total
588 3926 4653 9167 398 2397 4337 7132 316 1454 4612 6382 330 1055 4096 5481 279 876 3463 4618
56.1 (330) 58.2 (2284) 83.3 (3874) 70.8 (6488) 53.5 (213) 55.9 (1339) 85.1 (3689) 73.5 (5241) 51.9 (164) 64.4 (936) 80.3 (3702) 75.2 (4802) 46.4 (153) 66.5 (702) 81.3 (3330) 76.4 (4185) 49.8 (139) 65.8 (576) 78.8 (2730) 74.6 (3445)
2008
2009
2010
2011
a Among only those eligible for the first HPV vaccine dose (HPV1) as of January 1 of given year. b By December 31 of given year.
had undergone Pap screening in their lifetime. Of these, 31.4% had ≥1 abnormality. The majority (79.2%) had undergone Chlamydia screening in their lifetime; the cumulative proportion increased by age (11 year-olds: 0.1%; 12 year-olds: 0.6%; 13 year-olds: 2.6%; 14 year-olds: 8.0%; 15 year-olds: 18.4%; 16 year-olds: 31.4%; 17 yearolds: 44.9%; 18 year-olds: 55.8%; 19 year-olds: 64.2%). In total, 24.3% had ≥1 Chlamydia infection. In the subcohort sample examining concordance between Chlamydia screening and sexual experience, 51.2% (n = 212) had a documented age of sexual debut (mean: 15.7 years; range: 10–22 years). Only 9.4% (n = 20) underwent their first Chlamydia screening before this age of debut; half of these were within the preceding 6 months.
3.5. Sexual health screening before HPV vaccination initiation In the subcohort, two-thirds (66.7%, n = 10,038) had initiated HPV vaccination at a mean age of 16.7 years (SD 2.8). Of initiators, 36.9% and 16.6% had undergone Chlamydia or Pap screening, respectively, at some point before HPV1 receipt (Fig. 3). Of those with prior Chlamydia screening, 19.1% had ≥1 infection before HPV1 receipt. Of those with prior Pap screening, 32.1% had ≥1 abnormality before HPV1 receipt.
Fig. 3. Chlamydia and Papanicolaou (Pap) screening before HPV vaccination initiation among adolescent and young adult females.
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4. Discussion This study examined initiation of HPV vaccination among 22,900 urban, low-income, minority adolescent and young adult females. It reveals that, even in a setting with high initiation rates, HPV vaccination is frequently delayed beyond the recommended 11–12 years, and missed opportunities for HPV1 receipt are common in all age groups. It also illustrates the potential consequences of this delay. Over one-third already had undergone Chlamydia screening, suggesting prior sexual experience, and nearly one-third of those with Pap screening already had an abnormality, indicating prior HPV exposure. These findings, in addition to our understanding of health care utilization in this population [6], support a universal approach to timely initiation of HPV vaccination, per ACIP recommendations. Optimization of HPV vaccine delivery could potentially enhance the encouraging recent finding that HPV vaccine introduction has substantially reduced HPV prevalence at a population-level [23]. In this study, initiation rates of HPV vaccination improved significantly over time. By 2011, over two-thirds of subjects had initiated HPV vaccination. Comparatively, 2011 NIS-Teen data demonstrated that only half of 13–17 year-old females in New York State (46.6%) and nationally (53.0%) had received ≥1 dose [9]. Despite promising trends in initiation rates in the study population overall, there was some recent plateauing among 11–12 and 13–17 year-olds, the latter also shown nationally [9,10]. Moreover, HPV vaccination remained delayed, as evidenced by the unchanged mean age at HPV1 receipt of 16 years. This is concerning since earlier age at vaccination is associated with a more robust anti-HPV response [3–5], and HPV vaccine is most effective as a prevention strategy when received before sexual debut [1]. Delayed HPV vaccination in the present study could be explained by multiple factors. Spanish language was associated with early HPV vaccination initiation, consistent with its positive impact on influenza vaccination in this population [24,25]. Conversely, SBHC attendance was negatively associated with timely HPV vaccination, which may reflect parental preference for adolescent vaccination in a doctor’s office compared to school or public health clinic and lower willingness to consent to schoollocated administration of HPV vs. other vaccines [26]. The effect of SBHC attendance disappeared after adjusting for race, possibly due to the greater proportion of black adolescents in this setting (data not shown); black adolescents were recently shown to be less likely than white adolescents to initiate HPV vaccination [27]. General parental reluctance to vaccinate against HPV also could have played a role. Prior investigations have shown that parents often decline/defer HPV vaccination for a variety of reasons, including beliefs about the need for vaccination and perceptions of risk (i.e., not sexually active) [7,28–31]. Data, however, indicate that parents often underestimate their adolescent’s sexual experience [17,18]. Moreover, some parents worry that HPV vaccination could result in behavioral disinhibition and risky sexual behaviors [32], despite substantial evidence to the contrary [33–36]. Providers have the opportunity to clarify misconceptions and strongly recommend HPV vaccine, thereby positively influencing vaccine uptake [37–40]. In the present study, however, providers likely contributed to the frequent missed opportunities for timely HPV vaccination since even eligible patients who initiated HPV vaccination within the year (i.e., did not continuously decline/defer vaccination) had 2–3 missed opportunities before HPV1 receipt. Moreover, approximately half of eligible 11–12 year-olds had ≥1 missed opportunity to receive HPV1 at the recommended time, which is consistent with survey data indicating that providers less often/strongly recommend HPV vaccine to them [11–13]. These findings could be explained by a lack of provider
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awareness of adolescent sexual behaviors, including age of sexual debut [19] and HPV infection risk [11,13]. Moreover, perceived obligation to discuss sexuality before recommending HPV vaccine has been associated with not strongly recommending HPV vaccine to 11–12 year-olds [11]. These data illustrate the need for educational interventions tailored specifically to the informational needs of adolescents, parents, and providers. Electronic health record alerts that contain vaccine-related information and prompt discussions about HPV vaccine are one potential strategy that has been proposed [41]. They may be particularly beneficial during acute care visits since many adolescents do not present for timely preventive care [6] and for older patients who also commonly experienced missed vaccination opportunities. The potential consequences of delayed initiation of HPV vaccination in our study population are concerning since over one-third had undergone Chlamydia screening and nearly one-third of those with Pap screening had an abnormality at some point before initiating HPV vaccination. This indicates that many had engaged in sexual behaviors placing them at risk of HPV acquisition before HPV vaccination, consistent with a smaller recent study [16]. While our subjects may be at higher risk than observed nationally given their lower mean age of sexual debut and higher rate of abnormal screening [42–44], their risk may be similar to other urban, lowincome, minority adolescents and young adults [45]. Regardless, our findings as well as previous data illustrating the difficulties of predicting age of sexual debut [17–19] support the ACIP recommendation for HPV vaccination of all young adolescents. This study has some limitations. First, by focusing on individuals with clinic utilization during the study period, it may have overestimated HPV vaccination initiation rates and underestimated age at HPV1 receipt within the larger clinic population, community, and/or general population. Conversely, underreporting of vaccine administration may have occurred, although unlikely given routine vaccine data extractions and reporting mandates. Additionally, Chlamydia screening likely underestimated sexual experience since screening is typically performed based upon patient disclosure of sexual activity and at provider discretion. Nonetheless, we found strong concordance between first Chlamydia screening and documented age of sexual debut, consistent with another study showing longitudinal consistency in self-reported age at first sex [46]. Further, the use of Pap screening as an indication of associated morbidity likely had the greatest utility prior to the 2009 American College of Obstetrics and Gynecology recommendation that Pap screening begin at 21 years of age [47]. Lastly, these data did not permit further characterization of missed opportunities (i.e., type of visit, reason why vaccine was not given) or examination of other factors shown to impact HPV vaccination (i.e., parental beliefs, provider recommendation) [7,28–31,37–40].
5. Conclusion This large retrospective cohort study of low-income minority adolescent and young adult females found that, even in a setting conducive to HPV vaccination, initiation of the three-dose series was often delayed. Moreover, many who ultimately initiated HPV vaccination already had evidence of sexual experience and associated morbidity before HPV1 receipt. HPV vaccination in early adolescence is important for optimizing protection prior to exposure and necessary given the challenges of predicting which adolescents will engage in early sexual behaviors. Vaccination of young adolescents also aligns well with health care utilization patterns. Given the frequent missed opportunities for timely HPV vaccination, enhanced education of adolescents, parents, and providers is needed.
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Conflicts of interest statement This study was funded in part through an Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this manuscript are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. As of July 2013, Drs. Hofstetter and Rosenthal receive support from the Pfizer Medical Education Group for an investigator-initiated study. The other authors have no conflicts of interest to disclose. Acknowledgments We would like to thank NewYork-Presbyterian Hospital for its support of the EzVac immunization registry as well as the NewYork-Presbyterian Hospital Ambulatory Care Network. We ˜ and Balendu DasGupta would especially like to thank Oscar Pena for their work on EzVac and Alla Babina for her assistance with the sexual health screening data collection. References [1] Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent human Papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-2):1–24. [2] Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157(3):218–26. [3] Giuliano AR, Lazcano-Ponce E, Villa L, Nolan T, Marchant C, Radley D, Golm G, McCarroll K, Yu J, Esser MT, et al. Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine. J Infect Dis 2007;196(8):1153–62. [4] Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD, Castellsague X, Rusche SA, Lukac S, Bryan JT, et al. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 2006;118(5):2135–45. [5] Dobson SR, McNeil S, Dionne M, Dawar M, Ogilvie G, Krajden M, Sauvageau C, Scheifele DW, Kollmann TR, Halperin SA, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA 2013;309(17):1793–802. [6] Rand CM, Shone LP, Albertin C, Auinger P, Klein JD, Szilagyi PG. National health care visit patterns of adolescents: implications for delivery of new adolescent vaccines. Arch Pediatr Adolesc Med 2007;161(3):252–9. [7] Bair RM, Mays RM, Sturm LA, Zimet GD. Acceptability of the human papillomavirus vaccine among Latina mothers. J Pediatr Adolesc Gynecol 2008;21(6):329–34. [8] Dempsey AF, Abraham LM, Dalton V, Ruffin M. Understanding the reasons why mothers do or do not have their adolescent daughters vaccinated against human papillomavirus. Ann Epidemiol 2009;19(8):531–8. [9] Centers for Disease Control and Prevention. National and state vaccination coverage among adolescents aged 13–17 years—United States, 2011. MMWR Morb Mortal Wkly Rep 2012;61(34):671–7. [10] Centers for Disease Control and Prevention. Human papillomavirus vaccination coverage among adolescent girls, 2007–2012, and postlicensure vaccine safety monitoring, 2006–2013—United States. MMWR Morb Mortal Wkly Rep 2013;62(29):591–5. [11] Daley MF, Crane LA, Markowitz LE, Black SR, Beaty BL, Barrow J, Babbel C, Gottlieb SL, Liddon N, Stokley S, et al. Human papillomavirus vaccination practices: a survey of US physicians 18 months after licensure. Pediatrics 2010;126(3):425–33. [12] Vadaparampil ST, Kahn JA, Salmon D, Lee JH, Quinn GP, Roetzheim R, Bruder K, Malo TL, Proveaux T, Zhao X, et al. Missed clinical opportunities: provider recommendations for HPV vaccination for 11–12 year old girls are limited. Vaccine 2011;29(47):8634–41. [13] Kahn JA, Cooper HP, Vadaparampil ST, Pence BC, Weinberg AD, LoCoco SJ, Rosenthal SL. Human papillomavirus vaccine recommendations and agreement with mandated human papillomavirus vaccination for 11-to-12-year-old girls: a statewide survey of Texas physicians. Cancer Epidemiol Biomarkers Prev 2009;18(8):2325–32. [14] Wong CA, Taylor JA, Wright JA, Opel DJ, Katzenellenbogen RA. Missed opportunities for adolescent vaccination, 2006–2011. J Adolesc Health 2013;53(4):492–7. [15] Neubrand TP, Breitkopf CR, Rupp R, Breitkopf D, Rosenthal SL. Factors associated with completion of the human papillomavirus vaccine series. Clin Pediatr (Phila) 2009;48(9):966–9. [16] Widdice LE, Brown DR, Bernstein DI, Ding L, Patel D, Shew M, Fortenberry JD, Kahn JA: Prevalence of human papillomavirus infection in young women receiving the first quadrivalent vaccine dose. Arch Pediatr Adolesc Med, 166(8):774-776.
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