Human papillomavirus vaccine timing associated with eventual human papillomavirus diagnosis in women

Abstract

Nearly all cases of cervical cancer are attributable to human papillomavirus (HPV), making it a significant women’s health issue. Though there have been advances in the prevention of HPV via vaccination, significant barriers continue to suppress vaccination rates for girls. Delaying vaccination until after sexual debut increases a woman’s chance of HPV infection, but there has been no quantification of this risk in the literature. The present study sought to address this gap via secondary data analysis with 173 female participants from the 2015–2016 National Health and Nutrition Examination Survey dataset. Results indicate that women in the sample who received the HPV vaccine after their sexual debut were 2.63 times more likely than women who receive the vaccine before their sexual debut to report an HPV diagnosis. These results have clear public and sexual health implications.

Keywords

Human papillomavirus vaccines sexual behaviors sexually transmitted infections

Human papillomavirus (HPV) is a circular, double-stranded, non-enveloped DNA group of Papillomaviridae viruses¹ named from the papillomas or warts that are caused by certain strains of HPV.² Approximately 79 million Americans have been diagnosed with HPV, and roughly 14 million people are newly infected per year.² In 2014, the prevalence of HPV was 42.5% among adults aged 18–59.³ With 190 recognized strains, HPV causes a wide range of symptoms from genital warts to several cancers.^1,2,4 Nearly all cases of cervical cancer, 90% of anal cancers, and more than 70% of vulvar, vaginal, penile, and oropharyngeal cancers are associated with HPV.²

HPV typically does not show any signs or symptoms in a healthy immune system because most infections are cleared within two years.⁵ Some infections, however, may persist for many years, causing cellular alterations, which, if untreated, have the potential to develop into cancer of the ano-genital area.^6–8 It can take 10–20 years for the infection to become malignant and cause cancer in women.¹ Approximately 4000 women die from cervical cancer each year in the United States (US),⁹ with 70% of cervical cancer cases attributable to just two HPV stains (i.e. 16 and 18).² In 2015, 10,751 US women were diagnosed with cervical cancer and over 7000 US women were diagnosed with vulva, vaginal, or anal cancer caused by HPV.¹⁰ While men are typically less affected by HPV, if the infection persists through their lifetime it may cause cancers in sites where HPV is often found such as penis, anus, and oropharynx including the tongue and tonsils.¹⁰

HPV is primarily spread through skin-to-skin contact during sexual activity. This includes the areas around the mouth, anus, clitoris, vulva, penis, and scrotum.^2,4 Unless warts are visible, there are no signs or symptoms to indicate the possible presence of HPV in oneself or one’s sexual partners. Condoms, the most effective and versatile barrier safer sex method,¹¹ do not cover all possible contact points during sexual activity even when used properly.^12,13 As such, vaccination remains the most effective means of preventing HPV infection.¹⁴ Put simply by the Centers for Disease Control and Prevention (CDC),⁴ ‘every person who is sexually active will get HPV at some time in their life if they don’t get the HPV vaccine’ (para. 18). The preventative impact of contemporary HPV vaccinations has been quantified in several studies outside the US. Capra et al.¹⁵ found that modern vaccines can prevent 57–81% of high-grade cancerous lesions and 31–53% of low-grade cancerous lesions, significant increases over previous generations of vaccines. A similar study in France¹⁶ concluded that 90% of the ano-genital cancer cases included in their study could be prevented with modern HPV vaccines.

Gardasil 9, one such vaccine, is the only HPV vaccine available in the US.¹⁷ The initial vaccination is recommended to occur at age 11 or 12, though it can begin as early as age 9.²,¹⁴,¹⁷,¹⁸ Gardasil 9 is administered in two doses and the second dose works best if administered 6–12 months after the initial dose. If a person is older than 15 or if they did not receive both doses prior to the age of 15, they must receive three rounds of Gardasil 9 instead of two.^14,19 The average age of sexual initiation (often defined as penile–vaginal intercourse) is approximately 16 years old in girls,^20–22 with the possibility for non-penile–vaginal skin-to-skin sexual activities to occur prior to this (e.g. cunnilingus, fellatio, anilingus, anal sex, tribadism, non-penetrative frottage, and intergluteal sex).^23–26 As such, the effectiveness of the vaccine is highest if received prior to sexual debut (i.e. the age of first sexual activity).^2,14,17,19 At present, however, there is no known study specifically assessing the size of the risk of being diagnosed with HPV if the vaccine was received after sexual debut.

The aim of the present study is to address this gap by comparing HPV diagnosis rates in adult women who received at least the first dose of the HPV vaccine prior to sexual debut with women who received the vaccine after sexual debut. The current study focuses on women due both to the disproportionate HPV-related disease burden experienced by this population, as HPV is responsible for 12% of all female cancers,^27,28 and to the absence of an effective HPV test for men.^2,4 The goal of this study is to support sexual health advocacy, education, and clinical efforts by offering concrete data related to the long-term HPV risk associated with delaying vaccination in adolescent girls.

Methods

Participants

The present study conducted secondary data analysis with the 2015–2016 data collection round of the National Health and Nutrition Examination Survey (NHANES).²⁹ NHANES uses a multistage probability design to sample residents of the 50 states and DC. In the 2015–2016 data collection round, 15,327 persons were selected and 9971 chose to participate. Of those, and congruent with the study’s aim, the current study’s sample only included females over the age of 13 who reported having sex at some point in their life and who reported receiving at least the first dose of the HPV vaccine. This resulted in an initial study sample of n = 220. Of these, 20 reported that their sexual debut and the first dose of the HPV vaccine occurred in the same year and, because it could not therefore be determined if their HPV vaccine was initiated before or after sexual debut, were removed from the dataset. Finally, 27 participants had missing data related to control variables and were removed, leaving a final analytic sample of n = 173. Relevant participant demographics are available in Table 1.

Table 1.

Descriptive statistics for all study variables (n = 173).

Variable	M (n)	SD (%)
Age (years)	25.58	6.89
Race/ethnicity
White	(66)	(38.2)
Mexican	(29)	(16.8)
Other Hispanic	(18)	(10.4)
Black	(40)	(23.1)
Other	(20)	(11.6)
Income
<$55,000	(88)	(50.9)
≥$55,000	(85)	(49.1)
Number of sexual partners	8.90	12.85
Always wear condom during sex
Yes	(60)	(34.7)
No	(113)	(65.3)
HPV vaccine before sexual debut
Yes	(77)	(45.5)
No	(96)	(55.5)
HPV diagnosis
Yes	(58)	(33.5)
No	(115)	(66.5)

HPV: human papillomavirus.

Variables

The focal independent variable, HPV vaccine timing, was a calculated variable. The NHANES dataset includes the following two variables: ‘How old were you when you received your first dose of the vaccine?’ and ‘How old were you when you had sex for the first time?’. If the participant’s reported age of sexual debut was prior to the first dose of the vaccine, they were coded as ‘Not vaccinated before sexual debut.’ If the participant’s reported age of sexual debut was after the first dose of the vaccine, they were coded as ‘Vaccinated before sexual debut.’ Participants who reported that the two events took place at the same age (n = 20) were, as discussed above, removed from the sample. Other independent variables were entered into the model as control variables, as these variables were expected to be associated with the dependent variable: age, race/ethnicity, number of sexual partners, and condom use.

The dependent variable, eventual HPV diagnosis, was also a calculated variable. The NHANES dataset includes the following variable: ‘Has a doctor or other health care professional ever told you that you had human papillomavirus or HPV?’. Also, as part of the NHANES, participants received a Cobas® HPV swab test (Roche Diagnostics, Basel, Switzerland). Participants who answered ‘Yes’ to the first question or received a positive Cobas® test result were coded as ‘HPV Positive.’ All other participants were coded as ‘HPV Negative.’

Analysis

SPSS version 24.0 (SPSS Inc, Chicago, IL, USA) was used for the analysis. A hierarchical binary logistic regression was conducted using simultaneous entry. The aim of the analysis was to identify whether there was a significant association between HPV vaccine timing and later-life HPV diagnosis and, if so, whether that effect remained significant when controlling for relevant demographic and sexual behavior variables. As such, employing a hierarchical regression, wherein the first regression model included only the focal independent variable and the second model added the control variables, was the most appropriate approach to the analysis.³⁰ Two of the control variables, age and number of sexual partners, showed significant positive skew. As such, a log10 transformation was conducted on both of these variables during analysis.

Results

The first regression analysis, containing only the focal independent variable, HPV vaccine timing, produced a significant model to predict eventual HPV diagnoses among the sample, χ² (1) = 4.96, p = .03, R² = .04. Females receiving the first dose of the HPV vaccine after sexual debut were 2.09 times more likely than females who received the first dose of the HPV vaccine prior to sexual debut to eventually be diagnosed with HPV. The second regression analysis, adding all relevant control variables, yielded a statistically significant model as well, χ² (9) = 34.94, p < .001 (see Table 2). This model accounted for 25.4% of variance in HPV diagnosis, considered a medium effect.³¹ The significant independent predictors of HPV diagnosis were (a) age, (b) number of sexual partners, and (c) HPV vaccine timing. Increasing age was associated with significantly lower odds of having an HPV diagnosis. Conversely, increasing sexual partners was associated with significantly greater odds of having an HPV diagnosis. Also, the effect of HPV vaccine timing remained significant in the second model, showing that females receiving the first dose of the HPV vaccine after sexual debut were 2.6 times more likely than females who received the first dose of the HPV vaccine prior to sexual debut to eventually be diagnosed with HPV.

Table 2.

Results of logistic regression predicting eventual HPV diagnosis.

Variable	B	Odds ratio	95% CI
Age^a	−.7.09	.001**	(.000, .102)
Race (Ref: White)
Mexican	−.691	.501	(.169, 1.49)
Other Hispanic	.095	1.10	(.345, 3.51)
Black	−.669	.512	(.191, 1.38)
Other	−1.32	.266	(.065, 1.09)
Income (Ref: < $55,000)	−.684	.505	(.239, 1.06)
Number of sexual partners^a	1.36	3.91**	(1.62, 9.42)
Always wear condom (Ref: No)	.517	1.68	(.761, 3.69)
HPV vaccine before sexual debut (Ref: Yes)	.967	2.63*	(1.05, 6.61)
Nagelkerke R²		.25
χ²		34.94***

HPV: human papillomavirus.

^aA logarithmic transformation was done on this variable due to skewness; *p ≤ .05; **p ≤ .01; ***p ≤ .001.

Discussion

The present study identified age as a significant independent predictor of likelihood of reporting a later HPV diagnosis, with increasing age being associated with decreasing likelihood. This is congruent with past research that shows that older female cohorts evidence lower HPV prevalence.^28,32 In the current study, this result may be attributable to the fact that routine HPV testing began recently in 1999,³³ reducing older women’s likelihood of responding ‘yes’ to the question regarding past HPV diagnoses. A second hypothesis is population mortality as a result of HPV-related cancers,^34,35 reducing the number of older participants with a past or new HPV diagnosis. Both possibilities call attention to the important role of routine HPV testing, which should begin, according to the CDC, at age 21.³⁶,³⁷ Routine testing can aid public health efforts in properly tracking HPV-related factors and can detect precancerous and cancerous cells earlier in the disease progression, increasing survivability.

The present study also identified the number of sexual partners as a significant independent predictor of likelihood of reporting a later HPV diagnosis, with increasing number being associated with increasing likelihood. This is congruent with a wealth of past research indicating that HPV risk increases with greater numbers of sexual partners.^{28,32,38–40} In fact, past research^41,42 has shown that even a woman’s estimate of her male partner’s number of past sexual partners is significantly correlated with her HPV risk. What may be particularly poignant is the statement by Winer et al.⁴³ that there is ‘a high risk of HPV infection in women who acquire just 1 male sex partner’ (p.282). In the aggregate, there is strong indication that limiting the number of sexual partners can reduce a woman’s risk for HPV. At the very least, reducing the amount of skin-to-skin contact with sexual partners via barrier methods (e.g. internal condoms, external condoms, dental dams) can also reduce the risk of HPV. Given the still limited knowledge and use of such barrier methods,^44–46 it seems important for public health efforts targeting HPV to include elements of comprehensive sex education.

This study is the first known quantification of the risk of reporting an HPV diagnosis based on the timing of the HPV vaccine relative to sexual debut. Women in the sample who received the first dose of the HPV vaccine after their sexual debut were 2.63 times more likely than women receiving the first dose of the vaccine before their sexual debut to report an HPV diagnosis. Importantly, this analysis was conducted while controlling for the effects of age, number of sexual partners, and condom use. A recent large-scale study of 250,648 women⁴⁷ found that a single dose of the HPV vaccine lowered their risk of cancer by 35%, while women receiving all three doses evidenced a reduction of 41%. Taken together, the results of the present analysis and the result of Brotherton et al.⁴⁷ are congruent with Houlihan et al.’s⁴⁸ finding that HPV infection occurs soon after sexual debut (median = 4.9 months after sexual debut).

The results of this study should only be considered with due attention to the study’s limitations. First, the focal independent variable was limited to assessing the age that the participants received their first dose of the HPV vaccine; the full regimen is two doses. The present study was unable to assess for differences in HPV rates for those who received the full regimen versus those who received only the first dose relative to sexual debut. Future research should consider addressing this important limitation. A second related limitation is the lack of specificity within the NHANES dataset with respect to the definition of ‘sex.’ It is impossible to know how participants interpreted this question, as some may have counted oral sex, for example, while others did not. This is another opportunity for future research to clarify the results of this study. A third limitation is the cross-sectional nature of the study. Future research may consider a prospective study design wherein female young adults are surveyed over a significant enough time period to include HPV vaccination windows, sexual debut(s), and eventual HPV diagnosis windows. A fourth limitation is the study’s lack of inclusion of sexual and gender minority identity. Considering the differing risk profiles of sexual and gender minority women, this may be an important variable for future studies to include. Despite these limitations, the present study was able to achieve its aim, finding a significant difference in the likelihood of reporting an HPV diagnosis based on HPV vaccine timing.

Implications for practice and/or policy

In light of the preceding discussion, there are very practical implications of these results. Generally, these results support the recommendations for vaccination prior to sexual debut.^2,14,17,19 Delaying vaccination until after sexual debut is a significant health risk, doubling the risk of HPV and, subsequently, of HPV-related cancers, including cervical cancer. Since the recommended age for beginning the HPV vaccination is as early as 9 years old and typically at 11 years old,^2,14,17,18 it is important for healthcare providers to continue to adequately educate the parents/guardians of their young patients on the health risk of delaying HPV vaccination. This includes dispelling common myths about the vaccine (e.g. it causes infertility, it encourages sexual behavior).^13,49–51 Importantly, healthcare providers may want to initiate these conversations with parents/guardians in the year(s) leading up to the child reaching age 11 so that parents/guardians have time to understand and consider the information before needing to make a decision. Given the identified health risk of delaying vaccination, it is also critical for comprehensive sex education curricula to highlight the importance of vaccination in a developmentally age-appropriate way, congruent with World Health Organization recommendations.⁵² Sex education curricula published by both The Sexuality Information and Education Council of the United States⁵³ and the Future of Sex Education⁵⁴ outline the STD- and vaccine-related information that children should be taught. The Center for Sex Education⁵⁵ offers helpful HPV-related resources for sex educators, including the ‘The ABCs of HPV’ lesson plan. Delaying vaccination can also impact the vaccination schedule itself. The CDC¹⁸ recommends children ages 9–14 receive a two-dose regimen while those over 14 years old receive a three-dose regimen. Therefore, delaying vaccination beyond 14 years old may require additional medical appointments, increasing the possibility of a missed appointment and an incomplete regimen.

Footnotes

Acknowledgments

The authors wish to thank Lesley for assisting with the final edit.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Robert J Zeglin

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